By D. Sanford. La Salle University.

A cortical column refers to the smallest arrange- ment of neurons throughout the six cytoarchitectonic layers in the cerebral cortex that function together to define some feature of the environment purchase 300 mg wellbutrin free shipping depression in test. MOTOR LEARNING Our laboratory has been specifically interested in plasticity in the primary motor cortex (M1) during motor skill acquisition in both the normal and injured brain buy wellbutrin 300mg on-line mood disorder causes, and we have recently been investigating the relationship between M1 and the premotor areas (particularly the ventral premotor area, PMv ; see Figure 8. During the early stages of electrophysiology experiments such as those carried out by Sherrington and Penfield, M1 was thought to be involved with reflex activation of motor neurons and lacking plasticity necessary for volitional movements, espe- cially since it was known that there were many corticospinal neurons that synapsed directly onto motor neurons. By the mid 20th century it was clear that the motor cortex was somatotopically organized. Asanuma found that delivering a volley of short duration cathodal pulses at a high frequency would be effective when delivered through small tip electrodes using very weak currents (< 60 µA) thus limiting the spread of direct excitation in the cortex. The finer resolution allowed by ICMS has revealed that within the gross somatotopic organization of the motor cortex separating major body parts, specific areas such as the proximal and distal forelimb representations comprise a montage of movement representations due to extensive overlap of muscle representations. One way in which biologically impor- tant events can shift this balance towards strengthening new connections, and thus altering movement representations is through sensorimotor integration that occurs © 2005 by Taylor & Francis Group. Physiological evidence for this aspect of motor skill learning was demonstrated by Asanuma and colleagues using ICMS stimulation in cortical and subcortical sensory input areas while recording evoked potentials in M1. This coactivation of sensory inputs induces LTP and strengthens synaptic connections with the motor columns engaged while a movement is performed. Once these connections are made, input from the primary somatosensory cortex is no longer necessary for the skilled movement (see Figure 8. The central sulcus of the green monkey (and also macaque monkeys and humans) is significantly deeper rendering accurate topo- graphic mapping more challenging. Recent experiments in our laboratory have further characterized functional plas- ticity in the motor cortex using standard ICMS techniques as established by Asanuma and colleagues. This technique has been used by many investigators within rat, cat and monkey cerebral cortex to determine organization of movement representations with high spatial resolution. Because our interests have focused on skilled hand use and the consequences of motor learning within M1, we have concentrated our efforts on the distal hand and forearm representation in primates (see Figure 8. The dexterity and agility of the primate hand is ideal for studying motor skill learning, and because of the complex interaction of the intrinsic muscles and joints during motor skill learning, it is ideal for studying modifications in the central nervous system as optimal strategies are learned. In our ICMS experiments, we use glass micro- pettes with tips averaging about 10 to 20 µm in diameter. The stimulating electrode is placed perpendicular to the cortex and mechanically lowered to a depth of about 1,750 µm targeting layer V of M1, the location of the corticospinal cell bodies. Each electrode penetration is recorded on a digital picture of the exposed cortical surface at 250 µm increments © 2005 by Taylor & Francis Group. Thin black line circumscribes penetrations where ICMS evoked movements of the distal forelimb, or hand. Right: More detailed topography of distal forelimb movement representations in the same monkey. Note the mosaic appearance of interdigitated digit and wrist/forearm representations. This method allows us to create a detailed map, or topographic representation of movements in the tangential plane (see Figure 8. As this procedure induces negligible damage to the cortical tissue due to the small size of the microelectrodes, the mapping procedures can be repeated multiple times to detect changes in topography that may be associated with learning new motor- skills. Multiple maps in the same animal (within-subjects design) are necessary, since results from our motor mapping procedures demonstrate that baseline motor maps are highly individualized, presumably representing the personal history of each monkey before training. The wells differ in diameter ranging from wells large enough for the insertion of all digits, to wells that only allow one or two digits to be inserted. Monkeys are trained to make multiple retrievals of these food pellets for about one hour per day. ICMS maps are derived prior to motor skill training to establish a normal baseline for each monkey and then again following extensive training on the Klüver board. Caudally the hand representation is bordered by somatosensory cortex (specifically, area 3a) and no ICMS-evoked responses are elicited from stimulation at the low current levels used in our protocol. The first of these studies to demonstrate the dynamic relationship between movement representations and how they reflect the behavioral demands of varying environmental contingencies was reported in 1996.

