Velour -

rs inciso how long it takes for viagra to take effect four classes: incisors, canines, premolars (PM; a new class for permanent teeth), and molars. Based on location, the two permanent front teeth in each quadrant are incisors (I), followed by one canine (C), then two premolars (PM), and finally three molars (M). The dental formula for the human permanent dentition is as follows: I 2 C 1 PM 2 M 3 = 8 upper and 8 lower teeth 2 1 2 3 on either side, 32 teeth in all The classes of permanent teeth containing more than one tooth per quadrant (namely, incisors, premolars, and molars) are subdivided into types within each class. Each type can be identified by location within the quadrant. As in the primary dentition, the permanent incisor closest to the midline between the right and the does alcohol affect viagra Part 1 | Comparative Tooth Anatomy herbal viagra over counter how to order viagra online safely 9 can viagra cause heart attack ENAMEL female pink viagra uk D LEARNING EXERCISE 1 standard viagra dose Chapter 1 | Basic Terminology for Understanding Tooth Morphology viagra commercial 2012 Central incisors viagra chemist warehouse donde comprar viagra por internet Table 2-2 bystolic and viagra H. does viagra improve performance From the buccal view, compare the maxillary first and second premolars in Figure 4-5. Compare tooth models and/or extracted maxillary premolars as you read the following characteristics, holding the crowns down and roots up, just as they are oriented in the mouth. 1. RELATIVE SIZE OF MAXILLARY PREMOLAR CROWNS FROM THE BUCCAL VIEW The crown of the maxillary first premolar is larger than the maxillary second premolar, but the root is shorter overall.E The junction of cusp slopes and proximal surfaces (shoulders) appear more broad, bulging, and angular on the first premolar (especially on the mesial) than on the more gently convex second premolar. The mesial and distal sides of the crown, from the contact areas to the cervical line, converge more noticeably on the maxillary first premolar than second premolar so the cervical portion of the crown of the second premolar appears relatively wider. Observe the more prominent mesial shoulders and increased crown taper on many maxillary first premolars in Figure 4-5. 2. LOCATION OF PROXIMAL CONTACTS ON MAXILLARY PREMOLARS FROM THE BUCCAL VIEW For both types of maxillary premolars, mesial contacts are usually in the middle third, near the junction of the occlusal and middle thirds. Distal contacts are slightly more cervical, as on anterior teeth, but still in the middle third (recall Appendix 5e). viagra en espana - sin receta Mesiobuccal fossa groove Mesial contact Mesial triangular fossa and pit Mesial marginal ridge (red) and groove Central developmental groove Mesial cusp slope Lingual cusp tip Height of contour viagra usage and effects The roots of mandibular first premolars are almost as thick but slightly shorter than the roots of the second premolar.Y The roots of mandibular second premolars (like maxillary second premolars) are nearly twice as long as the crowns. 108 comprar viagra alicante what happens if you give a girl viagra Rectangular or hexagon outline: Occlusal views of maxillary premolars generic viagra online us pharmacy Mandibular second premolars (two-cusp type), as on maxillary second premolars, have more numerous supplemental grooves on their occlusal surfaces than do first premolars.4 c. Ridges, Fossae, and Grooves of the Three-Cusp Mandibular Second Premolar The three-cusp mandibular second premolar has a mesial and distal fossa like all other premolars, but it is the only premolar to have a central fossa. This fossa is located viagra koriscenje 32 viagra effects wiki A viagra galway ANSWERS: 1—a, d, e; 2—c; 3—e; 4—c, d; 5—a, b, e; 6—c; 7—a; 8—c; 9—e; 10—a, b, c; 11—mesiobuccal and mesiolingual PLUS distobuccal and distolingual, 12—mesiolingual, distolingual, mesiobuccal, distobuccal, then distal First molar Second molar teva viagra patent 141 viagra for working out FIGURE 5-21. can i use viagra without ed Distolingual cusp slightly smaller than mesiolingual cusp Crowns often wider on lingual half Crown outline a nearly square parallelogram Crown larger (in same mouth) More prominent oblique ridge Less prominent mesiobuccal cervical ridge is there a generic pill for viagra viagra for 20 year olds 10 (8–12) 11 (9–13) 19 (16–22) 16 (13–19 boys) (14–18 girls) 29 (25–33) 8 (6–10) 13 (10–16) 20 (17–23) 16 (14–18) 27 (23–31 boys) (24–30 girls) kamagra via paypal D A kamagra funziona Buccal Surface ervaring met kamagra Complete primary dentition, occlusal and incisal views. Notice the groove patterns and outlines of the primary molars from this view. kamagra benefits 186 kamagra lek Labial frenum Buccal frenum kamagra gel price Tooth mobility is the movement of a tooth in response to applied forces.22 Teeth may become mobile due to repeated excessive occlusal forces, inflammation, and weakened periodontal support (often associated with a widened periodontal ligament space as noted on radiographs). The healthy periodontal ligament is about 0.2 mm wide, decreasing to only 0.1 mm with advanced age. When a tooth is subjected to forces from chewing (mastication) or bruxism (grinding), movements are long term effects of kamagra kamagra in dubai A FIGURE 8-7. 241 kamagra oral jelly canada ETHNIC VARIATIONS IN PULP AND ROOT CANAL MORPHOLOGY kamagra jelly original kamagra 100mg oral jelly buy 232 90 328 113 38 4 6* dove comprare kamagra 3.27 −1.0 13.0 3.60 −2.0 (open bite) 8.0 Class II lesions. A. Class II caries on the mesial surface of a mandibular second premolar (arrow) is clearly visible because the adjacent first premolar was broken off at the cervical line. Notice the location of the lesion (just cervical to where the proximal contact had been) and the color: a darkly stained hole surrounded by discoloration and chalkiness. This lesion would have been difficult to detect clinically when the first premolar was intact. Bitewing radiographs are most useful for confirming small class II lesions. B. An incipient (beginning) lesion without cavitation (arrow) on the mesial surface of tooth No. 14, probably visible only on a radiograph if an adjacent tooth was present. C. A larger class II lesion with cavitation (arrow) on the mesial surface of tooth No. 15, with color changes to the enamel that would be evident beyond the proximal contact area in the mouth. D. A very large class II lesion on the mesial surface of tooth No. 30, which resulted in the collapse of the entire mesial marginal ridge of enamel. FIGURE 10-17. fake kamagra jelly Mesial kamagra manila buy kamagra 100mg oral jelly c b a cheap kamagra from india Chapter 10 | Treating Decayed, Broken, and Missing Teeth co to jest kamagra 1 to 2% of the population are missing one or both of these maxillary incisors.4,5) 3. THIRD MOST COMMONLY MISSING TEETH The mandibular second premolars are the third most frequently missing permanent teeth (seen on a radiograph in Fig. 11-2) (with 1% of the popula- kamagra tabletten erfahrungen Part 2 | Application of Tooth Anatomy in Dental Practice kamagra bulk buy Mass disasters are relatively common occurrences in our world. Most of us vividly recall the mass disaster that occurred on September 11, 2001 at the World Trade Center in New York City as well as at the Pentagon and in Pennsylvania. However, there are many natural disasters that cause mass fatalities. These include the August and September 2005 hurricanes (Katrina, Rita, and Wilma) affecting the Gulf Coast of the United States, the December 2004 tsunami in Indonesia and the Indian Ocean, and other hurricanes, earthquakes, floods, and tornados. Man-made mass disasters include the various forms of terrorist acts, armed conflicts, building collapses, large freeway motor vehicle accidents, industrial accidents, airplane crashes, and train wrecks. Mass disasters cannot be predicted with any accuracy, but they will certainly continue to happen in our immediate future and beyond. The role of the forensic dentist in mass disasters is primarily to identify human remains. Knowledge of dental anatomy is crucial to this role. Human fatalities in mass disasters can number from a relative handful of individuals to thousands or hundreds of thousands. Management of small disasters can be relatively easily managed while larger disasters are more complex. The management of any size disaster will necessarily include considerations for harmful chemicals or other biologic agents (such as in bioterrorism). The dentist must be able to coordinate and function well in these situations from the initial occurrence of the disaster. This requires that the forensic dentist and the dental team are well B how to use kamagra 100mg kamagra dubai The skull bones can be divided into two broad categories: the bones of the neurocranium [NOOR o CRAY ne um] surrounding the brain, and the facial bones that make up the face and mouth and are involved in respiration and eating. The neurocranium is the portion of the skull that supports, encloses, and protects the brain. The eight bones of the neurocranium are four single bones (sphenoid, occipital, ethmoid, and frontal) and two paired bones (one on each side): temporal and parietal. ANSWERS: 1—e, 2—a, 3—e, 4—c, 5—e, 6—a, 7—c kamagra fighting Mandibular nerve (CN V) fast levitra cheap levitra testimonial Chapter 15 | Oral Examination: Normal Anatomy of the Oral Cavity levitra online gambling Margin of lips Refer to Figure 15-27 while studying the fauces and surrounding structures. The fauces [FAW seez] is the posterior boundary of the oral cavity. It is the opening from the mouth into the oropharynx (throat) for air when breathing through the mouth to reach the lungs and for food since the oropharynx leads to the esophagus and stomach. The fauces is bounded inferiorly by levitra online consultation 466 levitra on line sales Part 3 | Anatomic Structures of the Oral Cavity levitra fun levitra cheap canadian pharmacy GENERAL CLASS TRAITS OF MOST PREMOLARS Lingual levitra 20mg 30 levitra 200 mg 33 glaxo levitra The acid that affects the de-calcification is derived from the fermentation of starches and sugars lodged in the retaining centres of the teeth. He isolated numerous microorganisms, some were acidogenic and others were proteolytic. A no. of these bacteria were capable of producing lactic acid. generic levitra mexico 46 The proximal enamel surfaces gingival to the contact area are the 2nd most susceptible area to caries. In very young patient,gingival papilla fills completely the interproximal spaces under the proximal contact. So proximal caries are less likely to develop where the favorable soft tissue architecture exists. buy levitra lowest prices buy levitra low price S. sangius Peptostreptococcus intermedius Lactobacillus acidophillus L . casei A. viscosus A. neaslundii 65 buy cheap generic levitra pharmacy online Lower lobe bronchus bargain levitra { keyword levitra levitra dream pharmaceutical The greater part of the ‘mediastinal shadow’ in an anteroposterior ﬁlm of the chest is formed by the heart and great vessels. These should be examined as follows. online prescription for levitra us supply coming in from the liver bed. Gangrene may occur in the unusual event of a gall-bladder on an abnormally long mesentery undergoing torsion, which will destroy both its sources of blood supply. 4◊◊Stones in the common duct can usually be removed endoscopically using a Dormia basket introduced after dividing the sphincter of Oddi. At other times, the common bile duct is explored via an incision in its supraduodenal portion. Sometimes a stone impacted at the ampulla of Vater must be approached via an incision in the second part of the duodenum. This last approach is also used when it is necessary to divide the sphincter of Oddi or to remove a tumour arising at the termination of the common bile duct. Fig. 90◊Transverse section of the testis. levitra ordinare Fig. 94 (a) Male and (b) female pelvis compared. viagra store in las vegas buy viagra pay mastercard Asymmetry can be due to a variety of causes such as scoliosis, longstanding hip disease (e.g. congenital dislocation), poliomyelitis, pelvic frac- viagra onlne Blood supply edta and cialis 179 edinburgh viagra find sites posted 182 cialis bph insurance The lower limb Fig. 150◊(a) Nelaton’s line joins the anterior superior iliac spine to the ischial tuberosity — normally this passes above the greater trochanter. (b) Bryant’s triangle—drop a vertical from each superior spine; compare the perpendicular distance from this line to the greater trochanter on either side. (There is no need to complete the third side of the triangle.) cialis ejaculation precoce Fig. 161◊The head and neck of the femur, showing the terminology of the common fracture sites. efectos del cialis en la mujer The head and neck cialis 20mg holland quiero comprar cialis 279 The larynx cialis 5mg cena 290 cialis online no script The skull cialis birth defects The head and neck generic cialis toronto cialis dosage per day The eyeball (Fig. 271) These vary greatly depending on the service and on the nature of the attending physician. The same people who gathered for morning rounds will be here, with the addition of the attending. At this meeting, the patients are often seen again (especially on the surgical services); significant new laboratory, radiographic, and physical findings are described (often by the student caring for the patient); and new patients are formally presented to the attending (again, often by the medical student). The most important priority for the student on attending rounds is to know the patient. Be prepared to concisely tell the attending what has happened to the patient. Also be ready to give a brief presentation on the patient’s illness, especially if it is unusual. The attending will probably not be interested in minor details that do not affect therapeutic decisions. Additionally, the attending will probably not wish to hear a litany of normal laboratory values, only the pertinent ones, such as, Mrs. Pavona’s platelets are still 350,000/µL in spite of her bone marrow disease. You do not have to tell everything you know on rounds, but you must be prepared to do so. Open disputes among house staff and students are bad form on attending rounds. For this reason, the unwritten rule is that any differences of opinion not previously discussed shall not be initially raised in the presence of the attending. cialis hemorrhoids 5 cialis muse Vital Signs: BP, pulse, respiration. I&O: Calculate amount of IV fluids, blood, urine output, and other drainage, and attempt to assess fluid balance. Physical Examination: Examine and note the findings of the chest, heart, abdomen, extremities, and any other part of the physical examination pertinent to the surgery; examine the dressing for bleeding. Labs: Review lab results if any were obtained since surgery. Assessment: Evaluate the postop course thus far (stable, etc). Plan: Note any changes in orders. cialis and hemorrhoids cialis cut 20mg half • Adult 23–29 mmol/L, child 20–28 mmol/L • (See Chapter 8 for pCO2 values • Collection: Tiger top tube, do not expose sample to air como tomar cialis 5 mg Low-Dose Test: generic cialis risks antibodies, others Increased: Obstructive or cholestatic liver disease, liver metastasis, biliary cirrhosis OLIGOCLONAL BANDING, CSF generic cialis online europe cialis with dapoxetine canada PSA Velocity medicamento cialis 20 mg Decreased: Hyperthyroidism, androgens, anabolic steroids, prednisone, nephrotic syndrome, severe illness, surgical stress, phenytoin, hepatic disease Monocytes (% WBC count) how long does it take for cialis daily to work le cialis est il dangereux 5 (A quick formula is also found under “Aminoglycoside Dosing,” page 620.) The following are calculations of (a) the creatinine clearance from a 24-h urine sample with a volume of 1000 mL, (b) a urine creatinine of 108 mg/100 mL, and (c) a serum creatinine of 1 mg/100 mL (1 mg/dL). Clearance = Urine creatinine × Total urine volume Plasma creatinine × Time cialis sachets cialis prices ireland A wide variety of diseases, most of them endocrine, can be diagnosed by assays of 24-h urine samples. The following information gives the normal values for certain agents and the conditions associated with changes in these values. Urine / Serum sodium Urine / Serum creatinine what is the drug cialis used for Darkfield examination is used to identify Treponema pallidum, the organism responsible for syphilis. Rectal and oral lesions cannot be examined by this technique due to the presence of nonpathogenic spirochetes. walgreens generic cialis TABLE 7–7 (Continued) Classic Clinical Presentation cialis to treat bph cialis diet pill — — — — — — — — — — 27 27 23 16 cout du cialis en pharmacie • Monitor patient on ECG if symptomatic or if K+ >6.5 mEq/L; discontinue all potassium intake, including IV fluids; order a repeat stat potassium to confirm. • Pseudo-hyperkalemia should be ruled out. If doubt exists, obtain a plasma potassium in a heparinized tube; the plasma potassium will be normal if pseudo-hyperkalemia is present. • Rapid Correction. These steps only protect the heart from potassium shifts, and total body potassium must be reduced by one of the treatments shown under Slow Correction. cialis 5 mg online kaufen Apheresis procedures are used to collect single-donor platelets (plateletpheresis) or white blood cells (leukapheresis); the remaining components are returned to the donor. Therapeutic apheresis is the separation and removal of a particular component to achieve a therapeutic effect (eg, erythrocytapheresis to treat polycythemia). Single Donor Plasma Like FFP, but lacks factors V and VIII About 1 h to thaw; 150–200 ml Rho Gam (Rho D immune globulin) Antibody against Rh factor (volume = 1 mL) 36 hour cialis price 12 cialis other uses Decreased Opaque Yellow to green >50,000† 75% or more Usually positive <25, Ӷserum buy real cialis cheap cialis for women uk The left subclavian approach affords a gentle, sweeping curve to the apex of the right ventricle and is the preferred entry site for placement of a temporary transvenous pacemaker without fluoroscopic assistance. Hemodynamic measurements are often easier to record from the left subclavian approach. From the left subclavian vein approach, the catheters do not have to negotiate an acute angle, as is commonly the case at the junction of the right subclavian with the right brachiocephalic vein en route to the superior vena cava. This is also a common site for kinking of the deep line. It also has the lowest risk of infection of various cen- cialis information sheet 296 cialis slogan 358 1 mm benefits of cialis daily Junctional rhythm with retrograde P waves (inverted) following the efecto del cialis en la mujer FIGURE 19–23 (LBBB) pattern. using cialis without ed *Normally in V1 to V6, the R-wave amplitude gradually increases and the S wave decreases with a “biphasic” QRS (R = S) in V3 or V4. With an anterior MI, there will be a loss of R-wave voltage and the biphasic QRS will appear more laterally in V4 to V6, hence the term poor R-wave progression. fake cialis pills the REF. Once REF and CO are known, the EDVI can be calculated. The EDVI is another measure of preload, and it allows a more accurate assessment of volume status regardless of pulmonary status. For example, a patient with severe ARDS may have markedly elevated peak inspiratory pressures. Although the CVP and PAOP may be falsely elevated, the EDVI is measuring a volume, not a pressure, allowing a more precise determination of volume status across a wide variety of clinical situations. The normal range for EDVI is 80–120 mL. best online pharmacy for generic cialis cialis est il dangereux Less compliant cialis liquid dosages (See also Algorithm, Chapter 21, page 460.) Shock is inadequate tissue perfusion, and is a syndrome with several possible causes. All four of these have in common a resultant poor perfusion of tissues that leads to tissue injury and death if untreated. The most common classification is based on etiology and includes hypovolemic, cardiogenic, septic, and neurogenic types. Treatment of shock is always directed at treatment of the underlying problem, maximizing cardiac performance to restore tissue perfusion, and maintaining essential physiologic support to keep oxygenation and renal function as normal as possible. Caused by inadequate circulating blood volume Physiology. Low cardiac output, low wedge pressure, elevated peripheral vascular resistance as a result of reflex vasoconstriction Therapy 1. Correct source of blood loss (hemorrhage). 2. Replete intravascular volume with packed cells, isotonic crystalloid fluids (normal saline, lactated Ringer’s), or colloid. crushing cialis 3 mg 250 mL D5W or PSS 5000 mg 500 mL D5W or PSS INDICATIONS: cialis augen 0.1 mg/mL in 1-mL vial. IV inf: Mix 1 mg in 250 mL NS or D5W. DOSAGE: Adults. 2–10 µg/min. Titrate to effect. cialis in thailand kaufen cialis tadalafil 50mg Severe cardiogenic shock and significant hypotension. Last resort for ischemic heart disease and shock 1 mg/mL in 4-mL amp. Mix 4 mg in 250 mL of D5W or D5NS DOSAGE: Adults. 0.5–1.0 µg/min titrated to 30 µg/min. Peds. IV inf: Initial 0.1–2 µg/kg/min to effect. Do NOT administer with alkaline solutions. is cialis time release DOSAGE: generic cialis tadalafil reviews Refractory invasive fungal infection in persons intolerant to conventional ampho- HTN ACE inhibitor DOSAGE: 10–40 mg/d PO SUPPLIED: Tabs 5, 10, 20, 40 mg NOTES: Symptomatic hypotension in patients taking diuretics; nonproductive cough cialis lilly forum viagra generic any good Cefaclor (Ceclor) Chlorpheniramine (Chlor-Trimeton, etc) soft tab viagra online viagra humana Cimetidine (Tagamet, others) Ciprofloxacin (Cipro) viagra ersatz ohne rezept precio del viagra en costa rica COMMON USES: Clinician’s Pocket Reference, 9th Edition indian viagra cipla Haemophilus B Conjugate Vaccine (Prohibit, Comvax, others) pastillas de viagra para mujeres what to take instead of viagra COMMON USES: ACTIONS: DOSAGE: formula quimica del viagra COMMON USES: DOSAGE: is generic viagra any good Lansoprazole (Prevacid) price of viagra in bangkok Hypothyroidism T3 replacement DOSAGE: Adults. Initial dose of 25 µg/24h, then titrate q 1–2 wk according to clinical response and TFT to maintenance of 25–100 µg/d PO. Myxedema coma: 25–50 µg IV. Peds. Initial dose of 5 µg/24h, then titrate by 5 µg/24h increments at 1–2-wk intervals; maintenance 25–75 µg/24h PO qd SUPPLIED: Tabs 5, 25, 50 µg; inj 10 µg/mL NOTES: ↓ Dose in elderly; monitor TFT Bronchodilator for asthma and reversible bronchospasm Sympathomimetic bronchodilator DOSAGE: Adults. Inhal: 1–3 inhal q3–4h to a max of 12 inhal/24h; allow at least 2 min between inhal. Oral: 20 mg q6–8h. Peds. Inhal: 0.5 mg/kg/dose to a max of 15 mg/dose inhaled q4–6h by neb or 1–2 puffs q4–6h. Oral: 0.3–0.5 mg/kg/dose q6–8h SUPPLIED: Aerosol 75, 150 mg; soln for inhal 0.4%, 0.6% 5%; tabs 10, 20 mg; syrup 10 mg/ 5 mL NOTES: Fewer β1-effects than isoproterenol and longer acting original viagra online kaufen ACTIONS: DOSAGE: COMMON USES: viagra boston ma buy pfizer viagra in canada 22 Commonly Used Medications where can buy viagra in bangkok COMMON USES: ACTIONS: DOSAGE: 594 where can i buy viagra over the counter in south africa dove acquistare viagra on line ACTIONS: DOSAGE: COMMON USES: cost of viagra in singapore COMMON USES: Adjunct to general anesthesia to facilitate endotracheal intubation and to induce skeletal muscle relaxation during surgery or mechanically supported ventilation Depolarizing neuromuscular blocking agent DOSAGE: Adults. 0.6 mg/kg IV over 10–30 s, followed by 0.04–0.07 mg/kg as needed to maintain muscle relaxation. Peds. 1–2 mg/kg/dose IV, followed by 0.3–0.6 mg/kg/dose at intervals of 10–20 min SUPPLIED: Inj 20, 50, 100 mg/mL; powder for inj 100 mg, 500 mg, 1 g/vial NOTES: May precipitate malignant hyperthermia; respiratory depression or prolonged apnea may occur; many drug interactions potentiating activity of succinylcholine; observe for cardiovascular effects; use only freshly prepared solutions; ↓ in severe liver disease viagra sellers uk concerta viagra COMMON USES: ACTIONS: Tolmetin (Tolectin) viagra minimum dosage 22 buy generic viagra safely viagra more than once a day UTI legal import viagra australia Valacyclovir (Valtrex) Procedure (Adult) viagra professional overnight delivery viagra si puo comprare senza ricetta Suspension* Drops and Original Drops 80 mg/0.8 ml Dropperful Peak levels: not recommended Trough level: just before next dose costo del viagra en ecuador viagra minimum dose 92. Hurwitz EL, Aker PD, Adams AH, Meeker WC, Shekelle PG. Manipulation and mobilization of the cervical spine. A systematic review of the literature. Spine 1996; 21:1746–59 93. Assendelft WJJ, Bouter LM, Knipschild PG. Complications of spinal manipulation. A comprehensive review of the literature. J Fam Pract 1996; 42:475–80 94. Lee KP, Carlini WG, McCormick GF, Albers GW. Neurologic complications following chiropractic manipulation: a survey of California neurologists. Neurology 1995; 45: 1213–15 95. Rothwell DM, Bondy SJ, Williams JI. Chiropractic manipulation and stroke. A populationbased case-control study. Stroke 2001; 32:1054–60 96. Shekelle PG, Adams AH, Chassin MR, et al. The Appropriateness of Spinal Manipulation for Low Back Pain: Indications and Ratings by a Multidisciplinary Expert Panel. Santa Monica, CA: RAND, 1991 should young people take viagra strength and normal function to reflexly inhibited pseudoparetic muscles, even without further treatment.) (3) Establish optimal motor patterns through retraining and education. In somatic dysfunction, even though the initiating event may have been traumatic, it appears that nociceptive stimuli from local tissues play a major role in initiating the spinal cord-level reflexes that, in turn, alter muscle length, tone and balance. Other somatic reflexes then play a role in maintaining and organizing these aberrant reflexes. Finally, because of cross-talk by the spinal cord-level segmental circuitry controlling autonomic and visceral functions, the local somatic findings of altered muscle length, tone and balance are frequently accompanied by segmentally related autonomic and visceral aberrations, completing the symptom complex of somatic dysfunction. In this manner, the central nervous system (CNS) functions both as an ‘integrator’ that senses and analyzes the environment, generating command signals along the motor pathways to muscles and other effectors65, and as an ‘organizer’ useful in interpreting segmentally related patterns of pain and dysfunction26,66 (Figure 3). The CNS interprets and assigns differing priorities to afferent nociceptive stimuli67 with subsequent automatic nocireflexive changes and adaptations largely occurring without conscious awareness. Because not all signals from the peripheral nociceptors reach the level of conscious pain perception, there is wide variability in the pain threshold and perceived pain intensity, even with the same stimulus in the same person68. Nonetheless, the barrage of nociceptive stimuli has significant physiological (nociflexive and nociautonomic) ramifications that are capable of manifesting as centrally organized peripheral tissue texture abnormalities. At the spinal cord level, these segmental and suprasegmental circuits maintain muscle length and tone and guide reflexes. Ultimately, short-term and chronic alterations in sensory input to the CNS can result in enduring changes in central processing69 and recurrent somatic dysfunction54. The physiological impact of somatic dysfunction is not limited to pain and peripheral palpatory changes. In addition to initiating protective reflexes and providing the CNS with Complementary therapies in neurology is it safe to take generic viagra viagra trade names Metal 1. Nader T. Human Physiology: Expression of Veda & Vedic Literature. Vlodrop, the Netherlands: Maharishi Vedic University Press; 1994 2. Maharishi. Maharishi Mahesh Yogi on the Bhagavad Gita. New York: Penguin, 1969 3. Jevning R, Wallace RK, Beidebach M, School of Human Behavior USIUSDCA. The physiology of meditation: a review. A wakeful hypometabolic integrated response. Neurosci Biobehav Rev 1992; 16:415–24 4. Wallace RK. Physiological effects of transcendental meditation. Science. 1970; 167:1751–4 5. Wallace RK, Benson H, Wilson AF. A wakeful hypometabolic physiologic state. Am J Physiol 1971; 221:795–9 6. Travis FT, Tecce J, Arenander A, Wallace RK. Patterns of EEG coherence, power, and contingent negative variation characterize the integration of transcendental and waking states. Biol Psychol 2002; 61:293–319 7. Travis F, Pearson C. Pure consciousness: distinct phenomenological and physiological correlates of ‘consciousness itself’. Int J Neurosci 2000; 100:1–4 8. Murphy MB. Theta bursts and rhythmical theta trains in the transcendental meditation technique and TM-Sidhi program: a qualitative and quantitative analysis of EEG theta activity. Dissertation Abstracts International: Section B: The Sciences & Engineering 2000; 61:125 9. Travis F. Autonomic and EEG patterns distinguish transcending from other experiences during Transcendental Meditation practice. Int J Psychophysiol 2001; 42:1–9 10. Banquet JP. Spectral analysis of the EEG in meditators. Electroencephalogr Clin Neurophysiol 1973; 35:143–51 11. Banquet JP, Sailhan M. Quantified EEG spectral analysis of sleep and Transcendental Meditation. Electroencephalogr Clin Neurophysiol 1974; 42:445–53 12. Levine P. The coherence spectral array (COSPAR) and its application to the study of spatial ordering in the EEG. Proceedings of the San Diego Bio-Medical Symposium. 1976; 15: 237–47 13. Dillbeck MC, Orme-Johnson DW, Wallace RK. Frontal EEG coherence, H-reflex recov-ery, concept learning, and the TM-Sidhi program. Int J Neurosci 1981; 15:3 14. Orme-Johnson DW, Haynes CT. EEG phase coherence, pure consciousness, creativity, and TM-Sidhi experiences. Int J Neurosci 1981; 13:4 15. Schneider RH, Staggers F, Alexander CN, et al. A randomised controlled trial of stress reduction for hypertension in older African Americans. Hypertension 1995; 26:820–7 16. Alexander CN, Schneider RH, Staggers F, et al. Trial of stress reduction for hypertension in older African Americans. II. Sex and risk subgroup analysis. Hypertension 1996; 28: 228–37 17. Barnes V, Schneider R, Alexander C, Staggers F. Stress, stress reduction, and hypertension in African Americans: an updated review. J Natl Med Assoc 1997; 89:464–76 18. Wenneberg SR, Schneider RH, Walton KG, et al. A controlled study of the effects of the Transcendental Meditation program on cardiovascular reactivity and ambulatory blood pressure. Int J Neurosci 1997; 89:15–28 19. King MS, Carr T, D’Cruz C. Transcendental meditation, hypertension and heart disease. Aust Fam Physician 2002; 31:164–8 20. Castillo-Richmond A, Schneider RH, Alexander CN, et al. Effects of stress reduction on carotid atherosclerosis in hypertensive African Americans. Stroke 2000; 31: 568–73 21. Zamarra JW, Schneider RH, Besseghini I, Robinson DK, Salerno JW, The Department of Medicine SUoNYBUSA. Usefulness of the transcendental meditation program in the treatment of patients with coronary artery disease. Am J Cardiol 1996; 77:867–70 22. Calderon R Jr, Schneider RH, Alexander CN, Myers HF, Nidich SI, Haney C. Stress, stress reduction and hypercholesterolemia in African Americans: a review. Ethn Dis 1999; 9: 451–62 23. Schneider RH, Nidich SI, Salerno JW, et al. Lower lipid peroxide levels in practitioners of the Transcendental Meditation program. Psychosom Med 1998; 60:3 8–41 maximum safe dosage viagra YOGA, PRANAYAMA, MEDITATION AND HEALTH CARE Hatha yoga, pranayama and meditation can be adapted for almost any patient. Most group Hatha yoga classes incorporate postures, breathing exercises and relaxation or meditation into a 1–2-h yoga class. It may be a challenge to locate a yoga teacher with the experience and patience to apply yoga therapeutically to a patient, particularly when the teacher may not have a medical background. It is important to remember that few yoga instructors are licensed health-care providers. Many yoga teachers are certified but the certification varies from correspondence courses to weekend training programs to a multi-year process with requirements for anatomy and physiology courses as with Iyengar yoga. It is important to ask teachers about their training and select one who has at least several years of teaching experience and continues to attend yoga teacher workshops. Certified yoga therapists who are experience in teaching Hatha yoga and comfortable working with patients are increasingly common, as Hatha yoga becomes more widely available and integrated with other medical therapies, from the Ornish program for cardiac rehabilitation to postpolio syndrome33. It may be useful to recognize that Hatha yoga can be viewed as an exercise system that provides a whole-body work-out or be used restoratively to alleviate fatigue. Medical studies have documented that there are many physical and mental benefits to exercise— improved fat metabolism, weight loss, increased circulation, decreased risk of cancer, to name but a few. Commonly, at any given moment, many of our small blood vessels are constricted, reducing blood flow and supply. During the practice of Hatha yoga the blood supply to these areas and the abdominal organs opens up through compression and expansion. This increased circulation supplies these areas with oxygen and other nutrients as well as improving waste removal. Bone density also increases when periosteal stresses can i get viagra from my doctor historias de viagra 198 cooking with viagra Complementary therapies in neurology METHODOLOGICAL ISSUES CONFOUNDING PLACEBO EFFECT STUDIES There are several methodological issues that have produced misinterpretations of studies relating to the placebo effect, even recent publications. These methodological concerns include natural history, the Hawthorne effect, regression to the mean, therapist and observer biases, direct treatment effects confounding the placebo arm of a study and other aspects of poor experimental design26. Natural history is simply what would have happened to a patient independently of any intervention (placebo or active treatment). In the most stringent definition it is also independent of being in a clinical trial. It is difficult to study placebo effects in diseases where the natural healing rate is high (e.g. ulcer disease) or where spontaneous fluctuations are common (e.g. multiple sclerosis). The natural history effect is important to take into account when studying the placebo effect. Unfortunately, it is rare in modern clinical trials to have untreated control groups. As a result, a recent systematic review of the placebo effect found only 114 clinical trials spanning several decades that had both a placebo treatment arm as well as a nontreatment arm in a clinical trial. Most of the studies were published prior to 1990, with 24 of them published prior to 198027. The effect of placebo in this meta-analysis was seen only in continuous outcome measures and not in binomial outcome measures. Many of the papers discussed in this chapter compare different placebo arms, but do not compare a placebo group to a non-treatment group in the same study. Thus, natural history may be confused with placebo effect in these papers and contribute to uncertainty about the frequency and magnitude of the placebo effect. There are some effects on outcome measures that result simply from being in a clinical trial, independent of any intervention, be it an active treatment or placebo. For example, subjects may change health habits simply from being in a study. This effect, related solely to a change in behavior secondary to simply being in a study and undergoing viagra ringing ears viagra for sale in spain Complementary therapies in neurology viagra clinical studies 55 41 32 where to buy viagra in leicester 350 dementia with appropriate medical and psychiatric exclusions order viagra trial viagra tablets information Haimou et al.49 438 use viagra fun jak dziala viagra na kobiete Complementary therapies in neurology michael youn viagra UGTs are responsible for glucuronidation of morphine, buprenorphine and some non-steroidal antiinﬂammatory drugs (NSAIDs). More than 18 UGT enzymes have been described in humans. Oral morphine is primarily metabolised in the liver, through the UGT system to morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) (Figure 4.2). Genetic polymorphisms have been identiﬁed for the UGT family of enzymes. However, polymorphisms in the gene coding for the UGT2B7 enzyme (which catalyses the formation of M6G and M3G from the parent drug morphine) have not been shown to alter the glucuronidation ratio of M3G–M6G with mean values 5.3–6.4. In addition, a number of studies have demonstrated wide variability in morphine and metabolite plasma concentrations, despite equivalent 27 vipps online pharmacy viagra • • • best deals on generic viagra viagra kupnja (b) BASIC SCIENCE viagra uk sellers No pain sensation priapism treatment viagra cheapest brand name viagra VAS – this consists of a line with an anchor at each end (Figure 11.1). The line may be horizontal or vertical, but it has been found that patients ﬁnd the vertical scale easier to use and it is more sensitive than the horizontal scale. NRS – consists of a line with anchors at either end, but in addition numbers between the anchors (Figure 11.2). It is sometimes used in response to the request ‘give me a number for your pain intensity from 1 to 10’. VRS – a group of ranked words is used (e.g. for pain intensity: mild, moderate and severe). This type of verbal scale is useful if a person has visual or motor impairment. urban dictionary viagra It is not uncommon for pain symptoms to be related to a life event (either made worse by or start in relation to it). Questions such as ‘Have you suffered a personal loss?’ are part of a pain history. Death, disease and divorce are commonly described. Patients may look sad, or have difﬁculty concentrating and are difﬁcult to communicate with. A tearful interview may follow such questions as ‘Do you feel sad?’ A referral to support services and other professional groups may be necessary. If the patient is accompanied, additional positive or negative factors may be revealed. Where trauma is the initiating event a history of legal activity should be taken. Financial rewards may be maintaining pain – a history of disability payments, compensation awards, etc. should be included in the history. A review of previous pain therapies may reveal patient preferences, beliefs, cognition and potential compliance. The list of therapies may include: • Physical therapies – for example, acupuncture, braces, casts, trigger point injections, exercises, trans-cutaneous nerve stimulation, chiropractic, homeopathy and physiotherapy. • Situational therapies – for example, hypnosis, relaxation and behavioural therapy. The choice of therapies selected by a patient may reﬂect economic circumstances or social pressures. History elicited from a patient may usefully start a dialogue with the patient about causes of pain and their relevant therapies. himalayan viagra wikipedia Only applies to the working population. Correlates poorly with biomedical measures of pain and clinical outcomes. Is also strongly inﬂuenced by the socio-economic climate. cara pemakaian viagra good examples. Tertiary prevention seeks not to prevent disease or symptoms, but to minimise disability and handicap arising from it. Illness behaviour and psychological morbidity can develop following the onset of chronic pain and tertiary prevention would be aimed at reducing these sequelae. Epidemiologists describe a web of causation and group aetiological factors under three headings: agent, host and environment. These factors do not act in isolation but interact and are often represented as the triangular web of causation (Figure 15.1). Causative agents include physical trauma (such as surgery, heavy lifting and accidents) and infective agents (including herpes zoster). Host factors can modify the impact of these physical factors. For example, the likelihood that herpes zoster will lead to post-herpetic neuralgia will depend on the age of the patient. Potential host inﬂuences, such as psychological, immunological, physiological and anatomical factors, are also important. Environmental factors comprising does 25mg viagra work In examining the muscular system, one should not only observe the volume, contour, power and tone of the muscle, but also evaluate the strength and function of muscle groups. This can be performed by: canada meds viagra But is visceral pain as so deﬁned a perceptual entity different from musculo-skeletal or cutaneous pain in a way that is useful clinically for diagnosis and therapy? acheter du viagra en pharmacie en france • • similar al viagra pero natural how much mg of viagra should i take Although studies have shown that non-steroidal antiinﬂammatory drugs (NSAIDs) are effective analgesics in many types of cancer pain, they are chieﬂy indicated for malignant bone pain or to reduce inﬂammation in pleuritic pain or liver capsular pain. They can be used preferentially or added to the analgesic ladder at any step. viagra wirkung wikipedia Marking a point to represent pain on a 10 cm line, where 0 cm represents no pain and 10 cm the worst imaginable pain. The scale needs explanation before surgery. precio del viagra en farmacias del ahorro Osteoporosis can be a feature of CRPS and one study using intravenous clodronate demonstrated signiﬁcant beneﬁts in analgesia. Intrathecal baclofen can reduce dystonias in the upper limbs (but inexplicably not those in the lower limbs). Sympathetic and somatic nerve blocks can be beneﬁcial, particularly in the early phase of the syndrome. Spinal cord stimulation in combination with physical therapy has a signiﬁcant but modest effect on pain at 6 months (but no effect on function or quality of life). The justiﬁcation for such costly and invasive treatments must be questioned, when the beneﬁts are so modest. viagra usage statistics Other lorazepam viagra interaction The importance of parents and family in the management of childrens’ pain must be recognized. The 186 viagra salesman movie forms of analgesia involve the recruitment of the endogenous opioid peptides. viagra for your brain NON-STEROIDAL ANTI-INFLAMMATORY AGENTS viagra kidney damage kesan viagra A rapidly evolving understanding of the neurobiology of pain has: Cannabinoids lloyds pharmacy viagra online generic viagra 130 mg Attention–diversion techniques viagra sale perth pathology could be found was referred to the pain clinic. During a detailed history it was found that the pain had occurred shortly after her father had slapped her on the cheek following her late return home after a date with her boyfriend. Subsequently she had gone to stay with her boyfriend and that night her father died of a heart attack. The reason for the persistence of this symptom is psychodynamically apparent in this case. Pain in dysfunctional families is often subtle and lacks logic. At ﬁrst sight it may be difﬁcult to see how there is any beneﬁt from the pain. Some spin offs may be easy to work out (e.g. not having to do homework). But if a socially easy child has pain causing him to stay away from school, friends, normal life and sport, what advantage can there be? One answer is that the child fears what will happen to him at school or what may happen at home in his absence (Scenario 3). viagra stores sydney • viagra funny stories Neurophysiology of Concussion can i split viagra pill how do i get my doctor to prescribe me viagra Pliiyer position mens viagra online Ried, S.E., Tarkington, J.A., Epstein, H.M., and O'Dea T.J. (1971). Brain tolerance to impact in football. Surgery Gynecology and Obstetrics, 133(6), 929-936. Morrison, W.E. (1983). Calibration and utilization of an instrumental football helmet for the monitoring of impact acceleration. Ph..D. unpublished thesis, PSU, Pellman, E.J., Viano, D.C., Tucker, A.M., Casson, I.R., & Waeckerle, J.F. (2003). Concussion in professional football: Reconstruction of game impacts and injuries. Neurosurgery, 53(4), 799-814. Newman, J., Beusenberg, M., Fournier, E., Shewchenko, N., Welbourne, E., & Withnall, C. (2000). A new biomechanical assessment of mild traumatic brain injury, part 11: Results and conclusions. Paper presented at the International Research Council on the Biomechanics of Impact, Montpellier, France. Newman, J., Beusenberg, M., Fournier, E., Shewchenko, N., Withnall, C, King, A., et al. (1999). A new biomechanical assessment of mild traumatic brain injury, part I: Methodology. Paper presented at the International Research Council on the Biomechanics of Impact, Sitges, Spain. Newman, J., Shewchenko, N., & Welbourne, E. (2000). A new biomechanical head injury assessment function: The maximum power index. Paper presented at the 44th Stapp Car Crash Conference, Atlanta, GA, USA. First of all, it is important to note that consciousness remains an elusive concept due to the difficulty of defining what has been regarded for many years as a subjective experience, therefore irrelevant for scientific study (Tassi & Muzet, 2001). According to these authors, consciousness, vigilance, arousal and alertness may involve different functional entities, which are probably not linked by single monotonous function. Consciousness at its different levels may essentially refer to awareness and the building up of mental representations with or without the possibility of patients' verbal responses. Clearly, verbal responses should not be used to assess the state of consciousness. On the other hand, vigilance may reflect the attentional capacities and mental resources at every moment. Arousal is, according to these authors, the only state immediately dependent on physiological status. Finally, alertness may reflect a subjective feeling of well-being related to the level of arousal and vigilance. In the following discussion, the very general concept of consciousness reflecting the subject' awareness and alertness will be used while defining consciousness and loss of consciousness (LOC). Sudden temporary loss of awareness is the most characteristic and enigmatic symptom of concussion (Shaw, 2002). According to Plum & Posner (1980), the maintenance of consciousness is dependent upon a complex interaction between brainstem, thalamus, hypothalamus and cortical activity. Conversely, loss of consciousness will occur following diffuse bilateral impairment of cortical activity. With regard to the issue of loss of consciousness in terms of the grading of concussion, there are now a number of papers that have prospectively studied concussion. The central message from these papers clearly shows that a brief loss of consciousness is not necessarily associated with concussion severity. Previous assumptions that a concussion was present only when individuals remained unconscious for a a long amount of time are just not right. Joe Maroon and Mark Lovell were the first who raised this concern in studying individuals that were briefly concussed. Concussion both in athletic and non-athletic events may be present within any even brief loss of consciousness. Specifically, one group of subjects who were unconscious and another without LOC at the time of brain injury were tested using standard neuropsychological test batteries. No differences in terms of cognitive scores were observed between these two groups of subjects. It can be inferred that LOC did not significantly influence the degree of cognitive deficits later on in recovery process. Neither the severity of concussion nor the rate of recovery following the concussion correlated with duration of LOC at the time of concussive blow. However, athletes who experienced retrograde and/or anterograde amnesia between 24 hours and forty-eight cheapest prescription viagra uk Rosenbaum, Arnett, Bailey buy pfizer viagra usa 2/58 (3%) 3/28 (11%) is generic viagra legal in united states 2 viagra for gastroparesis 4,2. selling viagra on ebay Neuroimaging in TBI mixing viagra and coke The prediction of other chronic complications of minor TBI was alluded to in the section above. These involve chronic neurobehavioral deficits whose focal or diffuse natures are sometimes rendered visible by SPECT (Goethals et al„ 2004; Agrawal et al., 2005), CT or PET scans, or chronic biochemical changes on MR spectroscopy (Hunter et al., 2005). MRI scans are especially useful in demonstrating diffuse (Scheid et al., 2003; Inglese et al., 2005) or focal injury (Fig. 27). viagra sublinguale viagra prezzo svizzera A contusion is a bruising or microscopic hemorrhage that occurs along the superficial levels of the brain. Lacerations are described as tears in the brain tissue that are often associated with penetrating or depressed skull fractures. Glasgow Coma Scale (GCS) is one of the most commonly utilized measures of injury severity (Teasdale & Jennett, 1974). It ranges from 3 to 15. Most health care providers use the GCS with both pediatric and adult population. Simpson and Reilly (1982) have modified the GCS for the use with children, scoring child's best responses in motor, verbal and eye-open modalities. The total sum of these scores is then compared to the logical (not empirical) normal aggregate score for children of compatible ages. With the maximum total score being 14, children over the age of 5 years without any evidence of head trauma would be expected to obtain the highest score. Children from 2 to 5 years may score as high as 13; ages 1-2 years- up to 12; 6-12 months- up to 11; and infants to 6 months- up to the highest score of 9. Others have also attempted to adapt the GCS for the use with pediatric population (Fay et al., 1993). While moderate and severe head injuries are defined more precisely, mild traumatic brain injuries (MTBI) are difficult to assess. Frequently, the definition of MTBI ranges from a bump on the head to a concussion. However, the importance of investigating the residual effects of mild head injury is crucial, as they are known to cause a large number of intracranial injuries (Schutzman et al., 2001). In fact, Schutzman and Greenes (2001) have shown that prevention of secondary injury associated with mild and moderate head trauma, in persons who initially appear to be at low risk, accounts for the largest reductions in head trauma mortality. Thus, without the definition of MTBI, the findings of various studies that look at residuals of MTBI are equivocal. The definition of the Mild Traumatic Brain Injury, developed by the Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation Medicine (ACRM, 1993) states that such "injury involves a traumatically induced physiological disruption of brain function, as manifested by at least one of the following: (1) any period of loss of consciousness, (2) any loss of memory for events immediately before or after the accident, (3) any alteration in mental state at the time of the accident, and (4) focal neurological deficit(s) that may or may not be transient, but for which the severity of the injury does not exceed the following: (5) loss of consciousness of approximately 30 minutes or less; (6) after 30 minutes, an initial GCS of 13-15; and (7) post-traumatic amnesia not greater than 24 hours." Traditionally, the GCS score has been used widely to assess neurological state of an injured brain. However, Post-Traumatic Amnesia viagra price bangkok 1 Table 3. Baseline and 24-72 Hours Post-concussion Descriptive Statistics for Aerobic Fitness on Immediate Postconcussion Assessment and Cognitive Testing (ImPACT) Module and Symptom Scores. Aerobic Fitness (i.e., estimated VO2 max) 24-72 Hours PostBaseline ImPACT Module M Total Symptoms Verbal Memory Visual Memory Processing Speed Reaction Time 7.66 0.78 0.75 35.3 0.52 Hi gh SD 8.14 0.09 0.15 10.4 0.05 M 12.27 0.75 0.63 33.2 0.56 Low SD 10.2 0.13 0.14 6.3 0.10 M 13.7 0.75 0.67 35.6 0.55 High SD 14.9 0.16 0.21 11.9 0.06 M \1A 0.76 0.66 33.2 0.58 Concussion Low SD 13.6 0.12 0.11 6.7 0.19 produit similaire au viagra The results of a 2 (aerobic fitness) x 2 (concussion history) x 2 (on-field PTA) ANOVA supported significant main effects for concussion history (F[l, 23]= 4.00, /?