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By D. Jensgar. Endicott College.

Thus generic desyrel 100mg line, plasticity experiment demonstrates that Hebbian synap- Plasticity in Sensorimotor and Cognitive Networks 43 EXPERIMENTAL CASE STUDIES 1–4: Sensory Map Plasticity Using a mapping technique with an array of microelectrodes over the cortical surface of monkeys buy desyrel 100mg otc, Merzenich and colleagues conducted a series of experiments that demonstrate the mutability of so- matosensory representations desyrel 100mg otc. In another experiment order 100 mg desyrel otc, monkeys were rewarded for touching a rotating disk that had an uneven sur- face with the tip of a digit for approximately 1 purchase desyrel 100 mg on-line. The cortical represen- tation of the stimulated phalanx enlarged immediately after stimulation and returned to the prestimu- lation size within 30 days. A cortical lesion in area 3b was made where stimulation of one of the fingers had produced neuronal activation. The in- vestigators induced the primate to use the same skin area of the hand in a reinforcing behavioral task by having it manipulate food pellets to eat. In addition, changes in synaptic effectiveness within the local intracortical somatosensory neural network seemed to account for some of the variations in representations they observed. Hori- zontal connections that link cortical neurons over 6 to 8 mm have been found in the visual system. Ax- ons of primary sensorimotor cortex pyramidal cells have as many as five intracortical collateral axons that form synapses over distances of 6 mm. Local anesthetic injected into dorsal column nu- clei resulted in the emergence of a new receptive field for each affected neuron within minutes, which suggests that new fields arise from unmasking previously ineffective inputs. These two mechanisms are related and account for much of the modulation of sensory representational plasticity in humans. Thus, tonic sensory input from cutaneous and In human subjects, studies of sensory rep- digital joint receptors affects the excitability of resentational plasticity and the effects of sen- M1. With practice, task-dependent somato- sory inputs on motor cortex point to the influ- sensory maps are acquired rapidly and are later ences that sensory inputs have on sensorimotor activated when that task is performed. For example, brief anesthesia of the somatosensory cortex switches between differ- median or radial sensory nerves immediately ent preexisting maps, as does M1, depending reduces the size of the representation of the on the requirements of the task. For rehabili- first dorsal interosseus muscle elicited by TMS tation, these studies provide more evidence of over the M1 representation. Many important issues have yet to be ex- creased the excitability of M1 and increased plained at the level of cell connections, cell the representation for ulnar, but not median- properties, and the molecules of neuron-to- innervated hand muscles during testing with neuron interactions at synapses. I emphasize information that may trig- the muscle within 30 minutes and the effect ger ideas relevant to rehabilitation training and lasted up to 1 hour. This example of lated by the strength of excitatory and in- artificially driving sensorimotor integration hibitory connections and the intrinsic ex- likely involves a thalamocortical interaction. Direct corti- cal stimulation of S1 or M1 in monkeys with Hebbian Plasticity small surface electrodes at 50 Hz or less, com- bined with training, would be of great interest In the 1940s, Hebb described an increase in to see if such drive alters the rate or level of synaptic strength between neurons that fire to- skills learning and sensorimotor representa- gether. In a more general sense, synaptic neuron with the firing of a presynap- however, the synaptic efficacy of motor repre- tic one. Subsequently, when a presynaptic sentations are enabled by repetitive activation neuron bursts, the postsynaptic one is more of somatosensory afferents, driven by spinal likely to fire. Whereas the active synapse segmental sensory information associated with strengthens, other unrelated synapses on the the kinematics, kinetics, and temporal features postsynaptic neuron do not. The As discussed in Chapter 3, peripheral nerve, Hebbian learning rule, then, states that con- brain, and spinal cord injury may lead to new nection weights will be increased or decreased somatosensory maps appreciated by fMRI, depending on whether presynaptic and postsy- PET, and other neuroimaging and stimulation naptic activity is correlated or uncorrelated, re- techniques. Studies suggest that this relation- ship maintains the capacity of a circuit to store new information and prevents the saturation of BASIC MECHANISMS OF connections. On the other hand, home- control and sensorimotor learning, I selectively ostatic plasticity may operate over longer time explore some of the burgeoning data at the scales and by altering postsynaptic receptor level of neurons and molecules that help ex- numbers, but still closely linked to the mech- plain remodeling of sensorimotor representa- anisms of Hebbian plasticity. The heterosy- data in humans of time-dependent plasticity naptic synapse ensures that the memory persists. A subgroup of M1 neu- in modulating Hebbian synaptic strengthening rons come to represent new and behaviorally to save an association. Whereas LTP may be relevant information by subtle changes in their critical for short-term homosynaptic Hebbian temporal patterns of firing, by more correlated plasticity, repeated heterosynaptic activity may firing, and by their firing rates. They are the most robust forms of a persistent mod- Cortical Ensemble Activity ification of synaptic transmission in response to a brief stimulus. The cascade for synaptic plas- Many experiments have shown that the selec- ticity involves the modulation of neuronal ex- tive response properties of single neurons can citability by N-methyl-D-aspartate (NMDA) change by associating inputs from other neu- receptor activation, induction by triggering rons across a narrow window in time or by ma- mechanisms for plasticity after NMDA recep- EXPERIMENTAL CASE STUDIES 1–5: Listening to Neuronal Ensembles Cortical ensemble activity can be studied during a motor learning task by listening to the activity of small groups of neurons, usually from 20 to 60 randomly chosen cells located near the tip of the in- tracerebral recording electrodes. For example, electrode recordings were made from sensorimotor stri- atal neurons of rats as they learned to correctly move through a maze by making turns when they heard a tone. These changes were found when the starting gate opened and locomotion began, at the onset of auditory cues, upon making turns to the left or right, and at the end of the maze when a reward was given.

