By X. Mason. North Carolina School of the Arts.

A third possibility is that the terminal arbors of corticospinal neurons activating deprived spinal motor pools enlarge to contact motor pools innervating intact muscles discount super levitra 80mg otc. There is some evidence against this possibility in that injections of a retrograde tracer bilaterally into the lower cervical spinal cord of two squirrel monkeys with an amputated forelimb labeled similar distributions of corticospinal neurons in the forelimb portion of M1 of both hemi- spheres proven super levitra 80mg. In rats with a transected corticospinal tract, cut axons sprout to contact local propriospinal neurons to create new and functionally useful circuits. Motor neurons pro- jecting to distal limb muscles have had their axons severed by limb damage and amputation. Nevertheless, most of these neurons survive and many sprout collaterals to innervate proximal muscles spared by the amputation. Thus, these damaged motor neurons recover and likely contribute to the activation of preserved proximal mus- cles. As more spinal cord motor neuron pools would be devoted to preserved proximal muscles in animals with amputations, the electrical stimulation of more cortical sites would activate muscles of the stump. Evidence for this possibility comes from comparisons of both sides of the cervical spinal cord in galagos and squirrel monkeys,25 and in the lumbar spinal cord of a macaque monkey39 after comparable injections of anterograde tracers into proximal muscles of the intact limb and stump of the amputated forelimb (galagos and squirrel monkeys) or ampu- tated hindlimb (macaque). In all these primates, motor neuron pools normally devoted to the muscles of the amputated limb were present in normal numbers, although these neurons were smaller in size than on the side with the intact limb. In addition, many of these neurons were labeled by the injection in the limb stump. Thus, neurons with severed axons survived for years after amputations, and acquired new or enhanced connections with remaining proximal muscles. Such new patterns of motor neuron connections most likely contribute to the reorganization of the motor map in M1 of all primates with amputations, including humans. REORGANIZATION AFTER FOCAL LESIONS OF MOTOR CORTEX IN MONKEYS The primary motor cortex may reorganize after part of the map is damaged. In such cases, the damaged representation reorganizes so that more sites in the remaining hand cortex evoke digit movements, especially after rehabili- tative training. These results suggest that the behavioral recoveries are mediated by modifications in primary motor cortex. The changes in the M1 motor map, according to this view, are driven by hand use and training on specific tasks. An extension of this view is that if motor cortex lesions result in reduced use of the opposite hand, M1 reorganizes in a nonproductive way causing further deterioration of skills. While behavioral recoveries after large lesions may be incomplete,48 recov- eries can be extensive. These monkeys had acquired a new, displaced, and relatively complete hand representation in M1 just medial to the site of the old lesion. When this new hand representation was inactivated by cooling, the use of the opposite hand was greatly impaired. MOTOR CORTEX REORGANIZATION IN HUMANS Noninvasive methods have been used to reveal changes in motor cortex contralateral to an amputated limb in patients. One procedure has been to measure evoked potentials in muscles in the intact proximal part of the amputated limb and the same muscles in the normal limb, while stimulating contralateral motor cortex with tran- scranial magnetic pulses. As larger evoked potentials were recorded in muscles of the amputated limbs, the motor cortex contralateral to the amputation was assumed to be more excitable for these muscles. In addition, optimal scalp positions for tran- scranial stimulation of these muscles were displaced medially toward the missing hand representation in M1 suggesting that M1 had reorganized to over represent the remaining arm muscles in hand cortex. For uncertain reasons, this change in repre- sentation seemed to occur only in patients with phantom limb pain. Finally, there was a correlation between motor and somatosensory cortex reorganization in these patients, as face stimulation activated somatosensory hand cortex in the same patients with evidence for motor cortex organization. These results suggest that motor cortex reorganization in humans with amputations can be very similar to that demonstrated with invasive methods in monkeys. Other results from humans indicate that some plastic changes in motor cortex can be very rapid. In a number of studies, a limb (arm) is made ischemic in order to temporarily and reversibly block nerve conduction. During the block of nerve conduction in the ischemic limb, transcranial magnetic stimulation of the motor cortex more effectively activates muscles proximal to the nerve block, suggesting that a rapid increase in motor cortex excitability has occurred. PLASTICITY