=.05, ri2= .25) and on-field PTA (F[l, 23]= 12.10, p=.005, ri2= .50) on recovery time. Specifically, athletes with no history of concussion recovered faster than those with a history of concussion (see Figure 4). Concussed athletes who were evaluated with no on-field PTA recovered faster than those who were evaluated with PTA. There was also a non-significant trend for aerobic fitness (F[l, 23]= 2.10, p= .07, ?/2= .15), suggesting that athletes high in aerobic fitness recovered faster than those low in aerobic fitness. The results did not support any interactions among the factors. lady era viagra can teenagers use viagra 333 jual obat viagra 2. costo de pastillas viagra 3064 viagra ottawa canada 433 viagra stores in mumbai Mader: Human Biology, Seventh Edition mesenteric arteries viagra bupropion buy genuine pfizer viagra - Understanding Key Terms Part 2 precio viagra original husband taking viagra Tropical rain forest inhabitants. viagra stockists Hypothesis Inductive reasoning is used to formulate a testable statement. is it safe for a woman to take viagra When studying the world of living things, biologists, like other scientists, use the scientiﬁc method, which consists of these steps: making an observation, formulating a hypothesis, carrying out an experiment or simply making further observations, and coming to a conclusion. can i buy viagra in tesco pH is deﬁned as the negative logarithm of the molar concentration of the hydrogen ion [Hϩ]. Primary Structure This level of structure is determined by the sequence of amino acids that join to form a polypeptide. viagra information from drugs.com abracadabra im up like viagra 2. Chemistry of Life Testing Your Knowledge of the Concepts viagra canada ottawa free viagra spam 3. Cell Structure and Function Organization and Regulation of Body Systems buying viagra dublin make viagra more effective Support and Movement making your own viagra Regulation of Body Temperature Maintenance of the Human Body comprar viagra tenerife acheter viagra tunisie 5. Digestive System and Nutrition 21 year old viagra Carbon Monoxide: A Deadly Poison 117 order viagra canada pharmacy viagra half tablet Red blood cells are small, biconcave disks that lack a nucleus. They live about 120 days and are destroyed in the liver and spleen when they are old or abnormal. The production of red blood cells is controlled by the oxygen concentration of the blood. 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Both interferon and interleukins, which are cytokines produced by various white blood cells, have been used as immunotherapeutic drugs, particularly to enhance the ability of the individual’s own T cells to ﬁght cancer. Interferon, discussed previously on page 150, is a substance produced by leukocytes, ﬁbroblasts, and probably most cells in response to a viral infection. Interferon still is being investigated as a possible cancer drug, but so far it has proven to be effective only in certain patients, and the exact reasons for this as yet cannot be discerned. 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The release of aldosterone is set in motion by the kidneys themselves. The juxtaglomerular apparatus is a region of contact between the afferent arteriole and the distal convoluted tubule (Fig. 10.9). When blood volume, and therefore blood pressure, is not sufﬁcient to promote glomerular ﬁltration, the juxtaglomerular apparatus secretes renin. Renin is an enzyme that changes angiotensinogen (a large plasma protein produced by the liver) into angiotensin I. Later, angiotensin I is converted to angiotensin II, a powerful vasoconstrictor that also stimulates the adrenal cortex to release aldosterone. The reabsorption of sodium ions is fol- 200 can you buy viagra in france 11. Skeletal System 15 year old taking viagra lateral malleolus talus can you cut a viagra in half kamagra philippines III. Movement and Support in Humans kamagra gold forum Mader: Human Biology, Seventh Edition 12. Muscular System ajanta pharma kamagra jelly 240 menshelp kamagra 13. Nervous System kamagra canada online Voltage (mV) kamagra how much to take kamagra cena apteka Chapter 13 kamagra gel 50 mg + 20 0 Voltage (mV) _ 20 _ 40 excitatory signal _ 65 inhibitory signal _ 75 b. Time (milliseconds) integration resting potential threshold © The McGraw−Hill Companies, 2001 cheap kamagra uk next day delivery © The McGraw−Hill Companies, 2001 kamagra slovenija IV. Integration and Coordination in Humans cheapest kamagra online uk kamagra 100 chewable tablet Mader: Human Biology, Seventh Edition 14. Senses kamagra 100 brausetabletten 14.1 Sensory Receptors and Sensations kamagra buyers In questions 1-4, match the sense to the descriptions. a. b. c. d. vision smell hearing cutaneous 1. A chemical sense that utilizes modiﬁed neurons that send nerve impulses directly to the brain. 2. Much integration occurs in the PNS before nerve impulses are sent to the brain. 3. Five types of senses associated with the skin. 4. Sensory receptors are hair cells that communicate with sensory ﬁbers. In questions 5–7, indicate whether the statement is true (T) or false (F). 5. The spiral organ is located in the semicircular canals. 6. The choroid, the middle layer of the eye, becomes the cornea of the eyeball. 7. The cone cells function in bright light and are sensitive to color. For questions 8 and 9, ﬁll in the blanks. 8. The and the of the inner ear contain mechanoreceptors for our sense of equilibrium. 9. Because nerve ﬁbers cross at the optic chiasma, the right cerebral hemisphere receives data about the side of the visual ﬁeld. c. d. e. 11. Match the terms to these deﬁnitions: a. b. One of the small bones of the middle ear-malleus, incus, stapes. Type of sensory receptor that responds to chemical stimulation; for example, the receptors for taste and smell. Visual pigment found in rods whose activation by light energy leads to vision. An awareness of a stimulus, occurs only in cerebral cortex. A mechanoreceptor that gives rise to nerve impulses in the cochlear nerve when its stereocilia are bent or tilted. kamagra soft tabs 100mg Sense of Taste Essential Study Partner Sense of Smell Essential Study Partner kamagra in dublin kamagra tablets review I 19 kamagra jelly schweiz kamagra prices uk 16. Reproductive System Couple and children. wo kann man kamagra kaufen kamagra jelly bijwerkingen V. Reproduction in Humans kamagra wien Congenital syphilis is caused by syphilitic bacteria crossing the placenta. The child is stillborn, or born blind, with many other possible anatomical malformations. kamagra oral jelly cena V. Reproduction in Humans kamagra kaufen erfahrungen Understanding Key Terms buy kamagra oral jelly australia from one or more of the following diseases rather than from the HIV infection itself: • Pneumocystis carinii pneumonia. The lungs become useless as they ﬁll with ﬂuid and debris due to an infection with a protozoan. • Mycobacterium tuberculosis. This bacterial infection, usually of the lungs, is seen more often as an infection of lymph nodes and other organs in patients with AIDS. • Toxoplasmic encephalitis is caused by a protozoan parasite that ordinarily lives in cats and other animals. Many people harbor a latent infection in the brain or muscle, but in AIDS patients, the infection leads to loss of brain cells, seizures, and weakness. • Kaposi’s sarcoma is an unusual cancer of the blood vessels, which gives rise to reddish-purple, coinsized spots and lesions on the skin. • Invasive cervical cancer. This cancer of the cervix spreads to nearby tissues. This condition was added to the list when AIDS became more common in women. Although there are newly developed drugs to deal with opportunistic diseases, most AIDS patients are repeatedly hospitalized due to weight loss, constant fatigue, and multiple infections (Fig. S.4). Death usually follows in 2–4 years. During the acute phase of an HIV infection, the person is highly infectious although there may be no symptoms; during the chronic phase, there may be swollen lymph nodes and various infections; during the last phase, which is called AIDS, the patient usually succumbs to an opportunistic infection. kamagra for women effects AIDS Supplement relationship with a partner who is free of HIV. soft chewable kamagra 5. buy kamagra oral jelly uk somites gut coelom does kamagra work for women The chorion and amnion surround the embryo. The two other extraembryonic membranes, the yolk sac and allantois, contribute to the umbilical cord. kamagra pas cher acheter kamagra novi sad Extraembryonic Membranes kamagra u apoteci Health habits. a. b. c. d. kamagra sildenafil citrate tablets buy kamagra online with paypal Meiosis animation activity Meiosis I art labeling activity kamagra gel 50mg e-Learning Connection 20.1 Genotype and Phenotype cheap kamagra next day delivery uk Mader: Human Biology, Seventh Edition Figure 21.8 Transcription. kamagra jelly info kamagra tabletten kaufen G Figure 21.14 Lampbrush chromosomes. donde comprar kamagra cloned insulin gene kamagra 20 mg kamagra 365 pharmacy Human Genetics kamagra jelly 5mg Cancer Cells Form Tumors © The McGraw−Hill Companies, 2001 kamagra 50 mg oral jelly Cells metastasize super kamagra forum kamagra mit paypal bezahlen migration of Homo erectus kamagra paypal bezahlen 476 kamagra 4 less Grazing food web Detrital food web kamagra 100mg ajanta Part 7 kamagra romania Humans don’t always realize the many ways in which they disturb local ecosystems. Disease kamagra kgr 100 kamagra soft chewable Part 7 Chapter 7 kamagra oral jelly buy uk 1. d; 2. a; 3. b; 4. c; 5. F; 6. T; 7. F; 8. synaptic cleft; 9. sensory, motor; 10. a. sensory neuron; b. interneuron; c. motor neuron; d. receptor; e. cell body; f. dendrites; g. axon; h. nucleus of Schwann cell; i. node of Ranvier; j. effector does kamagra work on women • • • • • • kamagra women does work • kamagra 100mg wirkung TRANSFERS kamagra tabletten bestellen CHAPTER 12 buy kamagra over the counter kamagra oral jelly female Fat (naturally occurring and added) Sugars (added) kamagra online schweiz 117 C h a p t e r kamagra oral jelly 50 mg • kamagra for women how does it work ( % %% o f kamagra 100mg test kamagra effects on women ( m s ) Intensity (x MT) (l ) (m) 1 4 Femoral nerve 0 5 0 4 0 5 0 4 0 5 0 4 0 5 0 4 0 5 29 31 33 35 0 4 29 31 33 35 0 5 10 -0,8 -0,4 0 Fig. 2.7. Wide range of electrical thresholds for human Ia afferents. (a ) Sketch of the pathway of heteronymous monosynaptic Ia excitation (dotted line) from quadriceps (Q) to a peroneus brevis motoneurone (MN). (b ), (d ), (f ), (h ), (j ) PSTHs (0.5 ms bin width) for a peroneus brevis unit with () and without stimulation of the femoral nerve (). (c ), (e ), (g ), (i ), (k ) Difference between control and conditioned histograms. (b )–(k ) Stimulation of the femoral nerve at 1 MT ((b )–(c )), 2 MT ((d )–(e )), 3 MT ((f )–(g )), 4 MT ((h )–(i )), and 5 MT ((j )–(k )). (l ), (m ) Mean results from 25 motor units. (l ) Mean amplitude of the excitation, expressed as the statistical signiﬁcance (␹ 2 ) of the difference between conditioned and control histograms during the ﬁrst two bins of the peak, plotted against the intensity of stimulation. (m ) Average decrease in latency of the monosynaptic peak (referenced to the latency at 1 MT, which is the zero of the ordinate), plotted against the stimulus intensity. Modiﬁed from Gracies, Pierrot-Deseilligny & Robain (1994), with permission. Difference between the full recruitment of Ia afferents in cat and human experiments This difference (at 2 and 8 Ia threshold, respec- tively) is probably due to the fact that in human experiments afferents are stimulated through elec- trodes on the skin surface, at a distance from the nerve. Human nerves have a larger diameter and the relevant fascicle may not always be optimally orientated to the surface. As a result, the thresh- old for a ﬁbre will be determined as much by its distance from the stimulating electrodes as by its size. Conclusions Whatever the mechanism responsible for the wide range of electrical thresholds of Ia afferents, this factor needs to be taken into account for two rea- sons. (i) Reﬂex latency approaches the ‘true mono- synaptic latency’ only at intensities far above motor threshold. (ii) If some Ia afferents are only activated by strong stimuli, the potential Ia reﬂex contribu- tion may be underestimated in human experiments, which are generally performed with much lower stimulus intensities (≤1 MT) in an attempt to acti- vate group I afferents selectively. Organisation and pattern of connections 79 Organisation and pattern of connections The efﬁcacy of a given Ia input in discharging a motoneurone is referred to as the ‘strength of Ia excitation’ in the following and depends on several factors: (i) the number of Ia afferents projecting to the tested motoneurone; (ii) the level of presynaptic inhibition and the level of post-activation depres- sion at Ia terminals; (iii) any limitation produced by inhibitory circuits activated by the test volley, and (iv) the motoneurone type. Homonymous monosynaptic Ia excitation Evidence for homonymous Ia excitation in all motoneurone pools H reﬂex At rest, H reﬂexes can be recorded from the soleus, quadriceps andFCRinmost healthy subjects (Fig. 2.8(b ), (d ), (g )), often from hamstrings (in thin subjects (e )), andrarely fromother muscles ((c ) , (f ), (h)). However, anHreﬂexcanbeobtainedinvirtually all limb muscles during a weak voluntary contrac- tion of the test muscle (see p. 69), without changing reﬂex latency signiﬁcantly (see thickandthinlines in Fig. 2.8). Homonymous monosynaptic Ia excitation in single motor units Stimulation of the parent nerve evokes an early peak of increasedprobability of discharge inPSTHs of sin- gle motor units in all limb muscles tested, and this has thecharacteristics of homonymous monosynap- tic excitation (see p. 69): soleus (Ashby & Labelle, 1977), tibialis anterior (Ashby & Zilm, 1982), gas- trocnemius medialis (Mao et al., 1984), peroneus brevis (Meunier, Pierrot-Deseilligny & Simonetta, 1993), quadriceps (Fournier et al., 1986), hamstrings (Bayoumi & Ashby, 1989), intrinsic foot muscles (Marque et al., 2001), biceps brachii (Cavallari & Katz, 1989), ﬂexor carpi radialis (FCR) and ﬂexor carpi ulnaris (FCU) (Malmgren&Pierrot-Deseilligny, 1988), deltoid, triceps brachii, extensor carpi radi- alis (ECR), ﬂexor digitorum superﬁcialis (FDS) and extensor digitorum (ED) (Gracies et al., 1991), ﬂexor pollicis longus (where the excitation is weak, Inglis et al., 1997) and the intrinsic hand muscles (Marchand-Pauvert, Nicolas & Pierrot-Deseilligny, 2000). It must be emphasised that these investiga- tions were performed during weak voluntary con- tractions (below5%MVC), andthe motor units stud- ied were all in the low-threshold range. Differences in the efﬁcacy of homonymous Ia excitation in ﬁring motoneurones Estimate of the efﬁcacy of the Ia input in ﬁring homonymous motoneurones This efﬁcacy may be assessedby the ease withwhich the H reﬂex can be elicited at rest and by the size of the peak of excitation elicited in the PSTHs of sin- gle motor units by stimulation subthreshold for the compound H reﬂex (e.g. 0.7 MT). Generally, these two measures are closely linked: e.g. in accordance with the ease with which the H reﬂex is obtained at rest in the soleus and FCR, the peak of homony- mous Ia excitation elicited by a Ia input of compar- able strength is signiﬁcantly larger in soleus than in tibialisanterior(Maoet al., 1984), andintheFCRthan in the ECR (Chalmers & Bawa, 1997). The difﬁculty in activating some motoneurone pools reﬂexly can- not be attributed to low excitability of the motoneu- rone pool: tibialis anterior is more excitable to corti- cospinal inputs than soleus, while the reverse is true for Ia afferent inputs. Preferential distribution of the monosynaptic Ia input to small motoneurones In the cat, homonymous monosynaptic Ia EPSPs are maximal in small motoneurones innervat- ing slow-twitch units (cf. p. 65). The size of the monosynaptic Ia peak should then decrease as larger motoneuronesof higher thresholdinnervating 80 Monosynaptic Ia excitation Soleus TA 0 10 20 30 40 50 60 ST ECR APB 0 10 20 30 40 50 Triceps Q FCR Biceps (b) (c) (d) (e) (f ) (g) (h) Latency (ms) (a) (i ) (j ) S i z e f a c i l i t a t i o n kamagra store erfahrung super kamagra online t r i g g e r s ) (a) Biceps FDS Wrist extensors 0 1 2 0 1 2 0 1 2 12 8 4 0 FDS MN Median Radial MC Propriospinal neurones C4 C5 C6 C7 C8 T1 Fig. 10.3. Propriospinally mediated facilitation elicited in the PSTHs of the same FDS unit by stimulation of various nerves. (a) Sketch of the presumed pathways. Propriospinally mediated excitation from each muscle is transmitted to a given motoneurone (MN) pool (here ﬂexor digitorum superﬁcialis, FDS) through different subsets of propriospinal neurones (PN) (see pp. 468–9). (b)–(d) PSTHs (after subtraction of the background ﬁring, 1 ms bin width) with the number of counts (expressed as a percentage of the number of triggers) plotted against the central latency after stimulation. Latencies are measured from the monosynaptic latency following median nerve stimulation at 1 MT, after allowance for the differences in peripheral afferent conduction times. (b) Stimulation of the median nerve (0.5 MT). (c) Stimulation of the radial nerve (0.6 MT). (d) Stimulation of the musculo- cutaneous nerve (MC, 0.7 MT). In all three cases, excitation occurred at the 6 ms central delay. Modiﬁed from Gracies et al. (1991), with permission. et al., 1992a; Mazevet & Pierrot-Deseilligny, 1994). This apparent weakness may reﬂect intrinsically weak peripheral excitatory connections to pro- priospinal neurones, as in the cat. However, it might also be the consequence of stronger projec- tions of peripheral afferents to feedback inhibitory interneurones which, when the peripheral volley is big enough, could cause the discharge of feedback inhibitory interneurones to overwhelm the facilita- tion in propriospinal neurones (see p. 464). Corticospinal excitation of propriospinal neurones In order to demonstrate that propriospinal neu- rones receive corticospinal excitation: (i) evidence has ﬁrst been sought for convergence of peripheral and corticospinal volleys onto common interneu- rones, a ﬁnding that would imply that part of the corticospinal excitation to motoneurones is medi- ated through an interneuronal relay; and (ii) it was then shown that transmission through this relay has the same features as propriospinally mediated excitation revealed in the PSTHs of single motor unitsdescribedabove(Pauvert, Pierrot-Deseilligny& Rothwell, 1998; Nicolas et al., 2001). Extra facilitation on combined stimulation Evidence for extra facilitation on combined stim- ulation has been sought by comparing the effects of peripheral and corticospinal volleys when deliv- ered separately and together on the PSTHs of fore- arm motoneurones. Thus, Fig. 10.4(b)–(e) shows that a musculo-cutaneous volley, which by itself hardly increased the ﬁring probability of a FDS unit 462 Cervical propriospinal system 0 15 2 4 6 8 10 0 10 0 6 25 27 29 0 8 0 8 (b) (c) 0 8 0 8 20 22 24 26 28 30 Latency (ms) N u m b e r kamagra 100mg erfahrung r e f l e x ) 100 125 150 175 200 10 15 20 25 Affected Unaffected Controls (c) (d) ISI (ms) 200 0 30 400 One stroke patient Lesion Two paraplegic patients (a) Q MN Ia Q TA PN Corticospinal Inhibitory IN FN CPN Group I ISI (ms) Fig. 10.17. Changes in the CPN facilitation of quadriceps motoneurones in spastic patients. (a) Sketch of the presumed pathways. Corticospinal projections revealed by TMS are interrupted by the lesion (horizontal dashed arrow) in spastic patients. The net result of the corticospinal lesion would be disfacilitation of feedback inhibitory interneurones (IN) inhibiting propriospinal neurones (PN). (b)–(d) Changes in the quadriceps H reﬂex (expressed as a percentage of its unconditioned value) elicited by common peroneal nerve stimulation at 3 MT (b) or 2 MT ((c), (d)) are plotted against the interstimulus interval (ISI). (b) Changes are compared in a healthy subject (, continuous line) and on the affected (●, dashed line) and unaffected (❍, dotted line) sides of a stroke patient. Each symbol represents the mean of 20 measurements. (c), (d) Data for two paraplegic patients ((c) and (d)). Vertical bars ±1 SEM. Modiﬁed from Marque et al. (2001b) (b) and from R´ emy-N´ eris et al. (2003) ((c), (d)), with permission. R´ esum´ e 505 Conclusions Organisation of the lumbar propriospinal system Striking differences exist between the organisation of the lumbar and cervical propriospinal systems. (i) The peripheral groupI excitatory input appears to be much stronger to lumbar propriospinal neu- rones, though this could be speciﬁc to the common peroneal nerve–quadriceps combination. (ii) Peripheral excitation is not counteracted by ‘homonymous’ inhibitory feedback, unless the cor- ticospinal system is activated. (iii) In the absence of cortical stimulation, there is no evidence for cutaneous inhibition of the relevant interneurones. Corticospinal excitation of feedback inhibitory interneurones seems to be stronger than that of the propriospinal neurones themselves. Voluntary contractions The main descending input during weak vol- untary contractions seems to be to feedback inhibitory interneurones, presumably to focus the command on the fewmotoneurones involved in the contraction. Changes in patients The excitability of propriospinal neurones is increased in spastic patients, probably because of the disruption of the strong corticospinal control on feedback inhibitory interneurones. R´ esum´ e Background fromanimal experiments Two systems of short-axoned lumbar propriospinal neurones have been described: (i) dorsolateral, located in L3–L5, projecting to distal motoneurones, the input of which is mainly (if not exclusively) from the corticospinal and rubrospinal tracts; (ii) ven- trolateral, located in L2–L4, projecting to proximal motoneurones with a strong input from peripheral afferents (in particular group II afferents) and from vestibulospinal and reticulospinal tracts. Methodology Most studies have been limited to the facilitation of quadriceps motoneurones byvolleys inthecommon peroneal nerve, though, as at cervical level, the dis- tribution of propriospinally mediated excitation is quite diffuse. Group I volleys evoke in the PSTHs of lower limb motor units an excitation occurring with a central delay that is 3–6 ms longer than the mono- synaptic Ia latency. The more caudal the motoneu- rone pool inthe spinal cord, the longer central delay, again suggesting mediation through premotoneu- rones located rostral to motoneurones. Peroneal- inducedfacilitationof thequadriceps Hreﬂexoccurs with a 3–3.5-ms central delay. Over its ﬁrst 3 ms, this facilitationis purelygroupI inorigin. Withallowance for the difference in the lengths of the afferent path- ways, theamount of groupI facilitationcanbemeas- ured at the 10-ms ISI to assess the excitability of the lumbar propriospinal neurones. The suppression of theHreﬂexproducedbytheconvergenceof peroneal and femoral test volleys onto interneurones medi- ating autogenetic ‘Ib inhibition’ constitutes an important limitation of the method during quadri- ceps contractions of 10% of MVC. Facilitation of the on-going quadriceps EMGby common peroneal nerve stimulation is a simple method, which can be used to compare propriospinally mediated excita- tion during different motor tasks. Organisation and pattern of connections Peripheral excitation of lumbar propriospinal neurones Thisperipheral excitationdiffersfromthat tocervical propriospinal neurones in several respects. (i) Lumbar propriospinal neurones are co- activated by group I and II afferents. 506 Lumbar propriospinal system (ii) The peripheral excitation is considerably stronger, eventaking intoaccount that it is not coun- teracted by ‘homonymous’ inhibition. (iii) Group I afferents fromquadriceps and pretib- ial ﬂexors converge onto common propriospinal neurones. However, both the potency of the group I excitation and the above convergence could be speciﬁc to the common peroneal nerve-quadriceps combination, the only one so far investigated in detail. Peripheral inhibition of lumbar propriospinal neurones In the absence of TMS, inhibition of propriospinal neurones has not been found after cutaneous stim- ulation and is weak and usually absent in homony- mous group I pathways. As a result the facilitation can increase with the stimulus intensity far above 1 MT, at least in the common peroneal nerve– quadriceps combination. By contrast, ‘lateral’ inhi- bition between the effects elicited by two different nerves is often found. Inhibition of motoneurones Inhibition of motoneurones has been regularly observed in motoneurones of leg and thigh exten- sors after stimulation of the tibial nerve but, despite its low threshold and long latency, its pathway remains uncertain. During voluntary dorsiﬂexion of the foot, there is a ‘longer-latency’ inhibition of soleus motoneurones. This inhibition is superim- posed on the disynaptic reciprocal Ia inhibition, occurs only during active dorsiﬂexion and, although fed by group I afferents, is mainly of supraspinal origin. Corticospinal excitation TMS produces activation of both propriospinal neu- rones and inhibitory interneurones projecting to propriospinal neurones. On combined stimulation, the latter effect dominates. Motor tasks and physiological implications Duringweakcontractions, thedominant descending effect is facilitation of feedback inhibitory interneu- rones inhibiting propriospinal neurones, probably to focus the command to the few motoneurones involved in such contractions. During gait, the pero- neal group I discharge is needed to depolarise pro- priospinal neurones so that the increased group II excitation of quadriceps motoneurones mediated through the same interneuronal pathway can mani- fest itself. Studies in patients and clinical implications The excitability of propriospinal neurones is increased in spastic patients, whether the cor- ticospinal lesion is hemispheric or spinal. This increased group I-induced excitability could be due to the disruption of the strong corticospinal control on feedback inhibitory interneurones. The greater increase in excitation in patients with spinal cord injury is considered inChapter 7. 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Neuronal organization and synaptic mechanisms of supraspinal motor control in vertebrates. Reviews of Physiological and Biochemical Pharmacology, 72, 1–54. Simonetta-Moreau, M., Marque, P., Marchand-Pauvert, V. & Pierrot-Deseilligny, E. (1999). The pattern of excitation of human lower limb motoneurones by probable group II muscle afferents. Journal of Physiology (London), 517, 287– 300. Simonetta-Moreau, M., Meunier, S., Vidailhet, M., Pol, S., Galitzky, M. & Rascol, O. (2002). Transmission of group II heteronymous pathways is enhanced in rigid lower limb of de novo patients with Parkinson’s disease. Brain, 125, 2125–33. Stinear, J. W. &Byblow, W. D. (2004). The contributionof cervical propriospinal premotoneurons in recovering hemiparetic stroke patients. Journal of Clinical Neurophysiology, 21, 426–34. Taylor, B. A., Ridding, M. C. & Rothwell, J. C. (1995). Some evidence for a mid-thoracic nucleus in the human motor pathway. In Alpha and Gamma Motor Systems, ed. A. Taylor, M. H. Gladden & R. Durbaba, pp. 629–31. New York: Plenum. Turton, A., Wroe, S., Trepte, N., Fraser, C. &Lemon, R. N. (1996). Contralateral and ipsilateral EMG responses to transcra- nial magnetic stimulationduring recovery of armandhand function after stroke. Electroencephalography and Clinical Neurophysiology, 101, 316–28. 11 Involvement of spinal pathways in different motor tasks If one excludes discrete movements of the ﬁngers (cf. p. 522), most motor tasks are accompanied by changes in transmission in spinal pathways, due to both the descending activity and changes in the peripheral afferent feedback related to the move- ment itself (‘reafference’). Both types of input are largely mediated through common spinal interneu- rones (cf. Jankowska & Lundberg, 1981). In the pre- ceding chapters, changes in transmission in seg- mental spinal pathways during various motor tasks have been described, and the presumed origin of these changes discussed. In addition, because of the focusing due to the stronger inhibitory control of propriospinal neurones in primates, it has been suggested that the propriospinal system might be used for a more diversiﬁed motor repertoire than in the cat (Chapter 10, see Lemon et al., 2004). The present chapter presents an overview of the relative contributions of different spinal pathways to var- ious natural motor tasks: isometric tonic contrac- tions, ﬂexion–extension movements at hinge and ball joints, coordination of multi-joint movements, co-contractionsof antagonistsat thesamejoint, pos- tural adjustments, andgait. Despite the risk inherent inspeculation, it is important topresent anoverview of the role of spinal cord circuits in the control of movement. This includes (i) adescriptionof therela- tivecontributionmadebyspinal pathways tothedif- ferent features of movement in various motor tasks, and(ii) anattempt toshowhowthesepathways work together harmoniously to achieve the movement. Experimental dataonwhichthis overviewrelies have been discussed in the preceding chapters, and refer- ence to the relevant sections is made. Reference is also made to original data and some papers which were not considered in the preceding chapters. Absence of redundancy A given motor task, for example, the excitation of the agonists and the inhibition of the antagonists duringﬂexion–extensionmovements at hingejoints, is accompanied by changes in transmission in sev- eral pathways. This might give the impression that there is some functional redundancy between the different spinal circuits. In fact, as discussed below, thedifferent features of themovement (suchas force, smoothness, selectivity, resistance tofatigue, timing, etc.) are not controlled to the same extent and at the same stage of the movement by the same pathways. Inpathological conditions, thefunctionof onespinal pathwaymaybepartiallytakenover byanother path- way (see Chapter 12), but the smooth development of force andaccurate achievement of the desiredtra- jectoryof amovement still requiretheintegrityof the different pathways. It must be emphasised that several reasons make the overview presented below speculative (i) Most of the available data dealing with changes in transmission in spinal pathways during voluntary ‘movements’ were obtained during isometric con- tractions. (ii) Given the different descending control of some spinal pathways in the cervical and lumbar enlargements, extrapolations from lumbar to cervi- cal level are uncertain. (iii) It cannot be taken for granted that spinal interneurones respond similarly to the phasic 511 512 Spinal pathways in different motor tasks artiﬁcial volleys generally used in the experiments described in the previous chapters and to a tonic input, as in the normal modus operandi of the cen- tral nervous system. In this respect, the newer tech- niques of cross-correlation and coherence analysis should allow further development of neuronal sig- nals to be studied without external interference (see pp. 48–9). (iv) Experiments described in the earlier chap- ters do not necessarily provide a quantitative assess- ment of the normal input to motoneurones, e.g. a reduction by half of the motoneurone pool response when suppressing an input does not imply that the input provided 50% of the excitatory drive to motoneurones. The motoneurone discharge is pro- ducedbythespatial andtemporal summationof sev- eral inputs, andremoval of anyonecouldhavealarge effect (e.g. see pp. 316, 474). Isometric tonic contractions Contraction under near-isometric circumstances occurs during many motor tasks, e.g. carrying lug- gage, grasping an object while displacing it, or pos- tural contractions of trunk and lower limb muscles. The excitation of agonist motoneurones is initiated by descending tracts, but their maintained activity may be favoured by different spinal mechanisms (cf. Fig. 11.1(a), (b)): (i) fusimotor-driven spindle afferent feedback, (ii) cutaneomuscular responses, and (iii) suppression of the transmission in some inhibitory pathways. Many isometric contractions involve co-contraction of antagonistic muscles (see pp. 531–5). Fusimotor-driven inﬂowfromprimary and secondary endings Activation of α motoneurones Ample evidence has been provided that, during tonicisometriccontractions: (i) thereis anenhanced inﬂowfromprimary and secondary spindle endings drivenbyfusimotor neurones, (ii) this afferent inﬂow has an overall autogenetic excitatory effect at spinal level andcontributessigniﬁcantlytomaintainingthe ﬁring of ␣motoneurones, but (iii) it has a limitedrole in compensating for muscle fatigue (see pp. 133– 5). This excitatory effect is not limited to homony- mous motoneurones. Heteronymous Ia and group II excitatory connections are widespread and often bidirectional in the lower limb and strong from dis- tal to proximal muscles in the upper limb, and their existence contributes to appropriate contractions of the synergistic muscles involved in a given task (see pp. 528–9). Servo-assistance through monosynaptic Ia connections Thebackgrounddischargeof spindles provides them with a dynamic working range, because their dis- charge can increase and decrease in response to external load variations. However, the ‘servo assis- tance’ from Ia afferent discharges is limited by post- activation depression (see pp. 96–9) and presynap- tic inhibition of Ia terminals (see p. 358), both of which would keep the efﬁcacy of the Ia ﬁbre- motoneurone synapse at a relatively low level dur- ing voluntary movements. The resulting lowgain for the stretch reﬂex helps to prevent oscillations and clonus from developing (see Matthews, 1972; Rack, 1981). Servo-assistance through group II pathways Group II excitation is not limited by post-activation depression, which is probably absent at synapses between spindle group II afferents and the rel- evant interneurones (see pp. 292, 310). Fusimo- tor activation of primary and secondary endings in ␥ s -assisted contractions can produce multiple mutual reinforcing interactions between the dis- charges from the two receptors, because lumbar propriospinal neurones mediating group II excita- tion are co-activated by Ia afferents and transmit part of the corticospinal command to motoneu- rones (see Chapter 7; see Fig. 11.1(b)). Thus: (i) both (a) (b) (c) Fig. 11.1. Changes in transmission in spinal pathways during voluntary contraction at a hinge joint. In this and subsequent ﬁgures, excitatory synapses are represented by Y-shaped bars and inhibitory synapses by small ﬁlled circles, excitatory interneurones by open circles and inhibitory interneurones by large ﬁlled circles. ␣ and ␥ motoneurones (MN) of a contracting ﬂexor muscle, Renshaw cells (RC), Ia afferents ((a)–(c) with their presynaptic inhibition (PAD INs, (c)) and Ia inhibitory interneurones (Ia IN) to antagonist extensor MNs (c) sketched in red; corresponding pathways of the extensor in black (c). Group II afferents exciting MNs through propriospinal neurones (PN) in blue ((a), (b)). Ib afferents, with their presynaptic inhibition (PAD INs), and Ib inhibitory INs in brown (a). Group muscle III afferents converging on PNs in violet (b). Descending tracts (corticospinal) in green. (a) Changes in some spinal pathways contributing to agonist excitation. The descending command (i) activates ␣ MNs, ␥ MNs and PNs, all of which are also affected by afferent inputs, (ii) inhibits RCs, and (iii) suppresses transmission in Ib inhibitory pathways (Ib IN) by presynaptic gating (PAD INs). (b) The ‘FRA hypothesis’: a movement, initiated by descending activation of MNs and/or PNs (thin dotted green arrow), is subsequently maintained by the combined effect of group II afferents (dotted blue arrow) driven by descending activation of ␥ s MNs (thick continuous green arrow) and by the contraction-induced group III afferent activity (dotted violet arrow). [Note that this hypothesis has so far not been supported by experimental evidence.] (c) Inhibition of antagonist extensor MNs during voluntary ﬂexion. Flexor-coupled Ia INs (red) project both to extensor MNs and the ‘opposite’ (extensor-coupled) Ia INs (black), and are inhibited from corresponding RCs. The descending command (green arrows) (i) activates ﬂexor ␣ MNs, ␥ MNs and corresponding ﬂexor-coupled Ia INs, which are also excited by the Ia discharge through the ␥ loop (red arrows), but (ii) depresses ﬂexor-coupled RCs and presynaptic inhibition (PAD INs) on ﬂexor Ia terminals. In contrast, extensor MNs and corresponding extensor-coupled Ia INs are inhibited by the ﬂexor-coupled Ia INs, while the descending command facilitates extensor-coupled RCs and presynaptic inhibition (PAD INs) on extensor Ia terminals. The pathway of propriospinally mediated reciprocal inhibition has been omitted. 514 Spinal pathways in different motor tasks Ia and group II discharges contribute to the activation of the relevant interneurones; (ii) at motoneuronal level, servo-assistance given by Ia monosynaptic connections depends on depolarisa- tion of ␣ motoneurones evoked through interneu- rones supported by secondary spindle afferents and vice versa. An hypothesis regarding the role of group II excitation has been advanced by Lundberg (1973, 1979; Lundberg, Malmgren & Schomburg, 1987). The hypothesis relies on: (i) the activa- tion by the contraction of high-threshold muscle afferents (groups III–IV, see Schomburg, 1990); (ii) the convergence of these afferents onto group II interneurones (see Lundberg, 1973, 1979); and (iii) the spatial speciﬁcity of the descending con- trol of ␥ s motoneurones (see Hulliger, 1984). A contraction could be initiated by descending acti- vation of group II interneurones, but might then be maintained by the combined effect of spindle secondaries activated by descending excitation of ␥ s motoneurones and by high-threshold muscle afferent activity evoked by the contraction (the ‘FRA hypothesis’, see p. 389; Fig. 11.1(b)). As in the original ‘follow-up length servo’ hypothesis (Merton, 1953), it was assumed that some stages of a contractioncanbe governed fromthe brainsolely or mainly via ␥ s motoneurones. However, Lundberg’s hypothesis postulates that the excitatory group II reﬂex connections are too weak at rest to activate motoneurones during passive movement, and that the increase in the gain of transmission during an active contraction is supplied by the contraction itself. The strong excitation of group II afferents on ␥ motoneurones may assist in sustaining their activation by positive feedback (see p. 291), and this would provide further excitation for the active ␣ motoneurones. A parallel descending activation of inhibitory pathways would prevent activation of muscles not required for a given contraction. This focusing action might be achieved through the corticospinal excitation of feedback inhibitory interneurones inhibiting the relevant propriospinal interneurones, and/or the monoaminergic gating from the brainstem of transmission in group II pathways (see pp. 311, 314). Intellectually, this hypothesis has many attractions, particularly for postural co-contractions which could be main- tained without signiﬁcant voluntary intervention (see p. 538). However, it has yet to be substantiated for the cat, and direct corticospinal activation of the motoneurone pool provides a simpler mechanism for initiating a voluntary contraction, particularly in human subjects (as acknowledged by Lundberg, 1979). Cutaneomuscular responses Tactile cutaneous inputs produce early excitatory cutaneomuscular responses that are spinally medi- ated. In the upper limb, spinal cutaneomuscular excitatory responses (E1) of different distal upper limb motor pools are facilitated during a power grip. The resulting reinforcement of the grip prevents grasped objects from slipping from the hand (see p. 428). Early excitatory cutaneomuscular responses in the lower limb could play a role in postural con- tractions when balance becomes unstable (see pp. 430, 540). Suppression of transmission in inhibitory pathways Excitationof activemotoneuronesisalsofavouredby the suppression of transmission in inhibitory path- ways activated by the contraction-induced affer- ent discharge (autogenetic Ib inhibition) or the discharge of motoneurones (recurrent inhibition) (Fig. 1.11(a)). The control of the transmission in these inhibitory pathways contributes to adjusting the force of the contraction. Changes in recurrent inhibition Changes during voluntary movement vary with the force of the contraction (see pp. 174–9). There is a descending facilitation of Renshaw cells dur- ing weak contractions. The resulting low gain for the motoneurone pool would allow supraspinal Movements involving hinge joints 515 centres to operate over a large part of their working range causing only small changes in muscle force, and this should improve resolution in the control of motor output. In contrast, during strong con- tractions, transmission in homonymous and het- eronymous recurrent pathways directed to active motoneurones is suppressed. This suppression is probably corticospinal in origin, and helps secure a high output gain for the active motoneurone pool(s). In addition, the removal of recurrent inhibi- tionfromhomonymous silent motoneurones would facilitate their recruitment, thus helping overcome fatigue. Suppression of autogenetic Ib inhibition Suppression of autogenetic Ib inhibition to active motoneurones increases withcontractionforce dur- ing sustained contractions, presumably because of presynapticgatingof Ibterminalsbythecontraction- induced Ib discharge (see pp. 268–71). This suppres- sion is functionally appropriate, because otherwise Ibinhibitionevokedbytheactivationof Golgi tendon organs would hinder the maintained ﬁring of active motoneurones and interfere with the recruitment of newunits when the effort had to be increased. How- ever, (i) even at strong tonic forces, there is suppres- sion rather than complete abolition of Ib inhibition, and this allows an operating level of inhibition that canbe modulatedineither direction, and(ii) Ibinhi- bitionis activewhentherearerapidincreases incon- traction force in order to help smooth the force pro- ﬁle (see p. 271). On the other hand, Ib inhibition can be restoredwhennecessary because transmissionin Ib pathways can be facilitated by other peripheral afferent inputs which converge onto the relevant Ib interneurones, andthereis descendingfacilitationof the transmission of these other inputs during strong contractions (see p. 267). Conclusions Several spinal mechanisms contribute to maintain- ing isometric tonic contractions. (i) The fusimotor-driven spindle afferent dis- charge contributes to the discharge of ␣ motoneu- rones, and the background spindle afferent dis- charge may be used to provide servo-assistance to the contraction; the combined effect of spin- dle secondaries activated by ␥ s motoneurones and of high-threshold afferent activity evoked by the contraction probably helps to maintain the contraction. (ii) Cutaneomuscular spinal responses in the upper limb may be used to prevent grasped objects from slipping from the hand and, in the lower limb, they play a role in postural contractions. (iii) Suppression of recurrent and Ib inhibitions to active motoneurones increases with contraction force, and thus contributes to regulating the force of isometric contractions. Flexion–extension movements involving hinge joints During a selective voluntary contractionof one mus- cle, changes in transmission occur in all tested spinal pathways (Chapters 2–10). Such changes are often used in attempts to explain the mechanisms underlying the activation of the agonists and/or the relaxation of the antagonists in ﬂexion-extension movements. However, because these data were obtained during isometric contractions, extrapola- tion to changes occurring in transmission in spinal pathways during dynamic movements should be madewithcaution. Thecontrol of muscles operating at ball joints (e.g. wrist) differs in many points from that of muscles acting at hinge joints (ankle, elbow, knee), andtheformer is consideredinaseparatesec- tion (pp. 522–6). Afferent discharges accompanying a voluntary ﬂexion–extension movement Flexion–extension movements produce activity in a variety of afferents. (i) Spindle Ia and group II discharges depend on the efﬁcacy of the ␥ drive in activating spindle 516 Spinal pathways in different motor tasks primary and secondary endings during a voluntary movement and the contraction-induced changes in muscle length (see pp. 133–5). Shortening (in a ‘con- centric’ contraction) will unload spindle endings, and an increase in spindle discharge will then occur onlyinslowcontractions. Duringanunloadedphasic shortening contraction, it is likely that the discharge of muscle spindle endings in the contracting muscle will decrease and many will be silenced, and affer- ent cues of spindle originthencome mainly fromthe stretchedantagonisticmuscle(s). However, whenthe contracting muscle is working against a load so that greater effort is required to performthe same move- ment, thedischargepatternbecomeslessmodulated by the change inmuscle length, and spindle endings behave more like tension-transducing organs. Dur- ing an ‘eccentric’ contraction, as, for example, when easing down an object, fusimotor activity combined with muscle stretch produces a marked increase in spindleactivity inparallel withthedeclining␣motor activity (see pp. 135, 521). (ii) Ibafferentsdischargereadilyduringshortening contractions, evenintheabsenceof anexternal load, the discharge increasing throughout the contraction as EMG builds up (see pp. 267–8). (iii) Joint afferents are activated as the joint approaches the extremes of movement (Chapter 6, p. 272). (iv) Cutaneous afferents will be also activated by contact with a target or an unexpected obstacle, but some cutaneous receptors are activated during movement without contact with an external object (Chapter 9, p. 388), largely due to stretching of the skin. Excitation of active motoneurones Excitationof agonist motoneurones is favouredboth byfacilitationof transmissioninexcitatorypathways to active motoneurones and suppression of trans- mission in inhibitory pathways to those motoneu- rones. Facilitation of the transmission in excitatory pathways Monosynaptic Ia excitation During eccentric contractions and loaded concen- tric contractions, the fusimotor-driven Ia discharge provides excitatory feedback to homonymous and heteronymous motoneurones involvedinthe move- ment. Thenon-linear characteristics of primaryend- ings allow them to respond briskly to the initi- ation of a length change, and the short-latency of the segmental stretch reﬂex makes this feedback capable of providing fast motor reactions to absorb mechanical disturbances. If the mechanical distur- bance is an unexpected obstruction to movement, such that there is a mismatch between the intended andtheachievedmovement, misalignment between intended and actual muscle length would increase the ﬁring of Ia afferents. If the disturbances result from irregularities in ␣ motor outﬂow during active, graded movements, the reﬂex can counterbalance the unwanted changes in trajectory. It might be argued that the ␥-driven Ia discharge is modest dur- ing shortening contractions, even when they are loaded, and that its efﬁcacy in activating motoneu- rones is reduced by post-activation depression at the Ia ﬁbre-motoneurone synapse. However, at the onset of avoluntarycontraction, thereisaprominent decreaseinpresynapticinhibitiononIaterminals on active lower-limb motoneurones, pre-programmed at cortical level according to both the strength and the speed of the movement (see p. 359). Thus, at the beginning of a movement, whenthe exact loadis not yet known, even a modest Ia discharge could help compensate rapidly andautomatically for any errors in the programmed movement. Propriospinally mediated excitation Propriospinal neurones are excited by the ␥-driven spindle discharge, and this may provide servo- assistance to motoneurones at propriospinal level, in addition to servo-assistance provided through segmental circuitry. Propriospinal neurones receive additional excitation from the Ib input, related Movements involving hinge joints 517 to muscle contraction rather than muscle length. Because the group I excitation of cervical pro- priospinal neurones is weak and gated by presy- naptic inhibition during voluntary contraction, it is unlikely to provide signiﬁcant reﬂex support in the absence of other drives. However, despite its weak- ness, thegroupI input is abletoproducepotent facil- itation of that part of the corticospinal command passing through the propriospinal relay, and could thereby provide a safety factor to propriospinal neu- rones that are being activated by on-going descend- ingactivity. This viewis supportedbytheﬁndingthat descending excitation is focused on the subset(s) of propriospinal neurones receiving the afferent feed- back from the contracting muscle (see pp. 476–7). Inhibition of the transmission in inhibitory pathways Suppression of the transmission in spinal segmen- tal inhibitory pathways to active motoneurones also favours the excitation of these motoneurones. Thus, there is suppression of: (i) recurrent inhibition to homonymous motoneurones towards the end of ramp contractions, due to corticospinal inhibition of Renshawcells (see p. 179); (ii) autogenetic Ib inhi- bition, via presynaptic gating of Ib afferents (see pp. 268–71); (iii) reciprocal Ia inhibition from stretched antagonists (seepp. 