A resident and two interns were huddled over the bedside table looking at one of the flow sheets generic 100 mg desyrel free shipping. Joyce lay unconscious order 100 mg desyrel amex, oblivious to the deliberate rush and hubbub that sur- rounded her purchase desyrel 100mg without a prescription. She was breathing in the classic Kussmaul manner purchase 100mg desyrel with visa, very deep and regular and rapid breaths cheap desyrel 100 mg fast delivery. Te insulin, along with the salt and water replacement, would allow her to do the rest. I have always thoroughly liked manipulating the biochemistry of the event. It takes a lot of knowledge of physiology and biochem- istry to go through the full and proper treatment of a patient in 124 Te Woman Who Could Not Tell Her Husband Anything 125 diabetic ketoacidosis. I had not been called to see Joyce to care for her diabetes but to try to unravel why she was being admitted in coma almost ev- ery month. She had been in the hospital seven times in the past ten months, each time unconscious and in ketoacidosis from un- controlled diabetes mellitus. It never works to pursue directly the possibility that someone stopped taking in- sulin on purpose to go into diabetic acidosis. Even raising the ques- tion with the patient builds resentment and resistance. Te list of other known causes is quite long and includes a number of infec- tious diseases. All had already been either tested for or ruled out on previous admissions. He had no clue why Joyce had such frequent and se- vere recurrences of acidosis. Extensive and exhaustive workups for the known precipitating causes had been negative on all prior ad- missions. He talked a bit about his feelings of failure for not keep- ing Joyce out of trouble. Tere is a belief common among some internists that they are responsible for the total health of their patients in a very direct way, even when the patient is at home. Tis comes from the strict training in hospitals, where indeed the physician bears a heavy re- sponsibility for the health and treatment of the hospitalized pa- tient. Tis sense of responsibility often carries over into the outside 126 Symptoms of Unknown Origin world. She was the young girl at Fort Hood, Texas, who had unregulated diabetes that became well regulated when a little girl and a kitten showed up on the scene. By late afternoon, when I returned to see her, she was talking and taking liquids by mouth. I never fail to get some equivalent of goose bumps every time I witness a completely unconscious patient recover from diabetic coma and begin to talk as though nothing had happened. I had the same feelings when I spoke briefly with Joyce and told her of my reasons for seeing her. Her internist had asked me to see her to try to find out why she had so many episodes of coma. I had found that many patients in hospitals are on the verge of crying almost all the time. Some people have said that hospitals are grieving institutions, and that the number of patients with hidden depression or unresolved grief is very large, even as high as 20 percent. In fact, it can Te Woman Who Could Not Tell Her Husband Anything 127 be counterproductive. I had learned to detect at their earliest stages grief or sadness or whatever other internal states can cause tears. Tere is a dictum that says that for every internal emotional state there is a full and visible external representation of that state, if you have the eyes and ears to detect it (Bandler and Grinder 1982). If I distracted the patient, the signs of near crying quickly changed to the distracted state. As best I can tell, people, for a brief moment, are often not aware that they are about to cry. I tested this in one patient whom I had known and trusted for a long time, and he said he was not aware of any sadness or grief even though I had seen his eyes get quite red and watery and his lower lip quiver before I distracted him. I believe there is a considerable delay in most patients between the time external signs are visible and the onset of conscious awareness of internal feel- ings.