AFTER LESIONS OF MOTOR CORTEX IN HUMANS Considerable behavioral recovery may follow strokes or tumors that damage parts of primary motor cortex in humans (see below), although full compensation may be unlikely. There is some evidence from focal transcranial magnetic stimulation that the intact motor cortex becomes more involved in eliciting ipsilateral muscle responses in patients with hemiparesis after ischemic strokes affecting M1 of the other hemisphere. As in monkeys, some reorganization may rapidly follow lesions as intra-operative mapping of cortically evoked hand and forearm movements in patients before and after therapeutic lesion demonstrated local changes in the motor map. SUMMARY AND CONCLUSIONS Placental mammals have a primary motor area, M1, of the frontal cortex that is identified by containing a characteristic map of movements of muscles of the con- tralateral body. Normally, M1 represents the hindlimb, trunk, forelimb, and head in a caudomedial to rostrolateral sequence across M1. The organization of M1 is revealed by evoking muscle movements in these body parts with short trains of electrical pulses via microelectrodes positioned in the lower layers of the cortex. At low levels of current, only a few muscles are activated, but higher levels of current stimulate more muscles and evoke more complex movements. In humans, crude but useful motor maps can be produced with noninvasive transcranial magnetic stimulation. Changes in the motor maps are revealed with noninvasive transcranial stimulation by shifts in the location on the scalp that is most effective in eliciting a specific movement, or a lowering of the stimulation threshold for a given movement at a given site. In rats, prosimian primates, monkeys, and humans, the motor map in M1 has been altered in internal organization by direct damage to parts of the map, lesions of corticospinal pathways and motor nerves, or by limb amputations. When motor maps in individuals with damage to the motor system are compared to those from © 2005 by Taylor & Francis Group. Reorganizations of M1 were first demonstrated in rats where cortex normally devoted to facial whisker movements, or forelimb movements, became devoted to other movements after cutting the motor nerve to the whisker muscles or amputating a forelimb.

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Brain damage from chronic the hangover super levitra 80mg low price, a condition characterized by headache generic 80 mg super levitra with amex, ethanol consumption can be especially severe in the nausea, sweating, and tremor. The fetal alcohol syndrome has three primary features: microcephaly, prenatal growth Treatment for Acute Intoxication deficiency, and short palpebral fissures. Other character- Generally, no treatment is required for acute ethanol in- istics include postnatal growth deficiency, fine motor toxication. Allowing the individual to sleep off the ef- dysfunction, cardiac defects, and anomalies of the exter- fects of ethanol ingestion is the usual procedure. A definite risk of producing Hangovers are treated similarly; that is, no effective fetal abnormalities occurs when ethanol consumption remedy exists for a hangover, except for controlling the by the mother exceeds 3 oz daily, the equivalent of amount of ethanol consumed. For example, prompt treat- ment is required if the patient is in danger of dying of Treatment for Alcoholism respiratory arrest, is comatose, has dilated pupils, is hy- pothermic, or displays tachycardia. The immediate concern in the treatment of alcoholics is Treatment for severe ethanol overdose is generally detoxification and management of the ethanol with- supportive. Once the patient is detoxified, long- lieved by intravenous administration of hypertonic term treatment requires complete abstinence, psychiatric mannitol. Hemodialysis can accelerate the removal of treatment, family involvement, and frequently support ethanol from the body. If ethanol is taken after disulfiram administration, blood acetalde- hyde concentrations increase 5 to 10 times, resulting in Alcoholism vasodilation, pulsating headache, nausea, vomiting, se- Alcoholism is among the major health problems in most vere thirst, respiratory difficulties, chest pains, orthosta- countries. In certain tive drugs, is expressed as drug-seeking behavior and is cases, marked respiratory depression, cardiac arrhyth- associated with a withdrawal syndrome that occurs after mias, cardiovascular collapse, myocardial infarction, abrupt cessation of drinking. The ethanol withdrawal acute congestive heart failure, unconsciousness, convul- syndrome is characterized by tremors, seizures, hyper- sions, and sudden death have been reported. Hepatic fatty infiltration and cirrhosis are common ticraving drugs, for example serotonin uptake inhibitors, 416 IV DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM dopaminergic agonists, and opioid antagonists. The only of the most abundant receptors in the CNS, and its dis- treatment that has shown considerable promise is one tribution within the brain reflects