223–5). Suppressionof thetrans- mission in these three pathways would help sustain the agonist contraction. Control of different features of the movement Changes in transmission in spinal pathways may contribute to controlling several features of ﬂexion– extension movements: selectivity, mechanical char- acteristics (force and speed), termination. Selectivity of the movement Thefocusingof thedescendingcommands responsi- blefor agivenﬂexion–extensionmovement is helped bythedescendingcontrol of several spinal pathways. (i) Presynaptic inhibition of Ia terminals is decreased at the onset of movement on active motoneurones but increased on inactive motoneu- rones linked in Ia synergism. This differential corticospinal control of presynaptic inhibition, selectively ‘opening’ Ia transmission to voluntarily activated motoneurones while ‘closing’ transmis- siontomotoneurones of relaxedmuscle(s), prevents those motoneurones from receiving heteronymous Ia excitation and increases the contrast between the active muscle and inactive synergists (see pp. 359– 60). (ii) Ib inhibition from the contracting muscle is suppressed to active motoneurones but increased on inactive synergists. Again, the resulting focusing action would increase ‘motor contrast’ (see pp. 272– 3). (iii) Spindle activation occurs even in rapid short- ening movements before the limb has actually started to move, but occurs only for spindles in the contracting muscle(s) (see p. 135). (iv) Increased recurrent inhibition of homony- mous motoneurones at the onset of movement (Chapter 4, pp. 174–5) helps sharpen activity within the active motoneurone pool(s) in the initial part of the movement. (iv) In the propriospinal system, muscle and cuta- neous volleys produced by the movement excite feedback inhibitory interneurones. Selection by the corticospinal command of the relevant feedback inhibitory interneurones prevents the activation of propriospinal neurones not required for the move- ment, and helps focus the propriospinally medi- ated part of the descending command on the active motoneurones (see p. 477). Control of mechanical features (force, speed) Adjustment of biomechanical features, such as the force and speed of the movement, can be achieved by appropriate descending inputs to motoneu- rones. However, the descending control of spinal pathways may also contribute to adjusting these features. 518 Spinal pathways in different motor tasks Force produced by the movement The stronger the force pre-programmed at the end of the dynamic phase of a ramp contraction, the stronger the suppression of various inhibitions directed to active motoneurones (see above): (i) autogenetic Ib inhibition, (ii) homonymous recur- rent inhibition, (iii) reciprocal inhibitionfromantag- onistic stretched muscles (see pp. 223–5), and (iv) presynaptic inhibition of Ia terminals in the initial phase of the movement. (v) In addition, the servo- assistance provided by the ␥-driven spindle dis- charge increases with the load on the contracting muscle (see p. 135). Speed of the movement Suppression of recurrent inhibition and presynaptic inhibition of Ia terminals is also regulated according to the speed of the desired movement. Thus, what- ever the duration of the dynamic phase of a ramp movement, the suppression of recurrent inhibition is adjusted to be maximal at the end of the dynamic phase (see p. 174), while presynaptic inhibition re- appears during the decelerating (braking) phase (see p. 358). Control through propriospinal pathways Group I inhibitory projections to propriospinal neu- rones can modulate the corticospinal excitation passing through this relay thereby helping to adjust the force and speed of the movement by control- ling the gain in the feedback inhibitory loop (see p. 477). Termination of the movement On several occasions, Lundberg has argued that it would be appropriate for a spinal mechanism to ensure terminationof a movement, because termin- ation must be one of the most difﬁcult parameters of a movement for the brain to calculate (e.g. Lund- berg, Malmgren & Schomburg, 1977). Several spinal mechanisms are capable of contributing to this role in human subjects. Cutaneous inhibition of propriospinal neurones The speciﬁc pattern of the cutaneous inhibition of cervical propriospinal neurones suggests a role in curtailing movement. The exteroceptive vol- ley evoked by contact with the target or with an unexpected obstacle would inhibit the descending command passing through propriospinal neurones, helping to terminate the movement. This view is supported by the ﬁnding that feedback inhibitory interneurones mediating cutaneous inhibition of propriospinal neurones receive a stronger descend- ing drive at the offset of a visually guided movement than at its onset (see p. 478). Restoration of Ib inhibition Ib inhibition to active motoneurones is suppressed during voluntary movements, but may reappear whenIbpathwaysarefacilitatedbyinputsfromother peripheral afferents. Thus, cutaneous facilitation of transmission in Ib pathways, which has a precise local sign, could be used to curtail an exploratory movement meeting anobstacle (see pp. 271–2). Sim- ilarly, facilitation of Ib inhibition from joint recep- tors activated at the extremes of joint movement will increase Ib inhibition and automatically con- tribute to curtailing the movement as it approaches the extremes of joint rotation (see p. 272). Recruitment of different types of motor units During voluntary contractions, motoneurones are generally recruited in an orderly sequence from small motoneurones supplying slow-twitch motor units to large motoneurones supplying fast-twitch units. Thus, the thresholds of units in the ﬁrst dor- sal interosseus for abduction of the index ﬁnger are ranked according to size both in slow ramp and in ballistic contractions, irrespective of whether the contractions are performed under isotonic or isometric conditions (see Desmedt, 1983). How- ever, there are circumstances when the preferen- tial recruitment of high-threshold, more powerful, motor units would be advantageous. Movements involving hinge joints 519 (i) Descending excitation mediated through the cervical propriospinal relay is evenly distributed to early- and late-recruited motoneurones. This distri- bution could be important when it is necessary to activate a wide range of motoneurones more or less simultaneously (see p. 477). (ii) During the natural cutaneous stimulation involved in precision grip and active manipulation, signiﬁcant decreases in the recruitment threshold of high-threshold more powerful motor units in hand muscles occur, and this could make prehension and manipulation stronger (see pp. 425–7). (iii) A lengthening contraction, when easing down aloadat aconstant smoothvelocity, wouldbehelped byrecruitingfast-twitchunits withafaster relaxation time (Nardone, Roman` o & Schieppati, 1989). Inhibition of antagonists Effective inhibition of the antagonistic muscle(s) is required during phasic ﬂexion–extension move- ments. For simplicity, this is discussed below with regard to a voluntary ﬂexion, but similar principles apply to extension movements at all hinge joints. A movement of ﬂexion produces a stretch-induced Ia discharge from the antag- onistic extensor muscle, especially when move- ment is rapid. This extensor Ia discharge could produce two undesirable effects: (i) excitation of extensor motoneurones, producing a contrac- tion that would slow the ﬂexion movement, and (ii) activation of ‘corresponding’ extensor-coupled Ia interneurones inhibiting ﬂexor motoneurones involved in the voluntary movement (see the sketch in Fig. 11.1(c)). There are no direct corticospinal inhibitory projections onto motoneurones, and the necessary inhibition of the antagonists is due to the activation of several spinal inhibitory pathways. Different spinal pathways contribute to inhibiting the antagonists Reciprocal Ia inhibition This is the best known spinal mechanism inhibit- ing the antagonists during ﬂexion–extension movements, and has been the most thoroughly investigated. When the fusimotor drive maintains a Ia discharge from a contracting muscle, the efﬁcacy of this discharge will be enhanced around the onset of the contraction by decreased presynaptic gating, and this may be able to activate Ia inhibitory interneurones, especially if they are depolarised by a descending drive and not inhibited by recurrent inhibition (Fig. 11.1(c)). However, post-activation depression could help keep the efﬁcacy of the Ia ﬁbre–Ia interneurone synapse at a relatively low level during ␥-assisted movements. In addition, activation through the ␥ loop only occurs during eccentric contractions and slow or loaded concen- tric contractions (see p. 516). Thus, during a rapid unloaded shortening contraction, i.e. the type of contraction that has greatest potential to trigger a stretch-induced Ia discharge from the antagonist, it is likely that many muscle spindle endings in the contracting muscle will be silenced. Unwanted acti- vationof bothextensor motoneurones andextensor- coupled Ia inhibitory interneurones would then require that ﬂexor-coupled Ia inhibitory interneu- rones receive a strong descending drive, sufﬁcient to ﬁre them without the support from Ia afferents in the contracting muscle (see pp. 222–3). Presynaptic inhibition of Ia terminals Presynaptic inhibition of Ia terminals on antago- nistic extensor motoneurones is increased during voluntary ﬂexion (Fig. 11.1(c); see pp. 360–1). The increase in presynaptic inhibition is modest, and is due mainly to the activation of PAD interneurones by the group I afferent discharge from contracting ﬂexors. Longer-latency propriospinally mediated inhibition The longer-latency propriospinally mediated inhi- bition of extensor motoneurones antagonistic to active ﬂexor motoneurones is revealed only dur- ing active movement, where it appears ∼50 ms before EMG activity, increases during the dynamic phase of the movement and is correlated with the strength of ﬂexion (see pp. 497–8). The fact that 520 Spinal pathways in different motor tasks this inhibition is not seen at rest is consistent with a weak afferent input to propriospinal neurones, and this implies that the descending drive provides sufﬁcient facilitation of the relevant propriospinal inhibitory interneurones to ﬁre them during volun- tary movement. Recurrent inhibition During a phasic ﬂexor contraction, extensor- coupled Renshaw cells receive descending facilita- tion. This may also contribute to curtailing a stretch reﬂexintheantagonist: theﬁrst motoneurones ﬁring inthe stretchreﬂex wouldactivate extensor-coupled Renshaw cells, which would inhibit other motoneu- rones and thus curtail the stretch reﬂex (Fig. 11.1(c); see p. 180). Non-reciprocal group I inhibition Interneurones mediating non-reciprocal group I inhibition to antagonistic extensor motoneurones receive corticospinal facilitationat the onset of a vol- untarycontractionof ﬂexors(seep. 273). Thestretch- induced Ia discharge in the antagonistic exten- sor would activate facilitated interneurones medi- ating non-reciprocal group I inhibition to extensor motoneurones, andthis wouldhelpprevent astretch reﬂex in that muscle. Absence of redundancy between the mechanisms inhibiting the antagonists All spinal inhibitorypathways that canbetestedcon- tribute tothe relaxationof antagonistic muscles dur- ing ﬂexion–extension movements (see above). How- ever, there is no redundancy between the different pathways, because they differ in their afferent input, their target neurones and the stage of the movement when they become active. (i) Propriospinally mediated inhibition is an almost purely descending mechanism, indepen- dent of afferent feedback and of controls on Ren- shaw cells, directed only to antagonistic motoneu- rones. The correlation of this inhibition with the strength and timing of the agonist contraction suggests a parallel corticospinal control of the rele- vant interneurones and ␣ motoneurones. (ii) Reciprocal Ia inhibition could be used to pro- vide servo-assistance to the contraction of ago- nists and relaxation of antagonists in those move- ments modulated by the ␥-driven Ia discharge from the contracting muscle. Ia interneurones are also activated by corticospinal drives, but the resulting motoneurone inhibition contributes less than the propriospinally mediated inhibition to relaxation of the antagonist. This weaker effect could result from the suppression of reciprocal Ia inhibition by recurrent inhibition activated by the agonist motor discharge. However, recurrent inhibition progres- sively decreases towards the end of the dynamic phase of the movement in order to leave recipro- cal Ia interneurones to exert their inhibitory action fully (see pp. 174–9). Effective reciprocal Ia inhi- bition could then be functionally crucial, because Ia inhibitory interneurones also inhibit ‘opposite’ Ia interneurones and can prevent the inhibition of active motoneurones by the stretch-induced Ia dis- charge in the antagonistic muscle (Fig. 11.1(c)). (iii) Given the weak sensitivity of the stretch reﬂex to presynaptic inhibition of Ia terminals, the main role of increased presynaptic inhibition on Ia termi- nals on antagonistic motoneurones could be to help prevent the Ia discharge produced by stretch of the antagonist (extensor) from ﬁring extensor-coupled Ia inhibitory interneurones andthus frominhibiting active ﬂexor motoneurones (see p. 361). (iv) Facilitation of recurrent and non-reciprocal group I inhibitions directed to antagonistic motoneurones contributes to curtailing a stretch reﬂex inthe antagonistic muscle, thereby smoothing the execution of the movement. Timing of the different effects Onset of movement Mechanisms ensuring selectivity are then favoured: (i) increased recurrent inhibition within the active motoneurone pool; (ii) decreased presynaptic Movements involving hinge joints 521 inhibition on Ia terminals on active motoneu- rones, andincreasedpresynaptic inhibitiononinac- tive synergistic motoneurones; (iii) Ib inhibition, decreasedonactivemotoneurones andincreasedon synergistic inactive motoneurones; and (iv) before the limb has commenced moving, ␥-driven Ia dis- charge focused on motoneurones of the contract- ing muscles. This focusing action is consistent with results in the monkey showing suppression of the activityof manycervical interneurones prior toavol- untarymovement, preventingtheovert expressionof the movement (cf. Fetz et al., 2002). Movements in progress Mechanisms favouring a stronger muscle contrac- tionprogressivelyappear asthemovement develops: (i) suppressionof autogenetic Ibinhibitionincreases with muscle force; (ii) homonymous recurrent inhi- bition decreases towards the end of the dynamic phase, helping maintain a high output gain; (iii) suppression of recurrent inhibition also favours increased reciprocal Ia inhibition which, via inhi- bition of opposite Ia inhibitory interneurones, pre- vents the Ia discharge from the stretched antag- onist from inhibiting the active motoneurones; (iv) increased presynaptic inhibition of Ia terminals on antagonist-coupledIainhibitoryinterneurones con- tributes to preventing this undesirable inhibition of theactivemotoneurones; (v) increasedafferent feed- back, in particular Ib, from the contracting muscle provides enhancedfacilitationof corticospinal com- mands passing through the propriospinal relay; and (vi) recruitment of more powerful fast-twitch motor units of hand muscles by contact of appropriate skin regions with an object will increase grip force. In parallel, relaxation of antagonists is ensured by: (vii) descending facilitation of propriospinally mediated inhibition of antagonistic motoneurones; and (viii) increasedreciprocal Ia inhibition. The latter is fedby the ␥-driven Ia discharge fromthe contracting mus- cle no longer gated by presynaptic inhibition of Ia terminals, facilitatedby corticospinal excitationof Ia interneurones, andis disinhibitedby the progressive suppression of recurrent inhibition. Easing off a contraction Braking and decelerating a movement when eas- ing down an object is controlled by (i) the servo- assistance provided by the ␥-driven spindle dis- charge associated with the lengthening contraction; and (ii) the recruitment of fast-twitch motor units which have a faster relaxation time. Cutaneous control of the end of movement The exteroceptive volley evoked by contact with the target or an unexpected obstacle helps terminate the movement because it causes facilitation of: (i) Ib interneurones mediating autogenetic group I inhi- bition to active motoneurones so that the obsta- cle is not displaced; and (ii) feedback inhibitory interneuronesinhibitingthepart of thecorticospinal command passing through the propriospinal relay. Different strategies for proximal and distal movements Given the large repertoire of human movement, the changes intransmissioninspinal pathways will vary according to the requirements of an inﬁnite number of possible movements. Different strategies may be requiredfor movementsat proximal anddistal joints, as discussed below for the upper limb. Elbowmuscles Elbow muscles have a load-bearing function for which the ␥-driven spindle discharge may provide useful servo-assistance, and have much spinal cir- cuitry at their disposal for reﬂex assistance: (i) a well- developedmonosynapticspinal stretchreﬂex, which contributes to the response of the triceps brachii in subjects fallingintentionallyforwardontotheir arms (see p. 89); (ii) potent reciprocal Ia inhibition (see p. 210); (iii) potent recurrent inhibitory projections to homonymous motoneurones and corresponding Ia inhibitory interneurones (see pp. 169–71); and (iv) corticospinal commands transmitted to 522 Spinal pathways in different motor tasks motoneurones through the propriospinal relay, where they canbe modulatedby the peripheral feed- back from the moving limb (see p. 477). Hand muscles Hand muscles are required to perform skilled man- ual tasks, which may involve rapid, essentially unloaded movements in which afferent-induced changes in motoneurone discharge could lag far behind the phase of movement that generated the feedback. It would therefore be sensible if such movements were performed with feedforward control, without potentially disruptive feedback. Accordingly, in these muscles, in which the largest responses to Ia input have been found in high- threshold units (see p. 81), the spinal Ia stretch reﬂex is poorly developed and positional servo- assistance is provided by a transcortical Ia path- way or by conscious intervention (see p. 92). Dis- tal movements are also not subjected to recurrent inhibition, because of the absence of recurrent col- laterals from motor axons innervating the relevant muscles (see p. 169). In addition, there are no pro- jections of propriospinal neurones to the intrin- sic muscles of the human hand (see p. 460). Many hand movements, such as writing, involve near- isometriccontractionsof intrinsicmusclesandthose of the forearm. Under these circumstances, feed- back from cutaneous and muscle receptors, acting through transcortical rather than spinal pathways (e.g. see Datta, Harrison & Stephens, 1989) can have signiﬁcant effects on the active motoneurone pools. Conclusions Hypotheses concerning the involvement of the dif- ferent spinal pathways in movements at hinge joints have been inferred from data obtained during iso- metric ramp contractions. It cannot be taken for grantedthat thedescendingcontrol isthesamewhen the brain programs isotonic movements at a single joint, or a fortiori a complex movement involving muscles operating at different joints andperforming various shortening and lengthening contractions, weight-bearing or unloaded. This holds particularly for upper limb movements, given their large motor repertoire. Now that techniques have been devel- oped, which enable one to explore changes in trans- mission in spinal pathways during gait (see pp. 545– 50), it is important that future research uses such techniquesinupper limbmovements(suchasreach- ing, grasping, manipulation). Movements involving ball joints Different organisation of the human spinal circuitry at wrist level Information regarding ball joints, i.e. joints with several degrees of freedom, is limited, for both human subjects and the cat. ‘This bears the prob- lem that many hypotheses have been derived from the situation at simple joints, which display only a rigid and stereotyped motor behaviour. It has to be expected that research of more differentiated and ﬂexible motor synergies will lead to drastic modi- ﬁcations of many of the present concepts’ (Hult- born & Illert, 1991). As discussed below, the organ- isation of the human spinal circuitry at wrist level differs from that at hinge joints (cf. the sketch in Fig. 11.2). This might result from an adaptive evo- lution to different requirements. (i) FCR and ECR may act as antagonists in ﬂexion–extension move- ments of the wrist, but they operate as synergistic muscles in wrist abduction movements. (ii) Some wrist ﬂexion–extension movements are rapid move- ments and, in them, muscle spindle endings in the contracting muscle will be unloaded and reﬂex cues may need to come from other receptors (see p. 135). The organisation of spinal circuits at wrist level differs fromthat at hinge joints in many aspects (i) There is mutual recurrent inhibition between ‘antagonistic’ FCRandECRmotor nuclei (seep. 171). Movements involving ball joints 523 ECR FCR Wrist extension Wrist flexion Ia Ia Ib Ib Median Radial FCR ECR Wrist flexion Wrist extension PAD INs Recurrent inhibition MNs Group I IN Group I IN Corticospinal RS Fig. 11.2. Some spinal pathways to wrist ﬂexors and extensors. ␣ Motoneurones (MNs), Renshaw cells (RC) and Ia afferents, with their presynaptic inhibition (PAD INs) and their projection to interneurones mediating non-reciprocal group I inhibition of antagonist MNs (Group I IN) in red for FCR and blue for ECR. Ib afferents in brown for FCR and violet for ECR. RCs activated by recurrent motor axon collaterals from one muscle project to MNs innervating both FCR and ECR, but not to INs mediating non-reciprocal group I inhibition. FCR-coupled Group I INs inhibit ECR MNs and ECR-coupled Group I INs, are activated both by Ia and Ib FCR afferents, and also receive excitatory projections fromECR group I afferents, and vice versa for ECR-coupled Group I INs. Corticospinal in green. During a voluntary wrist ﬂexion, the corticospinal command activates FCR MNs and FCR-coupled Group I INs, which inhibit opposite ECR-coupled Group I INs. After the onset of contraction, the group I feedback from the contracting muscle (and the Ia discharge from the antagonist stretched ECR) are channelled back into the reﬂex path already activated by corticospinal excitation, because transmission in the opposite pathway is inhibited, and vice versa for voluntary wrist extension. Presynaptic inhibition (PAD INs) of FCR Ia terminals is depressed by a descending inhibition, possibly reticulospinal (RS) in origin. 524 Spinal pathways in different motor tasks (ii) Radial-induced group I inhibition of the FCR H reﬂex and median-induced inhibition of the ECR H reﬂex are mediated through the pathway of non-reciprocal group I inhibition, not through Ia inhibitory interneurones transmitting reciprocal Ia inhibition (see pp. 211–14). (iii) GroupI afferents containedinthe medianand radial nerves convergeontotheinterneurones medi- ating disynaptic non-reciprocal groupI inhibitionof FCR and ECR motoneurones (see p. 212). (iv) Despite this convergence, these interneurones are arranged in subsets specialised with regard to their target motoneurones (see below). (v) Because of the mutual inhibition between the interneurones mediating non-reciprocal group I inhibition to FCR and ECR motoneurones, activa- tionof FCR-coupledgroupI interneurones produces inhibition of ECR-coupled group I interneurones, and vice versa (see p. 214). (vi) Corticospinal volleys facilitate presynaptic inhibition on Ia terminals on wrist motoneurones, while they depress it on Ia terminals on lower limb motoneurones (see p. 353). Non-reciprocal group I inhibition Non-reciprocal group I inhibition of wrist motoneu- rones is more profound at rest than any other non- reciprocal group I (or reciprocal Ia) inhibition at other joints: a conditioning volley at 0.95 MT usu- ally reduces the test reﬂex to ∼50% of its uncon- ditioned value. This is in keeping with the ﬁnding that, in the cat, non-reciprocal group I inhibition is larger in the forelimb than in the hindlimb (Illert, Lundberg & Tanaka, 1976). Corticospinal control Stimulation of the motor cortex produces potent disynaptic suppression of the radial-induced inhi- bition of the FCR H reﬂex. Through mutual inhibi- tion of ‘opposite’ interneurones, corticospinal facili- tation of FCR-coupled group I inhibitory interneu- rones would produce inhibition of ECR-coupled group I inhibitory interneurones (Fig. 11.2; Rothwell et al., 1984). This reveals a more potent corticospinal facilitation of non-reciprocal group I interneurones than found at ankle level (see p. 265). Non-reciprocal group I inhibition during wrist movements Non-reciprocal group I inhibition during voluntary wrist ﬂexion In two exceptional subjects, in whom it was poss- ible to evoke an ECR H reﬂex which did not disap- pear during the contraction of the antagonistic FCR, median-induced non-reciprocal group I inhibition of the ECR was found to be increased at the onset of FCR contraction (R. Katz & J. C. Lamy, unpub- lished data). In the other direction, the disynaptic radial-induced non-reciprocal group I inhibition of the FCR H reﬂex is suppressed prior to, and during voluntarywrist ﬂexion, andthestronger thecontrac- tion the more marked the suppression (Day, Roth- well & Marsden, 1983; Day et al., 1984). The ﬁnding that the above effects occur before the contraction- induced afferent feedback has reached the spinal cord, indicates a descending control. Given that cor- ticospinal volleys produceparallel facilitationof FCR motoneurones andcorrespondinggroupI inhibitory interneurones (cf. above; Fig. 11.2), the above effects are consistent with corticospinal facilitation of FCR- coupled group I inhibitory interneurones, with: (i) facilitation of group I inhibition to ECR motoneu- rones, and (ii) suppression of group I inhibition to FCR motoneurones, through mutual inhibition of opposite group I inhibitory interneurones. Non-reciprocal group I inhibition during voluntary wrist extension Is there descending facilitation of the pathway? The difﬁculty in proving descending facilitation of ECR-coupled group I inhibitory interneurones dur- ing voluntary wrist extensioncontrasts withthe ease withwhichcorticospinal facilitationof FCR-coupled group I inhibitory interneurones can be demon- strated during voluntary wrist ﬂexion. Prior to vol- untary wrist extension, radial-induced inhibition of Movements involving ball joints 525 the FCR H reﬂex has been reported to be increased, suggesting descending facilitation of ECR-coupled group I inhibitory interneurones (Day, Rothwell & Marsden, 1983), but this result has not been con- ﬁrmed by Raoul et al. (1999) and is not seen at the onset of the movement (Cavallari et al., 1984). Dur- ing tonic wrist extension, radial-induced inhibition of the FCR H reﬂex may be increased or unchanged in different subjects (Cavallari et al., 1984; Raoul et al., 1999). However, when the natural periph- eral feedback from the contracting wrist extensors is interrupted by a block of the radial nerve using lignocaine injected distal to the stimulation site, the radial-induced inhibition of the FCR H reﬂex is enhanced during attempted tonic wrist extension (Day et al., 1984). The most parsimonious explan- ation is that the descending facilitation of the rel- evant interneurones is difﬁcult to deﬁne because of an interaction between the peripheral feedback from the contracting muscle and the conditioning volley. Much as in the case of reciprocal Ia inhibi- tion (see pp. 220–1), several mechanisms dependent on the natural group I discharge during voluntary contraction could contribute to the decreased efﬁ- cacy of the conditioning volley in activating group I inhibitory interneurones: occlusion at interneu- ronal level, presynaptic inhibition of the condition- ing volley, and possibly post-activation depression at the synapse between group I ﬁbres and inhibitory interneurones at wrist level. Synergy between ECR and ﬁnger ﬂexors The functional synergy between wrist extensors and ﬁnger ﬂexors in clenching and grasping (see Liv- ingston et al., 1951) and the lack of selectivity of the recording conditions might account for the dif- ﬁculty in proving descending facilitation of ECR- coupled group I interneurones. The H reﬂex of fore- arm ﬂexor muscles to stimulation of the median nerve in relaxed subjects originates from both wrist and ﬁnger ﬂexors (cf. Day et al., 1984). Thus, sub- liminal excitation of ﬁnger ﬂexor motoneurones accompanying isometric ‘synergistic’ wrist exten- sion could favour their recruitment in the median- induced H reﬂex. Intuitively, there are no good reasons for these motoneurones receiving recip- rocal inhibition from the conditioning radial vol- ley, unless there is an associated voluntary ﬁn- ger extension. Variable results between subjects, and different groups, could result simply from whether care was taken that the wrist exten- sion was accompanied or not by ﬁnger extension. Functional implications Corticospinal excitation of the appropriate pathway During FCR contractions, FCR-coupled group I inhibitory interneurones projecting to ECR motoneurones receive descending facilitation, while ‘opposite’ interneurones projecting to FCR motoneurones are inhibited. This differential control indicates that interneurones mediating non-reciprocal group I inhibition to wrist motoneu- rones are arrangedinsubsets specialisedwithregard to their target motoneurones. The corticospinal facilitation of group I inhibitory interneurones precedes the parallel discharge of the corresponding motoneurones, and its main function is prob- ably to select the appropriate subset of group I interneurones, i.e. the subset directed to antag- onistic motoneurones. These interneurones also inhibit inhibitory interneurones projecting to active motoneurones. After the onset of contraction, the group I feedback from the contracting muscle is channelled back into the reﬂex path already activated by corticospinal excitation, because trans- mission in the opposite pathway is inhibited (see Fig. 11.2). Activation of the inhibitory pathway to antagonistic motoneurones prevents a stretch reﬂex in this muscle, while inhibition of the opposite interneurones prevents the Ia discharge from the stretched antagonists from inhibiting the active motoneurones. Peripheral activation of the relevant interneurones During rapid unloaded shortening contractions of wrist muscles, the discharge of spindle endings 526 Spinal pathways in different motor tasks in the contracting muscle will decrease (see p. 516). However, inhibitory group I interneu- rones to wrist motoneurones also receive Ib inputs, which are related to muscle contraction, not to muscle length. Moreover, the Ia afferent discharge from the stretched antagonists may also contribute to activation of the selected pathway because of the convergence of group I volleys from ﬂexors and extensors onto common interneurones (see p. 524). Thus, the particular organisationof the path- ways of non-reciprocal group I inhibition to wrist motoneurones ensures that the relevant interneu- rones receiveperipheral feedback, evenduringrapid movements. Changes in presynaptic inhibition on Ia terminals on wrist motoneurones Non-speciﬁc decrease in presynaptic inhibition Presynaptic inhibition of Ia terminals on FCR motoneurones is moderately depressed at the onset of and during isometric voluntary contractions of either FCR or ECR. It has been speculated that this non-speciﬁc effect might be due to reticu- lospinal depression acting on the last-order PAD interneurones (p. 363). The isometric contractions resemble postural co-contractions of wrist muscles. Assuming that there is the same descending con- trol of PAD interneurones in postural contractions, decreased presynaptic inhibition on Ia terminals on wrist motoneurones would reinforce the servo- assistance provided by the monosynaptic Ia stretch reﬂex of wrist muscles and improve the reﬂex sup- port to manipulatory movements of the ﬁngers. Corticospinal facilitation of PAD interneurones The corticospinal facilitation of presynaptic inhibi- tion on Ia terminals on wrist motoneurones, seen usingstimulationof themotor cortex(p. 353), hasnot been reproduced during the voluntary contractions so far tested(see pp. 362–3). This might be due to the isometric nature of the contractions studied. Facili- tationof PADinterneurones couldbe selectedby the motor cortex in order to turn off the monosynap- tic Ia assistance during rapid unloaded wrist move- ments, in which reﬂex feedback could have dele- terious effects (see p. 522). Testing this hypothe- sis would require further experiments using rapid isotonic movements. Other spinal pathways possibly involved in wrist movements Mutual recurrent inhibition between FCR and ECR motoneurones This particular pattern has been described during voluntary contractions of the target muscle in stud- ies of themodulationof thedischargeof singlemotor units and of the on-going EMGactivity, but there are no data on how transmission in the relevant path- ways is modulated during other types of contrac- tion. A functional explanation for these connections is proposed below (p. 534). Cutaneomuscular responses Cutaneomuscular responsescanbeelicitedinvolun- tarily active wrist muscles by low-intensity stimuli to theﬁngers. Innormal adult subjects, theseresponses aredominatedbythelong-latencytranscortical exci- tatory response. So far, there are limited data on the modulationof the responses inwrist muscles during different motor tasks (thoughsuchchanges are well- documented for the intrinsic muscles; Fig. 9.13). Propriospinal pathways Propriospinal pathways transmit some of the cor- ticospinal command for isometric contractions of wrist muscles (pp. 471–4). The extent to which they are involved inthe transmissionof the command for different motor tasks requires further studies. Activation of various synergies 527 Co-ordinated activation of various synergies Nonatural movement involves just onemuscle. Even planar movements at single joints involve the activa- tion of synergists operating at the same joint, and relaxation (or disfacilitation) of antagonists. Only under contrived conditions, such as the artiﬁcial constraints of the laboratory, does a natural move- ment consist of action at just one hinge joint. More often there is a co-ordinated activation of muscles across several joints. Thus, for example, reaching withtheupper limbinvolves displacements at shoul- der, elbow, wrist and ﬁngers, while kicking a ball involves displacements at hip, knee and ankle. The correct spatial and temporal pattern of muscle acti- vation is crucial for smooth and coordinated move- ments, and the question is where motor synergies are laid down in the central nervous system. Where are motor synergies laid down? Spinal origin? Although even the simplest movements involve a largenumber of muscles, thepatternof muscleactiv- ity is generally constant for a deﬁned type of move- ment (locomotion, postural adjustments [see, how- ever, ankleandhipstrategies inposture, p. 542]). This led Beevor (1904, cited by Hultborn & Illert, 1991) to claim that the neuronal arrangements for relatively stereotypedmovements were laiddowninthe spinal cord. Inthe cat, the isolatedspinal cordcangenerate complex activities such as scratching and locomo- tion. Accordingly, Sherrington (1906) believed that the spatial and temporal patterning of muscle activ- ity was driven by afferent input and linked by the pathways subserving reﬂex arcs. This viewhad been proposed by Michael Forster in his Textbook of Phys- iology (1879, cited by Hultborn, 2001). He wrote that ‘reﬂex action may be said to be, par excellence, the function of the spinal cord’, but added that ‘the cord contains a number of more or less complicated mechanisms capable of producing, as reﬂex results, co-ordinated movement altogether similar to those which are called forth by the will. Now it must be an economy to the body that the will should make use of these mechanisms already present, by acting directly on their centres, rather than it should have recourse to a special apparatus of its ownof a similar kind’. As discussed below, several spinal circuits may be usedbothinthe coordinationof muscle synergies involvedincomplexmovements andintheﬂexibility of these synergies. Hierarchical control schema Spinal pathways and higher centres also contribute to muscle synergies in complex co-ordinated move- ments. According to this view, originally raised by Bernstein (1967) and recently developed by Macpherson (1991), motor control would be organ- ised on the basis of hierarchical control schema in which descending motor commands are sent to groups of muscles that are then co-activated through appropriate spinal pathways. The higher level parameters of any motor act would be global and related to the goals of the movement. These global parameters would participate in determining the values of the more local, lower level variables. For example, ‘in a voluntary movement, such as goal- directed reaching movement, the end point posi- tion of the hand, and possibly its trajectory, would be higher level variables related to the goal of tar- get acquisition. Speciﬁed at a lower level are the individual joint angular displacements andthe mus- cle activation patterns needed to achieve adequate movement of the arm. . . The problem of selecting the correct muscles to be activated is simpliﬁed by certain basic rules of combination, rules that are probably formed during motor learning. One rule could be to minimise expenditure or energy, and another to make use of predictable forces such as gravity or inertial perturbation among the body seg- ments’ (Macpherson, 1991). It is suggested below that the command for propriospinally mediated reaching represents a goodexample of movement so organised. 