K secretion by the collecting duct vantage over either com ponent given separately and tend to restrict the ability of the clinician to principal cells is a passive phenom enon that depends on and is secondary to the active reabsorption of Na cheap wellbutrin 300 mg fast delivery anxiety therapy. Spironolactone H secretion by the late distal tubule and cortical collect- is a m ild diuretic and m ay be useful in treating the edem a that occurs in these two clinical conditions discount wellbutrin 300 mg otc depression brain, ing duct. Adverse Effects Pharmacokinetic Properties Serum electrolyte balance should be m onitored peri- Both triam terene and am iloride are effective after odically, since potentially fatal hyperkalem ia m ay occur, oral adm inistration. D iuresis ensues within 2 to 4 hours 21 Diuretic Drugs 249 after adm inistration, although a m axim um therapeutic m ent of the nephron is critical for determ ining the final effect m ay not be seen for several days. A s m uch as 20% of the filtered cause a m odest (2–3% ) increase in Na and H CO ex- Na m ay be reabsorbed by the loop of H enle. The im - 3 cretion, a reduction in K and H loss, and a variable ef- portance of the loop is further em phasized by the real- fect on Cl elim ination. A pproxim ately 80% of an ad- ization that drugs that prim arily inhibit proxim al Na m inistered dose of triam terene is excreted in the urine and fluid reabsorption have their natriuretic response as m etabolites; am iloride is excreted unchanged. Thus, any agent that greatly Clinical Uses Triam terene can be used in the treatm ent of conges- im pairs active reabsorption in the thick ascending lim b m ay induce a very large Na and water loss. It is frequently used in m ore, the relatively lim ited capacity of the distal tubule and collecting duct for Na reabsorption m akes it im - com bination with other diuretics except spironolactone. A m iloride, but not triam terene, possesses antihyperten- possible to recapture m uch of the suddenly increased tubular Na reaching them. These K -sparing diuretics have low efficacy when Since the thick ascending lim b is responsible for ini- used alone, since only a sm all am ount of total Na re- tiating events that lead to the hyperosm olar m edullary absorption occurs at m ore distal sites of the nephron. Thus, drugs that inter- ability of fixed-dose m ixtures of thiazides with nons- fere with this concentrating function will have m arked teroidal K -sparing com pounds has proved a rational effects on urinary output. Both triam terene and am iloride are available alone or in com bination with hy- Diuretic Response drochlorothiazide. D uring the peak effect of the loop diuretics, urine flow is greatly augm ented, as is the excretion of Na and Cl, Adverse Effects corresponding to as m uch as 20 to 30% of their filtered Because the actions of triam terene and am iloride load. K loss also occurs as an indirect effect of the large are independent of plasm a aldosterone levels, their pro- Na load reaching the distal tubules and is 2 to 5 tim es longed adm inistration is likely to result in hyper- above norm al levels of K excretion. Both am iloride and triam terene are con- erately effective doses, these drugs do not appreciably traindicated in patients with hyperkalem ia. Potassium intake m ust be reduced, especially bum etanide (Bum ex) possess som e carbonic anhydrase in outpatients. A folic acid deficiency has been reported inhibiting activity (about one-tenth that of chloroth- to occur occasionally following the use of triam terene. This property m ay account for the increased bi- carbonate and phosphate excretion seen after large doses of these diuretics. The elevated H CO loss prob- High-Ceiling, or Loop, Diuretics 3 ably indicates som e proxim al tubular effects for The com pounds known as high-ceiling or loop diuretics furosem ide and bum etanide. They can in- Pharmacokinetic Properties crease diuresis even in patients who are already re- sponding m axim ally to other diuretics. The drugs in this A ll of the loop diuretics are available for both oral and group available for use in the U nited States include parenteral adm inistration. Their onset of action is rapid, furosem ide (Lasix), bum etanide (Bum ex), torsem ide usually within 30 m inutes after oral and 5 m inutes after intravenous adm inistration. A lthough in about 2 hours, with a total duration of diuretic action these agents differ som ewhat, they share a com m on pri- of approxim ately 6 to 8 hours. A pproxim ately a third of an adm inistered dose The site of action of loop diuretics is the thick ascending is excreted by the liver into the bile, from where it m ay lim b of the loop of H enle, and diuresis is brought about be elim inated in the feces. Like the thi- pounds, well absorbed after oral adm inistration, freely azides, however, the loop diuretics are weak organic filtered at the glom erulus, poorly reabsorbed by the acids that are substrates for the organic acid secretory tubule, and devoid of pharm acological effects. A consequence of this ac- totype is m annitol (O sm itrol), an unm etabolizable poly- tive secretion is that the presence of other organic acids saccharide derivative of sucrose. O ther clinically avail- or certain form s of renal disease m ay im pair the thera- able osm otic diuretics include glycerin (G lycerol, peutic usefulness of the loop diuretics. O sm oglyn, and the topical agent O phthalgan), isosor- bide (Ism otic), and urea (Ureaphil, Urevert).

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