the pharmacological that uses the opioid antagonist naltrexone. High receptor densities in the extrapyramidal motor system and the cerebellum are consistent with the actions of cannabinoids on many MARIJUANA forms of movement. The effects of cannabinoids on cog- nition and memory may be due to the relatively dense The hemp plant, or cannabis (Cannabis sativa), contin- receptor populations in the hippocampus and cortex. The dried leaves and flowering tops of the medial striatum and nucleus accumbens suggests an as- plant are referred to as marijuana, and it is typically sociation with dopamine neurons hypothesized to me- smoked in pipes or rolled as cigarettes. Hashish is a solid black resinous material obtained from the leaves of the plant and is usually smoked in a pipe. Pharmacological Actions Central Nervous System Chemistry Marijuana produces a distinctive behavioral syndrome that is easily distinguished from that of most other The major psychoactive constituent in marijuana use is 9 drugs. The most prominent feature is the initial period -tetrahydrocannabinol (THC), the prototypical can- of euphoria, or high, which has been described as a nabinoid. Euphoria is fre- of cannabinoids, they lack behavioral activity with the quently followed by a period of drowsiness or sedation. Pharmacokinetic Aspects The subjective effects of marijuana vary from indi- 9 vidual to individual as a function of dose, route of ad- -THC is readily absorbed when marijuana is smoked. Motor coordination also may decrease, espe- dynamics of smoking (number of puffs, spacing, hold cially in situations requiring highly complex motor skills, time, and lung capacity) substantially influence how such as flying an airplane and driving an automobile. Although oral ingestion of mari- 9 Increased appetite is frequently attributed to smok- juana produces similar pharmacological effects, -THC ing marijuana. Impairment on particularly in treating emesis arising during chemo- various performance measures related to driving skills 9 therapy. This time discordance between blood concentrations of 9-THC and effects has The most consistent pharmacological effect produced made it difficult to establish a meaningful relationship by marijuana is tachycardia, which is closely associated between blood concentrations and effects. There is relatively lit- 9-THC is rapidly distributed to all tissues despite tle effect on blood pressure unless large quantities of being tightly bound by plasma proteins. Traces of 9-THC have been found vasodilatory, which results in the characteristic conjunc- in adipose tissue more than 30 days after the subject tival reddening following marijuana smoking. The terminal half-life of 9-THC reduce intraocular pressure and are capable of produc- in plasma ranges from 18 hours to 4 days. Mechanism of Action Adverse Effects A cannabinoid receptor identified in the brain of sev- Marijuana is unique among drugs of abuse in that there eral species, including humans, is termed CB1. The 35 Contemporary Drug Abuse 417 most prominent effect of acute marijuana use is intoxi- responsive fashion include phencyclidine (PCP), methyl- cation, which can impair the cognitive and motor skills enedioxymethamphetamine (MDMA), and methylene- needed to complete complex tasks. The indole alkylamines include LSD, psilocybin, 9-THC causes its greatest effects on short-term mem- psilocin, dimethyltryptamine (DMT), and diethyltrypta- ory, as measured in free-recall tasks. Marijuana does not mine (DET), all of which are structurally similar to affect the retrieval of previously learned facts. The other chemical subclass of hallucinogens trast to alcohol, there is no residual hangover from a contains phenylethylamine derivatives such as mesca- single use of high quantities of marijuana. A related stimulatory hallucinogen, PCP, is some individuals have evidence of precancerous lung a piperidine analogue that produces unique effects. However, definitive evidence of the rela- tionship between marijuana smoking and the incidence Extent and Pattern of Abuse of lung cancer is lacking. Because of the rapid tolerance produced does not result in severe withdrawal symptoms, numer- with these drugs, the typical abuser does not use the ous case reports attest to development of dependence drug on a daily basis. The most prominent symptoms were irritability and Illicit PCP abuse began in the 1960s, primarily by restlessness; others included insomnia, anorexia, in- oral ingestion. Cessation of mild or PCP frequently produced dysphoria, which was unpre- moderate use of marijuana, however, does not produce dictable. The HALLUCINOGENS specific acute effects of a drug like LSD include eupho- The term hallucinogen is often used to describe a drug ria, depersonalization, enhanced awareness of sensory that produces a change in sensory perception, usually ei- input, alterations in the perception of time or space or ther visual or auditory. Drugs commonly assigned to this body image, and to some extent, minor stimulant ef- class include lysergic acid diethylamide (LSD), mesca- fects.