528 Spinal pathways in different motor tasks Synergies based on ‘hardwired’ spinal connections Heteronymous projections of different afferents to a variety of motoneurones link muscles of the ipsilateral, and often contralateral, limbs in vari- ous synergies, represented by different groups of interneurones or monosynaptic connections. These correspond to Sherrington’s concept of a number of ‘spinal common paths’, in contrast to the ‘ﬁnal common path’, i.e. the motoneurones. The classi- cal example is furnished by the muscles which con- tract and relax in the ﬂexion withdrawal reﬂex (see pp. 404–5), although the responsible nociceptive afferents are not involved in the control of normal movement (however, see p. 389). It is likely that the brain acts by mobilising these spinal mechanisms during ‘voluntary’ movements. Whether monosy- naptically or interneuronally mediated, synergies transmitted through these spinal connections are ﬂexible because of the control exerted on the interneurones intercalated intheir pathways and/or PAD interneurones mediating presynaptic inhibi- tion of primary afferent terminals. Heteronymous monosynaptic Ia connections Heteronymous monosynaptic Ia connections repre- sent the simplest example of ‘hardwired’ connec- tions. Speculation about their function is based on the assumption that, in movements, an adequate contribution of Ia afferent activity to motor output depends not only onthe fusimotor drive but also the direct depolarisation by the central command of the relevant ␣ motoneurones (Hultborn & Illert, 1991). Lower limb Contractions of lower-limb muscles are usually weight-bearing and often eccentric. These are cir- cumstances when the co-activated ␥ drive can rep- resent a powerful input to muscle spindle endings (see p. 137). In striking contrast with data for the cat and baboon hindlimb, transjoint monosynaptic Ia connections are the rule in the human lower limb and are often bidirectional (Chapter 2, Table 2.1). The fact that this pattern exists indicates that the widespread Ia connections found in humans are of functional importance, adaptedto provide the reﬂex assistance required for bipedal stance and gait (see pp. 538, 550). Projections from a muscle to ‘antago- nists’ operating at another joint do not occur in the cat or baboonhindlimb, but arequitecommoninthe humanlower limb(seep. 83). They may beexplained in terms of the versatile synergisms required to accomplish the various postural tasks that are more variable in bipedal than in quadrupedal stance (see p. 94). Upper limb In the human upper limb, heteronymous monosy- naptic Ia projections are diffuse from distal mus- cles to both the ﬂexors and extensors of proximal joints. Proximal muscles have a load-bearing func- tion during grasping and manipulatory movements and, again, the co-activated ␥ drive can represent a powerful input to muscle spindle endings. Distal-to- proximal Ia connections might then be used to sta- bilise the wrist and elbow to provide a ﬁrm support for the hand (see p. 94). Relaxation of antagonistic muscles Co-ordinated synergies also imply relaxation of antagonistic muscles, whether by inhibition or disfacilitation. Discharge of remote motoneurones through heteronymous Ia excitation presupposes the direct depolarisation of the connected ␣ motoneurones by the central command (see above; Hultborn &Illert, 1991). The relaxation of the antag- onists at different joints during multi-joint move- ments may therefore be due to activation by the descending drive of the same spinal pathways as those ensuring the inhibitionof the antagonists dur- ing single hinge (pp. 519–20) or ball (pp. 524–6) joint movements. Activation of various synergies 529 Flexible synergies At times, aninvariant diffuse patternof monosynap- tic Ia connections in the human lower limb could be functionally inconvenient, because the activation of Ia afferents from a contracting muscle might then result in the automatic activation of unwanted mus- cle(s) linked in Ia synergism. Two mechanisms allow the selection of the heteronymous Ia connections appropriate for a given task: (i) increased presynap- tic inhibition of Ia afferents directed to ‘unwanted’ motoneurones (see pp. 259–60); and (ii) matched recurrent inhibition of ‘unwanted’ motoneurones (see pp. 183–4, 538). Activation of excitatory group II pathways. The FRA hypothesis The hypothesis regarding the role of group II path- ways in supporting isometric contractions, pre- sented above for one muscle (see p. 514), could be extended to complex movements involving sev- eral muscles, as proposed by Lundberg (1973). The FRA hypothesis suggests that a diffuse feedback sys- tem with a multisensory input, including group II afferents, could be used for the selective reinforce- ment andprolongationof the descending command (see p. 389 and Fig. 9.1(c)). In the human lower limb, heteronymous group II excitatory projections are widespread and strong (Chapter 7, Table 7.3). The group II excitatory input activated in ␥-assisted lengthening contractions could therefore help to maintaincontractionsinitiatedbydescendingdrives on motoneurones and/or group II interneurones. Again, the parallel descending activation of feed- back inhibitory interneurones inhibiting excitatory interneurones might prevent activation of muscles not required in a given co-contraction. Available experimental data provide more evidence for an important role of group II pathways in posture and gait (see pp. 537–49) than in voluntary movements (see pp. 310–12). This role should be seen as sup- porting the contraction, not driving it, much as the role of the fusimotor systemis nowknownto be sup- portive (Matthews, 1972). Cervical propriospinal system Synergies through the propriospinal system A substantial part of the corticospinal command to motoneurones of human upper-limb muscles is transmitted through the propriospinal relay rostral to motoneurones (see pp. 471–4). There is indirect evidence that, as in the cat, human propriospinal neurones have divergent projections to motoneu- ronesof variousmusclesactingat different joints(see p. 476). In the cat, propriospinal neurones have also beenshowntoproject toIainhibitoryinterneurones, thus contributingtothe relaxationof the antagonists (Chapter 10, p. 453). This creates a network ade- quate for translation of descending commands for multi-joint movements into the appropriate coordi- nated muscle synergies which underlie those move- ments. Synergiesproducedbysuchanetworkareless limited than the ‘hardwired’ monosynaptic Ia and corticospinal projections onto speciﬁc and smaller sets of motoneurones. The extensive convergence of descendingexcitation, feedforwardinhibitionand feedback inhibition onto C3–C4 propriospinal neu- rones allows the cortical command to be updated at the premotoneuronal level. Because of the prewired connections of each subset of propriospinal neu- rones with the different motoneurones involved in a multi-joint movement, integration at a premo- toneuronal level would allow the command to all these motoneurones to be simultaneously and ‘eco- nomically’ modulatedbythesameperipheral volleys (see pp. 477–8). Reaching: an example of hierarchical control It is likely that, as in the cat, the human cervical pro- priospinal systemis involved inthe control of reach- ingmovements. Georgopoulos&Grillner (1989) have proposed that, much as in locomotion, a signiﬁcant 530 Spinal pathways in different motor tasks part of such movements may be accomplished in the spinal cord, illustrating the concept of hierarchical control of co-ordinated synergies men- tionedabove. Thus, speciﬁcationof thedirectionand probably speed of the movement would be elabo- ratedby supraspinal motor structures, especially the motor cortex (the higher level). This contribution of the motor cortex tothe initiationof reaching is partly channelled through the spinal propriospinal system (the lower level). The requiredco-ordinatedmotions of the shoulder, elbowand wrist are then assisted by the divergent projections of propriospinal neurones to motoneurones and Ia inhibitory interneurones, while the movement is controlled accurately by the feedforward and feedback inhibitory interneurones of the propriospinal system. State-dependent modulation of sensory feedback The spinal cord contains the substrate for many complex motor actions (e.g. nociceptive with- drawal reﬂexes, locomotion, scratching). Interneu- rones involved in generating these complex move- ments are lumped together in ‘functional units’, but the interneurones participating in the ‘functional units’ are not independent and may be involved in many types of movement. ‘The understanding of how functionally distinct neuronal circuits can be built by altering the properties of individual neu- rones and their communication is now emerging from studies on simpler circuits in invertebrates with obvious implications for the vertebrates. This requires a dynamic regrouping of interneurones to construct different functional networks. . . As would beexpectedfromthis conceptual framework, experi- ments onreﬂex control of muscle activity during var- ious forms of movements, have revealed that the action from speciﬁc sensory inputs are not only gated, but actually re-routed and mediated via dif- ferent neuronal networks’ (Hultborn, 2001). State- dependent modulation of sensory feedback is well exempliﬁed by the reﬂex reversal of Ib inhibition under resting conditions to Ib excitation during gait (see pp. 248, 273–5), and constitutes a support for variable muscle synergies. Motor learning The motor performance of deafferented patients shows that reﬂex support is not indispensabletoper- forming or grading a contraction, at least in labo- ratory tasks. However, there is good evidence that afferent feedback and the resulting activity in spinal circuitry are important in reﬁning the motor output (see pp. 136–7), and probably play a crucial role in motor learning. ␥␥ drive Whenlearningamotor task, movementsareslowand often involve co-contraction of antagonists to brace thejoint. Suchcontractionswouldbeassociatedwith an effective increase in ␥ drive to the contracting muscles (seebelow). Thefeedbackfromspindleend- ings would be important, not only for smoothing the movement trajectory but also for providing the sensory cues that allow a more reﬁned voluntary command. This holds for both homonymous and heteronymous ␥-driven spindle discharges. As skill is acquired, the importance of spindle support for the contraction lessens, in parallel with a change in movement performance that decreases the efﬁcacy of the ␥ drive (see p. 138). Projections to ascending tracts Many ‘automatic’ movements are acquired by the internalisation of learnt programmes, and perfec- tion of the movement depends on trial and error. As learning progresses, a motor programme is shaped which is subsequently available to command the movement (see Windhorst et al., 1991). Setting up and maintaining a motor programme depends on detailed information from both the reafferent cues activated by the movement and the spinal cir- cuitry (‘the lower motor centres’) fed by these cues. Interneurones activated during movement, whether projecting to motoneurones or mediating presy- naptic inhibition of primary afferents, also have Co-contractions of antagonists 531 collateral projections to cell bodies of ascending tracts, especially spinocerebellar, which can signal information regarding the different spinal pathways (see Lundberg, Malmgren &Schomburg, 1987). This information is essential for calling up the coor- dinated synergies that characterise the movement when the motor programming has been learnt. Efference copy C3–C4 propriospinal neurones in the cat have ascending collaterals to the lateral reticular nucleus (LRN). Via these ascending collaterals, the LRN, which projects to the cerebellum, receives mirror information of the action that reaches motoneu- rones via the propriospinal neurones, and this con- stitutes a perfect efference copy. This may allow the cerebellum to take corrective measures with a mini- mal delay, for whichpurpose it has at its disposal the rubrospinal and reticulospinal tracts which project directly to C3–C4 propriospinal neurones (Chapter 10, p. 454). Internal feedback of this type may regu- late a forthcoming movement at its onset. Feed- back inhibitory interneurones also have ascend- ing projections to the LRN, indicating that correc- tion of the movement takes into account the out- put from propriospinal neurones and the input that they receive fromfeedback inhibitory interneu- rones. Such copies of the propriospinally medi- ated input to motoneurones and of their feed- back inhibition could play a crucial role when using trial and error in motor learning. Evidence for similar ascending projections of the cervical propriospinal relay has so far not been sought in humansubjects, but they exist inthe macaque mon- key (Chapter 10, p. 455), and there are so many analogies between the propriospinal systems in the cat and the human that the projections are likely. Co-contractions of antagonists at the same joint Since Sherrington’s demonstration of the recipro- cal innervation of opposing muscles, it was for long thought that antagonistic muscles wereinactivedur- ing most voluntary movements. Co-activation of antagonistic ﬁnger and wrist muscles is used in the precision grip and the power grip. Co-contractions of antagonists also occur in many voluntary tasks, such as when unpredictable perturbations may be encountered or when learning a new motor task (cf. Smith, 1981; Akazawa, Milner & Stein, 1983; Llewellyn, Yang & Prochazka, 1990). Control of spinal pathways during co-contraction of antagonists Hinge joints Acomprehensivereviewof theextensiveworkbyJens Nielsenonco-contractionat the ankle joint has been published in a thesis (1998). Reciprocal Ia inhibition Reciprocal Ia inhibition between antagonistic ankle muscles is almost completely suppressed when dor- siﬂexors andplantar ﬂexors are voluntarily activated simultaneously (see pp. 225–7). The suppression is greater than expected from the sum of the effects of separate dorsiﬂexion and plantar ﬂexion contrac- tions, and results from a suppressive central control speciﬁc to co-contraction (see below). Reciprocal Ia inhibition is depressed maximally even at low co- contractionlevels, and there is no modulationas the strength of co-contraction increases. Homonymous recurrent inhibition Homonymous recurrent inhibition of soleus motoneurones is increased during co-contractions with respect to rest, regardless of the strength of the contraction(see pp. 180–1). Because of the descend- ing inhibition of Renshaw cells during separate strong contractions of soleus (cf. p. 515), the higher the contraction strength the greater is increased the recurrent inhibition during co-contraction when compared to plantar ﬂexion at equivalent 532 Spinal pathways in different motor tasks EMG activity. Increased recurrent inhibition during co-contraction is greater than expected from the sum of the effects evoked by separate dorsiﬂexion and plantar ﬂexion and, again, this points to a control speciﬁc to co-contraction. The control could simplybeasuppressionof thedescendinginhibition of the recurrent pathway observed during separate plantar ﬂexion, leaving the motor discharge- induced excitation of Renshaw cells unopposed by descending inhibition. However, suppression of the descending control cannot account for all of the features of the increased recurrent inhibition during co-contraction, suggesting the existence of a supplementary descending facilitation of Renshaw cells (see Chapter 4, p. 181). The increased recurrent inhibition has two effects: (i) reduction of the gain of the motor output (see p. 534), and (ii) suppression of reciprocal Ia inhibition, via recurrent depression of Ia interneurones. Presynaptic inhibition of Ia terminals Presynaptic inhibition on Ia terminals on motoneu- rones of soleus and tibialis anterior is increased during voluntary co-contraction of the two mus- cles. This increased presynaptic inhibition is largely due to a descending control that could be speciﬁc for co-contraction (see p. 361). Increased presynap- tic inhibition also has two effects: (i) suppression of the monosynaptic Ia excitation of the involved motoneurone pools (see p. 534), and(ii) suppression of reciprocal Ia inhibition because of the reduction of the input to Ia inhibitory interneurones. Fusimotor drive Co-contractions may involve greater fusimotor drive to the contracting muscles than occurs during iso- lated contractions producing equivalent EMG (see p. 135). The increased ␥ drive would be required to maintain an effective Ia feedback despite increased presynaptic inhibition on Ia terminals (see above), and would be in line with the fusimotor activa- tion found in the cat in balancing tasks in which the animal has to co-contract antagonistic muscles (Hulliger et al., 1989). Reciprocal Ia inhibition vs. recurrent inhibition There is a conﬂict between the control of recipro- cal Ia inhibition and that of the motor pool out- put by recurrent inhibition at hinge joints: marked recurrent inhibition is required during strong co- contractions to suppress reciprocal Ia inhibition, but the more active the recurrent inhibition the smallerthegainof themotoneuronepool (seep. 179). Thus strong co-contractions that produce high joint stiffness (see below) occur at the expense of a relatively low output gain. This probably explains why, at hinge joints, less voluntary EMG is pro- duced during co-contraction tasks than during iso- latedcontractions of single muscles (Tyler &Hutton, 1986). Ball joints Non-reciprocal group I inhibition Radial-induced non-reciprocal group I inhibition of FCR motoneurones is moderately reduced during theco-contractionof antagonisticwrist muscles. The inhibition was greater than the sum of the inhibi- tions during separate ECR and FCR voluntary con- tractions in the two subjects investigated by Nielsen & Kagamihara (1992) during a power grip, but of the same magnitude in a larger population during co-contractionof ECRandFCRproducingtonicwrist abduction (Raoul et al., 1999). It is likely that more forearm and hand muscles would have been active in the former task than the latter. Presynaptic inhibition of Ia terminals Presynaptic inhibition on Ia terminals on FCR motoneurones is decreased to a similar extent dur- ing separate wrist ﬂexion or extension and during co-contraction of wrist muscles, whether associated with tonic wrist abduction or a power grip (R. Katz & J. C. Lamy, unpublished data). Co-contractions of antagonists 533 Control of the decreased inhibition between antagonists The suppression of reciprocal inhibition, whether Ia inhibition at hinge joints or non-reciprocal group I inhibition at ball joints, allows antagonistic motoneurone pools to be activatedtogether without the effects of the interposed reciprocal inhibition. Spinal mechanisms During co-contraction reciprocal inhibition between antagonistic ankle muscles is depressed with respect to rest, and this suggests that trans- mission through the pathway mediating reciprocal inhibition is actively depressed. Increases in recur- rent inhibition and presynaptic inhibition on Ia terminals (see above) contribute to an active inhi- bition. However, the relationship between these mechanisms and the strength of the contraction is different: reciprocal Ia inhibition is maximally depressed even at low co-contraction levels, but recurrent inhibition and presynaptic inhibition on Ia terminals increase with the strength of co- contraction. Moreover, there are no projections from Renshaw cells to the interneurones of non- reciprocal group I inhibition between wrist muscles (see pp. 207–8), and presynaptic inhibition on Ia terminals on wrist motoneurones is decreased during co-contraction (see above). This implies that other mechanisms contribute to the decoupling of motoneurones and interneurones mediating reciprocal Ia or non-reciprocal group I inhibition. Different cortical drive for ﬂexion-extension movements and co-contractions Results in the monkey The results suggest that there is a different cortical drive for these two types of contraction. (i) Some cortical cells are active during co- contraction tasks, but not during ﬂexion-extension movements (Humphrey & Reed, 1983). (ii) Fetz & Cheney (1987) found that some corti- cospinal neurones with a ‘reciprocal’ pattern dur- ing activity of antagonistic wrist motoneurones (i.e. with facilitation of agonist and inhibition of antag- onist) were vigorously active during ﬂexion– extension movements, but could stop ﬁring during a power grip involving co-contraction of wrist ﬂex- ors and extensors. Conversely, during power grip there was activation of cortical neurones that only excited agonist motoneurones (i.e. without inhibi- tion of the antagonist). Because only 2% of the cor- ticospinal (but 15% of the rubrospinal) cells have monosynaptic excitatory projections on both antag- onistic wrist ﬂexors and extensors (Fetz et al., 1989), Humphrey & Tanji (1991) suggested that the corti- cal commandfor co-contractionof antagonists must be mediated through common driving of cortico- motoneuronal cellswhichthemselvesinnervateonly one set of synergists, or through an oligosynaptic pathway with diverging projections on antagonis- tic motoneurones. The propriospinal system would be a good candidate since, apart frompropriospinal neurones that project to both motoneurones and Ia inhibitory interneurones, others project only to motoneurones and are assumed to subserve the co- contraction of antagonists (Alstermark et al., 1990). Results in human subjects Experiments using magnetic stimulation of the motor cortex have provided evidence for differen- tial cortical control of ﬂexion–extension movements and co-contractions (Nielsen et al., 1993). This ﬁnd- ing is also suggested by analyses of coherence in the time and frequency domains (cf. Chapter 1, pp. 48–9) for tibialis anterior and soleus units during co-contraction (Hansen et al., 2002). Joint stiffness Joint stiffness measured during voluntary contrac- tion as the stretch-induced torque increment, i.e. the resistance to external load, has two compo- nents, part caused by reﬂex mechanisms (reﬂex 534 Spinal pathways in different motor tasks stiffness), and the rest (non-reﬂex stiffness) by the active and passive properties of the muscle (build- ingof cross-bridges, tendoncompliance, etc). Strong co-contraction results in greater stiffness of the limb about the joint than with activity of any of the two antagonistic muscle groups separately. This holds true at all joints investigated: elbow, interphalangeal joints of the ﬁngers, thumb, and ankle (Feldman, 1980; Akazawa, Milner &Stein, 1983; Carter, Crago & Gorman, 1993; Nielsenet al., 1994). It hasbeenshown at ankle level that the increased stiffness during co- contraction occurs too early after application of the external load to be mediated through a reﬂex mech- anism (Nielsen et al., 1994). Thus, the main cause of the greater stiffness during co-contraction with respect to separate activation of one of the antag- onists could simply be that more muscles are then active(i.e. at ankle, not onlytheantagonisticpretibial ﬂexors andsoleus, but also the gastrocnemius medi- alis and peroneus longus). Control of the stretch reﬂex at hinge joints Because co-contraction of the different muscles operating at the ankle will stabilise the joint in dif- ﬁcult tasks (see above), there may be no need for additional stiffness through an active stretch reﬂex. On the contrary a low gain, ensured by increased presynaptic inhibition of Ia terminals and by facil- itated (or at least unsuppressed) recurrent inhibi- tion (see above), will prevent oscillations and clonus from developing (see Matthews, 1972; Rack, 1981). Accordingly, the stretch reﬂex is reduced during weak, and mainly unchanged during strong co- contractions (Nielsen et al., 1994). Control of the excitation at ball joints Renshawcells A different control of the motor output is likely at wrist level, because of the particular pattern of Renshaw cell projections (see p. 171). (i) Mutual recurrent inhibition between FCR and ECR motoneurones allows the gain of the motor output to be modulated in parallel in wrist ﬂexors and extensors during co-contractions. Thus, in a co- contraction intended to produce a power or preci- sion grip in a given wrist position, Renshaw cell dis- charge produced by the dominating contraction of either muscle (extensors or ﬂexors) can automati- cally adjust the contraction of the antagonist. (ii) The absence of projections from Renshaw cells to inhibitory interneurones mediating non- reciprocal group I inhibition between wrist ﬂexors and extensors enables a parallel increase in the out- put gain and joint stiffness at this joint. This is not possible at hinge joints (see above). In conclusion, during co-contractions, the partic- ular organisationof recurrent inhibitionat wrist level allows automatic adjustment of the output gain in the antagonistic pair, and a more ﬂexible descend- ing control of Renshaw cells because, during strong co-contractions, they canbe inhibited without jeop- ardising joint stiffness. Stretch reﬂex The ﬁndings that increased recurrent inhibition is not required and that presynaptic inhibition is not increased (see above) ﬁt with the need for a ﬁrmer mechanical muscle support during co-contractions at ball than at hinge joints. Under these conditions, several non-exclusive mechanisms might prevent the stretch reﬂex braking into oscillations. (i) Reciprocal Ia inhibition is almost completely suppressedat hinge joints, but non-reciprocal group I inhibition between wrist muscles is only moder- ately suppressed, and the group Ia and Ib feedback activatedduringisometric contractions canstill pro- duce signiﬁcant activation of the relevant inhibitory interneurones. (ii) Tactile cutaneous receptors provide critical informationfor the control of gripforce according to the physical properties (weight, slipperiness, shape and mass distribution) of the manipulated object. This is evidenced by the ﬁnding that subjects adapt tothelossof tactilesensibilitybyapplyingstronggrip Maintenance of bipedal stance 535 forces regardless of these properties (see Johansson, 2002). (iii) Although presynaptic inhibition is not increased during tonic co-contractions, this does not imply that the strong corticospinal facilitation of presynaptic inhibition on Ia terminals on wrist motoneurones cannot be activated if necessary (see p. 526). (iv) Similarly, the fact that recurrent inhibition may be suppressed during strong co-contraction at wrist level does not mean that the ﬂexible control of Renshaw cells cannot produce their facilitation if necessary. Conclusions The main cause of the greater joint stiffness dur- ing co-contraction is simply that more muscles are then active, not an increase in stretch reﬂex activ- ity. The decoupling of motoneurones and group I inhibition (whether Ia inhibition at hinge joints or non-reciprocal group I inhibition at ball joints) con- trasts with the linkage seen during simple ﬂexion- extension movements, and allows the simultaneous activation of antagonistic motoneurone pools to be relatively unhindered by reciprocal inhibition. This decoupling results from different drives for the two types of movements from higher centres. In addi- tion, the different organisation of the connections at hinge and ball joints accounts for the ﬁnding that, at hinge joints, the decoupling is completed by increased recurrent inhibition and presynaptic inhi- bition of Ia terminals. The absence of such mechan- isms at ball joints allows more ﬂexible descending control of co-contractions. Maintenance of bipedal stance Only the maintenance of upright bipedal stance is considered here. Postural adjustments occur in many other situations, e.g. in the upper limb to pro- vide support to hand movements, and have been considered above, with isometric contractions or co-contractions. Similarly postural adjustments occur in the lower limbs in standing subjects when the upper limbs are moved. Unlike the quadrupedal digitigrade stance of the cat, humans balance on their skeleton as an inverted pendulum (see below). They expend little energy in doing so, using limited muscle activity to correct reﬂexly for destabilising sway. The control of body sway during quiet stance and of responses to destabilising perturbations to stance may involve different mechanisms and are therefore treated separately. Normal quiet standing Because the centre of gravity is maintained over a relatively small base of support, human stand- ing posture is inherently unstable. Body instabil- ity, therefore, has a high potential energy, leading to the priority of equilibrium control during almost all motor tasks including quiet standing. During quiet standing, the body’s centre of mass is maintained a few centimetres in front of the ankle joint. This posture requires a background triceps surae activity, which is, however, not continuous, and little mus- cular activity is needed to maintain balance (Bon- net et al., 1976). The main body sway occurs in the sagittal plane, wheretherearequasi-randomsponta- neous alternating movements of the centre of mass, which happen mostly at the ankle joint (e.g. Diener et al., 1984a; Horak & Nashner, 1986; Gatev et al., 1999). It has thereforebecomecommontoregardthe body as an inverted pendulum pivoted at the ankle joint (e.g. Gurﬁnkel &Osevets, 1972; Fitzpatricket al., 1992; Fitzpatrick, Burke & Gandevia, 1996; Winter et al., 1998; Loram, Kelly &Lakie, 2001). Smaller sway movements also occur inthe frontal plane, mostly at hip level, where they are stabilised by hip abductor– adductor activity (Deniskina & Levik, 2001). Multiple sources of feedback Afferent cues from multiple sources Several sources of afferent feedback are used to stabilise body sway during quiet standing: visual, 536 Spinal pathways in different motor tasks vestibular, proprioceptive, and tactile. Many stud- ies have shown that, when various sensory systems are manipulated, body sway is affected: (i) absence of visual input increases the amplitude and speed of the ﬂuctuations of the body (e.g. Day et al., 1993) andpostural responses areinducedbymovingvisual scenes (Dichgans et al., 1972; Lestienne, Soecht- ing & Berthoz, 1977); (ii) loss of vestibular function alters low-frequency stabilisation of the body (Dich- gans &Diener, 1989), andpostural responses may be induced by galvanic vestibular stimulation (Lund & Broberg, 1983; Fitzpatrick, Burke & Gandevia, 1994; Day et al., 1997); (iii) ischaemic blockade of group I afferents produces 1Hzsway(Mauritz&Dietz, 1980), and postural responses are induced by vibration of ankle muscles (Eklund, 1972); (iv) a role of group II muscle afferents is suggested by balance abnor- malities observed in patients with different types of peripheral neuropathy (Chapter 7, p. 320); (v) block- ade of the afferent input from the foot sole by cool- ing the feet increases body sway (Magnusson et al., 1990), and speciﬁc postural responses are induced by vibration of various zones of the sole of the foot (Kavounoudias, Roll & Roll, 1999). Redundancy of the different feedbacks? Signals coming from these multiple sensory sources co-vary with every postural change. Because exclu- sion of any of the above cues may be compensated for in normal subjects with a small (but signiﬁcant) increase in body sway, the question of redundancy arises. However, once again, redundancy is more apparent than real. For instance, tactile afferents fromthesoleof thefoot areinvolvedintheregulation of small-amplitude sway, whereas the muscle affer- ent discharge fromankle muscles is greater for larger andfaster body movements at the ankle. Inaddition, evidence for the necessity of an interaction between information from multiple sensory sources comes frominvestigations showing that the directionof the postural response produced by one cue varies with the position of the limb, trunk or head (for refer- ences see Kavounoudias, Roll & Roll, 2001). Such an integration is necessary because (i) precise informa- tion about the movement of the centre of gravity with regard to the feet is necessary at all times, and (ii) balance has to be maintained during body conﬁgurations that may be continuously changing. Intrinsic stiffness of the ankle Intrinsic spring-like properties of the calf muscles The extent to which the intrinsic spring-like prop- erties of the calf muscles contribute to stabilising the body during standing has recently become the subject of much debate. A model has been pro- posed in which the intrinsic elastic properties of the activated ankle musculature alone would be suf- ﬁcient to stabilise the upright posture. The stabil- isation of quiet standing would then be an essen- tially passive process without any signiﬁcant active or reactive component, except for the background setting of the triceps surae tonic activity. In this case, any deﬂection from the body’s equilibrium position wouldgeneratearestoringtorquethat wouldcauseit to regain that position after a decrementing series of oscillations; as the body sways the energy could be stored and released in the stretching and shorten- ing of the spring (Horak &Macpherson, 1996; Winter et al., 1998, 2001). Contrary arguments However, attractive as it may be, this simple hypoth- esis does not explain a number of ﬁndings. (i) Other calculations have shown that ankle stiffness was overestimated in the above model and is actu- ally insufﬁcient to stabilise the body (Morasso & Schieppati, 1999; Morasso & Sanguineti, 2002). (ii) Aponeurosis, tendon and foot rather than muscle ﬁbres appear to be the main source of ankle stiff- ness in quiet standing (Loram & Lakie, 2002b). (iii) There is clear evidence that the EMG is modu- lated in anticipation of postural sway (see below), and this is directly contrary to the theory that the central nervous system is not involved in reg- ulating balance sway by sway. (iv) In different subjects and patients with modiﬁcations of their Maintenance of bipedal stance 537 postural patterns the main problem is not a reduc- tion of muscle force (and thus of muscle stiff- ness) but, rather, a sensory deﬁcit. In them, the reduced efﬁcacy of predictive control due to unreli- able sensory informationis frequently compensated for by increased ankle stiffness resulting from co- contractionof ankle muscles (Morasso&Sanguineti, 2002). Stretch reﬂex It was initially assumed that shifts in the centre of gravity stimulated stretch afferents of postural mus- cles that contracted reﬂexively (Hellebrandt, 1938). This strategy was questioned because the angu- lar motion at the ankle was less than necessary to elicit a stretch reﬂex (Kelton & Wright, 1949). It was then demonstrated repeatedly that spinal stretch reﬂexes are not relevant to the maintenance of quiet standing (Gurﬁnkel, Lipshits & Popov, 1974; Soames & Atha, 1981; Loram & Lakie, 2002a). Accordingly, (i) quiet stance is only slightly destabilised by selec- tivesuppressionof thegroupI input fromanklemus- cles (see pp. 89–90), and (ii) reﬂex responses evoked in the soleus by changes in the proprioceptive affer- ent input due to near-physiological perturbations have a low loop gain (∼1), which is insufﬁcient to explain stable standing as a feedback control task (Fitzpatrick, Burke & Gandevia, 1996). This low gain may be due in part to increased presynaptic inhibi- tiononIaterminals onsoleus motoneurones inquiet standing(seepp. 363–5), andis desirablebecausethe combination of high gain and the long latencies of humanstretchreﬂexes might have introducedinsta- bility (Matthews, 1972; Rack, 1981). Anticipatory control of the body sway The low loop gain of the soleus EMG response evoked by small perturbations and the fact that they lead ankle movements with a phase advance that increases with frequency are consistent with a feed- forward process (Fitzpatrick et al., 1992; Fitzpatrick, Burke & Gandevia, 1996). Thus, the afferent infor- mation produced by one sway would be used to predict and generate an appropriate reﬂex response for future sway. Positive correlations, with time lags in cross-correlations of 200–300 ms between triceps surae EMG activity and antero-posterior motion of the centre of gravity have been interpreted simi- larly as a feedforward modulation of muscle activ- ity. This modulation would aim at establishing the minimal ankle stiffness needed to restrict the allow- able amount of sway (Gatev et al., 1999). Finally, the low intrinsic ankle stiffness found by Loram & Lakie (2002a,b) implies the existence of an active neural control for modulating ankle torque, and they sug- gest that this control is predictive, possibly origin- ating from muscle spindles. Interestingly, changes in voluntary set can minimise body sway when the subject attempts to be still (Fitzpatrick et al., 1992), but the predictive process is also operative when the subject is paying minimal attention (Loram & Lakie, 2002a). Conclusions In quiet standing, attenuation of body sway is due to a combination of the visco-elastic stiffness of the ankleandapredictiveneural responsetosway. Affer- ent cues from multiple sources evoked by previous swaying movements interact toorganise a predictive neural response producing the least ankle stiffness needed to keep the extent of sway minimal. Unstable postural tasks requiring prolonged muscle contractions During quiet standing, because the knee joint is locked in extension and crossed by the gravitational action line, there may be little or no activity in thigh muscles (Kelton & Wright, 1949; Clemensen, 1951; Joseph, 1962; de Vries, 1965; Soames & Atha, 1981). In contrast, when leaning backward or for- ward, co-contractions of quadriceps and tibialis anterior or hamstrings and triceps surae, respec- tively, are required to maintain the upright stance, and quadriceps and triceps surae are co-contracted when standing on tip of toes with knees and hips 538 Spinal pathways in different motor tasks slightly ﬂexed (a position referred to as ‘preparation for hopping’, see p. 183). Spinal mechanisms contributing to the maintenance of balance during unstable stance Muscle spindle discharges Inthe postural tasks describedabove, excessive sway would produce a lengthening contraction. The co- activated ␥ drive would then represent a powerful input to muscle spindle endings and produce large Ia and group II afferent discharge fromthe receptor- bearingmuscle(s). Inthis respect, eventheveryweak tonic or phasic contractions occurring during quiet stance to maintain balance are accompanied by increased fusimotor drive sufﬁcient to affect spindle afferent discharge (see p. 135), and co-contraction is associated with increased fusimotor activity. Ia and group II discharges contribute to maintaining ﬁring of homonymousmotoneurones(cf. p. 512). Theyalso favour the associated co-contraction of heterony- mous muscle(s) operating at another joint, through the strong transjoint excitatory connections that link human lower-limb muscles, whether monosynap- tic Ia (Chapter 2, Table 2.1) or group II (Chapter 7, Table 7.3) (pp. 528–9). Group II excitation Transmission of heteronymous group II excitation from tibialis anterior to quadriceps and from gas- trocnemius medialis to semitendinosus is facilitated when leaning backwards and forwards, respectively. This facilitation is probably due to decreased activ- ity in the monoaminergic control of transmission in group II pathways from the locus coeruleus in the brainstem (see pp. 313–14). Transmission of the group II discharge from stretched leg muscles, tuned up by decreased activity in the monoamin- ergic control system, might thus contribute to the co-contraction of leg and thigh muscles required to maintain bipedal stance when leaning backwards or forwards. Heteronymous excitation frommuscle spindles Monosynaptic Ia excitation Transjoint monosynaptic Ia connections often link a muscle or group of muscles to a pair of antag- onists operatingat another joint (Table2.1). Through focused corticospinal drive, recurrent inhibition of ‘unwanted’ motoneurones allows the selection of the heteronymous Ia connections appropriate for a given task (see pp. 183–4). Heteronymous group II excitation Group II pathways also link one muscle to antago- nists operatingat another joint (Table7.3). Theselec- tion of the appropriate group II pathway for a given postural task might be ensured by the parallel acti- vation of inhibitory pathways preventing activation of muscles not required in this task (see p. 514). Conclusions During unstable upright stance, co-contractions of ankle and knee muscles are required to maintain posture. Fusimotor-driven spindle discharges con- tribute to the discharge of homonymous and het- eronymous motoneurones, the latter through trans- joint excitatory projections of Ia and group II afferents. Transmissionof groupII excitationis facili- tated, possibly due to decreased monoaminergic ga- ting. Ia and group II excitations can be focused by descendingcontrol of Renshawcellsandof interneu- rones controlling the transmission of spindle group II inputs to motoneurones. Responses to fast transient perturbations of stance A sudden and unexpected perturbation to posture canoccur whenstanding onunstable groundor ona minimal area. The mechanisms involved in the con- trol of quiet standing are then not sufﬁcient to sta- bilise the body, and transient perturbations produce Maintenance of bipedal stance 539 complex reﬂexes with short-, medium- and long- latency responses involving the stretchedmuscle, its antagonists and synergists operating at other joints. Reﬂex responses in ankle muscles The responses of ankle muscles have been investi- gated extensively, and conﬂicting results have been obtained due to different experimental approaches: (i) perturbations produced by rotating the platform on which the subjects stood (toe-up/toe-down), translating the platform (backward–forward), or by applying brisk acceleration impulses during stance on a treadmill, all stimuli that are unusual in real life, but convenient toanalysethedifferent responses producedbytheperturbation; (ii) different velocities of displacement; and (iii) responses in ankle exten- sors recorded either in the gastrocnemius medialis or in the soleus. The issue is further complicated by discrepancies in the deﬁnition of the various EMG responses according to their latencies, and it is not always clear whether latencies were measured to the onset or the peak of the response (latencies to the onset are given below). It is now agreed that, provided the ankle rotation is fast enough (>40 ◦ s −1 , Diener et al., 1984a), passive ankle dorsiﬂex- ionevokes aresponsewiththreecomponents: short- and medium-latency responses in the triceps surae, and long-latency responses in the antagonistic tib- ialis anterior (Diener et al., 1984a; Dietz, Quintern & Berger, 1984; Nardone et al., 1990; Allumet al., 1998). Usually, there is noshort-latency response inthe tib- ialis anterior (see p. 90), where the ﬁrst response produced by passive plantar ﬂexion is a medium- latency response. This is followed by a long-latency response in the triceps surae. These responses have been shown to be mediated through different pathways. Short-latency responses (M1) M1 responses occur at latencies compatible with a monosynaptic response, and several other argu- ments indicate that it can be attributed to the short- latency Ia spinal stretch reﬂex, without a signiﬁcant contribution fromcutaneous afferents fromthe foot (see p. 89). They are larger in soleus than in gastroc- nemius medialis, inaccordancewiththegreater sen- sitivity of small motoneurones (slow-twitch motor units) to Ia inputs (see pp. 79–81). Medium-latency responses (M2) M2 responses occur with a latency of ∼80 ms in the soleus and tibialis anterior (Fig. 7.2(c),(m); Schiep- pati et al., 1995; see p. 293). Several lines of evidence indicate that they are mediated through a muscle group II spinal pathway without a signiﬁcant con- tribution from cutaneous afferents from the foot (see pp. 297–9). The picture is, however, complicated by three features, which may explain the discrep- ancies between the different groups: (i) the larger the short-latency response the smaller the medium- latency response in the triceps surae, because of an interaction between group Ia and group II exci- tations at motoneuronal and interneuronal levels (see p. 301); (ii) because of the mechanical delay produced by muscle stretch, the latencies of both short- and medium-latency responses are slightly longer after translation than after rotation (Schiep- pati et al., 1995); (iii) a later response often occurs in the stretched muscle (M3, see below) where it may merge with the medium-latency response (Diener et al., 1986). Long-latency responses in the stretched muscle (M3) M3 responses have a latency of ∼120 ms in the triceps surae. Such long-latency responses in tri- ceps surae were described during stepping, hop- ping and landing and referred to as the ‘func- tional stretch reﬂex’ (Melvill Jones & Watt, 1971a, b). Then, Nashner (1976), using small platform dis- placements described a similar ‘functional stretch reﬂex’ in the gastrocnemius medialis occurring at 120 ms. The ability of these responses to be mod- iﬁed by will (Melvill Jones & Watt, 1971a, b) sug- gests that they are, in part, voluntary reactions. However, the possibility exists that a transcortical 540 Spinal pathways in different motor tasks reﬂex pathway is also involved in their generation, eventhoughthelatencyof thetranscortical response evoked by stretch of the tibialis anterior during vol- untary contraction is shorter, ∼95 ms (see the Dis- cussion in Petersen et al., 1998). In further studies more rapid stretches were shown to produce gas- trocnemius medialis responses at earlier latencies (95–120 ms; Nashner, Woollacott & Tuma, 1979; 73– 110ms, Horak&Nashner, 1986), compatiblewiththe medium-latency responses described above. Long-latency responses in the antagonist Long-latency responses in the antagonist of the stretched muscle appear with a latency of ∼130– 140 ms. Thus, after passive dorsiﬂexion, short- and medium-latency responses in the triceps surae are followed by a long-latency response in the tibialis anterior (Diener et al., 1984a; Nardone et al., 1990; Schieppati et al., 1995), and vice versa after pas- sive plantar ﬂexion. The neural pathway of these responses has not been elucidated. The only exist- ing indications are: (i) they occur at a latency shorter than a voluntary movement triggered by a somatosensory stimulus (Diener et al., 1984a); (ii) skin receptors from the foot and joint receptors from the ankle are not essential for their genera- tion (Diener et al., 1984b); (iii) because, when hold- ing a stable frame, the time courses of the suppres- sion of the medium- and long-latency responses with respect to the go-stimulus are the same, it has been suggested that they would be both medi- ated through group II afferents and subjected to a similar monoaminergic control from the brainstem (see below; Schieppati & Nardone, 1995); (iv) the ﬁnding that, in patients with absent Achilles ten- don jerks due to a peripheral neuropathy, the long- latency response in the tibialis anterior is hardly modiﬁed (Allum et al., 1998) is also consistent with mediation by group II afferents; and (v) given that the latency of the transcortical response evoked by stretch of the tibialis anterior during voluntary con- traction, probablymediatedbyIaafferents, is∼95ms (Petersen et al., 1998), the longer latency of the long- latency responses in antagonists during stance is compatible witha response to stretchfedby groupII afferents transmitted over a transcortical pathway. Cutaneous reﬂexes The different responses described above are not modiﬁed signiﬁcantly after ischaemic blockade of cutaneous afferents (Diener et al., 1984b). This ﬁnd- ing does not exclude a role for cutaneous informa- tion in rapid postural control. In a further inves- tigation, blocking the afferent input from feet and ankles resultedinachangeinthestrategy(seebelow) used to restore balance (Horak, Nashner & Diener, 1990). In addition, there is evidence that early exci- tatory (E1) spinal cutaneous reﬂexes from the foot, which are not apparent during voluntary contrac- tion, are revealed during active stance, especially when it is unstable (see p. 430). It is also worth not- ing that the withdrawal responses of tibialis anterior are suppressed when the leg has a supporting role (see p. 414). Function of the short-, medium- and long-latency responses The stabilising function of the different responses describedabove is well illustratedby the markeddif- ferences observed in their magnitude (i) when the ‘postural set’ is changed, and (ii) when changing the nature of the pitch perturbation (rotation or trans- lation) while keeping the same angular velocity at the tibio-tarsal joint (Schieppati et al., 1995). Mus- cle stretch by itself is not responsible solely for these responses: (i) the responses are greatly attenuated when the same kind of stimulus is applied in seated subjects (Bussel et al., 1980; Diener et al., 1984b); and (ii) the ‘functional stretch reﬂex‘ provides compen- sationfor postural disturbances only whenthe reﬂex is appropriate to the task (Nashner, 1976). Monosynaptic Ia responses in triceps surae M1responses intriceps suraemight havearolewhen subjects have to correct rapid unexpected perturba- tions of stance (Dietz, Mauritz & Dichgans, 1980), Maintenance of bipedal stance 541 but their functional value is questioned by the ﬁnd- ing that they are not modiﬁed when the ‘postural set’ is changed so that they can make only a lim- itedcontributiontomaintainingposture(seep. 413). When the perturbation is a rotation, they may actu- ally destabilise balance. The large increase in presy- napticinhibitiononIaterminals onsoleus motoneu- rones duringactivestandingprobablyhelps limit the efﬁcacy of the Ia spinal stretch reﬂex in this muscle (see pp. 363–5). Medium-latency group II-mediated responses Group II-mediated M2 responses are markedly reduced when subjects support themselves by hold- ing onto a stable frame, i.e. when the responses are no longer required to ensure the equilibrium (Nardone et al., 1990). The response suppression is related to the transition to a new stabilised ‘postu- ral set’. Presumably there would then be a reduc- tion in descending inhibitory control on the locus coeruleus, leading to increased activity from the locus, and thereby to increased gating of group II volleys. In contrast, when balance is unstable, trans- mission in group II pathways is tuned upwards by decreased activity in this monoaminergic control system (see pp. 312–14). The inﬂuence of the ‘cen- tral set’ on medium-latency responses is demon- strated also when perturbations of various velocities and amplitudes are delivered under variable condi- tions (Horak, Diener & Nashner, 1989): (i) the scal- ing of the response disappears when perturbations arerandomised; (ii) theresponseis directionallyspe- ciﬁc, and related to expectation of the amplitude of perturbation(e.g. a smaller response whena smaller perturbation is expected); and (iii) the response is greater whenthevelocityof theperturbationis unex- pected. Medium-latency responses are minimised withrotationsaroundanaxisco-linear withtheankle joint, because suchperturbations produce little shift in the centre of mass, and large responses would destabiliseposture. Incontrast, translations produce a shift in the centre of mass in the opposite direc- tion to the perturbation, and large medium-latency responses are then required to prevent the subject from falling (Schieppati et al., 1995). This is so when the perturbationis producedby unexpectedacceler- ationimpulses during stance ona treadmill. Accord- ingly, medium-latency responses are then larger in the tibialis anterior thaninthe triceps surae because the shifts in the centre of mass are larger when for- wardtranslations are produced(Dietz, Horstmann& Berger, 1988). Long-latency responses in the antagonist Long-latency responses in the antagonist of the stretched muscle are suppressed, much as are M2 responses, when the subject holds onto a stable frame and postural reactions are no longer needed (Schieppati & Nardone, 1995). Dependence on pos- tural set is alsoindicatedbythechanges inamplitude and latency which occur when the subject actively leans forwards or backwards prior to the platform tilt (Diener et al., 1983; Schieppati et al., 1995). They are also inﬂuenced signiﬁcantly by the type of pitch perturbation. Thus, long-latency responses in the antagonist are consistent and strong after pitch rotations, where they compensate for the destabil- isation produced by earlier (short- and medium- latency) responses. Incontrast, after pitchplane per- turbations, the main postural reaction is exerted by the medium-latency responses, and long-latency responses inthe antagonist are attenuatedconsider- ably (tibialis anterior) or even absent (triceps surae), becausethereislittleornoneedformuchfurthercor- rection. They reappear, however, after translations of unexpected or unpractised amplitude because they aim at correcting the errors in the magnitude of the initial response (Horak, Diener & Nashner, 1989). Responses in the kinematic chain Muscles operating at joints other than ankle Responses produced by transient postural pertur- bations are not limited to ankle muscles. Short-, medium-, and long-latency stretch responses in the triceps surae are accompanied and completed by analogous activity in the ﬂexor digitorum bre- vis, which creates a background torque securing 542 Spinal pathways in different motor tasks contact of the foot with the ground. Tibialis ante- rior responses are accompanied by reﬂexes in the extensor digitorum brevis (Schieppati et al., 1995). Importantly, group II mediated medium-latency responses in ankle muscles also radiate in a distal- to-proximal sequence to thigh and trunk mus- cles on the same dorsal or ventral aspect, invol- ving triceps surae, hamstrings and paraspinals or tibialis anterior, quadriceps and abdominals (Nash- ner, 1977; Horak &Nashner, 1986). It is probable that increased transmission in heteronymous group II pathways from ankle to knee muscles contributes to this radiating activation, much as it does in pro- longed co-contractions of ankle and knee muscles when leaning forwards and backwards (see p. 538). Ankle and hip strategies To maintain stability following a perturbation, the subject must restore the centre of mass to a posi- tion within a point of support bounded by the heels and toes. To that end, the nervous system has, at its disposal, two distinct strategies that can either be used separately or be combined to produce adapt- able control of the centre of mass in the sagittal plane(Nashner &McCollum, 1985; Horak&Nashner, 1986). In the ‘ankle strategy’ the body is conﬁgured as a single-segment inverted pendulum that sways about the ankle joints. Sway is reduced by exerting torque about the ankles and changing the centre of pressureunder thefeet. Thisstrategyisachievedwith the distal-to-proximal activation of the muscles on the same aspect (see above). For this strategy to be effective mechanically, the support surface must be relatively ﬁrm and in contact with the full length of thefoot. Whenthefeet arenot infull contact withthe ground, i.e. when standing on tip of toes, another strategy is required mechanically. This is the ‘hip strategy’, in which the body conﬁguration is actively changed. Rotations at the hip are used to propel the trunk and produce horizontal shear forces between the feet and the ground. This strategy is achieved by activation of abdominals, quadriceps and tib- ialis anterior in a proximal-to-distal sequence. The two strategies become mixed when: (i) the support surface is of intermediate size; (ii) the velocity of the pitch plane translation is increased (Runge et al., 1999); or (iii) the somatosensory input