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In psychological therapies generic desyrel 100mg line, especially in the field A further thorny issue is that of co-morbid of psychosis discount 100mg desyrel amex, there has been a dilemma about substance abuse desyrel 100mg sale. Most studies will exclude indi- whether to adopt medical diagnosis as entry cri- viduals when the abuse is severe 100 mg desyrel fast delivery, but the cri- teria to studies cheap desyrel 100 mg with amex. Clearly if a treatment produces high levels are unlikely to be free of recreational drug use. A precise description of the therapy efficacy, but it is not clear whether drop-outs is required but, from the trials submitted any use of class A drugs affects the therapeu- so far this is missing in all but a few cases. The new guidelines on research governance40 fering from schizophrenia and substance abuse) do not allow for the harassing of people who in which the substance abuse is thought to have dropped out of trials for their reasons increase the risk of poor outcomes in the primary for dropping out or for data on their current disorder. They had a lengthy duration of illness be a reasonable exclusion criterion as CBT relies although at the time of discontinuation they were on the carry-over of changes in one session to not severely ill and functioned at a reasonable subsequent sessions. They were likely to be paranoid but not learning disabilities may also have some difficul- suspicious of the therapist. They were unlikely ties with CBT as it is currently devised, although to be grandiose. They did not understand the therapists have extended treatment for depression rationale for therapy or the potential for benefit to the learning disabilities field. This information Drop-out or Lost to Follow-up may consist of health service contacts kept on health care databases such as case notes as Two main issues affect the inferences about the well as information from third parties. The first is the effect of those people involving people with severe disorders, third- who drop out of the therapy and the second party information from key workers is nearly is those people who are lost to contact at any always included as part of the measurement of stage of the trial. Some systems the relevance and benefit of the trial results to the assume that the person would not have changed wider community. It may therefore be unethical at all since leaving the trial (LOCF), but this not to collect as much of it as possible. Drop-outs may be those people who the idiosyncratic interpretations made by local COGNITIVE BEHAVIOUR THERAPY 285 Research Ethics committees will lead to further ways. Recruitment may be affected by what ser- confusion in this already complicated area. For example, recruitment is likely to be different if there is free universally available PLATFORM AND ORDNANCE health care provided by a service committed to research and development. A large proportion of A naval military analogy between the vehicle the population will use this service and poten- of delivery, the platform (e. This case is very the difference between service organisation and different when health care is provided, funded by therapy. In and so on; whereas ordnance would consist this case the proportion of the population avail- of different types of therapeutic intervention, able for recruitment will be much reduced and such as CBT and family interventions. This biased towards certain subgroups who may, for distinction is useful in clarifying what is being whatever reasons, have no access to private care. For example a trial of different service Here recruitment is likely to be highly selective organisations (platforms) would be the UK 700 and potentially biased. The provision of different trial,43 in which 708 psychotic patients in four services to different income groups or other popu- centres were randomly assigned to standard or lation subgroups mitigates against representative- intensive case management. In this trial the only ness of trial populations in the USA, Australia specific difference between the two trial limbs and some European countries44,45 and compro- was the number of patients the case managers mises the value of such trials. No investigation was made about the therapeutic input that the case RANDOMISATION managers implemented. The results indicated that there was no advantage in clinical or social Purpose outcomes of intensive case management. In contrast there are examples of therapy trials in To give an equivalent chance of a recruit being which a comparison was made between CBT in any of the groups in the trial design. Some plus routine care, supportive counselling plus researchers think that one of the purposes is routine care, and routine care alone for chronic to balance the groups on every factor that patients15 and acute patients. It may be questioned whether particular factor may affect the outcome then trials of services are of much value if they do this should be included as a factor in the not include effective therapies. In the past researchers have said they unlikely to perform well in a naval engagement have provided evidence of the equivalence of firing a bow and arrow! The current advice is not accessibility may affect trials in a number of to carry out such pre-treatment comparisons 286 TEXTBOOK OF CLINICAL TRIALS but to include pertinent factors in the outcome to significant treatment effects. However, there is a need for a clear recent study has not found this to be true,38 description of the people who dropped out of trialists should consider this factor in their treatment in relation to those who remained as analysis if only to counter such criticisms.