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Open injection of analgesic produced greater pain reduction as measured by less need for on-demand analgesics than hidden injections super levitra 80mg with amex. This increased variability was quite prominent in these studies because the measure being evaluated discount super levitra 80mg with amex, total analgesic dose required by the patients, was significantly lower in the open than the hidden condition but still had a greater variance. In some sense, responsiveness to placebo varied more across subjects than truly blinded (i. The same research group evaluated post- thoracotomy patients to evaluate response expectancies. Subjects given saline but told it was pain medication had significantly less need for analgesic medication than those not told anything. Subjects told they were in a double-blind study of a pain medication and had a 50% chance of receiving pain medication or placebo had a lowered need for analgesics, approximately half-way between the subjects not told anything and the 136 subjects deceptively told they were getting an analgesic medication. In addition to opioids, cholecystokinin has been related to the placebo analgesic effect. Cholecystokinin has a distribution in the CNS similar to that of the opioid peptides and Placebo effect: clinical perspectives and potential mechanisms 265 inhibits the analgesic effects of morphine. Proglumide, a cholecystokinin antagonist, has been shown to increase the placebo effect in an experimental pain condition 137 (submaximum effort tourniquet technique). It is of some interest that this effect was seen only in placebo responders and that placebo non-responders had no change in pain 138 with proglumide. Drugs altering cholecystokinin are related to placebo pain responses but these are unlikely to be general mediators of placebo effects. Positron emission tomography (PET) in healthy subjects during an experimental pain protocol was used to provide some information on cerebral localization of placebo effects. Opioid and placebo analgesia were both associated with increased activity in the rostral anterior cingulate cortex. This contrasted with greater activation in the caudal anterior cingulate cortex from pain. The spatial extent and degree of cerebral activation was much greater for the opioid effect than for the placebo effect. There were differences in activation between the high and low placebo responders, with the high responders having greater activation in rostral anterior cingulate and ventromedial prefrontal 127 cortex. Subjects receiving placebo demonstrated a significant decrease in raclopride binding in the neostriatum consistent with endogenous dopamine release Color Plate 2. The raclopride binding changes reflecting dopamine release in the caudate and putamen were approximately 20% and of similar magnitude to the changes observed following administration of levodopa or apomorphine. Motor testing was not performed, since it would alter the PET scanning, and so it is unclear how the PET results directly relate to motor improvements. Depression Placebo effects have been a significant concern in evaluating depression treatments for decades. There has even been a gradual increase in the percentage of depressed subjects Complementary therapies in neurology 266 143 responding to inert drugs in the placebo arm of antidepressant drug trials. The increase in response to placebo as measured by the Hamilton Rating Scale for Depression score has increased from about 20% to 35% over the past 20 years. This meta-analysis did not find obvious factors related to severity or earlier diagnosis that may have contributed to this change over time. The large response to placebo, albeit related at least in part to natural history, has caused difficulty interpreting some clinical trials. However, this same paper found no advantage of selegiline over placebo in the primary outcome measures, letting one conclude that placebo was quite effective in this study, although 145 alternative conclusions are possible. There has been an attempt to define the brain changes that relate to placebo responsiveness in depression. Changes in brain glucose metabolism using PET were similar in patients responding to placebo and to fluoxetine for treatment of depression. The overlapping brain regions included increases in prefrontal, anterior cingulate, premotor, parietal, posterior insula and posterior cingulate, and decreases in subgenual cingulate, parahippocampus and thalamus. Fluoxetine response was also associated with 146 additional subcortical and limbic changes. In another study, two 9-week placebo- controlled trials of fluoxetine and venlafaxine produced approximately equal numbers of 147 responders (medication or placebo) and nonresponders (medication or placebo). Using cordance, a quantitative EEG analysis technique developed by Leuchter and colleagues, the researchers observed differences in frontal EEG between medication and placebo responders in contrast to the previously mentioned PET study. In both of these studies, the placebo arm contained some intervention, either the therapeutic milieu and group sessions of an in-patient psychiatry service or brief sessions of supportive psychotherapy. A formal meta-analysis suggested that non-suppression of cortisol on a dexamethasone 148 suppression test predicted a poorer response to placebo. Duration of a depressive episode lasting more than 1 year has also been associated with a lower response to 149 placebo. Other predictors of a better placebo response in depression, which may simply reflect milder disease with better natural history, include a lower Hamilton Rating Scale for Depression score and being married. Multiple sclerosis 108 There is a significant interaction between the brain and the immune system, and thus there is a potential mechanism for a placebo effect in multiple sclerosis, a neuroimmunological disorder. Some intervention studies have had more than one assessment prior to beginning active treatment, so the placebo effect can be partially evaluated by comparing the placebo treatment data to the baseline period data. The placebo control group in one interferon β-la study had a 20% decrease in magnetic resonance imaging (MRI) lesion number compared with the 151 baseline period. In another interferon β-la trial with just a single baseline assessment, there was also a placebo group improvement in MRI, as assessed by the number of Placebo effect: clinical perspectives and potential mechanisms 267 152 gadolinium-enhanced lesions. However, given the unpredictable course of the disease, it is difficult to differentiate placebo effect clearly from natural history in the published multiple sclerosis trials. Epilepsy Significant improvements in frequency of seizures, usually defined as a reduction by 153,154 more than 50%, are not uncommon in placebo arms of anticonvulsant trials.

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