from the feet and ankles is blocked by ischaemia (Horak, Nashner & Diener, 1990). Conclusions To maintain stability following a perturbation in the sagittal plane, an‘anklestrategy’ is generallyadopted inwhichtheresponseinitiatedinthestretchedankle muscle radiates in a distal-to-proximal sequence to thigh and trunk muscles on the same dorsal or ven- tral aspect. Besides the monosynaptic stretch reﬂex, transient postural perturbations produceamedium- latency response in the stretched ankle muscle, mediated through a spinal group II pathway, and a long-latencyresponseintheantagonist, presumably mediatedthroughatranscortical pathway. Thesetwo responses depend heavily on ‘postural set’ and have a functional value in stabilising the upright posture. Gait Spinal pathways play two roles in the control of human gait (see Nielsen & Sinkjær, 2002a): (i) a con- tribution to the activation of muscles during normal unperturbed gait; and (ii) the mediation of some of the reactions to sudden external perturbations dur- ing gait. Pioneering studies of the changes in trans- mission in spinal pathways during human gait were performedbythegroupsinEdmontonandNijmegen (for reviews, see Stein&Capaday, 1988; Zehr &Stein, 1999; Duysens, Clarac & Cruse, 2000). Characteristics of human walking Biomechanical characteristics Peculiarities of human walking Human walking is unique because it is bipedal and plantigrade, with the knee nearly fully extended throughout a stride. Thus, in the main part of the Gait 543 Gluteus maximus Iliopsoas Quadriceps Hamstrings Triceps surae Tibialis anterior Hip Knee Ankle HS op.TO op.HS TO HS 0 15 45 60 100 Stance Swing Single limb support Yield Extension Flexion Fig. 11.3. The timing of the movements of lower limb joints and of the EMG activity of the main extensors and ﬂexors during a stride. Vertical lines indicate the time of ipsilateral heel strike (HS, continuous thick lines) and toe-off (TO, thick dashed line), and contralateral toe-off (op.TO, thin dashed line) and heel strike (op.HS, thin dotted line). Abscissa, step cycle normalised as percentage of the duration of one stride from HS (0%) to the next HS (100%). Stance (continuous thick line) and swing (dashed thick line) phases, and the period of single limb support (continuous thin line) are indicated below the abscissa. The movements of the hip, knee and joint are sketched extension upwards, and ﬂexion downwards. The timing of the EMG activity of the main extensors (ﬁlled boxes, gluteus maximus at the hip, quadriceps at the knee, triceps surae at the ankle) and ﬂexors (open boxes, iliopsoas at the hip, hamstrings at the knee, tibialis anterior at the ankle) is indicated. stance phase, when only one leg is on the ground, a sudden perturbation may endanger balance seri- ously, and reﬂex mechanisms are required to restore it more than in quadrupeds. The contact with the ground throughout the stance phase is made suc- cessively by the heel, foot sole, and toes, with the result that the movements of the knee and ankle are almost out of phase (see Fig. 11.3), contrary to digitigrade animals, such as cats, where they are in phase. Finally, the almost full knee extension throughout astrideallows thelower limbs tobe‘used more like struts’ (Capaday, 2002) and to minimise 544 Spinal pathways in different motor tasks muscle activity, and thus energy expenditure. Indeed, at full extension the tibia rotates slightly on thefemur andthis ‘locks’ thekneesothat muchforce is then required to ﬂex it. As a result patients with severe proximal weakness can stand reasonably sta- bly once they are upright. Similarly, they may have less problem when walking with the stance phase thanthe swing phase, during which the foot must be lifted to clear the ground. Use of external energy As in other walking animals, human walking uses external energy. Thus, there is an alternate trans- fer between gravitational–positional energy and for- ward kinetic energy within each stride, as takes place in an inverted pendulum pivoted at the ankle joint. This transfer is greatest at intermediate walk- ing speeds andcanaccount for upto 70%of the total energy changes taking place in a stride, leaving only 30%to be supplied by muscles (Cavagna, Heglund & Taylor, 1977). Thus, after theyieldof theknee, despite theunipedal stance, kneeextensionis ensuredbythe resultant of kinetic and gravitational forces, without quadriceps activity (Fig. 11.3). Similarly, at normal speed, knee ﬂexion is not produced by contraction of hamstrings, but mainly results from the mechan- ical effect of hip ﬂexion. Pattern of muscle activation Timing of activation of the main muscles The timing of activation of the main extensors and ﬂexors operating at hip, knee and ankle joints, and the movements of these joints throughout a step cycle are sketched in Fig. 11.3. The major groups of muscles are active at or around the beginning and termination of the stance and swing phases, and most of themare quiet during midstance. Thus, at heel strike, contractions of the gluteus maximus, quadriceps and tibialis anterior stiffen the lower limb. In early stance the gluteus maximus continues to extendthe hip, quadriceps controls the slight pas- siveﬂexionof theknee(yieldof theknee), andtibialis anterior controls the rapid passive plantar ﬂexion of the ankle. During the ensuing period, the hipcontin- ues to extend, the knee begins an extension move- ment (without quadriceps contraction, see above), and the ankle yields in dorsiﬂexion. Among mus- cles represented in Fig. 11.3, triceps surae is then the only one to be active, controlling the rotation of the body about the ankle joint. This contraction is accompaniedbythat of theintrinsicplantar muscles. In the pre-swing period, the triceps surae contrac- tionproduces active ankle extensioncontributing to the push-off of the body, and initiates knee ﬂexion through the contraction of the biarticular gastroc- nemius muscles. At around the time of toe off, the contractionsof theiliopsoasandtibialisanteriorpro- duce hip and ankle ﬂexion, so that the leg can swing through. Lengthening loaded contractions Normal gait is relatively slow, so that many mus- cles undergoslowloadedcontractions, that areoften eccentric (e.g. quadriceps during the yield of the knee, tibialis anterior in early stance, triceps surae during most of the stance, see Fig. 11.3). These are circumstances when the co-activated ␥ drive can represent a powerful input to muscle spindle end- ings, driving spindle discharges at high rates (see pp. 135, 137). Conclusions During the main part of the stance phase of human walking, only one leg is on the ground. In addi- tion, while walking on even ground, muscle con- tractions are minimised to reduce energy expendi- ture. Reﬂex mechanisms must therefore be ready to compensate for any perturbation resulting for unex- pected ground unevenness. The inherent instability of human walking may explain the development of some reﬂex activities (e.g. transcortical) that are par- ticular to humans. Gait 545 Changes in transmission in spinal pathways during normal walking Evidence for changes in transmission in spinal pathways Several lines of evidence showthat changes intrans- mission in spinal pathways occur during human walking. These changes are speciﬁc to gait, as revealedbystudiescomparingtransmissioninspinal pathways during walking and during voluntary con- tractions when standing using comparable EMG levels and limb positions. Monosynaptic Ia excitation of soleus motoneurones The modulation of the soleus H reﬂex has been investigated extensively throughout the step cycle. The soleus H reﬂex increases progressively during stance in parallel with the on-going EMG of soleus, reaching a maximum at ∼30% of the step cycle, but it is still inhibited with respect to its size in the standing position. It then decreases abruptly at the end of the stance phase to disappear more or less completely during the swing phase (Capaday & Stein, 1986; Crenna & Frigo, 1987; Yang & Whe- lan, 1993; Simonsen & Dyhre-Poulsen, 1999; Ferris et al., 2001). The smaller amplitude of the H reﬂex during walking than standing for comparable EMG levels has been attributed to increased presynap- tic inhibition on Ia terminals on soleus motoneu- rones during gait (Morin et al., 1982; Capaday & Stein, 1987). Evidencefor increasedpresynapticinhi- bitionwas later demonstrated, andit was shownthat the modulation of presynaptic inhibition through- out a stride parallels that of the H reﬂex (Faist, Dietz & Pierrot-Deseilligny, 1996; see p. 366). It has been argued that the phase-dependent presynaptic inhi- bition of the soleus H reﬂex results from proprio- ceptive feedback produced by passive movements about the knee and hip joints (Brooke et al., 1995). However, investigations limiting knee joint move- ments during walking have demonstrated that the reﬂex inhibition is of central origin (Garrett, Kerr & Caulﬁeld, 1999; Schneider, Lavoie &Capaday, 2000). The even lower amplitude of the soleus H during difﬁcult beam walking presumably results from a greater increase in presynaptic inhibition of soleus Ia terminals (Llewellyn, Yang & Prochazka, 1990). This ﬁndingsupports theviewthat, indifﬁcult motor tasks, increased ␥ drive (as recorded in the cat, cf. Hulliger et al., 1989) provides supraspinal centres withincreasedfeedbackgainandresolution, but that this increasedgaincouldcause instability of the seg- mental stretch reﬂex and is therefore controlled by increased presynaptic inhibition on Ia terminals on motoneurones. Increased presynaptic inhibition of homonymous soleus Ia terminals also accounts for two further ﬁndings: (i) The suppression of the on-going soleus EMG caused by unloading soleus during the stance phase is modiﬁed little by ischaemic blockade of Ia affer- ents, though it is slightly delayed. This indicates that these afferents contribute little to the soleus con- traction, except by depolarising the relevant pro- priospinal neurones, thereby potentiating any sub- sequent excitatory input (see pp. 315–16). (ii) Transmission of vibration-induced homony- mous Ia excitation to soleus motoneurones does not increase during walking (see p. 365). Monosynaptic Ia excitation of quadriceps motoneurones The modulation of the quadriceps H reﬂex also par- allels that of the on-going EMG activity throughout a stride, and the reﬂex is maximal in early stance. At heel strike, there is indirect evidence for a decrease in presynaptic inhibition of homonymous Ia termi- nals on quadriceps motoneurones. Later, presynap- tic inhibition of quadriceps Ia terminals increases progressively to become greater than during stand- ing at the moment of the yield of the knee (see p. 365). Group II excitation Homonymous group II excitatory discharges pro- duced by the lengthening contraction of the 546 Spinal pathways in different motor tasks triceps surae during the stance phase contribute sig- niﬁcantly to the discharge of soleus motoneurones (see pp. 315–16). On the other hand, transmission of heteronymous group II excitation from pretibial ﬂexors to quadriceps motoneurones is facilitated in early stance with respect to voluntary contraction in standing. However, here again depolarisation of the relevant propriospinal neurones by groupI afferents might play a crucial role by potentiating the group II excitation. (see pp. 318–20). Non-reciprocal group I inhibition Non-reciprocal groupI inhibitionfrompretibial ﬂex- ors tobiceps femoris, seenduringvoluntarycontrac- tions when standing or at the end of the swing phase of walking, is reversed to oligosynaptic group I exci- tation in early stance (see pp. 274–5). Recurrent inhibition Heteronymous recurrent inhibition from soleus to quadriceps is suppressed during the stance phase when there is a simultaneous contraction of soleus and quadriceps (Iles, Ali & Pardoe, 2000). Reciprocal Ia inhibition Modulationof reciprocal Iainhibitionbetweenankle muscles during the walking cycle helps ensure that antagonistic motoneurones are not activated inap- propriately (i.e. triceps surae during the swing phase and tibialis anterior during the stance phase). How- ever, the modulation is less marked than during vol- untary movements (see pp. 227–9). Mechanisms operating at ankle level Stabilisation of the ankle The appearance in humans of Ia connections, not matchedby equivalent projections of recurrent inhi- bition, between ankle muscles that are not syner- gistic in ﬂexion–extension movements (from tibialis anterior to gastrocnemius medialis, and soleus to peroneus brevis [see p. 170]), might helpstabilise the ankle during the stance phase of locomotion. As dis- cussed above the modulation of reciprocal Ia inhi- bition is less marked than during voluntary move- ments, andthis couldalsoreﬂect theneedtostabilise the ankle. However, the main source of stabilisation of the ankle comes from the large stretch responses, spinal or transcortical, produced in both the soleus and tibialis anterior during the stance phase (see pp. 548–9). Prevention of excessive reﬂex activity in triceps surae Because the homonymous group II excitation of the triceps surae contributes to the excitation of soleus motoneurones during the stance phase (see pp. 315–16), less central drive is necessary to acti- vate the motoneurones. The lengthening contrac- tion of triceps surae also evokes a strong Ia dis- charge, but Ia spinal pathways are not responsible for the decrease in soleus EMG activity when the muscle is unexpectedly unloaded (see above). Actu- ally, the Ia spinal stretch reﬂex of gastrocnemius- soleus does not contribute greatly to the push-off of the body produced by the triceps surae contrac- tion during the late stance phase (see p. 89). The role of this reﬂex is to help resist and thereby slow the passive ankle dorsiﬂexion produced by extrin- sic mechanisms, such as kinetic and gravitational forces. However, the calf muscle resistance must be overcome if the body is to be brought forward, and excessive reﬂex activity in triceps surae should be minimised or a stiff gait would appear, much as may be seen in spastic patients (see p. 575). Sev- eral mechanisms help to limit the reﬂex activation of triceps surae motoneurones: (i) the absence in humans of heteronymous Ia connections from gas- trocnemius medialis to soleus, and their weakness from soleus to gastrocnemius medialis or from gas- trocnemius medialis to gastrocnemius lateralis, as compared with the cat (see p. 93); (ii) the strong increase in presynaptic inhibition on Ia terminals on triceps surae motoneurones (see above); (iii) the Gait 547 absence of depression of Ib inhibition to soleus motoneurones by cutaneous afferents from the foot sole (see p. 274); and (iv) the strong propriospinally mediated inhibition of triceps surae motoneu- rones by group I discharges from intrinsic plan- tar muscles, which are activated in midstance (see p. 503). Mechanisms operating at knee level Quadriceps contraction is important in the early stance phase of human walking At this time, theweight of thebodyis shiftedtotheleg that is about tobeginthestancephase(Fig. 11.3), and the quadriceps contraction is required to stabilise the knee joint inorder tosupport the body weight. In this phase of gait, several spinal mechanisms help the quadriceps contraction (see above): (i) trans- mission to quadriceps motoneurones of the strong group I–group II excitation due to the lengthen- ing contraction of the tibialis anterior is facilitated; (ii) Ib inhibition of quadriceps motoneurones may be suppressed by the cutaneous volley created by the foot contacting the ground (see p. 274); (iii) recurrent inhibition to quadriceps motoneu- rones is decreased; and (iv) presynaptic inhibition of Ia terminals on quadriceps motoneurones is decreasedat heel strike, althoughit is increasedlater in order to allow for the yield of the knee and hence the smoothness of the gait. Reversal of Ib inhibition to biceps femoris Ib inhibition from pretibial ﬂexors to biceps motoneurones is reversed to facilitation in early stance. Thus, at this time of the gait cycle, the muscle afferent discharge elicited by the lengthening con- traction of ankle dorsiﬂexors facilitates both quadri- ceps (see above) and biceps motoneurones. Facilita- tion of the antagonists operating at knee level con- tributes to their co-contraction, and helps ensure maximal stability of the knee joint when the leg is about to carry the body weight. Transition Proprioception might be involved in timing the dif- ferent phases of locomotion, and both load- and position-dependent triggering of phase transition have been proposed in cat investigations. (i) Decrease in Ib excitatory input from extensors due to unloading of these muscles appears critical to terminating the stance phase and initiating the swing in the cat but, so far, there is no conclusive evidence for such a mechanism in human walking (see p. 273). (ii) A speciﬁc degree of hip extension must be reached before the leg is lifted (Grillner & Rossig- nol, 1978), and this position-dependent triggering foundinthe cat is probably controlledby the length- sensitive Ia afferent input from stretched hip ﬂexors (Andersson & Grillner, 1983). Vibration of the rectus femoris produces an earlier onset time of the swing phase (Verschuerenet al., 2003). Although this effect was modest, it suggests the involvement of Ia affer- ents from thigh muscles in triggering the transition from the stance phase to swing in humans. Conclusions In agreement with the different functional role of ankle and knee extensors during human walking, spinal mechanisms are tuned to have opposite effects on these two motoneurone pools. Thus, they provide a safety factor for the quadriceps contrac- tion and contribute to locking the knee in early stance, while they prevent excessive reﬂex activity from occurring in the triceps surae. Reactions to external perturbations Unexpected perturbations may occur during walking: the foot may slip, the ground may give way under the weight of the body, or the swinging leg or foot may hit an obstacle. In all these cases, compensatory reactions signalled by changes in the afferent muscle and/or cutaneous feedback are 548 Spinal pathways in different motor tasks required to restore balance (see Nielsen & Sinkjær, 2002a,b). Stretch-induced responses Ia spinal stretch reﬂexes These responses are consistently observed intriceps surae, provided the velocity of the perturbation is high enough. (The absence of a stretch reﬂex fol- lowing acceleration of a treadmill on which the sub- jects were walking was probably because the per- turbation was not of sufﬁcient velocity; see p. 89.) Given the strong presynaptic inhibition of Ia termi- nals on soleus motoneurones during walking, and the concordant absence of involvement of Ia affer- ents in the unloading-induced decrease in on-going soleus EMG activity (see above), the existence of a signiﬁcant stretchreﬂexmayseemsurprising. Infact, presynaptic inhibitiononIa terminals does not have the same effect on a reﬂex response to an abrupt stretch in which Ia afferents may discharge at rel- atively high frequency as on the Ia afferent feed- back evokedby anon-going movement inwhichdis- charge rates are lower (see Nielsen & Sinkjær, 2002a; see pp. 354–5). Ia spinal stretch-induced responses appear in the soleus only during the stance phase, and in particular in early stance (10–20% of the step cycle), when the torque resulting from the soleus stretch reﬂex is greatest. This timing suggests that these responses play a role in the stabilisation of the supporting limbduring walking rather thancon- tributing to propulsion during late stance (Zehr & Stein, 1999). Only small variable stretch-induced responses appear at monosynaptic Ia latency in the tibialis anterior, when it is active in the swing phase (see p. 89). Stumbling over an obstacle Monosynaptic responses occur simultaneously in ankle and knee ﬂexors and extensors when stum- bling over an obstacle during the swing phase of walking. These responses have been attributed to transmission through the limb of the sudden jar created by the collision with the obstacle, caus- ing widespread muscle spindle activation. However, it is possible that the widespread heteronymous monosynaptic Ia connections between ankle and kneemuscles alsocontributetothediffusionof these monosynaptic responses (see p. 94). Medium-latency responses GroupII responses are alsoconsistently producedin the soleus by stretchwhensoleus is active during the stance phase (Grey et al., 2001), in particular in early stance (10–20% of the step cycle, Nielsen & Sinkjær, 2002a). Incontrast, M2 stretch-inducedresponses in tibialis anterior are smaller when it is active during the swing phase than during voluntary contractions (see p. 318). Studies of stretch-induced group II- mediated medium-latency responses in the tibialis anterior during the stance phase have yielded dis- cordant results: the absence of the M2 response to a vertical displacement (Christensen et al., 2001) con- trasts with the large group II responses radiating to the quadriceps and contralateral tibialis anterior in response to a horizontal displacement of the whole body, due to deceleration of a treadmill on which the subjects were walking (Berger, Dietz &Quintern, 1984; pp. 316–18). In fact, contrary to a vertical dis- placement that is limited to the ankle, deceleration of a treadmill results in a large postural disturbance, which favours group II-mediated medium-latency responses to stretch (see p. 541). Long-latency responses Long-latency stretch responses (M3) in soleus are elicited rarely during voluntary plantar ﬂexion, but are recordedreadily during the stance phase of walk- ing in healthy subjects. The latency of these long- latency responses is compatible with a transcorti- cal pathway, and this is supported by the ﬁnding that they are not seen in patients with corticospinal lesions (Sinkjær et al., 1999). Duringthestancephase of walking, despite the inhibition of tibialis ante- rior motoneurones due to reciprocal Ia inhibition (seep. 546), long-latencystretchresponses mediated Gait 549 by Ia afferents are much larger than in the swing phase when the muscle is active (Christensen et al., 2001). These long-latency responses to stretch are not present in patients with corticospinal lesions (Christensen et al., 2000), and there is evidence that they result from increased excitability of tibialis anterior-coupled cortical neurones (Capaday et al., 1999; Christensen et al., 2001). They are the only signiﬁcant responses in tibialis anterior after ver- tical displacement of the ankle in the stance phase. Functional implications In both soleus and tibialis anterior, stretch-induced responses of signiﬁcant size, whether spinal reﬂexes mediated by Ia or group II afferents or transcorti- cal responses, are elicited only during the stance phase. Based on this, Christensen et al. (2000) pro- posed that stretch responses play little or no role in the regulation of limb trajectory during the swing phase of gait, but are involved mainly in ensuring the stability of the supporting limbduring the stance phase. During the unipedal part of the stance phase, a sudden perturbation would jeopardise balance. The large stretch responses in antagonistic ankle ﬂexors and extensors, as the heteronymous mono- synaptic Ia connections linking the different muscles acting around the ankle, may help counteract surfaceunevennessandprevent atwisted ankle. Cutaneous reﬂexes Cutaneous responses during the swing phase Reﬂex responses produced by low-threshold cuta- neous afferents occur mainly duringtheswingphase in ﬂexors of the ankle and knee (see pp. 430–2). The available evidence suggests that they are medi- ated largely through a supraspinal pathway, possi- bly transcortical, although this does not exclude a contribution from other supraspinal (spino-bulbo- spinal) or even spinal pathways (see p. 432). The pattern and timing of the cutaneous responses depend on the skin ﬁeld stimulated. In early swing, stimuli to the sural and peroneal nerves have opposite effects on the on-going EMG of tibialis anterior: suppression by peroneal but facilitation by sural stimuli. There are also cutaneous responses in the contralateral muscles during walking and run- ning (see p. 432). Functional implications The skin ﬁeld-speciﬁc phase-dependent patterns of cutaneous reﬂexes indicate a dynamic control of cutaneous informationfromthe foot throughout the step cycle (Van Wezel, Ottenhoff & Duysens, 1997). These reﬂexes appear tobe adaptedtomove the per- turbed leg away from the stimulus, with the general constraint of preserving the cadence and balance during the stepcycle. For example, whenthe dorsum of the foot, innervated by the peroneal nerve, meets an obstacle during the swing phase, the suppressive response in the tibialis anterior combined with the excitation of hamstrings is adequate to clear the foot from the obstacle and prepare the leg to step over it, so enabling continuation of the walking pattern. However, when the tip of the foot strikes an obsta- cle in the transition from stance to swing, a cuta- neous reﬂex originating from the skin ﬁeld inner- vated by the sural nerve would provide anautomatic mechanism to help dorsiﬂex the foot (see p. 432). Cutaneous afferent facilitation of reciprocal Ia inhi- bition of ankle extensors would help produce this ankle dorsiﬂexion (see pp. 214–15). Conclusions Stretch-inducedresponses ensure the stability of the supporting limb in the stance phase, while cuta- neous reﬂexes allow the foot to clear an unexpected obstacle, in a manner analogous to the ‘stumbling corrective reaction’ observed in chronic spinal cats (see p. 387). An important difference from animal data is that, in humans, the responses evoked by muscle stretch or cutaneous stimulation are also, if not mainly, mediated through transcortical path- ways. Because of this particular organisation, it is 550 Spinal pathways in different motor tasks possible, after any early spinal reﬂex compensation to make an ‘additional voluntary reaction such as stopping the movement and/or shifting the body weight onto the other leg or – depending onthe situ- ation – continue the movement’ (Christensen et al., 2000). Running, hopping, landing Contrary to walking, during the stance phase of run- ningandhoppingandafter theimpact of landing, the short-latency Ia spinal stretch reﬂex of the triceps surae is superimposed on pre-programmed activ- ity and contributes to the muscle contraction pro- ducing the pushing off of the foot. There is prob- ably also a concomitant short-latency Ia stretch response in the quadriceps (see pp. 87–89). The Ia spinal stretch reﬂex can produce a mechani- cally effective contraction and provides a pathway through which rapid automatic load compensa- tion to an unexpected disturbance can be gener- ated. During such motor tasks, all extensors (plan- tar muscles of the foot, triceps surae, quadriceps and hamstrings [acting as hip extensors]) undergo a lengthening contractionthat evokes a strong spindle afferent discharge. 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This descending control is exerted on all interneurones, whether they mediate presynaptic inhibition of primary afferent terminals or postsynaptic effects. Transmission in multiple spinal pathways may be altered after a lesion of the central nervous system. These alterations contribute tothe pathophysiologi- cal mechanismsunderlyingmovement disordersfol- lowing upper motor neurone lesions and basal gan- gliadiseases. Atonicimbalancebetweendescending excitatory and inhibitory inputs on various spinal pathways accounts for the changes in muscle tone of spasticity and parkinsonian rigidity at rest. On the other hand, the loss of the normal descending modulation of these pathways during motor tasks, together with the abnormal descending command to motoneurones, contributes to the motor impair- ment of the patients. Methods used in clinical neu- rophysiology help determine the extent to which spinal pathwaysmalfunctionafteralesionof thecen- tral nervous system. Only spasticity following upper motor neurone lesions and Parkinson’s disease are consideredinthe overviewgiveninthis chapter. The involvement of spinal pathways in the pathophysi- ology of other motor disorders, suchas dystonia, has been discussed in previous chapters. Spasticity Spasticity is one of the components of the upper motor neurone syndrome, and occurs in a variety of diseases and disorders of the central nervous sys- tem, suchas spinal cordinjuries anddiseases, multi- plesclerosis, braininjuries, strokeandcerebral palsy. These conditions deserve special consideration because they are common (e.g. annually ∼750 000 new stroke cases in USA, see Smith et al., 1999), and they may cause a persistent handicap. Even though its contribution to the motor disability of patients needs to be revisited (see pp. 558–60), spasticity has given rise to much attention for two reasons: (i) it is the component of the upper motor neurone (or corticofugal, see below) syndrome most acces- sible to therapy; and (ii) it remains a key dividing point among major schools of physiotherapy, with some aiming at inhibiting spasticity (see Bobath, 1990) and other at encouraging it (see Brunnstr¨ om, 1970). It is generally assumed (e.g. Delwaide, 1985a), but so far not demonstrated, that analyses of the pathophysiological mechanisms underlying spas- ticity provided by clinical neurophysiological stud- ies may be important, because therapeutic inter- ventions might be more effective if targeted to the underlying pathophysiology. If this were so, accu- rate evaluation of the mechanisms underlying spas- ticity in individual patients would become increas- ingly important as appropriate treatment modalities were developed to reduce spasticity. These thera- pies include: botulinum toxin injection, blockade of peripheral nerves by alcohol or phenol, intrathe- cal and oral medication, and physical/occupational therapy (for review, see Satkunam, 2003). Moreover, clinical neurophysiological techniques may provide 556 Spasticity 557 the objective and quantitative data necessary for clinical trials and longitudinal studies and to follow the progress of individual patients. What is spasticity? What is it not? The title of this section has been borrowed from a paper by Landau (1980) who pointed out the care- less use of the word spasticity, emphasising that it is only a facet of the upper motor neurone syn- drome, not necessarily the one that causes the great- est disability. Inthe upper motor neurone syndrome, Jackson(1958) made the distinctionbetween(i) neg- ative symptoms due toloss of functionsuchas weak- ness andloss of dexterity, and(ii) positivesymptoms, due to exaggeration and/or distortion of normal behavioural responses tostimuli. Reﬂex release phe- nomena involving both stretch and ﬂexor reﬂexes fall into this grouping. The differentiation into ‘minus’ and ‘plus’ symptoms may have outlived its usefulness. (i) A ‘minus’ symptom may be due to a ‘plus’ symptominthe antagonistic muscle (Thilmann, 1993). This leads to a discussion of the motor impairment produced by spasticity (see below). (ii) The loss of dexterity after stroke is not just a ‘minus’ symptom, because associated involun- tary contractions (synkinesia) due to the trans- mission of the descending command by path- ways other than the corticospinal tract (see p. 579) may impair co-ordination. Deﬁnition Spasticity and stretch reﬂex exaggeration The most commonly used deﬁnition of spastic hypertonia, or spasticity, has been given by Lance (1980): ‘spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reﬂexes (‘muscle tone’) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reﬂex as a component of the upper motor neuron syndrome’. The tonic stretch reﬂex has been shown to have a low correlation with the briskness of the tendon jerks (Fellows, Ross & Thilmann, 1993), and this deﬁnition is far from perfect, but it remains the lowest common denominator on which most neu- rologists and physiologists may agree. Accordingly, in a subsequent workshop held in Essen in 1992, substantial discussion failed to formulate a better deﬁnition. Either the description was too simplistic, and therefore unhelpful, or the participants could not agree on the detailed quantitative features of the exaggeratedstretchreﬂexinspastichypertonia. Con- ﬂicting views were presented concerning the domi- nant abnormality of the increased resistance to pas- sivestretchinspasticmuscles: loweringof thestretch reﬂex threshold (Katz & Rymer, 1989), increase in the stretch reﬂex gain (‘stiffness’, Thilmann, Fellows & Garms, 1991), or mainly changes in the intrinsic properties of themuscle(‘contracture’, Dietz, Trippel & Berger, 1991). Corticofugal syndrome In the same workshop, it was proposed to rename theupper motor neuronesyndromethe‘corticofugal syndrome’ to reﬂect the fact that other descending pathways are involved, not solely the corticospinal projection. The alternative deﬁnition proposed of the corticofugal syndrome is ‘a disorder of motor control due in part to reduction in cortical inﬂu- ences onthe spinal cord, characterisedby weakness, impaired coordination, spasticity, increased tendon jerks, and release of cutaneomuscular reﬂexes such astheBabinski response’ (seeThilmann, 1993). How- ever, attractive as it may be, it must be recognised that this proposition has not echoed as much, and the termupper motor neurone syndrome continues to be used in the literature. Pathophysiology of spasticity varies with the causative lesion Whatever the lesion of the central nervous system responsible for spasticity, the corticospinal tract is damaged. However, because the other descending pathways involved by the lesion are different after 558 Pathophysiology of movement disorders cerebral and spinal lesions, it is not surprising that the pathophysiology of spasticity is different after stroke and spinal cord injury (pp. 575–82). Clinical features of spasticity Muscle tone and exaggerated tendon jerks According to Lance’s deﬁnition (see above), the clin- ical features required for spasticity are increased muscle tone and tendon jerk hyperreﬂexia, the increase in tone being more apparent the faster the stretching movement, often undetectable if extremely slowmovements are used. There are other features of spasticity, such as clonus and the clasp- knife phenomenon, but these are not invariably demonstrable. Clonus Clonus is an oscillating reﬂex contraction of mus- cle, most easily produced for triceps surae, and now believed to be due to repetitive elicitation of the ten- don jerk by the stretch-evoked muscle spindle vol- ley triggered by the relaxationof the preceding reﬂex contraction (Szumski et al., 1974; Hagbarth et al., 1975). Thus, the relaxation of a vigorous reﬂex con- traction stretches muscle spindle endings and can produce a volley that, given the hyperactivity of the reﬂex arc, is sufﬁcient to trigger another reﬂex con- traction. The presence of clonus is directly related to the tendon jerk hyperreﬂexia, and whether it can be elicited depends on the skill of the examiner who may needtoadjust thestretchput onthecontracting muscle to be optimal. As clonus subsides, the spin- dle discharge produced by relaxation of the twitch contractiongraduallybecomesdispersed. Therateof clonus is thus determinedbythemechanical proper- ties of muscle and the conduction time for the reﬂex arc. Clasp-knife phenomenon The clasp-knife phenomenon consists of the col- lapse in reﬂex tension during stretch of a reﬂexly contracting muscle, and is only demonstrable clin- ically for the quadriceps muscles, where the range of possible movement is large, allowing a rela- tively high velocity of passive movement. This pro- duces a ‘catch-and-give’ sensation – the ‘catch’ due to the build-up of the resistance to stretch, the ‘give’ due to its subsequent suppression. This suppression is due to an autogenetic inhibitory process caused not by the activation of Ib affer- ents but by the convergent actions of FRA, par- ticularly non-spindle group II and smaller mus- cle afferents, and cutaneous and joint afferents (see p. 326). It should be distinguished from the decreaseintheresistancetostretchthat occurs when a dynamic reﬂex response subsides as movement slows or ceases. This latter process underlies thefeel- ing of the ‘catch’ when passively stretching mus- cles such as biceps and triceps brachii and, unlike the ‘true’ clasp-knife phenomenon at the knee, there is no true ‘give’ and it is not associated with an autogenetic inhibitory process (Ashby & Burke, 1971). To what extent does spasticity contribute to motor impairment? In neurological practice, the crucial question about spasticity is the extent to which it contributes to the motor impairment and limitation of activity in patients with a corticofugal syndrome. It is often assumed that a voluntary movement that stretches a spastic muscle might be expected to produce reﬂex activity that would oppose the movement. However, stretch reﬂex activity during movement depends both on the exaggeration of the stretch reﬂex and changes in the transmission in spinal pathways during active motor tasks (see pp. 573–5). Accordingly, it has been demonstrated repeatedly that neither the exaggeration of tendon jerks nor the increased resistance to passive stretch in the relaxed state can predict the contribution of spas- ticity to the disorders of voluntary movement or gait (e.g. see McLellan, 1977; Dietz, Quintern & Berger, 1981; Fellows et al., 1993; Yelnik et al., 1999). Spasticity 559 Spastic restraint – a debated proposition The contribution of spasticity to motor impair- ment has been the subject of vigorous discussion, and some divergences exist about whether stretch reﬂexes in an antagonistic muscle impede move- ment due to agonist contraction, by either limiting the amplitude of the movement and/or slowing it down. Several reports suggest that voluntary move- ments in spastic patients may be disrupted by exag- geratedstretchreﬂexes (Dimitrijevi´ c&Nathan, 1967; Mizrahi & Angel, 1979; Benecke et al., 1983; Corcos et al., 1986; Knutsson, M˚ artensson & Gransberg, 1997). In contrast, Dietz & Berger (1983) found no evidence for a signiﬁcant contribution of exagger- ated stretch reﬂexes in the gastrocnemius to the ‘spasticgait’ of post-strokehemipareticpatients, and concluded that the increased resistance to stretch of spastic muscles mainly results from changes in non-neural factors (see pp. 572–3). Theseapparently conﬂicting views are actually due to the fact that dif- ferent results may be obtained in patients with dif- ferent lesions of the central nervous system, and/or in different muscle groups, in subjects performing different tasks. Stroke patients In stroke patients, there is evidence that the increased resistance to stretch in the triceps surae is due to mechanical rather than reﬂex causes (Perry et al., 1978; Berger & Dietz, 1993; Ada et al., 1998; Dietz, 2003; Sommerfeld et al., 2004). Spasticity of the quadriceps and the resulting inability to ﬂex the knee during the swing phase does not seem to affect the patient’s speed of gait (Bohannon & Andrews, 1990), andisonlydisablingonstairs(Yelnik et al., 1999). That reductionof spasticity will improve gait remains to be ﬁrmly established (Landau, 2003; Cramer, 2004) and, on the contrary, its reduction might be counterproductive as spasticity oftenhelps support the body during locomotion (see Dietz, 2003). Conﬂicting results have been obtained con- cerning the resistance opposedby the biceps brachii to voluntary elbow extension: decreased stretch reﬂex threshold (Powers, Marder-Meyer & Rymer, 1988), increased stretch reﬂex gain (Thilmann, Fellows & Garms, 1991), but no evidence for abnor- mal stretch reﬂex (Dietz et al., 1993; O’Dwyer, Ada & Neilson, 1996). Recently, Rymer’sgrouphavedemon- strated that exaggerated stretch reﬂexes in the ﬁn- ger ﬂexors contribute to the impairment of ﬁn- ger extension in stroke survivors (Kamper et al., 2003). Patients with cerebral palsy In patients with cerebral palsy, the role of spastic- ity in the impairment of voluntary movement or gait has also been challenged (see Vaughan, Neilson & O’Dwyer, 1988; Neilson, O’Dwyer & Nash, 1990; Berger & Dietz, 1993). However, the prevailing view is that the exaggeration of stretch reﬂexes in some of these patients may give rise to crucial restraint to gait movements (e.g. Perry et al., 1974; Knutsson, 1985; Tuzson, Granata & Abel, 2003). Accordingly, the usefulness of reducing spasticity is now gener- ally accepted (using, e.g. botulinumtoxin injections, for review, see Davis & Barnes, 2000). Patients with spinal cord lesions In patients with spinal cord lesions, in particular in spinal cord compression, chronic myelopathies or hereditary spastic paraparesis, there is evi- dence that exaggerated stretch reﬂexes can disrupt movement (Dimitrijevi´ c & Nathan, 1967; Mizrahi & Angel, 1979; Corcos et al., 1986). Thus, abnor- malities found in paraspastic patients investi- gated during the locomotor-like tasks of bicy- cling (Benecke et al., 1983) and treadmill walk- ing (Conrad, Benecke & Meinck, 1985) were more in favour of a neural origin of spastic hyperto- nia than of changes in the muscle itself. More recently, unwanted stretch reﬂex activity in the antagonist triggeredby the dynamic concentric con- traction of the agonist has been shown to limit the amplitude and/or to slow down the movement of knee muscles (Knutsson, M˚ artensson & Gransberg, 1997). 560 Pathophysiology of movement disorders Conclusions Spasticity is characterised by an exaggeration of the stretch reﬂex. However, the exaggeration of the tonic stretch reﬂex has only a low correlation with the briskness of the tendon jerks. Moreover, the increased resistance to stretch is also, and perhaps mainly in some cases, due to changes in the intrin- sic properties of muscle ﬁbres. The contribution of exaggerated stretch reﬂexes to motor disability of patients with corticofugal lesions has been overes- timated, and varies with the underlying cause, being more important in patients with spinal cord lesions than in stroke patients. Spasticity and animal decerebrate rigidity are unrelated If one admits, with most authors, that spasticity is characterised by an exaggeration of the stretch reﬂex (see above), two questions arise concerning its pathophysiology. (i) What are the spinal mechanisms underlying this exaggeration? (ii) Why do spinal pathways malfunction? At ﬁrst sight, humanspasticity andanimal decere- brate rigidity following intercollicular transection of thebrainstemhavesomecharacteristicsincommon: the main feature of both is the increased reactivity to a stretch stimulus which is (i) more pronounced the faster the stretch is applied, and (ii) preferen- tially distributedto antigravity muscles. It was there- fore presumed that the same spinal mechanisms might be responsible for the stretch reﬂex exagger- ation characterising the two conditions. In decere- brate rigidity of the cat, the mechanisms include ␣ hyperexcitability, ␥ over-activity, suppression of Ib inhibition, closure of pathways mediating FRA inhibition to extensor motoneurones, and possibly opening of pathways mediating oligosynaptic Ia and group II excitations (for review, see Matthews, 1972). The existence of an appropriate animal model of spasticity would have allowed the effects of pharma- cological substances acting on speciﬁc spinal mech- anismstobetestedinthepreclinical phase. However, there are important differences between spastic- ity and animal decerebrate rigidity (Burke et al., 1972; Denny-Brown, 1980). In particular, decere- brate rigidity immediately follows the causal lesion, while spasticity takes days, often weeks to develop. This gives time for rearrangements to occur at spinal level (see pp. 571–2). Possible spinal mechanisms underlying the pathophysiology of spasticity at rest As indicated in Fig. 12.1, many spinal mechanisms control the excitability of the stretch reﬂex, and an abnormality in any one of them might, theoreti- cally at least, produce stretch reﬂex exaggeration. The functional derangements that could theoreti- cally give rise to an exaggerated stretch reﬂex are listed below, with for each: (i) how it could produce spasticity; (ii) the method(s) currently used to inves- tigate the mechanism, given that, in patients the methodology should be simple and rapid; and (iii) whether it actually contributes to spasticity. Reduction of spasticity accompanies selective blockade of speciﬁc pathways (e.g. ␥ axons), andthis hasoftenbeentakenasanargument that overactivity of that pathway was a primary factor in the patho- physiology of spasticity. Infact, the excitability of the stretch reﬂex depends on an intact reﬂex arc and on several excitatory and inhibitory mechanisms. Blockade of any excitatory mechanism and/or facil- itation of an inhibitory one will reduce the stretch reﬂex, even though its exaggeration (spasticity) is caused by other mechanisms. Hyperexcitability of ␣␣ motoneurones Here, a normal stretch-induced reﬂex volley would produceanexaggeratedresponsebecausemotoneu- rones are closer to their discharge threshold. Lan- dau & Clare (1964) did not ﬁnd evidence for fusimo- tor hyperactivity, and assumed, in accordance with ‘the law of parsimony’, that hyperexcitability of ␣ motoneurones was sufﬁcient to account for spasti- city. Hyperexcitability of ␣motoneurones may result Spasticity 561 PAD INs α MN γ MN PAD INs PN Feedback inhib. IN Ib IN RC Ia II Ib Descending tracts NA Cutaneous Joint Fig. 12.1. Sketch of some spinal pathways that underlie the stretch reﬂex exaggeration in spasticity. Excitatory synapses are represented by Y-shaped bars and inhibitory synapses by small ﬁlled circles, excitatory interneurones by open circles and inhibitory interneurones by large ﬁlled circles. ␣ and ␥ motoneurones (MN) of a muscle, and Renshaw cells (RC) sketched in black. Ia afferents with their presynaptic inhibition (PAD INs) sketched in continuous red. Group II afferents with their presynaptic inhibition (PAD INs) sketched in dotted blue. Ia and group II afferents converge onto propriospinal neurones (PN) and feedback inhibitory interneurones (inhib. IN) inhibiting PNs. Group II afferents also have monosynaptic projections on ␥ MNs (projections of PNs on ␥ MNs have been omitted). Ib afferents (dashed) and Ib inhibitory INs sketched in brown. Cutaneous and joint afferent exciting ␥ MNs sketched in dotted pink (with a normal tonic descending inhibitory control in green). Descending tracts controlling transmission in spinal pathways sketched in green. Noradrenergic (NA) gating from the brainstem of the transmission of group II excitation (exerted pre- or post-synaptically) sketched in dashed green. The double-headed horizontal dashed arrow indicates the lesion interrupting the descending projections. fromchanges inthe intrinsic properties of motoneu- rones associated with loss of activity due to inter- ruption of the motor command (see p. 572), and/or imbalance between excitatory and inhibitory inputs fromdescending tracts. Inanimal experiments, such an imbalance occurs following anaemic decerebra- tion (producing so-called ‘␣ rigidity’, which persists despite section of the posterior roots; see Pollock & Davis, 1931). There is currently no method that allows the selective assessment of ␣ motoneurone 562 Pathophysiology of movement disorders excitability in humans, and a change in the baseline excitability of ␣ motoneurones can only be inferred by elimination of other possibilities by appropriate control studies. Increased H reﬂex Increased excitability of ␣ motoneurones can be inferred when an increase in the H reﬂex cannot be explained by a change in transmission of the afferent volley of the reﬂex. To do this requires elimi- nationof: (i) mechanisms actingontheIavolley(pre- synaptic inhibition of Ia terminals with PAD, post- activation depression, oligosynaptic propriospinal transmission); (ii) mechanisms that help limit the size of the H reﬂex (Ib inhibition, pp. 14–16); and (iii) changesinmotoneuroneexcitabilityduetoalter- ations in tonically transmitted effects (e.g. group II excitatory effects produced by the posture in which the reﬂex is explored, release of Ib excitation, sup- pression of reciprocal Ia inhibition). Hence, an increase in the H max /M max ratio by itself does not establish increased ␣ motoneurone excitability. Sev- eral methodshavebeenproposedtoassesstheextent to which H reﬂexes are increased. (i) TheH max /M max ratiointhesoleus is consistently increased with respect to healthy subjects (e.g. Angel & Hoffmann, 1963; Landau & Clare, 1964; Sommerville & Ashby, 1978; Delwaide, 1985a, 1993; Yanagisawa et al., 1993; Ongerboer de Visser et al., 1993; Faist et al., 1994; Aymard et al., 2000). Because of the large interindividual variability dueinpart tothedecreaseintheratio withage, thereis apoor correlationbetweenthis ratio and clinical spasticity. (ii) The threshold of the H reﬂex is decreased with respect to that of the Mwave. However, this fac- tor is correlated even less well with spasticity than the H max /M max ratio (Angel & Hoffmann, 