Constricted pupils (from contraction of the circular cAMP concentrations buy cheap desyrel 100mg on-line, resulting in bronchodilation muscle of the iris) and accommodation to near vision (see Chap desyrel 100 mg otc. Contraction of smooth muscle in the urinary bladder receptors is thought to stimulate the production of cAMP discount 100mg desyrel mastercard, 9 generic desyrel 100 mg free shipping. Contraction of skeletal muscle as does activation of beta1 and beta2 receptors order desyrel 100 mg with mastercard. No apparent effects on blood coagulation, blood sugar, • Dopaminergic receptor D2: Activation of this receptor mental activity, or muscle strength is thought to inhibit formation of cAMP and to alter cal- These responses are regulated by acetylcholine, a neuro- cium and potassium ion currents. D3 and D4 receptors transmitter in the brain, ANS, and neuromuscular junctions. After its release from the nerve end- • Muscarinic5 receptors: Receptor activation results in a ing, acetylcholine acts briefly (milliseconds), then is rapidly molecular response similar to M1 receptor activation. The metabolized by acetylcholinesterase (an enzyme present in receptor has been identified in central nervous system tis- the nerve ending and on the surface of the receptor organ). Acetylcholinesterase splits the active acetylcholine into in- • Nicotinicn receptors: These receptors are located on active acetate and choline; the choline is taken up again by autonomic ganglia and the adrenal medulla. Acetylcholine ex- results in enhanced transmission of nerve impulses at all erts excitatory effects at nerve synapses and nerve–muscle parasympathetic and sympathetic ganglia, and release junctions and inhibitory effects at some peripheral sites such of epinephrine from the adrenal medullae. Cholinergic Receptors • NicotinicCNS receptors: These receptors are located on When acetylcholine acts on body cells that respond to presynaptic nerve fibers in the brain and spinal cord. When they are activated by acetylcholine, the cell membrane depolarizes and produces muscle contraction. Muscarinic CHARACTERISTICS OF receptors are located in most internal organs, including the AUTONOMIC DRUGS cardiovascular, respiratory, gastrointestinal, and genitourinary systems. When muscarinic receptors are activated by acetyl- Many drugs are used clinically because of their ability to stim- choline, the affected cells may be excited or inhibited in their ulate or block activity of the SNS or PNS. These receptors have been further subdivided, with activity act like endogenous neurotransmitter substances; two types of nicotinic and five types of muscarinic receptors drugs that block activity prevent the action of both endogenous identified. Although the subtypes of cholinergic receptors have not Drugs that act on the ANS usually affect the entire body been as well characterized as those of the adrenergic re- rather than certain organs and tissues. Drug effects depend on ceptors, the intracellular events (of signal transduction) which branch of the ANS is involved and whether it is stimu- after stimulation are thought to include the following lated or inhibited by drug therapy. Thus, knowledge of the mechanisms: physiology of the ANS is required if drug effects are to be un- • Muscarinic1 receptors: Activation of these receptors re- derstood and predicted. In addition, it is becoming increasingly sults in a series of processes during which phospholipids important to understand receptor activity and the consequences in the cell membrane and inside the cell are broken down. More drugs are being developed One of the products of phospholipid metabolism is ino- to stimulate or inhibit particular subtypes of receptors. The inositol phosphate acts as a second part of the continuing effort to design drugs that act more messenger to increase the intracellular concentration of selectively on particular body tissues and decrease adverse calcium. Calcium also acts as a second messenger and effects on other body tissues. For example, drugs such as terbu- functions to activate several intracellular enzymes, initi- taline have been developed to stimulate beta2 receptors in the ate contraction of smooth muscle cells, and increase se- respiratory tract and produce bronchodilation (a desired effect) cretions of exocrine glands. As a result, less cAMP is formed to confusing because different terms are used to refer to the act as a second messenger and stimulate intracellular ac- same phenomenon. Receptor stimulation also results in activation of alpha- and beta-adrenergic agonists are used to describe a potassium channels in cell membranes of the heart. The drug that has the same effects on the human body as stimula- overall consequence of M2 activation is inhibition of tion of the SNS. There are also the same cascade of intracellular processes as with acti- drugs that oppose or block stimulation of these systems. In addition, nitrous oxide is patholytic, antiadrenergic, and alpha- and beta-adrenergic generated from vascular endothelial cells, resulting in blocking drugs inhibit sympathetic stimulation. Their loca- adrenergic, antiadrenergic, cholinergic, and anticholinergic tion and function have not yet been delineated. CHAPTER 17 PHYSIOLOGY OF THE AUTONOMIC NERVOUS SYSTEM 267 SELECTED REFERENCES Review and Application Exercises Hoffman, B.

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