1963; Yanagisawa et al., 1993). (iii) The ratio of the developmental slope of the H reﬂextotheslopeof theMwave(Hslp/Mslp) has been recently proposed. This ratio is increased in stroke patients and may be better correlated to spasticity (Higashi et al., 2001). (iv) When investigating the recovery cycle of the H reﬂex (pp. 10–11), it has beenclaimed that spas- tic patients have a quicker and higher initial peak of recovery (the ‘secondary facilitation’ at ISIs > 150ms) thannormal subjects. This abnor- mality of the recovery cycle was taken as a sign of increased ␣ motoneurone excitability (e.g. Magladery et al., 1952; Olsen & Diamantopou- los, 1967; Garcia-Mullin & Mayer, 1972). How- ever, it has been recently suggested that this apparent abnormalitywas simplyduetothefact that larger reﬂexes were used in the studies on spastic patients (Kagamihara et al., 1998). Increased F waves An increased mean F wave amplitude has been described in spasticity, with values above 10% of M max , instead of below 5% as in normal subjects (Schiller & St˚ alberg, 1978; Eisen & Fisher, 1999). The duration and persistence was of the F wave are also increased in patients with stroke (Milanov, 1992) and spinal cord injury (Dressnandt, Auer & Con- rad, 1995). However, these ﬁndings are not constant since, in other studies in spastic patients, the ampli- tude of the F wave was not altered and its persis- tence was either increased (Eisen & Odusote, 1979) or unchanged(Tsai, Chen&Chang, 2003). It has been claimed that the F wave would provide a better mea- sure of motoneurone excitability than the H reﬂex, because its amplitude, a priori, does not depend on the transmission of the afferent volley (Delwaide, 1985a, 1993; Milanov & Georgiev, 1994). However, several factors limit the size of the F wave in spas- tic patients and probably account for the inconsis- tencyof theincreasedamplitudeandduration: (i) the sensitivity of the F response to changes in motoneu- rone excitability is ten times less than that of the H reﬂex (see p. 23); (ii) an H reﬂex discharge protects motoneurones fromantidromic invasion, sothat the increased H reﬂex occurring with higher motoneu- ronal excitability would decrease the number of motoneuronesthat couldproduceanFresponse(see pp. 23–4); and (iii) the antidromic motor discharge which evokes the F wave activates Renshaw cells, Spasticity 563 and the increased recurrent inhibition observed in most spastic patients (see p. 569) could oppose the increased motoneurone excitability. (Note, however, that this last point cannot beafactor withdistal mus- cles becausetheir motor axons donot haverecurrent collaterals.) Plateau potentials Motoneurones in reduced animal preparations can develop plateau potentials which amplify their response to synaptic drive and can lead to peri- ods of sustained motor output. Plateau potentials have been documented in motoneurones of chronic spinal rats and may be an important factor in the associated spasticity. There is mounting evidence that plateau potentials can be induced in humans (see p. 20). Plateau-like behaviour can be recorded in spinal cord-injured patients, where it could con- tribute to a patient’s clinical manifestations, and in particular spasticity (Gorassini et al., 2004; Nickolls et al., 2004). In this respect, it is of interest that the depression by baclofen of both spasticity and the H reﬂex has been ascribed to direct depression of motoneuronal excitability (Azouvi et al., 1993; Ørsnes et al., 2000), and this drug has been shown to inhibit plateau potentials in animals (Russo, Nagy &Hounsgaard, 1998). One group reports that, if any- thing, plateau-like behaviours are less easy to record in spinal cord-injured patients than in normal sub- jects (Nickolls et al., 2004). However, this could have beendue toa limitationof the technique of inducing such behaviour, and the role of plateau potentials in spasticity remains to be clariﬁed. Certainly in the chronic spinal rat, plateau potentials seem to play a signiﬁcant role in spasticity (Bennett et al., 2001, 2004) and this may also be so in patients (Gorassini et al., 2004). Changes in axonal excitability Chronic changes in the excitability and activity of the motoneurone will lead to changes in the expres- sion of conductances and pumps on the motoneu- rone, and it is a reasonable assumption that there might be changes in the excitability of motor axons reﬂecting these changes. Accordingly, in patients with amyotrophic lateral sclerosis, evidence has been presented suggesting a decrease in voltaged- gated K ÷ conductances (Bostock et al., 1995) and an increase in persistent Na ÷ conductances (Mogyoros et al., 1998). However, whether these changes reﬂect the upper motoneurone abnormality or the lower motoneurone abnormality has not been clariﬁed. In patients hemiparetic following a hemispheric stroke thereis evidenceof adecreaseininwardrectiﬁcation due to diminished activity of the hyperpolarisation- activated cation conductance, I H (Jankelowitz et al., 2004). These changes occured in motor axons on the paretic side only. They were signiﬁcant when the ﬁndings for the two sides were compared and when the pathological side was compared with con- trol data for healthy age-matched volunteers. There were no such changes in cutaneous afferents in the same nerve. Conclusions There are no methods to allow the assessment of hyperexcitability of ␣ motoneurones in human experiments. Most experiments using the H reﬂex have neglected to ensure that there were no asso- ciated changes in transmission in spinal pathways. Because it is probable that the excitability of ␣ motoneurones as assessed by the F wave is under- estimated, an increase in amplitude, duration and persistence of the F wave in spastic patients might be a better argument in favour of ␣ motoneu- rone hyperexcitability. To sum up, hyperexcitability of ␣ motoneurones has never been demonstrated unequivocally, although it is likely. Increased fusimotor activity If there were heightened fusimotor drive, particu- larly ␥ d , the response of primary endings to stretch would be increased. As a result, the enhanced Ia dis- charge would produce an increased stretch reﬂex and exaggerated tendon jerks. As with the hyper- excitability of ␣ motoneurones (see above), that of 564 Pathophysiology of movement disorders ␥ d motoneurones might result fromchanges in their intrinsic properties following their inactivation due tothe impairment of the motor commandand/or an imbalance between excitatory and inhibitory inputs from descending tracts. Fusimotor overactivity as a cause of spasticity was a popular hypothesis in the 1960s This was primarily because of the superﬁcial resem- blance of human spasticity to decerebrate rigidity in the cat, in which heightened fusimotor tonus con- tributes to the exaggeration of the stretch reﬂex (see above). Arguments from human experiments were then presented to support this view: (i) Thetendonjerkwas foundtobemoreenhanced than the H reﬂex in the soleus of spastic patients, a ﬁnding that was attributed, not unreasonably at the time, to the fact the H reﬂex bypasses the muscle spindle while the tendon jerk does not (Dietrichson, 1973). However, we now know that the two reﬂexes differ in so many other respects that comparison of them as a measure of fusimotor function is invalid (see pp. 117–18). (ii) Spasticity can be reduced by a block of small ﬁbres using local anaesthetics (Dietrichson, 1973), but, in human subjects, local anaesthetic nerve blocks cannot produce selective de-efferentation of muscle spindles (see pp. 118–19), and the reduction of spasticity might have been due to a reduction in the afferent trafﬁc entering spinal cord circuits. (iii) The failure of the Jendrassik manoeuvre to potentiate the tendon jerk of spastic patients was attributed to an inability to increase further an already high level of background fusimotor activity (Buller, 1957; Dietrichson, 1971); however, the view that the Jendrassik manoeuvre potentiates tendon jerks through activation of ␥ d motoneurones is seri- ously ﬂawed (see pp. 131–3). When examining fusimotor drive in spastic patients, it is pertinent to ask two questions: (i) Is increased fusimotor drive sufﬁcient to cause spasticity? (ii) Does increasedfusimotor driveoccur inspastic patients? The answer to the ﬁrst question is no: without other changes in the nervous system, increased fusimotor drive cannot cause spasticity. Vibration canproduceamoreintensespindledischargethanis ever seeninhumansubjects, bethey normal or spas- tic. At most, the vibrationwill produce a TVRbut that can be readily controlled by normal subjects. Typi- cally spastic patients cannot control the TVR, and this points to a defect in the control of spinal path- ways in these patients. These arguments have been presentedelsewhere(Burke, 1980, 1983). Theanswer to the second question is probably yes, at least in some patients, and the question is then the extent to which fusimotor overactivity can contribute to the patient’s deﬁcit. Animal models Evidence for fusimotor overactivity has not been found in animal models designed to reproduce the deﬁcits seen in patients, e.g. ablation of areas 4 and 6 in monkeys (Gilman, Lieberman & Marco, 1974), medullary pyramidotomy in monkeys (Gilman, Marco & Ebel, 1971), various spinal and cerebral lesions in monkeys (Meltzer, Hunt & Landau, 1963), chronic spinal transectionincats (Bailey, Lieberman & Kitchell, 1980), and chronic spinal hemisection withterminal transectioninmonkeys andcats (Fuji- mori et al., 1966; Aoki, Mori & Fujimori, 1976). Recordings from spindle afferents Evidence for fusimotor overactivity has not been found in recordings made from spindle afferents in triceps surae and forearm extensor muscles of hemiplegic patients (see p. 139). In neither muscle were the background discharge and the response to stretchfor spindleendingsinrelaxedmusclesgreater than those in control subjects. These results argue against a contribution of ␥ d overactivity to spastic- ity, but it would be imprudent to discard completely heightened fusimotor excitability as a possible con- tributing factor to spasticity: (i) only in two patients Spasticity 565 were triceps surae afferents so explored; (ii) in the upper limb, spasticity is preferentially distributed on forearm ﬂexors, not extensors; (iii) recordings have only been made in stroke patients, and not in patients with cerebral palsy or spinal cord injury in whom the contribution of exaggerated stretch reﬂexes to motor disability of patients is more likely; (iv) results obtained with monoamines in paraspas- tic patients suggest that theactivationof ␥ motoneu- rones by the stretch-induced group II volley could be a factor in the exaggeration of the stretch reﬂex of such patients (see Chapter 7, p. 325, and p. 581). Conclusions The arguments in favour of fusimotor overactivity are seriously ﬂawed. On the other hand, the absence of evidence for this mechanism in recordings from muscle spindles needs conﬁrmation from a greater number of patients, in particular, frompatients with spinal cord injury. Fusimotor overactivity is not the primary abnormality driving spasticity; the extent to whichit contributes tothedeﬁcit of patients remains an open question (see p. 140). Decreased presynaptic inhibition of Ia terminals with PAD A decrease in presynaptic inhibition of Ia terminals would increase the efﬁcacy of the stretch-induced Ia volley in ﬁring motoneurones, and might there- fore be one of the spinal mechanisms underlying the stretch reﬂex exaggeration. Because presynaptic inhibition of Ia terminals with primary afferent de- polarisation (PAD) is subject to potent control from higher centres (p. 339; Fig. 12.1), it is conceivablethat a corticofugal lesion would alter the level of presy- naptic inhibition. It should be pointed out, however, that (i) decreased presynaptic inhibition of Ia termi- nals with PAD would have only a small effect on the reﬂex responses to abrupt stretch (see pp. 354–5); and (ii) no decrease in presynaptic inhibition of Ia terminals has been found in the chronic spinal cat (Hultborn & Malmsten, 1983b). Inhibition of the H reﬂex produced by prolonged vibration of the homonymous tendon does not assess presynaptic inhibition selectively It was postulated, not unreasonably at the time (Delwaide, 1973), and for long accepted that the degree of reﬂex suppression so produced faith- fully reﬂected the excitability of PAD interneurones mediating presynaptic inhibition of Ia terminals. Accordingly, the decreased reﬂex suppression seen in most spastic patients was thought to reﬂect a decrease in presynaptic inhibition of Ia terminals with PAD (Chapter 8, p. 368). In fact, when the conditioning and test volleys are both mediated by the same afferents, post-activation depression of transmission at the Ia-motoneurone synapse will depress the H reﬂex (Chapter 8, p. 341). The ﬁnd- ing that diazepam increases the vibration-induced suppression of the reﬂex (Delwaide, 1985a) sim- ply suggests that presynaptic inhibition of Ia ter- minals with PAD contributes to the reﬂex suppres- sion, not that it is the only mechanism underly- ing it. The problem is accentuated by the fact that post-activation depression is decreased in spastic patients (see below). The vibration-induced depres- sion of the H reﬂex cannot therefore be used to estimate presynaptic inhibition of Ia terminals with PAD. Suppression of the H reﬂex by a heteronymous group I volley The conditioning volley involves different afferents to the test Ia volley, and activates PAD interneu- rones mediating presynaptic inhibition of the ter- minals of the test volley so reducing the test H reﬂex (see pp. 341–5). The lower the excitability of PAD interneurones in patients, the smaller the reﬂexdepressionwithrespect tocontrols. For clinical studies, electrically induced D1 inhibition is a suit- able method, at least at rest (Chapter 8, pp. 343–4). In the lower limb, the soleus H reﬂex is conditioned by a peroneal volley (train of three shocks, 300 Hz, 1.2 MT, 21 ms ISI between the ﬁrst shock of the train and the test stimulus). In the upper limb, the 566 Pathophysiology of movement disorders FCR H reﬂex is conditioned by a single shock to the radial nerve (0.95 MT, 13 ms ISI). Suppres- sion of the H reﬂex by a tap to the tendon of a het- eronymous muscle (40–60 ms ISI) is also a conve- nient method. In order to eliminate the possibil- ity of a change in recruitment gain of the reﬂex, the more demanding method of the heteronymous monosynaptic Ia facilitation of the H reﬂex may be used in parallel (the larger the facilitation, the smaller the presynaptic inhibition, cf. Chapter 8, pp. 345–7). Conclusions Investigations using homonymous vibratory inhibi- tion of the H reﬂex largely have overestimated the role of decreased presynaptic inhibition of Ia ter- minals in the exaggerated stretch reﬂex of spastic patients. As discussed below, the changes in pre- synaptic inhibition of Ia terminals with PAD are not uniform in spastic patients, and vary with the level of the lesion (e.g. they are absent in the lower limb of stroke patients, see p. 576). Moreover, sev- eral ﬁndings suggest that the changes in presynap- tic inhibition of Ia terminals observed in spastic patients could be an epiphenomenon that plays a limited, or no, pathophysiological role in spasti- city as assessed under resting conditions (Chapter 8, p. 370). Decreased post-activation depression at the Ia-motoneurone synapse When an impulse train is conducted, there is, at the Ia-motoneurone synapse, an early transient facil- itation, superimposed on a dominant depression (‘post-activation depression’) lasting several sec- onds (seepp. 96–9). Post-activationdepressionhelps to keep the efﬁcacy of the Ia ﬁbre-motoneurone synapse at a relatively low level. Decreased post- activation depression would increase the efﬁcacy of thestretch-inducedIavolleyinﬁringmotoneurones, and thereby would enhance the stretch reﬂex. Methodology The best method to assess the amount of post- activation depression is to measure the depressive effect of stimulus rate on the size of the test reﬂex: i.e. in practice, to compare the size of the H reﬂex when elicited repeatedly at rest at 0.1 and 0.5 Hz. The dramatic decrease observed at 0.5 Hz in normal subjects is muchless inthe lower and upper limbs of all testedspastic patients, regardless of the causative lesion (Chapter 2, pp. 97–9). Conclusions Although the phenomenon of post-activation depression has been known from the early 1950s, it has been neglected as a factor in spasticity. Instead, attention was focused on decreased presynaptic inhibition of Ia terminals, without realising that much of the depression of the H reﬂex following vibrationtothe homonymous tendonis actually due to post-activation depression, that post-activation depression is reduced in spasticity, and that this abnormality may be a major spinal mechanism underlying spasticity (Hultborn & Nielsen, 1998). If homonymous vibratory inhibition of the H reﬂex results mainly from post-activation depression, the hypothesis that decreased post-activation depres- sioncouldbeanimportant factor inspasticityis sup- ported by the observation that this formof vibratory inhibition decreases in parallel with the develop- ment of reﬂex exaggerationafter the causative lesion (Ashby, Verrier & Carleton, 1980). Increased oligosynaptic propriospinally mediated group I excitation Facilitation of transmission in oligosynaptic path- ways mediating group I excitation to motoneurones wouldassist inthe development of the stretchreﬂex. Cervical propriospinal neurones mediate an impor- tant part of the corticospinal command to upper limb motoneurones and also receive some excita- tion from group I afferents in the upper limb (see p. 460). Lumbar propriospinal neurones receivetheir Spasticity 567 main excitatory input from group I and group II muscle afferents (see p. 494). A number of different mechanisms could increase propriospinally medi- atedgroupI excitation: (i) Decreasedpost-activation depression at the synapses of peripheral afferents with lumbar propriospinal neurones is unlikely, because post-activation depression is only marginal at this synapse in normal subjects (see p. 310). (ii) A decrease in presynaptic inhibition of Ia terminals is possible. (iii) A decrease in the noradrenergic gating of group II excitation could indirectly be responsi- ble (Chapter 7, see p. 324). (iv) Changes in the corti- cospinal control of propriospinal neurones are likely (Fig. 12.1; p. 503). Methodology The best method to assess the excitability of lumbar propriospinal neurones bygroupI volleys is tomeas- ure the peak of early facilitation (10 ms ISI) of the quadriceps Hreﬂex produced by low-intensity com- monperoneal nerve stimulation(1 MT). The pero- neal propriospinally mediated group I excitation of quadriceps motoneurones is increased in spastic patients, regardless of the causative lesion. Given the convergence of group I afferents from quadri- ceps and the pretibial ﬂexors onto common lum- bar propriospinal neurones projectingtoquadriceps motoneurones (see p. 496), it has been suggested that the exaggeration of the homonymous stretch reﬂex, including the tendon jerk, in the quadriceps involved facilitation of these interneurones (see p. 324). Disruption of the strong corticospinal con- trol on feedback inhibitory interneurones inhibit- ing propriospinal neurones (Fig. 12.1) wouldexplain the facilitation of the transmission of group I pro- priospinally mediated excitation in spastic patients (see, pp. 322–4, 503). Propriospinal relay for upper limb motoneurones A greater part of the descending command to upper limb motoneurones is relayed through cervical pro- priospinal neurones in hemiplegic patients with poor recovery (see pp. 483–4). The easiest method toassess this increaseddescending excitationof cer- vical propriospinal neurones is to measure the sup- pression of the on-going EMG activity of ECR by a brief train of stimuli to the superﬁcial radial nerve (three shocks at 300 Hz at 0.5 MT, window of analysis 32–41 ms after the onset of the train, see pp. 458–9). If there were increased excitability of these neurones at rest, this might contribute to the stretch reﬂex exaggeration. Conclusions The contribution of heightened propriospinally mediated group I excitation to spasticity has been revealed only recently. This contribution is probably important regardless of the causative lesion, at least in the lower limb. Increased group II excitation Muscle stretchalsoactivates spindle secondary end- ings. The stretch-induced homonymous and het- eronymous group II discharges from leg muscles play a major role in the control of perturbations to normal upright stance (see pp. 312–14). Facilita- tion of the transmission of this group II excitation couldproduce exaggerationof the stretchreﬂex, and thereby contribute to spasticity. Facilitation of the transmission may result from a change in the corti- cospinal control of the relevant propriospinal neu- rones, and/or disruption of the normal noradren- ergic gating from the brainstem of transmission of group II excitation (Fig. 12.1). Methodology The best method to assess the transmissionof group II excitationis tomeasure the peak of late facilitation (15–20ms ISI) of thequadriceps Hreﬂexproducedby high-intensity common peroneal nerve stimulation (2–3 MT). Peroneal-induced early group I and late groupII excitations of quadriceps motoneurones are both increased in spastic patients, regardless of the causative lesion (see p. 322). In patients with spinal cord lesions, the contribution of increased group II 568 Pathophysiology of movement disorders excitation to spasticity could be ampliﬁed by the projections of lumbar group II interneurones to ␥ motoneurones, which would produce positive feed- back from spindle afferents to ␣ motoneurones (see below). This latter factor is not taken into account when group II excitation is assessed electrically, and this might explain the weak correlation between increased peroneal-induced group II excitation of the H reﬂex and the stretch reﬂex exaggeration (see see p. 325). Effects of monoaminergic agonists If an increase in the late peroneal-induced facilita- tion of the quadriceps H reﬂex reﬂected increased group II excitation, it should be suppressed by monoamine agonists, which selectively gate the transmission of this action. Note, however, that monoaminergic suppression is a condition neces- sarybut insufﬁcient byitself toattributeanincreased late facilitation of the reﬂex to increased group II excitation. Anormal groupII input reachinghyperex- citable␣motoneurones wouldproduceanincreased reﬂex facilitation, which would be similarly sup- pressed by monoamines. It is therefore important that changes produced by monoamine agonists in the group II excitation have been observed with- out changes in ␣ motoneurone excitability (see pp. 321–2). The concomitant monoaminergic depre- ssionof the groupI facilitationprobably results from the suppression of the background group II dis- charge from pretibial ﬂexors due to static stretch (Chapter 7, p. 324). Conclusions Despite the reservations expressed above about pathophysiological conclusions based on selective blockade of particular pathways, the reduction of spasticity produced by monoaminergic agonists is so complete that a contribution of group II excita- tion to spasticity is likely to be signiﬁcant. This con- tributioncould be particularly important inpatients with spinal cord lesions, because the lesion would disrupt the normal noradrenergic gating of group II excitation from the brainstem. Importantly, this component of spasticity can be treated selectively using monoaminergic drugs, such as tizanidine. Decreased non-reciprocal group I inhibition The adequate stimulus for Golgi tendon organs is not muscle stretch, to which they have a high threshold and rapid adaptation. However, (i) once a stretch reﬂex contraction occurs, autogenetic Ib inhibitionof motoneuronesmayhelplimit thereﬂex, and (ii) interneurones mediating non-reciprocal group I inhibition are also excited from Ia afferents (see pp. 260–1). Interneurones mediating non- reciprocal group I inhibition are subjected to potent descending control (Fig. 12.1), and a change in this control (inhibition or disfacilitation) would make the non-reciprocal group I inhibition less effective in opposing spindle excitation when a muscle is stretched, again favouring the stretch reﬂex. Methodology The best method to assess the transmission of non- reciprocal groupI inhibitionis toassess the suppres- sion of the soleus H reﬂex produced by stimulation of the gastrocnemius medialis nerve (0.95 MT, 5 ms ISI). However, the reﬂex suppression so deter- mined is inconstant and, when present, is modest in normal subjects. This makes it difﬁcult to determine the signiﬁcance of a reduction of the suppression in patients (see p. 256). Change in Ib inhibition or in group I excitation? A decrease in Ib inhibition of the soleus H reﬂex has been reported in spastic patients, but this does not obligatorilyimplydecreasedtransmissionacross the Ib inhibitory pathway. The inhibition tends to be replaced by facilitation, and this could indicate that facilitated group I excitation (e.g. through pro- priospinal neurones, see above) overwhelms the Ib inhibition, whether or not there is decreased Ib inhi- bition (see p. 277). Spasticity 569 Conclusions A decrease in non-reciprocal group I inhibition might contribute to spasticity, but is probably not a major factor. Increased reciprocal Ib facilitation Oligosynaptic group I (‘Ib’) excitation between antagonists operating at the same joint is rare and weak in normal subjects (at least in the lower limb), possibly because the activity in the relevant path- wayisnormallysubjectedtostrongtonicsupraspinal inhibition (see p. 278). Disruption of this inhibitory control could result in facilitation of motoneurones and exaggeration of the stretch reﬂex. Methodology The best method to assess transmission in the path- way of Ib facilitation is to condition the soleus H reﬂex by a volley to the common peroneal nerve (1 MT, 2–4 ms ISIs). In spastic patients the reciprocal Ia inhibition is replaced by facilitation. Several lines of evidence suggest that this facilita- tion involves not only decreased reciprocal Ia inhi- bition (see below), but also increased Ib excitation (see pp. 277–8). The Ib facilitation appeared in par- allel with the development of hyperactive Achilles tendon reﬂexes, the only clinical ﬁnding that could be correlatedwiththe facilitation. Sucha correlation suggests that Ib facilitation could contribute to the development of spasticity (see p. 279). Mechanism of the facilitation Ib facilitation may be regarded as a ‘release phe- nomenon’ due to suppressionof either a descending tonic inhibitory control on Ib excitatory interneu- rones or of a facilitatory control on PAD interneu- rones mediating presynaptic inhibition of Ib affer- ents (see p. 278). However, here also, an alterna- tive possibility would be facilitated oligosynaptic group I excitation transmitted through lumbar pro- priospinal neurones (see above). Conclusions There is no experimental evidence that increased Ib excitationcontributes tospasticity, but this mechan- ism cannot be disregarded. Alterations in recurrent inhibition Renshawcells are subject to potent descending con- trols, bothexcitatoryandinhibitory(seep. 153). The- oretically, decreased recurrent inhibition could con- tribute tothe stretchreﬂex exaggerationthat charac- terises spasticity: activity of the motoneurone pool would then be less effectively opposed by recurrent inhibition, and a greater discharge would ensue. Methodology The best method to assess homonymous recurrent inhibition of soleus motoneurones is the paired H reﬂex technique (pp. 184–7). Increased recurrent inhibition Recurrent inhibition is commonly increased after corticospinal lesions, whether cerebral or spinal. In chronicspinal cats, thereis similarlyincreasedrecur- rent inhibition on the hemisected side (Hultborn & Malmsten, 1983b). The increased recurrent inhibi- tion implies that Renshaw cells are released from a descending tonic inhibitory control (see p. 186). This change is the opposite of that required for abnormal recurrent inhibitiontoplay a role inthe stretchreﬂex exaggeration of spasticity. Decreased recurrent inhi- bition has been claimed in spastic stroke patients, but this was due to a technique that tested not trans- missioninthe recurrent pathway but the excitability of the monosynaptic reﬂex arc (pp. 154–5). Conclusions Decreased recurrent inhibition at rest has been observed only in relatively rare patients with slowly progressive paraparesis (Chapter 4, pp. 184–6) and, in most cases, does not contribute to spasticity. 570 Pathophysiology of movement disorders Changes in reciprocal Ia inhibition Ia interneurones to ankle extensors probably receive tonic descending facilitation. The disfacilitation of these interneurones by the corticospinal lesion would remove a tonic inhibition on ankle extensor ␣ motoneurones, and thereby contribute to spasti- city (see p. 232). Methodology The best method to assess reciprocal Ia inhibition is to condition the soleus H reﬂex by a volley to the common peroneal nerve (1 MT, 2 ms ISI). Reciprocal Ia inhibition at rest At rest, reciprocal Ia inhibition of soleus is reduced and that to the pretibial ﬂexors is increased. Thus, corticospinal lesions release reciprocal Ia inhibi- tion from ankle extensors to ﬂexors and reduce the reciprocal Ia inhibition of ankle extensors, probably through mutual inhibition of opposite Ia interneu- rones (cf. Fig. 11.1(c)). This could contribute to the hyperexcitability of triceps surae ␣ motoneurones. Conclusions There is no experimental evidence that decreased reciprocal Ia inhibition of lower limb extensor motoneurones contributes to spasticity, but this mechanism cannot be disregarded. Reﬂex irradiation Reﬂex irradiation is common in spastic patients. It is associated with the transmission through skele- tal structures of a vibration wave set up by percus- sion of bone or tendon, so that spindles are acti- vated in muscles throughout the limb (Lance & de Gail, 1965). However, the widespread heteronymous Ia connections present in the upper and lower limbs also contribute to reﬂex irradiation and could be a more important mechanism (see p. 96). Conclusions concerning spinal mechanisms underlying spasticity Much of the evidence on which spinal mechan- isms have been implicated or not in spasticity was collected when techniques available to investigate transmissioninspinal pathways inmanwere intheir infancy. This has led to many fallacious interpret- ations, concerning, e.g. the role of the fusimotor system, presynaptic inhibition of Ia terminals and recurrent inhibition. The contribution of the differ- ent pathways to spasticity assessed under resting conditions, as it appears from the more recent data, may be summarised as follows. Several spinal mechanisms probably contribute to spasticity (i) Decreased post-activation depression is present whatever the causative lesion, and seems to be a major mechanism underlying spasticity. It may be the result of lack of use of the circuitry following the impairment of the descending command. (ii) Increased propriospinally mediated group I excitation is often found, and could contribute to spasticity. (iii) Increased transmission of group II excita- tion could be a major cause of spasticity in spinal cordlesions. Decreasedmonoaminergicgatingof the transmission of group II excitation would produce hyperexcitabilityof propriospinal neurones, andthis could be accentuated by the projection of lumbar propriospinal neurones to ␥ motoneurones. (iv) Changes in transmission in Ib pathways (decreased Ib inhibition, increased Ib excitation) have been reported, but their importance remains to be determined. (v) Decreased reciprocal Ia inhibition to extensor motoneurones may play a role, but its importance also remains to be determined. (vi) Decreased presynaptic inhibition of Ia ter- minals can occur but depends on the level of the lesion and, in any event, probably plays little role in the spasticity as assessed under resting conditions. Spasticity 571 (vii) Hyperexcitability of ␣ motoneurones has never been demonstrated unequivocally, although it appears probable. Other spinal mechanisms unlikely to contribute to spasticity (i) Fusimotor hyperactivity has beeneliminatedas a consistent pathophysiological mechanism, but it remains possiblethat reﬂexexcitationof ␥ motoneu- rones plays a signiﬁcant role in spasticity of patients with spinal cord lesions. (ii) Recurrent inhibition is, if anything, increased and does not contribute to spasticity, except in patients with slowly progressive paraparesis, where it is decreased. Whatever the spinal mechanism tested, no statistically signiﬁcant relationship has been found between the degree of abnormality and the intensity of the spasticity This is often taken as an argument to refute the con- tribution of a given mechanism to the exaggeration of the stretch reﬂex. However, a number of reasons make a signiﬁcant correlation unlikely. (i) Several pathophysiological mechanisms can contribute to spasticity, and they do not necessarily co-vary. (ii) Changes in one mechanism may act on motoneurones through different pathways (e.g. changes in presynaptic inhibition on Ia terminals may modify monosynaptic and oligosynaptic pro- priospinally mediated excitations and reciprocal Ia and non-reciprocal group I inhibitions). (iii) Different ﬁbres, with different presynap- tic controls, converge onto common interneu- rones (e.g. group I and group II afferents on lum- bar propriospinal neurones, Ia and Ib afferents on the interneurones of non-reciprocal group I inhibition). (iv) Conﬂicting results concerning some mech- anisms have been found with different causative lesions and, in many studies, spastic patients with different lesions were mixed together. (v) The number of patients tested in each investi- gation is often small. (vi) Changes in the stiffness of muscle must affect clinical assessments of spasticity as the resistance to passive stretch. The contribution of muscle stiffness may be signiﬁcant (see pp. 572–3). Why do spinal pathways malfunction? Abnormal descending control Because spinal pathways are under powerful control by descending tracts, it has long been thought that their dysfunctioninspasticity, muchas inthe animal decerebrate rigidity, resulteddirectly fromanabnor- mal descending control due to the interruption of the tonic activity of descending tracts. Thus, there wouldbeinhibitionor disfacilitationof thetransmis- sionininhibitory pathways, andfacilitationor disin- hibition of the transmission in excitatory pathways. As discussedabove, interruptionof various descend- ing tracts are likely to be responsible for the changes observed in many spinal pathways: PAD interneu- rones mediating presynaptic inhibition of Ia termi- nals, propriospinal neurones, group II pathways, Ib pathways, recurrent pathway, pathway of reciprocal Ia inhibition. Plastic changes Contrary to animal decerebrate rigidity, which is present as soon as anaesthesia wears off, spasticity takes weeks or months to develop. This gives time for synaptic rearrangements to occur at the spinal level. Thus, it is highly probable that, in addition to the ‘direct’ effects of the interruption of descend- ing tracts, lack of activity due to impairment of the descending motor command contributes to the increased resistance to stretch characterising spas- ticity. Several arguments support this view. 572 Pathophysiology of movement disorders Experimental support for ‘plastic’ changes After hemisection of the spinal cord in the rat and cat, Hultborn &Malmsten (1983a,b) observed below the lesion the expected increase in monosynaptic and polysynaptic reﬂexes with respect to the unaf- fected side, starting no later than 2 days after the lesion and lasting for at least 1 year. The impor- tant point is that the asymmetry persisted after acute spinal transection below the initial hemisec- tion, demonstrating that it was not a direct effect of disturbed descending control of spinal pathways, but the result of adaptive changes resulting from the loss of that control. They hypothesised that the partial denervation following the initial cord hemi- section would lead to supersensitivity of the post- synaptic membrane and a stronger response to the – still unchanged – presynaptic activity in the remaining ﬁbres. Later, the supersensitivity would subside as intact ﬁbres sprouted to form new synapses at vacant sites. The new synapses would, in turn, give permanently enhanced input from the remaining ﬁbres. Hyperexcitability of ␣ motoneurones The above changes could result in hyperexcitability of αmotoneuronesafterchroniclesionsof thecentral nervous system, though they have not been demon- strated unequivocally yet (see pp. 560–3). Similar plastic changes could also affect the excitability of ␥ motoneurones and various interneurones. Decreased post-activation depression at the Ia-motoneurone synapse Several lines of evidence, including the time course of the development of spasticity after the causative lesion, suggest that the development of adap- tive changes in the efﬁcacy of the Ia-motoneurone synapse follows the changes in activity of motoneu- rones and Ia ﬁbres associated with the impaired motor command (see pp. 99–100). Prevention of plastic changes Inspastic patients receiving frequent peroneal nerve stimulation (‘functional electrical stimulation’ using an external peroneal stimulator to assist walking), peroneal reciprocal Ia inhibition of the soleus H reﬂex, which is markedly reduced in such patients (see p. 570), was as pronounced as in normal sub- jects. The patients did not differ from the other patients in their degree of spasticity or other clinical features. This suggests that regular peroneal nerve activationis important for the maintenance of activ- ity in the spinal pathway of reciprocal Ia inhibi- tion. It may be assumed that decreased transmis- sion in other pathways mediating inhibitory effects, whether acting presynaptically (PADinterneurones) or postsynaptically (e.g. Ib inhibitory interneu- rones), canalsoresult fromnon-utilisationfollowing the motor impairment. Conclusions The loss of the normal tonic descending (in particu- lar corticospinal) control of various spinal pathways plays a role in the abnormal transmission observed in these pathways after a corticospinal lesion. How- ever, there is some evidence that lack of activity of these pathways results in denervation supersensi- tivity and collateral sprouting and contributes fur- ther to the malfunction. This evidence is important because it has implications for the rehabilitation of spastic patients. Changes in the intrinsic properties of muscle ﬁbres (contracture) Another type of plastic change concerns the muscle itself and is often referred to as ‘contracture’. Alter- ations in muscle ﬁbres are probably not related only to inactivity of the muscle, but could also result from inactivity of motoneurones (see Dietz, 1992). As pos- tulated from animal experiments (Buller, Eccles & Eccles, 1960), it is possible that, in motoneurones deprived of their supraspinal control, changes in Spasticity 573 trophic inﬂuences fromthe motoneurone transform muscle ﬁbres. Arguments against a signiﬁcant contribution of the stretch reﬂex to the passive resistance to stretch Dietz and colleagues investigated triceps surae of stroke patients during the stance phase of gait (for reviews, see Dietz, 1992, 2003). In the 1980s, they foundthat, innormal subjects andonthe unaffected side of stroke patients, the tension developed by tri- ceps surae correlated with the modulation of on- going EMG activity. However, on the spastic side, it was associated with a tonically low-amplitude acti- vation of the triceps surae due to passive stretching. Onthis side, thespinal stretchreﬂexgeneratedonlya small part of the overall muscle activity, and this was reduced compared to healthy subjects, and under- went reduced modulation during the gait cycle. Mechanical properties of muscle The above changes were taken as suggestive of alter- ations in the mechanical properties of muscle ﬁbres on the spastic side, and several lines of evidence supported this hypothesis: (i) investigations of sin- gle motor units revealed prolonged twitch contrac- tion times; (ii) experiments using stretches applied by a torque motor suggested a peripheral contri- bution to increased muscle tone; and (iii) morpho- metric and histochemical investigations of spastic leg muscles revealed changes in muscle ﬁbres that were speciﬁc to the spastic muscle (for review, see Dietz, 1992). A number of authors have emphasised that the increased resistance to passive stretch of contracting upper and lower limb muscles in stroke patients cannot be explained by increased EMG activity in the relevant muscle, and that increased spinal stretch reﬂex activity played a minor role in the genesis of the ‘spasticity’ in these patients (e.g. Davies, Mayston & Newham, 1996; O’Dwyer, Ada & Neilson, 1996; Sommerfeld et al., 2004). In relaxed muscles, the increase in tone is associated with an exaggerated reﬂex EMGresponse, but it is likely that this is insufﬁcient by itself to produce the increase in tone, i.e. that thepassivestiffness of non-contracting muscle is also increased. Clinical assessments of spasticity The Ashworth score is not the ideal tool to assess spasticity, because the resulting measure involves both the neural stretch reﬂex activity which is velocity-dependent andthe contracture whichis not (Vattanasilp, Ada &Crosbie, 2000). The Tardieu scale may be better at identifying a neural component to stiffness because the test involves moving the limb at different velocities and comparing the difference intheresponse(Tardieu, Shentoub&Delarue, 1954). An English translation of this work is now available (Boyd et al., 1998). Changes in muscle properties must be distinguished fromﬁbrosis contracture Fibrosis contracture is the common form of muscle shortening, that inevitably follows prolonged ﬁxa- tionandcompleteinactivityof anormallyinnervated muscle (as inbrokenlimbimmobilisedby cast). This ﬁbrosis contracture complicates both weakness and spasticity, and must be prevented by appropriate physiotherapy withpassive stretching of the affected muscles. Conclusions Dietz’s view of ‘spasticity located in the muscle’ has long been an isolated view that was eccentric and was expressed perhaps a little dogmatically. How- ever, thereisgrowingevidencethat, instrokepatients at least, increased resistance to passive stretch is due not only to increased reﬂex activity but also to changes in the intrinsic properties of muscle. Changes in spinal pathways during movements in spasticity Often, discussions about the pathophysiology of spasticity have been centred on the stretch reﬂex 574 Pathophysiology of movement disorders exaggeration passively produced at rest. However, as discussed above (see pp. 558–60), the important question for the patient (and the neurologist) is the extent to which stretch reﬂexes in an antagonistic muscle prevent the agonist from moving the limb during an intended movement. Because the mech- anisms involved in gait or performing a voluntary movement alter thegainof thestretchresponses (see Chapter 11), theamplitudeof theresponsetopassive stretch is a poor indicator of the amount of restraint imposed by spastic antagonists during an intended movement. Thus, for example: (i) even when there is abnormal stretch reﬂex activity under relaxed con- ditions in stroke patients, stretch reﬂexes evoked in voluntarily active muscles under conditions simu- lating walking are of similar magnitude as in normal subjects (Ada et al., 1998); (ii) in patients with mul- tiple sclerosis or focal spinal cord injury, baclofen was found to suppress passive stretch responses in the quadriceps without appreciably changing the amount of inappropriate activity during voluntary ﬂexion of the knee at the same angular velocity (McLellan, 1977). The contribution of spasticity to motor impairment depends not only on the hyper- excitability of the stretch reﬂex but also, and per- haps more, on alterations in the many mechanisms that normally control the relaxation of antagonists (see Chapter 11, pp. 519–20, 524–6) and ensure the smoothness of the movement. Thus, several mech- anisms, which are of little importance under rest- ing conditions, may restrain intended movements because they are deprived of their normal descend- ing control during voluntary contraction. Evidence for abnormal reciprocal inhibition Evidence for abnormal relaxation of the antag- onist during voluntary contraction of knee mus- cles has been sought in patients with multiple scle- rosis and focal spinal cord injury. Responses to stretch in quadriceps and hamstrings were present at rest, suppressed by voluntary effort in patients with mild spasticity, but enhanced in severe spas- ticity (McLellan, 1977). This ﬁnding was conﬁrmed by Knutsson, M˚ artensson & Gransberg (1997), who showedthat concentriccontractionsof kneemuscles at high velocity were disrupted by a stretch reﬂex in the antagonistic muscle. The appearance of this stretch reﬂex attests that reciprocal inhibition from agonist to antagonist motoneurones is reduced dur- ing dynamic actions involving strong effort. In con- trast, increased reciprocal inhibition in the opposite direction, i.e. from stretched antagonists to volun- tarily activated agonist motoneurones, may accen- tuate the weakness of paretic muscles (Knutsson, M˚ artensson & Gransberg, 1997; see also Yanagi- sawa, Tanaka & Ito, 1976). Changes in transmis- sion in several spinal pathways may contribute to this abnormal reciprocal inhibition. They have been investigated mainly at ankle level and are discussed below. Alteration in transmission in spinal pathways during attempted movements Reciprocal inhibition The absence of a contraction-associated increase in reciprocal inhibition directed to motoneurones of the antagonistic muscle, whether reciprocal Ia and/or propriospinally mediated inhibition (see below), could be a major factor in the unwanted stretch reﬂex activity triggered by contraction of the agonists in spastic patients (see above). Such unwanted stretch reﬂexes might explain some of the functional disabilities of patients with spasticity, in particular inpatients with spinal cord injury or cere- bral palsy. An increase in peroneal reciprocal Ia inhibition of the soleus H reﬂex occurs consistently at the onset of voluntary dorsiﬂexion in healthy sub- jects, but not in spastic patients with multiple sclerosis (Morita et al., 2001; see pp. 231–2). The absence of the normal increase in reciprocal Ia inhibition may be due to several mechanisms (see Fig. 11.1(c)). (i) Ia interneurones do not receive their corti- cospinal drive. (ii) They do not receive their Ia input because of a loss of the descending drive to ␥ motoneurones and/or of the descending suppression of presynap- tic inhibition on Ia terminals on tibialis anterior- coupled Ia interneurones (see below). Spasticity 575 (iii) Recurrent inhibition of Ia interneurones acti- vated by the natural motor discharge is no longer disinhibited (see below). (iv) InhibitionfromoppositeIainterneuronesacti- vatedbytheIadischargefromtheantagonisticsoleus can manifest itself because this Ia input is no longer gated by increased presynaptic inhibition. Ontheother hand, propriospinally mediatedinhi- bition is a major mechanism in the relaxation of the antagonists (Chapter 11, pp. 519–20). There are, so far, no experimental data on this pathway in spastic patients, but it is likely that the suppression of the descending drive to the relevant interneurones (as on Ia inhibitory interneurones) also helps prevent relaxation of the antagonists in these patients. Presynaptic inhibition of Ia terminals Changes inpresynaptic inhibitionmay contribute to restraining voluntary movements and gait in spas- tic patients, eventhoughpresynaptic inhibitionof Ia terminals is not or is only slightly altered at rest (see p. 566). Normally during movement the descending modulation of PAD interneurones enhances presy- naptic inhibition on Ia terminals on motoneurones antagonist to the contracting muscle (p. 361). This modulation is lost in spastic patients (see p. 370), and this could contribute to the occurrence of a stretch reﬂex in the antagonistic muscle during vol- untary movement. Moreover, the absence of gat- ing of the Ia discharge from the antagonist allows activation of antagonist-coupled Ia interneurones and, through mutual inhibition of Ia interneurones (see Fig. 11.1(c)), this could contribute to reducing reciprocal Ia inhibition of antagonistic motoneu- rones. Abnormalities in the modulation of reﬂexes during gait, in particular in patients with spinal cord injury, probably result from a lack of modu- lation of presynaptic inhibition of Ia terminals (see pp. 370–1). Ib facilitation Increased Ib facilitation (p. 569) might also con- tribute to adverse co-contraction of antagonistic muscles during voluntary movement: the Ib dis- charge from Golgi tendon organs produced by the agonist contraction would produce Ib facilitation of antagonistic motoneurones. Recurrent inhibition Recurrent inhibition is increased or not modiﬁed in most spastic patients (see above). However, here again, the modulation of recurrent inhibition seen in normal subjects during movements is lost (see p. 187): (i) there is no facilitation of antagonist- coupled Renshaw cells, a process that normally helps curtail the stretch reﬂex in the antagonist; and (ii) recurrent inhibitionof Ia interneurones activated by the natural motor discharge is not suppressed. Conclusions The corticofugal lesion disrupts the command not only for the activation of the agonists, but also for the relaxation of the antagonists. Thus, the loss of the descending controls on spinal pathways that normally contribute to the relaxation of the antagonist during voluntary movement or gait can explain the unwanted stretch reﬂex activity trig- gered during intended movements, even though transmission in these pathways may not be altered at rest. Pathophysiology of spasticity after cerebral lesions Exaggeration of stretch reﬂexes in stroke patients The incidence of spasticity in stroke patients has been questioned recently. In a study of 95 stroke patients (Sommerfeld et al., 2004), only 19%of these patients had increased tendon jerks after 3 months, considerably less than in most other investigations. On the other hand, in accordance with classical data, the study of Thilmann, Fellows, & Ross (1993) on 63 stroke patients reported that Achilles and biceps brachii tendon jerks were increased signiﬁ- cantly in most patients, and that the tonic stretch 576 Pathophysiology of movement disorders reﬂex generally was increasedinthese muscles, even though there was a low correlation between this increase and the briskness of the tendon jerks. Changes in transmission in spinal pathways on the affected side of stroke patients The methods described on pp. 560–70 have shown that many spinal pathways malfunction in stroke patients. Hyperexcitability of the monosynaptic reﬂex arc (i) TheH max /M max ratiointhesoleusisconsistently increased on the affected side of stroke patients (e.g. Angel &Hoffmann, 1963; Landau &Clare, 1964; Sommerville & Ashby, 1978; Delwaide, 1985a, 1993; Yanagisawa et al., 1993; Ongerboer de Visser et al., 1993; Faist et al., 1994; Aymardet al., 2000). However, asmentionedonp. 562, changesinmanyspinal path- ways can alter this ratio, and an increase cannot be taken by itself as evidence of hyperexcitability of ␣ motoneurones. (ii) The H reﬂex of FCR is not increased signiﬁ- cantlyontheaffectedsideof strokepatients (Aymard et al., 2000). This suggests that the mechanisms tending to increase the FCR H reﬂex (decrease in presynaptic inhibition of Ia terminals and in post- activation depression, see below) must be coun- teracted by an inhibitory mechanism limiting the size of the FCR H reﬂex. It has been shown that, because of the rise time of the compound Ia EPSP, there is ample time for a disynaptic IPSP to sup- press the spike in the last motoneurones contribut- ing to the test reﬂex discharge (see pp. 9–10). Recur- rent inhibition could be a good candidate to do this, sincerecurrent inhibitionmay beincreasedinstroke patients (see p. 569) and, inFCRmore thaninsoleus, the H max response is generally obtained with stim- ulation that also evokes a direct M response. Thus recurrent inhibitionelicited by both the discharge of early orthodromically recruited motoneurones and by the antidromic volley due to direct stimulation of motor axons could prevent the recruitment of high- threshold motoneurones, so limiting the size of the H max . (iii) The increase in F-wave amplitude, duration and persistence (Milanov, 1992; Fierro, Raimondo & Modica, 1990) could provide an index of hyperex- citabilityof ␣motoneurones, but inconsistent results have been reported (Eisen & Odusote, 1979). (iv) Plateau-like behaviours have so far not been investigated in stroke patients. Fusimotor over-activity Evidence for ␥ over-activity was absent in record- ings made from spindle afferents in triceps surae andforearmextensor musclesof hemiplegicpatients (see p. 139). Presynaptic inhibition on Ia terminals (i) In the lower limb on the affected side, presy- naptic inhibition of Ia terminals, as assessed with two independent and reliable methods (heterony- mous IafacilitationandD1inhibition), is unchanged at rest (see pp. 368–9; Faist et al., 1994; Aymard et al., 2000). The decreasedsuppressionof the soleus H reﬂex produced by vibration of the homony- mous Achilles tendon (e.g. Delwaide, 1973, 1993; Delwaide & Pennisi, 1994; Ongerboer de Visser et al., 1993; Stein, 1995) does not reﬂect a change inpresynaptic inhibitionof Ia terminals and is prob- ably due to decreased post-activation depression at the Ia-motoneurone synapse (see p. 368). (ii) In contrast, in the upper limb on the affected side, presynaptic inhibition on FCR Ia terminals, as assessed with the D1 inhibition of the FCR H reﬂex, is signiﬁcantly decreased (Chapter 8, p. 369; Nakashima et al., 1989; Artieda, Queseda & Obeso, 1991; Aymard et al., 2000). The normal corticospinal control of PADinterneurones mediating presynaptic inhibition on Ia terminals on FCR motoneurones is facilitatory, and the decrease in presynaptic inhibi- tion of Ia terminals on FCR motoneurones observed after corticospinal lesions therefore suggests that the corticospinal control is exerted tonically (see pp. 369–70). Spasticity 577 Post-activation depression Post-activationdepressionis consistentlyreducedin boththe lower (soleus) andupper (FCR) limbs onthe affected side of stroke patients (p. 99; Aymard et al., 2000). As discussed above, the reduced depression may be a consequence of the lack of activity of the synapse due to the motor impairment. Lumbar propriospinal pathways Group I and group II excitations mediated through lumbar propriospinal neurones are increased on the affected side of stroke patients (p. 322; Marque et al., 2001; Maupas et al., 2004). Given the normally strong corticospinal control on feedback inhibitory interneurones inhibiting lumbar propriospinal neu- rones, disruption of this control by the corticospinal lesion could explain the facilitation of group I and group II propriospinally mediated excitations. Non-reciprocal group I (Ib) inhibition Ib inhibition is decreased (p. 276; Delwaide &Oliver, 1988). It is possible that the decreased inhibition results from an increased facilitation overwhelming the inhibition rather than a reduction in disynap- tic inhibition (see p. 568). Alternatively, the suppres- sion of the inhibition in patients with corticospinal lesions would suggest that there is normally tonic corticospinal facilitation of Ib interneurones. In the upper limb, the early phase of disynaptic radial- inducednon-reciprocal groupI inhibitionof theFCR H reﬂex is consistently decreased in patients with spasticity (Nakashima et al., 1989; Artieda, Quesada & Obeso, 1991), but not in patients with normal muscle tone or ﬂaccid hemiplegia (Nakashima et al., 1989). Reciprocal Ib facilitation Ib facilitation is increased (p. 277; Crone et al., 2003). The enhancedfacilitationhas beenregardeda ‘release phenomenon’ (cf. Yanagisawa, 1980), due to either suppression of a descending tonic inhibitory control on Ib excitatory interneurones or alterna- tively of a facilitatory control on PAD interneurones mediating presynaptic inhibition of Ib afferents. Reciprocal Ia inhibition Corticospinal lesions release reciprocal Ia inhibi- tion from ankle extensors to ﬂexors and reduce the reciprocal Ia inhibition of ankle extensors (Yanagi- sawa, Tanaka&Ito, 1976; Yanagisawa&Tanaka, 1978; Crone et al., 2003), probably through mutual inhi- bition of opposite Ia interneurones. The better the recovery, the greater the reciprocal Ia inhibition of the soleus H reﬂex (p. 230). Recurrent inhibition Recurrent inhibition is, if anything, increased (Katz & Pierrot-Deseilligny, 1982; p. 184). Conclusions In stroke patients, there is no evidence that hyperex- citability of ␥ motoneurones, decreased presynap- tic inhibition on Ia terminals or decreased recur- rent inhibition contribute to the exaggeration of the stretchreﬂexinthelowerlimb. Transmissionismodi- ﬁedintheother spinal pathwaysthat canbetested, in thedirectionthat wouldproduceincreasedexcitabil- ity of the reﬂex arc (see Table 12.1). Changes in transmission in spinal pathways on the unaffected side of stroke patients Abnormal transmission in some pathways Abnormal transmissioninsomespinal pathways has been described on the ‘unaffected’ side of patients with a unilateral focal lesion. (i) Incontrast withnormal subjects, theH max /M max ratio in the soleus may increase along with the static stretch of the triceps surae (Castaigne et al., 1966). (ii) Theresponseof thesoleus toimposeddynamic stretch is increased on the affected spastic side, but 578 Pathophysiology of movement disorders Table 12.1. Spinal mechanisms underlying spasticity in the lower limb of patients with stroke and spinal cord injury Stroke Spinal cord injury Exaggeration of facilitatory mechanisms: grey cells (‘facilitated’). Decrease of inhibitory mechanisms: grey cells (‘decreased’). Changes in recurrent inhibition in spinal cord injury are those observed during pro- gressive paraparesis. The number of asterisks indicates the presumed importance of the mechanisms in the genesis of the stretch reﬂex exaggeration. Although there is no direct evidence, hyperexcitability of ␣ motoneurones appears probable. There is also no direct evidence for hyperexcitability of ␥ motoneurones, but this remains a possibility in spinal cord injury, due to reﬂex activation from afferents (group II, cuta- neous, joint) projecting to␥ motoneurones. The decrease inIbinhibitioninpatients withspinal cordinjury is not signiﬁcant. Spasticity 579 is decreased on the apparently unaffected side. This depression diminishes over time, but is still present 1 year after stroke (Thilmann, Fellows &Ross, 1993). (iii) On the affected side the response to stretch in biceps brachii is enhanced and that in tri- ceps reduced with respect to normal subjects, but opposite results (decreased response in biceps and increasedresponse intriceps) are foundonthe unaf- fected side (Thilmann, Fellows & Garms, 1990). (iv) D1 inhibition of the FCR H reﬂex, reﬂecting presynaptic inhibition of Ia terminals, is decreased onthe unaffectedside, thoughtoa lesser extent than on the affected side (Aymard et al., 2000). (v) Reciprocal Ia inhibition from ankle ﬂexors to extensors is suppressed (Crone et al., 2003). Origin of the abnormalities on the unaffected side Slight weakness has also been reported in the unaffected upper limb, possibly reﬂecting ipsilat- eral corticofugal projections (see Gandevia, 1993). It is similarly tempting to attribute abnormalities in transmission in reﬂex pathways on the unaffected side to ipsilateral corticofugal projections. However, thealterationsof transmissionontheunaffectedside do not involve all spinal pathways. Thus, transmis- sion is unchanged on the unaffected side in several pathways in which it is altered on the affected side: (i) post-activationdepressionat theIa-motoneurone synapse (Aymard et al., 2000); (ii) propriospinally mediatedgroupI andgroupII excitations (Maupas et al., 2004); (iii) Ibinhibition(Delwaide&Oliver, 1988); and (iv) reciprocal Ib facilitation (Crone et al., 2003). The lack of change in these circuits might indicate that there is astrictly unilateral control fromthe con- tralateral hemisphere of the relevant interneurones (as is probably the case for propriospinal neurones). Alternatively, the abnormality on the affected side might be related to the lack of normal activity (as is likelytobethecasewithpost-activationdepression). Increased excitability of cervical propriospinal neurones There is evidence that the component of the descending command for movement relayed through cervical propriospinal neurones is greater on the affected side of stroke patients with poor recovery than in normal subjects (Mazevet et al., 2003; pp. 481–4). Reticulospinal pathways project to propriospinal neurones in the cat, and it is likely that analogous projections mediate the greater propriospinal contribution to movement in patients with a damaged corticospinal system. Unmasking and/or reorganisation of connections from the ipsilateral undamaged hemisphere to the reticular formation, resulting in increased efﬁcacy of retic- ulospinal projections to propriospinal neurones could account for the greater excitability of these neurones. The greater reliance on the propriospinal system for the movement repertoire of the upper limb would be accompanied by synkinetic move- ments in patients with poor recovery from stroke (see p. 484). Increased excitability of cervical pro- priospinal neurones activated by antagonistic group I volleys could also be a cause of disruption of the movement by an exaggerated stretch reﬂex in the antagonist. Spasticity in cerebral palsy In most patients with cerebral palsy, spasticity and athetosis are mixed. In these patients, there have been few investigations of transmission in speciﬁc spinal pathways, other than reciprocal Ia inhibition. The ﬁrst evidence for reciprocal Ia inhibition from ankle ﬂexors to soleus in humans was provided in patients with athetosis (Mizuno, Tanaka & Yanagi- sawa, 1971), in whom the inhibition was profound. Using PSTHs, Berbrayer &Ashby (1990) showed that reciprocal Ia inhibition from ankle extensors to tib- ialis anterior is also increased in patients with cere- bral palsy, whether they have mainly athetosis or spasticity. This contrasts with the reciprocal Ia exci- tation elicited in similar patients, at the latency of the monosynaptic reﬂex, by a tap to the antagonis- tic tendondescribedby Gottlieb&Myklebust (1993). However, spreadof themechanical stimulus toexcite receptors in the agonist and/or ﬁeld-spread of the EMG response from the agonist could also account for the latter ﬁnding (cf. Chapter 2, p. 86). 580 Pathophysiology of movement disorders Pathophysiology of spasticity after spinal lesions In many patients with spinal cord lesions the domi- nant reﬂex dysfunction is the exaggeration of ﬂexor reﬂexes, whose pathophysiology is discussed in Chapter 9. Such reﬂexes fall outside the deﬁnition of spasticity (see pp. 557–8), and are not considered here. Exaggeration of stretch reﬂexes in patients with spinal lesions There is no doubt that the exaggeration of stretch reﬂexes characterising spasticity may be a major cause of restraint to movement in patients with spinal cord lesions, such as hereditary spastic paraparesis (Str¨ umpell–Lorrain disease), progres- sive spinal cord compression, cervical spondylitic myelopathy and multiple sclerosis (which behaves like spinal spasticity, presumably because of the dif- fuse nature of the lesions). Such spinal cord lesions represent thebest indicationsforaspeciﬁctreatment of spasticity. Changes in transmission in spinal pathways in patients with spinal lesions Transmission is altered in all spinal pathways that have been investigated in these patients, always in the directionthat wouldexaggerate the stretchreﬂex (see Table 12.1). Hyperexcitability of the soleus monosynaptic reﬂex arc Hyperexcitabilityhasbeenfoundconsistently, asevi- denced by an increase in the H max /M max ratio (e.g. see Delwaide, 1993; Ongerboer de Visser et al., 1993) or in the F wave amplitude (Dressnandt, Konstanzer & Conrad, 1993). Plateau-like behaviours can be recorded in spinal cord-injured patients (Gorassini et al., 2004; Nickolls et al., 2004) but may be less easy to obtain than in normal subjects (Nickolls et al., 2004), at least with that paradigm. Fusimotor activity There are, as yet, nopublishedrecordings fromspin- dle endings in patients with spinal spasticity. Intu- itively, one might expect there to be disinhibition of reﬂex pathways acting on ␥ and ␤ motoneu- rones, such that normally innocuous stimuli such as stroking the skin would cause a heightened spindle discharge (cf. Fig. 12.1). If this proved to be the case, it is possiblethat theskin, bladder andbowel compli- cations of paraplegia would result in a steady affer- ent input to ␥ motoneurones in such patients, pro- ducing widespread ␥ activity even in the absence of EMGactivity. Similarly, stretch-inducedgroupII vol- leys, released from the monoaminergic gating from the brainstem, could play a major role in the spas- ticity of patients with spinal cord lesions by reﬂexly activating ␥ motoneurones (see below). Presynaptic inhibition on Ia terminals in the lower limbs Presynaptic inhibition is decreased in patients with focal spinal cord lesions (Faist et al., 1994), amy- otrophic lateral sclerosis (Pierrot-Deseilligny, 1990), and multiple sclerosis (Nielsen, Petersen & Crone, 1995). This cannot be due to the interruption of the corticospinal tract (which, if anything, would produce increased presynaptic inhibition of Ia ter- minals, given the normal inhibitory corticospinal control onPADinterneurones inthelumbar enlarge- ment). It therefore probably results from interrup- tionof other descendingpathways whichhelpmain- tainatoniclevel of presynapticinhibitionof Iatermi- nals innormal subjects under restingconditions (e.g. descending suppressionof inhibitory interneurones transmitting cutaneous inhibition of ﬁrst-order PAD interneurones, pathway [2] in Fig. 8.1. p. 338). Post-activation depression Post-activation depression at the Ia-motoneurone synapse is decreased in patients with spinal cord lesions duetotraumaticinjuryandmultiplesclerosis (Hultborn & Nielsen, 1998; see p. 99). 581 Propriospinally mediated group I excitation Oligosynaptic group I excitation is increased (Remy- N´ eris et al. 2003; p. 503), probably because of dis- ruption of the normal corticospinal control on feed- back inhibitory interneurones inhibiting lumbar propriospinal neurones. Group II excitation The ﬁnding that the increase in the late per- oneal group II excitation of the quadriceps gen- erally is much greater than the increase in the early group I excitation, suggests interruption of the normal monoaminergic gating of group II excita- tion from the brainstem (Remy-N´ eris et al., 2003; p. 324). Because the increase in peroneal excitation of quadriceps motoneurones is not correlated with spasticity, facilitation of the transmission in lumbar propriospinal pathways to ␣ motoneurones is likely tobeaccompaniedbychanges inother mechanisms, such as a parallel excitation of ␥ motoneurones by group II afferents (see p. 325). Ib inhibition Ib inhibition has been found to be only slightly decreased with respect to normal subjects (Downes, Ashby & Bugaresti, 1995; p. 276). Reciprocal Ib facilitation Ib facilitation is increased (Crone et al., 2003), probably the result of a ‘release phenomenon’ (pp. 277–9). Recurrent inhibition Variableresults havebeenobtained, accordingtothe nature of the causative lesion. (i) In patients with complete or partial spinal cordinjury, recurrent inhibitionisincreased(Shefner et al., 1992). (ii) Inpatients with progressive paraparesis, either amyotrophic lateral sclerosis (Raynor & Shefner, 1994) or hereditary spastic paraplegia (Mazzocchio &Rossi, 1997), recurrent inhibition is decreased and contributes to the stretch reﬂex exaggeration. In such cases, it is likely that the spinal lesion involves the descending inhibitory pathways less than the descending facilitatory pathways to Renshaw cells, so shifting the balance in favour of the former (see p. 186). Reciprocal Ia inhibition Reciprocal Ia inhibitionis decreasedfromankle ﬂex- ors to extensors in patients with multiple sclerosis. However, this is not a major factor in spasticity at rest, because repeated high-frequency stimulation of the peroneal nerve can lead to a normalisation of reciprocal inhibition, though this is not accom- panied by signiﬁcant changes in spasticity (Crone et al., 1994; p. 233). In patients with focal lesions, reciprocal Ia inhibition of the soleus H reﬂex is also decreased (Okuma, Mizuno & Lee, 2002), while it is increasedtoankledorsiﬂexors (Ashby&Wiens, 1989) (see pp. 230–2). Conclusions Not surprisingly, there are alterations in all spinal pathways in patients with spinal cord lesions. The dominant abnormalities are probably the decrease in post-activation depression and the decreased gating of group II excitation. Fromspinal shock to spasticity Adaptive changes in excitability of spinal neural cir- cuits below the level of a lesion have been investi- gatedfromspinal shock to spasticity inpatients with acute spinal cord injury (Hiersmenzel, Curt & Dietz, 2000). During spinal shock, the loss of tendon jerks was associatedwitha lowpersistence of Fwaves, but Hreﬂexes could still be elicited in soleus. During the transition to spasticity, the reappearance of tendon jerks was associatedwiththerecoveryof Fwaves, but 582 Pathophysiology of movement disorders the H max /M max ratio remained stable over months. A longitudinal study of one patient with spinal cord injury found that the reduction of post-activation depression developed with the transition from ﬂac- cid to spastic paralysis (Chapter 2, p. 100). Further studies are required of the evolution of the changes in transmission in speciﬁc spinal circuits, preferably longitudinal studies on individual patients. Conclusions Table 12.1 compares the spinal mechanisms under- lying spasticity in the lower limb of stroke and spinal cord injury patients (data in the upper limb are moresparseandhavebeenomitted). Post-activation depression at the Ia-motoneurone synapse is sim- ilarly reduced in the two groups of patients but, otherwise, abnormalities in spinal cord injury patients involve more spinal pathways and are more prominent. This is consistent with a greater contri- bution of spasticity to motor disability in patients with spinal cord lesions than in stroke patients. Parkinson’s disease Transmission in spinal pathways has been investi- gated inpatients with Parkinson’s disease less exten- sively and less thoroughly than in spastic patients. It would not be surprising if there were abnormal- ities due to defective supraspinal control of spinal circuits. Whether spinal mechanisms contribute to the disorder of parkinsonian patients at rest is not yet resolved, and the issue is complicated by incon- sistencies in the published ﬁndings. Possible mechanisms underlying Parkinsonian rigidity Rigidityis acardinal symptomof Parkinson’s disease, andis characterisedclinicallybyasustainedincrease in resistance to passive stretch of ﬂexor and exten- sor muscles throughout the full range of motion. Increasedmuscle stiffness due toalteredviscoelastic properties of muscle(cf. below) andinabilityof these patients to ‘relax’ and to eliminate entirely voluntary activation of the muscles are likely to be important variables in different studies (see below). Rigidity depends on the muscle afferent inﬂow, as demon- strated many years ago by the observation that it is abolished or markedly reduced by interruption of the inﬂow by section of the dorsal roots (Foer- ster, 1921) and by anaesthetic block of intramuscu- lar nerve terminals, sufﬁcient to abolish the tendon jerk, while leaving power intact (Walshe, 1924). The question then arises which afferents and which cen- tral pathways are involved in the production of the kamagra experience • • pharmacy 365 kamagra informed abo being taken by ut all the med the client, to ications decrease risk able drug inte s of undesirractions. ive heat. Som ications may e of these med cause fever and heat prostration environmental with high temperatures. In hot weather keep the client or climates, indoors and use during the hou air conditioning rs of highest hea or fans t levels. kamagra 247 co uk Nursing Notes: 1. What is the difference between local and systemic effects of drugs? 2. Can a client experience systemic effects of local drugs and local effects of systemic drugs? Why or why not? 3. Why is it helpful for nurses to know the generic names of commonly used medications? 4. Why is it helpful to study prototypes of drug groups? 5. List at least three strategies for studying pharmacology. 6. List at least three authoritative sources of drug information. kamagra online review Lipid-soluble drugs dissolve in the lipid layer of the cell membrane and diffuse into or out of the cell. kamagra como tomar free viagras TABLE 2–1 buy generic viagra 50mg Ibuprofen 800 mg every 4 hours Prednisone 5 mg daily Lasix 20 mg twice a day Captopril 25 mg twice a day Pepcid 20 mg at bedtime 77 buy viagra with echeck viagra gold for sale Pain Dysmenorrhea Osteoarthritis Rheumatoid arthritis and is excreted about equally through urine and feces. Piroxicam has a half-life of about 50 hours. The long half-lives allow the drugs to be given once daily, but optimal efﬁcacy may not occur for 1 to 2 weeks. Diclofenac sodium (Voltaren) is chemically different from but pharmacologically similar to other NSAIDs. Formulations are delayed or extended-release and onset of action is therefore delayed. Peak action occurs in about 2 hours and effects last 12 to 15 hours. The formulation of diclofenac potassium (Cataﬂam) is immediate-release; action starts quickly, peaks in about 20 minutes to 2 hours, and also lasts 12 to 15 hours. As a result, the potassium salt may be given for rapid relief of pain and primary dysmenorrhea. Diclofenac has a serum halflife of about 2 hours and is excreted mainly in the urine. Cyclooxygenase-2 inhibitors block production of prostaglandins associated with pain and inflammation without blocking those associated with protective effects on gastric mucosa. Thus, they produce less gastric irritation than aspirin and other NSAIDs. In addition, they are not associated with increased risks of bleeding because they do not have the antiplatelet effects of aspirin and other NSAIDs. Despite the rel- buy viagra without presciption (7) Nephrotoxicity—decreased urine output, increased blood urea nitrogen (BUN), increased serum creatinine, hyperkalemia, retention of sodium and water with resultant edema viagra sal decisions, and praise efforts to accomplish tasks. These actions promote a positive self-image. • When signs and symptoms of depression are observed, initiate treatment before depression becomes severe. Institute suicide precautions for clients at risk. These usually involve close observation, often on a one-to-one basis, and removal of potential weapons from the environment. For clients hospitalized on medical-surgical units, transfer to a psychiatric unit may be needed. discount 100mg viagra fects (eg, tachycardia, increased rate of respiration, agitation, tremors, convulsive seizures, sweating, heart block, hypotension, delirium, coma). Management consists of diuresis, acidiﬁcation of urine, or hemodialysis to remove the drug from the body. Bupropion overdose: Symptoms include agitation and other mental status changes, nausea and vomiting, and seizures. General treatment measures include hospitalization, decreasing absorption (eg, giving activated charcoal to conscious clients), and supporting vital functions. If seizures occur, an intravenous benzodiazepine (eg, lorazepam) is the drug of ﬁrst choice. Nefazodone or venlafaxine overdose: Symptoms include increased incidence or severity of adverse effects, with nausea, vomiting, and drowsiness most often reported. Hypotension and excessive sedation may occur with nefazodone, seizures and diastolic hypertension with venlafaxine. There are no speciﬁc antidotes; treatment is symptomatic and supportive. Lithium overdose: Toxic manifestations occur with serum lithium levels above 2.5 mEq/L and include nystagmus, tremors, oliguria, confusion, impaired consciousness, visual or tactile hallucinations, choreiform movements, convulsions, coma, and death. Treatment involves supportive care to maintain vital functions, including correction of ﬂuid and electrolyte imbalances. With severe overdoses, hemodialysis is preferred because it removes lithium from the body. cheap indian viagra online viagra online without prescription reviews NURSING ACTIONS NURSING ACTIONS brand viagra paypal Use in Renal Impairment generic viagra per pill CHAPTER 14 ANESTHETICS • • • • viagra seychelles chapter 16 Central Nervous System Stimulants viagra money pak female viagra buy in australia chapter 17 Physiology of the Autonomic Nervous System Critical Thinking Scenario Jill, 8 years old, is brought to the clinic for allergy desensitization. She is starting on a new concentration of allergy extract today. After her injection, as usual, you ask her to remain in the waiting room for 30 minutes. After 20 minutes, her mother comes to get you. Jill is restless, her voice is high-pitched, she feels odd, and her respiration rate has increased to 30 breaths per minute. Reﬂect on: ᮣ What data would you collect next? ᮣ How could you differentiate anaphylaxis from anxiety? ᮣ If Jill were experiencing an anaphylactic reaction, what would be the treatment of choice? pfizer viagra cheap online NE NE NE NE NE NE generic 50 mg viagra online 2 sprays/nostril of 0.03% spray bid–tid. cheap sydney viagra buy brand viagra australia Hormone Pharmacokinetics viagra with dapoxetine cheap hormones produced by the adrenal cortex. These hormones affect almost all body organs and are extremely important in maintaining homeostasis when secreted in normal amounts. Disease results from inadequate or excessive secretion. Exogenous corticosteroids are used as drugs in a variety of disorders. Their use must be closely monitored because the drugs produce profound therapeutic and adverse effects. To understand the effects of corticosteroids used as drugs, it is necessary to understand physiologic effects and other characteristics of the endogenous hormones. viagra online gr of amino acid transport to the liver and conversion to glucose. ↓Rate of new protein formation from dietary and other amino acids (antianabolic effect) The combination of ↑breakdown of cell protein and ↓protein synthesis leads to protein depletion in virtually all body cells except those of the liver. Thus, glycogen stores in the body are ↑ and protein stores are ↓. buy viagra online in canada paypal drugs. This condition is largely a glucocorticoid deﬁciency; mineralocorticoid secretion is not signiﬁcantly impaired. • Congenital adrenogenital syndromes and adrenal hyperplasia result from deﬁciencies in one or more enzymes required for cortisol production. Low plasma levels of cortisol lead to excessive corticotropin secre- SECTION 4 DRUGS AFFECTING THE ENDOCRINE SYSTEM generic viagra canada mastercard generic viagra without perscription Teriparatide (Forteo) is a recombinant DNA version of parathyroid hormone. It is approved for the treatment of osteoporosis in women. Other drugs for osteoporosis slow bone loss; teriparatide increases bone formation by increasing the number of bone-building cells (osteoblasts). It also increases serum levels of calcium and calcitriol (a metabolite of vitamin D that promotes absorption and use of calcium in bone-building). In clinical trials, it increased vertebral bone mineral density and decreased vertebral fractures. It is recommended for use in patients with severe osteoporosis or those who have not responded adequately to other treatments, partly because osteosarcoma developed in some animals given high doses for long periods. None developed in humans during clinical trials, but the longest of these trials was two years. Teriparatide is rapidly and well absorbed with subcutaneous injection. Bioavailability is 95% and peak serum levels occur in 30 minutes. The drug is metabolized and excreted through the liver, kidneys, and bone. It is not expected to accumulate in bone or other tissues, to interact signiﬁcantly with other drugs, or to require dosage adjustment with renal or hepatic impairment. Adverse effects include nausea, headache, back pain, dizziness, syncope, and leg cramps. 3. What are some nursing interventions to prevent hypocalcemia? 4. What signs and symptoms may indicate hypocalcemia? 5. How is hypocalcemia treated? 6. What signs and symptoms may indicate hypercalcemia? 7. How is hypercalcemia treated? 8. Why is it important to have an adequate intake of calcium and vitamin D throughout life? 9. What are the main elements of prevention and treatment of osteoporosis? viagra online sales in australia generic viagra aus Basil, which is commonly used in cooking, is also available as an herbal supplement. The amounts used in cooking are unlikely to affect blood sugar, but larger amounts may cause hypoglycemia or increase the hypoglycemic effects of insulin and oral antidiabetic drugs. The use of supplemental amounts should probably be avoided by people with diabetes. If used, blood glucose levels should be closely monitored. Bay leaf is commonly used in cooking (it should be removed from the food before eating) and is also available as an extract made with ground leaves. It increases the effects of insulin and is sometimes recommended by nutritionists for diabetic diets. If used, blood glucose levels should be monitored closely. Chromium is a trace mineral required for normal glucose metabolism. It may increase production of insulin receptors and insulin binding to the receptors, thereby increasing insulin effectiveness, lowering blood glucose levels, and decreasing insulin requirements in people with diabetes. It also may have beneficial effects on serum cholesterol levels. However, evidence for these effects is inconsistent, with some supporting and some negating the use of chromium supplements. • Check glycosylated hemoglobin reports when available. • Interview and observe for therapeutic and adverse responses to antidiabetic drugs. sexviagra viagra free sites computer edinburgh ✔ find sites computer shop viagra anterior pituitary gland. Progesterone also may help maintain pregnancy by decreasing uterine contractility. This, in turn, decreases the risk of spontaneous abortion. Progesterone, in general, has opposite effects on lipid metabolism compared with estrogen. That is, progestins decrease high-density lipoprotein (HDL) cholesterol and increase lowdensity lipoprotein (LDL) cholesterol, both of which increase risks of cardiovascular disease. Physiologic progesterone increases insulin levels but does not usually impair glucose tolerance. However, long-term administration of potent synthetic progestins, such as norgestrel, may decrease glucose tolerance and make diabetes mellitus more difficult to control. Like estrogen, progesterone is metabolized in the liver. is a conjugated estrogen (eg, Premarin) 0.625 mg to 1.25 mg daily for 25 days of each month, with a progestin, such as Provera, 10 mg daily for 10 days of each month, on days 15 to 25 of the cycle. The main function of the progestin is to decrease the risk of endometrial cancer; thus, women who have had a hysterectomy do not need it. Another regimen uses estradiol as a transdermal patch (Estraderm), which releases the drug slowly, provides more consistent blood levels than oral formulations, and is applied weekly. A newer synthetic conjugated estrogen (Cenestin) is also approved for short-term treatment of hot ﬂashes and sweating; it is not approved for long-term use in preventing osteoporosis in postmenopausal women. Prevention and Treatment of Osteoporosis Estrogen or estrogen/progestin therapy is effective and has been widely used to prevent or treat osteoporosis and prevent fractures in postmenopausal women (see Chap. 26). Estrogenic effects in preventing bone loss include decreased bone resorption (breakdown), increased intestinal absorption of calcium, and increased calcitriol concentration. Calcitriol is the active form of vitamin D, which is required for absorption of calcium. These hormones may be used less often for osteoporosis in future for two main reasons. First, recent evidence (see Box 28–2) indicates that the risks of estrogen/progestin hormonal therapy outweigh the beneﬁts. The effects of estrogen alone are not yet known. Second, there are other effective measures for prevention and treatment of osteoporosis, including calcium and vitamin D supplements, bisphosphonate drugs (eg, alendronate and risedronate), and weight-bearing exercise. xanax viagra diazepam * Weight ( pounds) BMI = 2 × 704.5 Height (inches) Example: A person who weighs 150 lbs. and is 5´5˝ (65 inches) tall: BMI = 150 lbs 105, 675 × 704.5 = = 25 4225 65 in × 65 in viagras effect on women Hypokalemia 1. Inadequate intake. Uncommon in clients who can eat; may occur in those unable to eat or receiving only potassiumfree intravenous ﬂuids for several days. 2. Excessive losses from the gastrointestinal tract (vomiting, gastric suction, diarrhea, overuse of laxatives and enemas) or urinary tract (polyuria from diuretic drugs, renal disease, excessive aldosterone) 3. Movement of potassium out of serum and into cells. This occurs with administration of insulin and glucose in treatment of diabetic ketoacidosis and in metabolic alkalosis. viagra weekenders Lead poisoning viagra testimony viagra suicide osmotically active alcohol that has a laxative effect. The sorbitol offsets the constipating effect of the resin and aids in its expulsion. Oral administration is preferred, and several doses daily may be given until serum potassium is normal. When given as an enema, the solution must be retained from 1 to several hours, or repeated enemas must be given for therapeutic effect. 5. If the preceding measures fail to reduce hyperkalemia, peritoneal dialysis or hemodialysis may be used. viagra specs SECTION 6 DRUGS USED TO TREAT INFECTIONS c. With carbapenems: (1) For IV imipenem/cilastatin, mix reconstituted solution in 100 mL of 0.9% NaCl or 5% dextrose injection. Give 250- to 500-mg doses over 20 to 30 min; give 1-g doses over 40 to 60 min. (2) For IM imipenem, inject deeply into a large muscle mass with a 21-gauge, 2-inch needle. (3) For IV meropenem, give as an injection (5–20 mL) over 3 to 5 min or as an infusion over 15 to 30 min. (4) For IV ertapenem, infuse over 30 min. d. With aztreonam: (1) For IM administration, add 3 mL diluent per gram of drug, and inject into a large muscle mass. (2) For IV injection, add 6 to 10 mL sterile water, and inject into vein or IV tubing over 3 to 5 min. (3) For IV infusion, mix in at least 50 mL of 0.9% NaCl or 5% dextrose injection per gram of drug and give over 20 to 60 min. e. With imipenem/cilastatin: IV: Mix reconstituted solution in 100 mL of 0.9% NaCl or 5% dextrose injection. Give 250- to 500-mg doses over 20 to 30 min; give 1-g doses over 40 to 60 min. IM: Inject deeply into a large muscle mass with a 21-gauge, 2-inch needle. 2. Observe for therapeutic effects a. Decreased signs of local and systemic infection b. Decreased signs and symptoms of the infection for which the drug is given c. Absence of signs and symptoms of infection when given prophylactically 3. Observe for adverse effects a. Hypersensitivity—anaphylaxis, serum sickness, skin rash, urticaria See Nursing Actions in Chapter 33 for signs and symptoms. Reactions are more likely to occur in those with previous hypersensitivity reactions and those with a history of allergy, asthma, or hay fever. Anaphylaxis is more likely with parenteral administration and may occur within 5 to 30 min of injection. Parenteral solutions are irritating to body tissue. See Chapter 33 for signs and symptoms. May occur with all beta-lactam drugs, especially with high oral doses Diarrhea commonly occurs with beta-lactam drugs and may range from mild to severe. The most severe form is pseudomembranous colitis, which is more often associated with ampicillin and the cephalosporins than other beta-lactams. See Chapter 33. viagra soft tabs generic 100mg Critical Thinking Scenario George Masury, accompanied by his wife Jennie, visits his primary care provider complaining of upper respiratory symptoms. George and Jennie have been married for 52 years and Jennie has always cared for George when he was sick and helped make decisions for him. George is hard of hearing, has some “forgetfulness,” and does not talk very much. His physician prescribes ciproﬂoxacin (Cipro) 250 mg bid for 10 days. Reﬂect on: ᮣ How you will include George and Jennie in the teaching session. ᮣ Essential information to teach about Cipro. ᮣ Teaching strategies to individualize for hearing deﬁcits and memory deﬁcits. ᮣ How you will evaluate George and Jennie’s learning and their ability to comply with the newly prescribed medication. viagra sample overnight viagra oyster Routes and Dosage Ranges Generic/Trade Name Tetracycline (Achromycin,others) Demeclocycline (Declomycin) Characteristics 1. Prototype drug 2. Marketed under generic and numerous trade names 1. The tetracycline most likely to cause photosensitivity 2. Primarily used to treat inappropriate secretion of antidiuretic hormone 1. Well absorbed from the gastrointestinal tract. Oral administration yields serum drug levels equivalent to those obtained by parenteral administration. 2. Highly lipid soluble; therefore, reaches therapeutic levels in CSF, the eye, and the prostate gland 3. Can be given in smaller doses and less frequently than other tetracyclines because of long serum halflife (approximately 18 h) 4. Excreted by kidneys to a lesser extent than other tetracyclines and is considered safe for clients with impaired renal function 1. Well absorbed after oral administration 2. Like doxycycline, readily penetrates CSF, the eye, and the prostate 3. Metabolized more than other tetracyclines, and smaller amounts are excreted in urine and feces Adults PO 1–2 gm/d in 2 or 4 equal doses Children Age>8 y: PO 25–50 mg/kg/d in 4 divided doses Age>8 y: PO 6–12 mg/kg/d in two to four divided doses viagra online money order save Age 6–12 y: PO 500 mg four times daily Age <6 y: PO 50 mg/kg/d, in 3 divided doses Burn wounds may be cleansed by whirlpool, shower, or spot cleansing with sterile saline, gauze pads, and gloves. Food decreases nausea, vomiting and diarrhea. Therapeutic effects depend on the reason for use. viagra finder Answer: An indwelling catheter signiﬁcantly increases the incidence of urinary tract infection (UTI). Cloudy, foul-smelling urine with lots of sediment also supports the presence of a UTI. Because of their depressed immune function, elderly clients do not always experience common symptoms of UTI such as fever or pain. Obtain an order for a urine culture and sensitivity so appropriate antibiotics can be prescribed. Encourage ﬂuids, at least 8 glasses per day unless contraindicated. Work on a long-term plan for bladder retraining or intermittent catheterization to decrease risk of chronic, recurrent UTIs. viagra clearance The macrolides are widely used for treatment of respiratory tract and skin/soft tissue infections caused by streptococci and staphylococci. Erythromycin is also used as a penicillin substitute in clients who are allergic to penicillin; for prevention of rheumatic fever, gonorrhea, syphilis, pertussis, and chlamy- viagra and memory loss viagra ads funny 552 Most of the macrolides and miscellaneous drugs may be taken in the home setting. The role of the home care nurse is generally the same as with other antibiotic therapy; that is, the nurse may need to teach clients or caregivers about drug administration and expected effects. For clients taking oral metronidazole or vancomycin for pseudomembranous colitis, stool specimens may need to be collected and tested in the laboratory for C. difﬁcile organisms or toxins. viagra 24 hours delivery Manufacturer’s recommendations viagra 100mg free shipping ups shipping viagra Spontaneous healing in 6 months top 5 viagra 563 tadalafil vs generic viagra SECTION 6 DRUGS USED TO TREAT INFECTIONS ≥3 y and weight 10–40 kg (22–88 lbs): PO 200– 400 mg, depending on weight Weight >40 kg: PO same as adults Dosage not established oyster viagra • Interview outpatients regarding their compliance with online viagra testosterone nonperscription viagra Use in Hepatic Impairment never mix viagra Cytokines (Table 42–1) are substances produced by bone marrow stromal cells, activated helper T cells, activated macrophages, and other cells. They regulate many cellular activities by acting as chemical messengers among cells. Some cytokines are growth factors that induce proliferation and differentiation of blood cells. These cytokines comprise a large group of proteins that are structurally and functionally diverse. They were initially named and deﬁned by their action on one type of blood cell, but some of them act on multiple types of blood cells. The term cytokine includes lymphokines secreted by lymphocytes and monokines secreted by monocytes and macrophages. The terms lymphokines and monokines Pluripotential stem cells natural viagra woman keywords buy viagra People at high risk for exposure, including newborns of women with tuberculosis >10 y: SC 0.5 mL for two doses at least 4 wk apart, then a booster dose of 0.5 mL at least every 3 y for repeated or continued exposure Age 6 mo–10 y: SC 0.25 mL for 2 doses, at least 4 wk apart, then a booster dose of 0.25 mL (or 0.1 mL intradermal) every 3 y if indicated >6 y: PO same as adults 1–12 y: SC 0.5 mL in a single dose Adolescents, 13 y and older: SC, 0.5 mL, followed by a second dose of 0.5 mL 4–8 wk after the ﬁrst dose >6 mo: SC same as adults kamagra good as viagra dressing changes, and any other invasive diagnostic or therapeutic measures. • Screen staff and visitors for signs and symptoms of infection; if infection is noted, do not allow contact with the client. • Allow clients to participate in self-care and decision making when possible and appropriate. interaction of clonidine with viagra generic viagra sale on line Blood Cell and Immune System Stimulants generic viagra buy form John Miller is receiving monthly chemotherapy. The nadir is expected 10 days after treatment. Last month, the nadir lasted for 6 days, during which his neutrophil count was less than 1000/mm3. This month he is given ﬁlgrastim (granulocyte colony-stimulating factor [G-CSF]). Why is the G-CSF given, and how will you evaluate its effectiveness? Answer: G-CSF is given to decrease the length and severity of bone marrow suppression after chemotherapy. Laboratory values (white blood cell count and differential) evaluate the degree of bone marrow suppression and whether G-CSF is effective. In this situation, the nadir (lowest neutrophil count) should be above 1000/mm3 and should last for less than 6 days. Although bone marrow suppression can affect red blood cells and platelets, white blood cells (neutrophils) are most signiﬁcant because a low neutrophil count increases infection risk. Infection in a neutropenic patient can be life-threatening. generic viagra and generic soma develops serious infections and other adverse effects because the drug actions that slow the proliferation of activated lymphocytes also affect any rapidly dividing nonimmune cells (eg, epithelial cells of the gastrointestinal [GI] tract and hematopoietic stem cells of the bone marrow). Serious complications can occur. generic viagra 100mg soft pills generic pack sample viagra Bone Marrow Transplantation and Graft-Versus-Host Disease CHAPTER 45 IMMUNOSUPPRESSANTS generac viagra Review and Application Exercises gel tab viagra SECTION 8 DRUGS AFFECTING THE RESPIRATORY SYSTEM erection after orgasm viagra lungs through the pulmonary veins. The ventricles are distributing chambers. The right ventricle sends deoxygenated blood through the pulmonary circulation. It is small and thin walled because it contracts against minimal pressure. The left ventricle pumps oxygenated blood through the systemic circuit. It is much more muscular and thick walled because it contracts against relatively high pressure. The right atrium and right ventricle form one pump, and the left atrium and left ventricle form another. A muscular wall called the septum separates the right and left sides of the heart. effects of viagra soft tabs does viagra enlarge the penis Several drugs are used to treat acute HF, and a combination of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) and a diuretic is ﬁrst-line therapy for chronic failure. Increasingly, digoxin, a betaadrenergic blocking agent, or spironolactone is being added to the ACE inhibitor or ARB and diuretic regimen. Drug therapy of HF continues to evolve as the pathophysiologic mechanisms are better understood and research studies indicate more effective regimens. Combinations of drugs are commonly used in efforts to improve circulation, alter the compensatory mechanisms, and reverse heart damage. Most of the drugs used to treat HF are also used in other disorders and are discussed in other chapters; their effects in HF are described in Box 51–2. The primary focus of this chapter is inotropic agents, which include digoxin, a cardiac glycoside, and the phosphodiesterase inhibitors inamrinone and milrinone. These drugs are discussed in the following sections and in Drugs at a Glance: Drugs for Heart Failure. Routes and Dosage Ranges Generic/Trade Name Inotropic Agents CARDIAC GLYCOSIDE Digoxin (Lanoxin) Adults Children doctor online order viagra visit Herbal and Dietary Supplements discount viagra offers disclaimer for viagra PO 6 mg/kg q4–6h cheep viagra uk Interventions cheapest viagra prices uk 790 cheap man viagra Nursing Diagnoses • Excess Fluid Volume in edematous clients, related to retention of sodium and water Home Care cheap generic 50 mg viagra caverta versus viagra SECTION 9 DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM canadian supplier viagra Chylomicrons, the largest lipoprotein molecules, are synthesized in the wall of the small intestine. They carry recently ingested dietary cholesterol and triglycerides that have been absorbed from the gastrointestinal tract. Hyperchylomicronemia normally occurs after a fatty meal, reaches peak levels in 3 to 4 hours, and subsides within 12 to 14 hours. Chylomicrons carry triglycerides to fat and muscle cells, where the enzyme lipoprotein lipase breaks down the molecule and releases fatty acids to be used for energy or stored as fat. This process leaves a remnant containing cholesterol, which is then transported to the liver. Thus, chylomicrons transport triglycerides to peripheral tissues and cholesterol to the liver. Low-density lipoprotein (LDL) cholesterol, sometimes called “bad cholesterol,” transports approximately 75% of serum cholesterol and carries it to peripheral tissues and the liver. LDL cholesterol is removed from the circulation by receptor and nonreceptor mechanisms. The receptor mechanism involves the binding of LDL cholesterol to receptors on cell surface membranes. The bound LDL molecule is then engulfed into the cell, where it is broken down by enzymes and releases free cholesterol into the cytoplasm. Most LDL cholesterol receptors are located in the liver. However, nonhepatic tissues (eg, adrenal glands, smooth muscle cells, endothelial cells, and lymphoid cells) also have receptors by which they obtain the cholesterol needed for building cell membranes and synthesizing hormones. These cells can regulate their cholesterol intake by adding or removing LDL receptors. Approximately two thirds of the LDL cholesterol is removed from the bloodstream by the receptor-dependent mechanism. The number of LDL receptors on cell membranes determines the amount of LDL degradation (ie, the more receptors on cells, the more LDL is broken down). Conditions that decrease the number or function of receptors (eg, high dietary intake of cholesterol, saturated fat, or calories), increase blood levels of LDL. The remaining one third is removed by mechanisms that do not involve receptors. Nonreceptor uptake occurs in various cells, especially when levels of circulating LDL cholesterol are high. For example, macrophage cells in arterial walls can attach LDL, buy viagra from safeway SECTION 9 DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM buy viagra cheaply Generic/Trade Name Lansoprazole (Prevacid) Indications for Use Routes and Dosage Ranges (Adults) Duodenal ulcer, PO 15 mg daily for healing and maintenance Gastric ulcer, PO 30 mg once daily, up to 8 wk Erosive esophagitis, PO 30 mg daily up to 8 wk; maintenance, 15 mg daily H. pylori infection, PO 30 mg (with amoxicillin and clarithromycin) twice daily for 14 d Hypersecretory conditions, PO 60–90 mg daily Gastric ulcer, PO 40 mg once daily for 4–8 wk Duodenal ulcer, PO 20 mg once daily for 4–8 wk GERD, PO 20 mg once daily Zollinger-Ellison syndrome, PO 60 mg once daily GERD with erosive esophagitis, PO, IV 40 mg once daily Zollinger-Ellison syndrome, PO, IV 40–80 mg q12h Duodenal ulcer, PO 20 mg once daily up to 4 wk GERD, PO 20 mg once daily for healing and maintenance Zollinger-Ellison syndrome, PO 60 mg once or twice daily buy viagra at safeway 877 Miscellaneous Laxatives buy prescription vaniqa viagra buy pharmacy pill viagra chapter 62 Antidiarrheals buy online drug viagra pharmacy Dronabinol is a cannabinoid (derivative of marijuana) used in the management of nausea and vomiting associated with anticancer drugs and unrelieved by other drugs. Dronabinol causes the same adverse effects as marijuana, including psychiatric symptoms, has a high potential for abuse, and may cause a withdrawal syndrome when abruptly discontinued. As a result, it is a Schedule II drug under federal narcotic laws. Withdrawal symptoms (eg, insomnia, irritability, restlessness, others) may occur if dronabinol is abruptly stopped. Onset occurs within 12 hours, with peak intensity within 24 hours and dissipation within 96 hours. These symptoms are most likely to occur with high doses or prolonged use. Sleep disturbances may persist for several weeks. Metoclopramide (Reglan) is a prokinetic agent that increases GI motility and the rate of gastric emptying by increasing the release of acetylcholine from nerve endings in the GI tract (peripheral cholinergic effects). As a result, it can decrease nausea and vomiting associated with gastroparesis and other nonobstructive disorders characterized by gastric retention of food and fluids. Metoclopramide also has central antiemetic effects; it antagonizes the action of dopamine, a catecholamine neurotransmitter. Metoclopramide is given orally in diabetic gastroparesis and esophageal reflux. Large doses of the drug are given intravenously during chemotherapy with cisplatin (Platinol) and other emetogenic antineoplastic drugs. buy form generic viagra PRINCIPLES OF THERAPY Overview of Cancer Treatment Drugs at a Glance: Cytotoxic Antineoplastic Drugs buy discount viagra online a href GI upset, hot ﬂashes, injection site reactions Hot ﬂashes, nausea, vomiting, vaginal discharge, risk of endometrial cancer in nonhysterectomized women Hot ﬂashes, nausea, hypercalcemia, tumor ﬂare buy can reply viagra bigger erection with viagra Guidelines for Handling Cytotoxic Antineoplastic Drugs australian viagra alternative (continued ) 946 atenolol viagra interactions Children may develop a wide range of dermatologic disorders, including dermatitis and skin rashes in younger children and acne in adolescents. Few guidelines have been developed for drug therapy of these disorders. Infants, and perhaps older children, have more permeable skin and are more likely to absorb topical drugs than adults. In addition, absorption is increased in the presence of broken or damaged skin. Therefore, cautious use of topical agents is advised. With topical corticosteroids, suppression of the HPA axis (see Chap. 24), Cushing’s disease, and intracranial hypertension have been reported in children. Signs of impaired adrenal function may include delayed growth and low plasma cortisol levels. Signs of intracranial hypertension may include headaches and swelling of the optic nerve (papilledema) on ophthalmoscopic examination. The latter may lead to blindness if pressure on the optic nerve is not relieved. Because children are at high risk for development of systemic adverse effects with topical corticosteroids, these drugs should be used only if clearly indicated, in the smallest effective dose, for the shortest effective time, and usually without occlusive dressings. In addition, a low-potency agent should be used initially in infants and in intertriginous areas of older children. If a more potent drug is required for severe dermatitis, the child should be examined often and the strength of the drug reduced as skin lesions improve. airport security viagra BOX 67–1 air order travel viagra plasticity for specific tasks in brain and spinal circuits. Just as an enriched environment may lead to synaptogenesis in rodent cortex, an enriched environment and task-specific behavioral learning after a cortical injury may lead to growth of dendrites and dendritic spines and improved behavior. Representational Plasticity Nudo and colleagues have developed a cortical injury model in the squirrel monkey that allows the study of aspects of plasticity and the effects of rehabilitation training. The model is less a duplication of changes associated with stroke than a method to drive cortical representational plasticity in a state of partial reduction of critical neurons. The investigators perform tedious cortical microstimulation with glass electrode penetrations into layer 5 of M1 or related regions. They delineate the movement representations for the digits, wrist, and proximal arm of the monkeys. Such studies show that motor skills training with the digits as the monkeys grasp pellets in a small well leads to an expansion of the representation for the wrist and digits and a reduction in the representation for the arm in M1 (see Chapter 1). The investigators induced a small infarct, less than 1–2 mm wide and 2–3 mm deep in M1, within the representation for the digits. The lesion aims to destroy 30% to 50% of the digit representation. Animals that do not receive any specific retraining to use the hand to pick up food pellets evolved a 30% smaller representational map for the hand.80 Approximately 5 days after inducing the infarct, the investigators instituted motor skills training that emphasized wrist and finger extension to grasp food pellets. From 10 to 12 hours of training and greater success in pellet retrieval was associated with reorganization of the cortical representations in M1 for the fingers and wrist.26 The representation became considerably larger compared to the baseline map and the map of spontaneous recovery. When practice for grasping food pellets was delayed for 2 months after the digit region infarct, the hand map in the monkeys was larger than after spontaneous recovery, but smaller than baseline.81 In addition, general daily use of the affected limb did not induce representational plasticity after an M1 infarct. When the 50mg viagra softtabs 50mg viagra retail price tonergic influence on the sublesional spinal cord’s central pattern generators for stepping (see Chapter 1). Many studies have pointed to the beneficial effect of serotonergic input to locomotor neurons, including the use of a direct 5-hydroxytryptophan agonist combined with an embryonic transplant.278 Overground locomotion in these rats may require some additional propriospinal or other supraspinal input. After the thoracic cord was more than hemisected in another rat model, spinal embryonic transplants supported the regeneration of brain stem–spinal and segmental dorsal root projections, associated with recovery of hindlimb placement and aspects of locomotion; this growth was enhanced by providing neutralizing antibodies to neurite inhibitors.279 Descending serotonergic, noradrenergic, and corticospinal fibers traversed the transplant only in neonates. In adults, the implant seemed to serve as a relay, rather than as a bridge. Propriospinal neurons sent axons into the embryonic tissue, providing segmental and intersegmental input that could account for the locomotor gains in the adults. Clinicoanatomical correlations between behavioral gains and the regeneration of axons have improved as investigator experience has increased, especially with the addition of behavioral training and other repair strategies.224,280,281 Overall results have been promising, but not behaviorally robust. A more recent study in adult rats by Bregman and colleagues showed that the transplantation of fetal rat spinal cord tissue, plus the administration of BDNF or NT-3, improved outcomes when delayed for a few weeks after a low thoracic spinal transection.282 The growth of axons across the transplant into host cord and improvements in hindlimb motor function were more robust than after giving only neurotrophins or only fetal tissue shortly after a hemisection. Brainstem nuclei, propriospinal neurons, and scattered corticospinal neurons were among the cells that contributed the modest number of regenerating axons. A reinjury of the wall at the site of transection at the time of delayed implantation may contribute to gene expression for regeneration in this model.283 The feasibility and safety of embryonic spinal cord tissue transplants is being assessed in eight patients who had a progressively enlarging syrinx after SCI.284 The investigators 286. 3 generic sildenafil viagra 12 online generic viagra maceuticals that are given intravenously or by inhalation. Radioisotopes that emit gamma rays include xenon-133, iodine-123, and technetium-99m. Single photon emission computerized tomography does not directly assess neuronal function. The procedure measures cerebral perfusion, blood volume, and the distribution of several receptors, which indirectly reflect metabolism and network activity.7 Early after stroke, SPECT tends not to differentiate between viable and irreversibly ischemic tissue, because the uptake of the radiotracer is not linearly related to perfusion. For postacute ischemia studies applicable to rehabilitation interventions, SPECT’s spatial resolution is just under 1 cm3. Ionizing radiation, nonuniform spatial resolution, low temporal resolution, and the relativity of measures from one region of interest to another limit its usefulness in the functional imaging of plasticity. Many of the pitfalls of SPECT are found among the methods and paradigms of components of functional imaging listed in Table 3–3. HEMIPARETIC STROKE Positron emission tomography, fMRI, and TMS have been most useful in revealing plasticity at various times poststroke and in association with levels of improvement in motor skills. The following general observations have held across most studies. 1. Recruitment of remote regions evolves over time with a reweighting of the contributions from other regions of the network. The ipsilateral sensorimotor cortex, for example, shows a much larger activation than normal, even when mirror movements of the unaffected hand can be excluded. Mechanisms include activity of the uncrossed corticospinal tract, transcallosal activation or disinhibition, polysynaptic activity and feedback through other parts of the motor network in the cortex and brain stem, and sensory drives from bilateral thalamic or callosal inputs. This activity is suppressed as skilled use of the affected hand improves. The ipsilesional premotor cortex is also often activated during simple tapping with the affected fingers. Brief suppression of the dorsal premotor area by single pulse TMS contralateral to the hemiparetic hand may prolong the simple reaction time, whereas stimulation of the ventral premotor area does not; a TMS pulse over M1 also delays the reaction time in the contralateral hand in patients and healthy contols.93 A decrease in the level of premotor activation is associated with better hand function. Thus, this region with its corticospinal projections plays an important substitutive role. 2. The primary representation for a movement, such as M1 for hand movement, may expand if spared and later contract as movements regain some of their skill (see Color Fig. 3–5 in separate color insert). This evolution parallels changes in S1M1 observed during normal motor learning of a complex finger sequence.94,95 use paypal to buy cialis Figure 4–2. The Lokomat exoskeleton assists body weight-supported treadmill stepping without on-line sensory feedback. buy cialis with paypal payment generic cialis no prescription paypal 220 blood flow in the right hemisphere’s homologue region for Wernicke’s area and increased flow to the left hemisphere, especially in Broca’s area and adjacent prefrontal cortex.151 Melodic intonation therapy, then, induces a systematic change in how the acoustic features of spoken and perceived speech are engaged by the brain after a left hemispheric stroke. Intensive practice in the approach may help to reactivate the left prefrontal region in relation to improved expression. As described in Chapter 3, functional imaging studies suggest that greater recovery in aphasics occurs when peri-injury language areas are activated, rather than when nondominant homologuous cortical regions are engaged. When a single sound, word, or phrase overwhelms any other attempted output, the voluntary control of involuntary utterance (VCIU) program can help the patient gain control over perseverative intrusions.152 The agrammatism of Broca’s aphasia has been treated with the Helm-elicited language program for syntax stimulation (HELPSS),153 which uses a series of drawings that picture common activities. The therapist provides a brief verbal description that ends with a question about the story and contains a target sentence. After the patient responds with the target words, the patient is asked to complete the story without benefit of having heard the target sentence. Each probe seeks a target response that requires an increasingly more difficult syntactic construction. Some patients with little or only stereotyped output, even with impaired comprehension, have responded to multiple input phoneme therapy (MIPT).154 The theory behind the approach is that markedly apractic-aphasic patients who produce only stereotypies are caught in a verbal motor loop. Once an utterance is made, the loop strengthens and each attempt at volitional speech elicits the loop. Multiple input phoneme therapy is a 22-step hierarchic program that builds from an analysis of phonemes produced by the patient. The therapist controls the patient’s struggle to articulate, then elicits a target phoneme to build consonant blends, multisyllabic words, and eventually sentence production. Response elaboration training (RET) shapes and chains the responses patients give to their descriptions of familiar activities in line drawings.155 The technique reinforces informational content, rather than linguistic form. cialis without presciption 105. 106. 107. buy cialis use paypal 260 buy generic cialis 5mg canadian pharmacy cialis paypal SPASM SCORE257 0-Anesthesia 1-Hyperesthesia/dysesthesia 2-Normal __________ 0-No sensation 1-Three quarters of answers are correct, but considerable difference in sensation compared with unaffected side 2-All answers are correct, little or no difference overnight cialis with dapoxetine cialis rush Instrumental Activities of Daily Living EXPERIMENTAL CASE STUDIES 8–1: Posttraumatic Stress Disorder order cialis online us Stroke cialis best offer trained patients with microcomputer games.215 It took 3 years to enroll subjects and 5 years to complete the trial. Patients were evaluated by a variety of tests at a median of 10 days after the stroke and retested at 1, 3, and 6 months. Subgroups of 64 severe and 57 mildly affected patients were also compared. The primary effect of the enhanced intervention, that included about twice the amount of therapy time, was improved arm function at 1 month. At 6 months, the mildly affected, but not the severely impaired subgroup that received enhanced therapy, had significantly improved in the 9-Hole Peg Test and a motor score. Thus, a moderate addition to usual interventions had some benefit in patients with selective upper extremity movement at entry. Perhaps a better defined and more intensively applied set of enhanced interventions and measures with less serious floor and ceiling effects would generate greater efficacy. The individual trials comparing schools of therapy include many methodologic flaws.216,217 For example, the studies entered too few subjects, given the spectrum of impairments and disabilities of stroke patients, to detect real differences if such differences exist. Thus, they are at risk for a type II statistical error. The trials did not clearly address principles for training skills. The therapists concentrated on movement, rather than upon the ADLs that served as the measure of efficacy. The trials did not include outcomes related to how the therapists’ efforts affected behavioral compensation for the hemiplegia, compared with changes in the performance of the affected limbs. Indeed, indices of independence in ADLs, the primary outcome measure in these trials, may reflect poorly the primary intention of the schools of physiotherapy, which traditionally has been to improve patterns of movement.202 buy cialis in australia by paypal 414 cialis black for no prescription cialis with dapoxetine overnight to 101. cheap cialis with dapoxetine of voluntary movement in hemiplegic patients. Brain 1990; 113:177–189. Miyai I, Suzuki T, Kii K. Wallerian degeneration of the pyramidal tract does not affect stroke rehabilitation outcome. Neurology 1998; 51:1613–1616. Miyai I, Blau A, Reding M, Volpe B. Patients with stroke confined to basal ganglia have diminished response to rehabilitation efforts. Neurology 1997; 48:95–101. Hochstenbach J, van Spaendonck K, Cools A, Horstink M, Mulder T. Cognitive deficits following stroke in the basal ganglia. Clin Rehabil 1998; 12: 514–520. Miyai I, Suzuki T, Kang J, Kubota K, Volpe B. Middle cerebral artery stroke that includes the premotor cortex reduces mobility outcome. Stroke 1999; 30: 1380–1383. Macdonell R, Donnan G, Bladin P. Serial changes in somatosensory evoked potentials following cerebral infarction. Electroencephalogr Clin Neurophysiol 1991; 80:276–280. Chester C, McLaren C. Somatosensory evoked response and recovery from stroke. Arch Phys Med Rehabil 1989; 70:520–525. Pavot A, Ignacia D, Kutavanish A, Lightfoote E. Prognostic value of somatosensory evoked potentials in cerebrovascular accidents. Electromyogr Clin Neurophysiol 1986; 26:333–340. Gott P, Karnaze D, Fisher M. Assessment of median somatosensory evoked potentials in cerebral ischemia. Stroke 1990; 21:1167–1171. Feys G, Van Hees J, Bruyninck F, Mercelis R, De Weerdt W. Value of somatosensory and motor evoked potentials in predicting arm recovery after a stroke. J Neurol Neurosurg Psychiatry 2000; 68:323–331. Macdonell R, Donnan G, Bladin P. A comparison of somatosensory evoked and motor evoked potentials in stroke. Ann Neurol 1989; 25:68–73. Pennisi G, Rapisarda G, Bella R, Calabrese V, de Noordhout A. Absence of response to early transcranial magnetic stimulation in ischemic stroke patients. Prognostic value for hand recovery. Stroke 1999; 30:2666–2670. Dominkus M, Griswold W, Jelinck V. Transcranial electrical motor evoked potentials as a prognostic indicator for motor recovery in stroke patients. J Neurol Neurosurg Psychiatry 1990; 53:745–780. Heald A, Bates D, Cartlidge N, French J, Miller S. Longitudinal study of central motor conduction time following stroke: 2. Central motor conduction measured within 73 h after stroke as a predictor of functional outcome at 12 months. Brain 1993; 116:1371– 1385. Vang C, Dunbabin D, Kilpatrick D. Correlation between functional and electrophysiological recovery in acute ischemic stroke. Stroke 1999; 30:2126–2130. Alagona G, Delvaux V, Gerard P, DePasqua V, Pennisi G, DelWaide P, Nicoletti F, Maertens de Noordhout A. Ipsilateral motor responses to focal transcranial magnetic stimulation in healthy and acute stroke patients. Stroke 2001; 32:1304–1309. Marchal G, Serrati C, Rioux P, Petit-Taboue M, Viader F, de la Sayette V, LeDoze F, Lochon P, Derlon J, Orgogozo J. PET imaging of cerebral perfusion and oxygen consumption in acute ischaemic stroke: Relation to outcome. Lancet 1993; 341:925–927. cheapest 10mg cialis 287. Independent, standard wheel rims tadalafil citrate cialis pharmacy india viagra cialis Rehabilitation of Specific Neurologic Disorders over seas cialis computer programs, and other stimuli to encourage cognitive processing. Mental jumping jacks, however, are not likely to recondition the brain for the acquisition and retention of skills and strategies that reduce disability. Cognitive remediation takes a more theoretic approach. Cognitive remediation has many nuances, but usually includes a cognitive process-specific approach that articulates subroutines of a mental process. Therapists aim to ameliorate impairments in problem-solving, often use feedback, and consider that their methods reorganize the function of cognitive neural networks.160,161 The approach targets distinct, if theoretic, components of separable cognitive processes. Repetition of a task at one level of difficulty or related to one subcomponent of the cognitive process continues until the goal is reached. Then the task is enlarged within its presumed hierarchic organization. For example, once 2-dimensional constructions are copied, 3-dimensional drawings are practiced. Once auditory attention is achieved, auditory encoding is practiced. Gains are expected to generalize to related tasks and to transfer into real-world activities. In practice, when cognitive impairments are mapped by neuropsychologic testing, early interventions are often designed to boost the efficiency of a domain for which the patient has demonstrated some capacity, rather than tackle domains for which the patient’s ability is poor. When possible, a relatively intact cognitive skill is emphasized to compensate for a severely impaired one. For example, impaired auditory encoding may be compensated for by writing what was said and by using a visual memory strategy. Cognitive remediation techniques have been carried out for many of the common sequelae of TBI. The techniques are less successful as the severity of impairments increases. Specific approaches, based upon still inexact theories of cognitive processing, have been outlined for generic disorders of orientation, attention, memory, visuoperception, language, executive functions, and problem-solving.151,155,162 For example, selective attention, which is the ability to focus on a particular stimulus or response, can be reinforced behaviorally, compensated for by placing the patient in a nondistracting environment, possibly improved by withdrawing medications that reduce arousal, attention, and the speed of mental processing, and possibly remediated by dealing individually with ADLs, socialization, or work. These sometimes lengthy programs are generally associated with gains in some important outcomes, although the content and duration of therapy is moot. In one interdisciplinary program, 18 highly selected patients received cognitive and psychologic therapies that emphasized awareness of deficits, along with skills training for social, work, and family activities.173 The subjects had good family support, no premorbid psychiatric history, and had moderate to severe cognitive dysfunction. Mostly one-on-one therapies were given 6 hours a day for 4 days a week and lasted at least 6 months. In comparison to 17 matched patients who received a traditional approach, 50% of the intensively treated group and 36% of the control group were employed 6 to 26 months later. The intensive therapy group also tended to do better in some cognitive tests, including the Wechsler Memory Scale. The self-selection of these patients for participation in the experimental group may have been an uncontrolled factor that accounted for the modest findings. A similar scheme of therapy was used in a larger group of patients who had completed traditional therapy and had failed to regain employment.174 The patients received approximately 400 hours of cognitive remediation, instruction on interpersonal communication and social skills, and counseling to understand and accept their disability. The patients continued with 3 to 9 months of supervision in a work setting. Six months later, 84% were employed, about half in a competitive setting. At a 3-year follow-up of a subgroup of these patients, 76% were still employed, half in a competitive job. Other single institution reports of late rehabilitation have also found a positive effect on posttreatment work status, attendant care, and independent living that the authors believed were cost-effective.122,175 Much has been written about the confusing and poor methodologies of studies of multimodal programs of rehabilitation.176,177 Publications from single institutions about their results in uncontrolled trials must be viewed with caution; however, the effects of programs that use multiple, simultaneous interventions can be evaluated systematically. In one approach, three matched groups were assigned to three different mixes of remedial interventions.178 All subjects received the same number of hours of therapy over 20 weeks, counseling, and interaction with peers in group generic viagra versus generic cialis pills generic viagra versus cialis pills l Fronta generic cialis softtabs php Chemical reactions are denoted in a standard manner. generic cialis softtabs online 23 generic cialis soft from india Epithelial Tissue Skin 7-dehydrocholesterol generic cialis pills best price lowing time for the air to be saturated with water and warmed to body temperature. In addition, the conchae help direct the air toward the roof of the nasal cavity where the olfactory nerves are located. generic cialis experiences experiences with generic cialis Each vertebra consists of three parts: the body, vertebral arch, and articular processes (see Figure 3.18). The body is thick, disk-shaped, and located anteriorly. The bodies are interconnected by ligaments. Interspersed between each vertebra are ﬁbrocartilage pads called intervertebral disks (see page ••). Two vertebral arches lead off posterolaterally from the body. The two, short, thick processes leading off from the body are known as pedicles. The pedicles have depressions on the superior and inferior surfaces (vertebral notches). The pedicles join the laminae, the ﬂat, posterior part of the arch. These arches meet posteriorly to enclose an opening called the vertebral foramen. Because the vertebrae lie on top of each other, the successive vertebral foramen form a vertebral canal. The spinal cord lies in the vertebral canal. Laterally, a small foramen is formed where the notches on the pedicles of successive vertebrae align. This is the intervertebral foramen. The spinal nerves exit from the vertebral canal through these foramen. Posteriorly, each vertebra has a projection called the spinous process. This forms the bumps that are seen in the middle of the back in a lean individual. The most prominent of these bumps at the base of the neck indicates the location of the C7 spinous process. C7 is, therefore, called the vertebra prominens (also see Fig. M 3). A large elastic ligament, the ligamentum nuchae, is attached to the spinous process of C7. From here, it continues upward, attached to the spinous processes of the other cervical vertebrae before it reaches the prominent ridge on the occipital bone, the external occipital crest. This ligament maintains the cervical curvature, even without the help of muscular contraction. If the head is bent forward, this elastic ligament helps bring the head to an upright position. Transverse processes project laterally on both sides. The processes are sites for muscle attachment. Each vertebrae has articular processes that project inferiorly (inferior articular process) and superiorly (superior articular process). This is the area where adjacent vertebrae articulate. The superior articular processes of the lower vertebra articulate with the inferior articular processes of the vertebra located above. The articulating surface of the processes are known as facets. Olecranon of ulna Brachioradialis Olecranon of ulna Anconeus Extensor carpi radialis longus Extensor carpi radialis brevis Extensor digitorum Medial epicondyle of humerus Brachioradialis Olecranon of ulna Anconeus Extensor carpi radialis longus Extensor carpi radialis brevis Extensor digitorum Extensor carpi ulnaris Flexor carpi ulnaris discount cialis uk cialis pharmacy rx viagra Medial supracondylar ridge cialis online online get cialis cheapest Ligaments Many muscles participate in shoulder movement. Of these, the tendons of four muscles provide stability to the joint and are known as the rotator, or musculotendinous, cuff. The four muscles involved are the supraspinatus, infraspinatus, teres minor, and subscapularis (you can remember it by the acronym SITS). The tendons of these muscles blend with the joint capsule. When the arm is hanging at the side, the tension of the superior aspect of the joint capsule is sufﬁcient to keep the two articulating surfaces in contact. When the arm is moved from the side, the rotator cuff muscles must contract to keep the head of the humerus in position. Muscles that help with ﬂexion: Primary ﬂexors Deltoid (anterior portion) Coracobrachialis Secondary ﬂexors Pectoralis major Biceps brachii Muscles that help with extension: Primary extensors Latissimus dorsi Teres major Secondary extensors Teres minor Triceps (long head) The muscles that help with abduction: Primary abductors Deltoid (middle portion) Supraspinatus Secondary abductors Serratus anterior Deltoid (anterior and posterior portions) The muscles that help with adduction: Primary adductors Pectoralis major Latissimus dorsi cialis online get cialis cheapest cialis medicine online order rx viagra radial side of the scaphoid form the radial side. The tendons of the ﬂexor digitorum superﬁcialis and ﬂexor digitorum profundus, surrounded by a common synovial sheath, pass through the carpal tunnel. The tendon of the ﬂexor carpi radialis, the tendon of ﬂexor pollicis longus, and the median nerve also pass through the tunnel. cialis lowest prices on the internet Short head Long head Sartorius G cialis de cialis copy Medial (1st) cuneiform Medial (2nd) cuneiform Medial (3rd) cuneiform Cuneonavicular joint continuous with cubonavicular joint Chapter 4—Muscular System cialis clinical trial The chicken breast has “white” meat because the chicken uses the muscles to move the wings for only a short period, such as in getting away from a predator. The “red” meat that you see in the delicatessen contains more slow ﬁbers. The thigh and drumstick of chicken meat is red because the chicken uses these muscles continually for walking. cialis canada online pharmacy viagra Motor root cialis best price buy online One signiﬁcant adaptation is the improvement in breathing efﬁciency. Changes in the respiratory muscles result in reduced use of oxygen for respiration. This, in turn, reduces the fatiguing effects of exercise on the respiratory muscles and frees oxygen for use by the active muscles. In trained individuals, the respiratory rate is decreased during exercise and the tidal volume (volume of air breathed in per breath) is increased. This is advantageous because it allows for a longer time for oxygen extraction from the inspired air. It must be noted that these adaptive changes are chemical formula of cialis Intertransversarii buy cialis online dream pharmaceutical buy cialis in south africa online Because the liver is below the diaphragm, the left side of the diaphragm is higher than the right. Pregnant women tend to rely more on the movement of the intercostal muscles for breathing because the diaphragmatic movements are restricted, especially late in pregnancy. Because the diaphragm is supplied by the phrenic nerve arising in the cervical region, irritation to the diaphragm can often reﬂect as pain (referred pain) in the shoulder because the skin of the shoulder is supplied by sensory nerves arising in the cervical regions C3–C5. buy cialis from icos These muscles (see Figure 4.27 and Chapter Appendix Table 4.8) stabilize the scapula and clavicle. As mentioned, the only joint in the pectoral girdle that articulates with the axial skeleton is at the sternoclavicular joint. The scapula and the clavicle are Biceps brachii Supinator buy cialis dream online pharmaceutical Plantaris Gastrocnemius, lateral head buy cheap cialis softtabs Shinsplints buy by cialis money order A best generic cialis pills price 5 cialis generic viagra Rectus abdominis 4 generic cialis softtabs Trapezius O 20mg generic cialis pills cialis pill cutters Gluteus maximus cialis generic lowest price viagra Obturator externus Insertion Medial aspects of the bases of the proximal phalanges of the 3rd–5th toes; dorsal digital expansions Adducts 3rd–5th toe; ﬂexes the metatarsophalangeal joints S2–S3 Action Nerve Supply Muscle Diagram cutting 20mg cialis Nervous System weekend pill cialis imitation cialis 304 zoloft and cialis interactions Neuroglias are the supporting cells. They are ﬁve times more abundant than neurons. There are four types of glial cells in the CNS: the ependymal cells, astrocytes, microglia, and oligodendrocytes and two types in the PNS: Schwann cells, or neurolemmocytes, and satellite cells, or ganglionic gliocytes. The ependymal cells line the cavities in the brain and spinal cord and are responsible for producing, circulating, and monitoring the cerebrospinal ﬂuid— Secretory granules Mitochondria yahoo viagra spam Neuroﬁbromatosis womens viagra free sample Receptive fields Skin surface will viagra give you an erection weight pill cialis The Brachial Plexus water soluble viagra The sciatic nerve is located midway between the greater trochanter and the ischial tuberosity, deep to the gluteus maximus and the piriformis. Then it travels vertically down the thigh to the apex of the popliteal fossa, deep to the hamstring muscles. The lower border of the muscle piriformis can be mapped as follows: Draw an imaginary line from the posterior superior iliac spin to the tip of the coccyx; the lower border runs along a line that joins the midpoint of the imaginary line to the top of the greater trochanter. The sciatic nerve is often injured when there is a posterior dislocation of the hip. The nerve roots may be compressed by a herniated disk or by the enlarging uterus during pregnancy. If injections are administered improperly to the gluteal region, this nerve may become damaged. This condition is referred to as sciatica. Typically, there is a sharp pain felt in the buttock and on the posterior and lateral aspect of the thigh, leg, and foot. Most often, the common peroneal nerve on the lateral aspect of the Injury to Common Peroneal Nerve leg is affected, resulting in a typical position of the foot referred to as footdrop. Here, the foot is plantar ﬂexed and inverted, with loss of sensation on the lateral aspect of leg and dorsum of foot. If the tibial nerve is affected, the foot takes on a typical position of dorsiﬂexion of the foot and eversion, with loss of sensation in the sole of the foot. walgreens coupons viagra 2 viva cialis B viagra zenerx The receptors for smell are located in the nasal mucosa, in a small area about 5 cm2 (0.8 in2) in the roof of the nasal cavity and upper portion of the nasal septum (see Figure 5.40). There are about 10–20 million receptor cells here. Each receptor is the end of a neuron; this region is obviously the closest the nervous system gets to the external world. The axons of the neurons go through the cribriform plate of the ethmoid bone and enter the paired projections of the brain—the olfactory bulb and tract. They synapse at the olfactory bulb from which other neurons convey the impulses to the olfactory cortex. The olfactory cortex consists of two major areas of the brain—the medial olfactory area and the lateral olfactory area. The medial area lies in the middle of the brain, superior and anterior to the hypothalamus and is responsible for reﬂexes such as licking the lips viagra without priscription Facial Nerve Lesions viagra without a percription FIGURE Epilepsy is a group of disorders characterized by chronic, repeated, periodic changes in nerve function caused by abnormalities in the electrical activity of the brain. Each episode of abnormal neural function is called a seizure. The episode may be in the form of convulsions when there is abnormal motor activity or in the form of abnormalities in other neurologic functions such as sensations, emotions, and cognition. viagra viagra pages edinburgh find generic Cochlea viagra useage B Rotating left viagra title object object viagra title object RETICULAR ACTIVATING SYSTEM AND AROUSAL MECHANISMS viagra testimonies 391 Each sperm (Figure 7.3B) has a rounded head and a long tail. The head houses the nucleus with densely packed chromosomes. The head is covered by a cap (acrosomal cap), which contains the enzymes required for digesting the outer layer of the ova at the time of fertilization. The long tail helps the sperm propel forward with a rapid, corkscrew motion. Because the sperm does not have energy reserves, it relies on the surrounding ﬂuid for survival. viagra technique viagra st cialis st viagra cialis Epididymis the superﬁcial inguinal ring (superﬁcial aspect of the anterior abdominal wall), and descend superﬁcially to reach the testis (the route taken by the testis as it descends). In males, as a result of the presence of the spermatic cord, this region of the anterior abdominal wall is weaker. In situations where the pressure in the abdominal cavity is chronically increased, the contents of the abdomen tend to push through this weak point, a condition known as inguinal hernia. In females, only a nerve and a ligament of the uterus pass through this canal and inguinal hernia rarely occurs. After passing through the deep inguinal ring, the vas deferens passes posterior to the urinary bladder toward the superior and posterior margin of the prostate gland. At this point, the vas deferens enlarges slightly to form the ampulla. The duct from the accessory gland (seminal vesicle) joins it here to form the ejaculatory duct. This duct passes through the prostate gland and empties into the prostatic urethra. The urethra extends from the urinary bladder to the tip of the penis. It is about 20 cm long (7.9 in) and passes through the prostate (prostatic urethra), connective tissue in the perineum (membranous urethra), and the penis (penile urethra). viagra soft tabs overnight delivery viagra soft information Clinical Terms viagra single dose Lobe viagra sale free generic Mature follicle viagra real mail First Trimester: • Nausea and vomiting (morning sickness): probably a result of increased hormonal levels in the blood; the symptoms usually disappear by week 16 • Frequent urination • Constipation: may be a result of lowered gut motility and the pressure of the uterus on the gut. • Lower blood pressure: associated with feeling of faintness, especially after prolonged standing • Breast changes: sense of increased fullness; tenderness • Musculoskeletal changes: aching feet, pain over symphysis pubis, and sacroiliac joint, etc., as a result of increased weight bearing, shift in center of gravity, and laxity of joints • Alteration of taste and smell • Mood swings: Irritability, anxiety, depression. Second Trimester: • Sensation of fetal movement: between 18 and 21 weeks • Edema • Hypotension when supine • Shortness of breath • Backache • Varicose veins and hemorrhoids as a result of pressure on abdominal veins • Pigmentation: darkening of freckles; butterﬂy distribution of pigmentation over the nose and cheeks (chloasma); darkening of the region of the linea alba (linea nigra) • Stretch marks: tissue overlying rapidly enlarging structures (e.g., breasts; abdomen) • Heartburn: relaxation of the esophageal sphincter and the increase intra-abdominal pressure as a result of the growing fetus may precipitate this. • Vaginal discharge: increase in vascularity in the perineal region induces increase in vaginal discharge. The warmth and moisture in this region encourages growth of microorganisms. Third Trimester: • Edema; compression syndromes, such as thoracic outlet syndrome; carpel tunnel syndrome, etc., secondary to edema • Backache; sacroiliac sprain; leg cramps; costal margin pain • Frequent urination; incontinence • Fatigue • Insomnia; restlessness Postpartum Changes: • Symptoms associated with postsurgical recovery, e.g., cesarean section; episiotomy(incision in the perineum made just before birth to prevent tearing of tissue) • Soreness and tenderness of breasts • Mood changes: postpartum blues (postpartum depression is more serious and involves feelings of extreme anxiety, hopelessness, and sadness that last for more than a few weeks) LABOR viagra questions for the doctor AGE-RELATED CHANGES IN THE REPRODUCTIVE SYSTEM Reﬂexology and Symptoms viagra pulmonary hypertension and dogs viagra price shopper 7. viagra actors Red blood cells (see Figure 8.1), also known as erythrocytes, are packages that carry the oxygencarrying protein pigment hemoglobin in the circulation. The red coloration is a result of the presence of hemoglobin. The red cells are biconcave and do not have a nucleus and other organelles. Hence, these cells cannot reproduce or perform complex metabolic activities as other typical cells. Under the microscope, they look like doughnuts because the central portion of the disk is indented. This shape and small size enables them to squeeze single ﬁle through the smallest blood vessels. The biconcave shape also allows the cell to swell without rupturing, if the surrounding environment becomes hypotonic. There are about 5.4 million cells per cubic millimeter in males and about 4.8 million cells per cubic millimeter in females. Each of these cells has about 280 million hemoglobin molecules. Visualize the volume of blood that contains this number of red cells by identifying a millimeter on your tape measure. FIGURE viagra penis before and after Limbic system viagra no prescription needed cheap DO GIRAFFES DEVELOP EDEMA? viagra no perscription usa Chapter 8—Cardiovascular System viagra no perscription in usa viagra in prison An individual can be immunized in emergencies by injecting large quantities of antibodies (produced outside) against the speciﬁc disease. For example, in a cholera epidemic, a large population may need to be immunized quickly before the disease spreads. In this case, direct injection of antibodies provides a temporary form of immunity. Rh-negative mothers carrying Rh-positive fetuses are routinely given antibodies against Rh antigens soon after delivery. These antibodies protect against Rh antigens that may have leaked into the mother’s circulation from the fetus. If antibodies do develop, they can attack the next Rhpositive fetus and jeopardize its life. These are both examples of passive immunization, in which the individual’s immune system is not stimulated to produce his or her own antibodies. C. How should she deal with the present situation? D. What could be the cause of Gina’s swelling ? Explain in terms of forces that affect ﬂuid movement in and out of the interstitial compartment. 8. The young physician, newly appointed in the rural area where the therapist worked, is enthusiastic and sincere. He cares about the community and wants to concentrate more on preventive medicine. The therapist learns through the grapevine that the physician is going to recommend that all women—especially those of reproductive age—are immunized against German measles. The therapist has not been immunized. Some of her clients expressed concern because they heard that immunization can produce adverse effects. A. What is immunization? B. How does it work? C. Against which diseases can an individual be immunized? D. Should therapists be immunized against speciﬁc diseases? E. What are the potential adverse effects of immunization? viagra in iraq Larynx Lungs viagra in enema viagra histamine The larynx, or voice box (see Figure 10.6), is the region that connects the pharynx to the trachea (windpipe). It can be felt just below the jaw in the upper, anterior part of the neck. The larynx is largely carti- Plasma Red blood cell O2 Pickup O2 Delivery viagra for pigs viagra for minors The layer surrounding the lumen is the mucosa. The mucosa consists of single layer of epithelium, a supportive connective tissue layer (lamina propria), and a thin, muscle layer (muscularis mucosae). The type of lining epithelium varies from region to region according to function. In areas where this is a likelihood of excessive friction and injury, the epithelium is nonkeratinized, stratiﬁed squamous (ﬂat, pavementlike). This type of epithelium is found in the mouth, pharynx, esophagus, and the anus. In areas where absorption or secretion must occur, the epithelium is a simple, columnar type. Most of the gut has this type of epithelium. Scattered between the columnar epithelial cells are exocrine cells (goblet cells) that secrete mucus into the lumen and endocrine cells (enteroendocrine cells) that secrete hormones into the blood. To increase efﬁciency, the epithelium is thrown into folds called villi in regions where absorption takes place. The folds also allow for expansion when a large meal is ingested. The individual epithelial cells also have folds on the surface facing the lumen known as microvilli. The presence of microvilli increases the surface area by 20% and helps improve absorption of nutrients. The epithelium proliferates rapidly and is replaced every 5 to 7 days. The lamina propria consists of connective tissue. In some areas, this connective tissue contains glands, which open into the lumen and secrete the enzymes and ﬂuids required for digestion. The lamina propria also has nerve endings, blood vessels, and lymphoid tissue. The lymphoid tissue, consisting of lymphocytes and macrophages, protects the GI tract from entry of microorganisms. Some smooth muscle—the muscularis mucosae—is also seen in the lamina propria. Muscle contraction causes the mucosa to be viagra find online search free B B B B B B B B B B B B THE COMPOSITION OF URINE viagra find free edinburgh computer viagra female orgasm Urinary Tract Infection (UTI) Velour -

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