M. Raid. University of Maine at Presque Isle.

After determining the Talairaich will likely be developed for relating the two discount 120 mg isoptin. Finally cheap isoptin 40 mg online, using stereo- Interaction of the Transcranial Magnetic tactic guidance (49) isoptin 40 mg generic, they positioned the coil over this point generic 240mg isoptin, Stimulation Coil and ImageAcquisition in effect ensuring that they were probably stimulating the functional location of the behavior in all subjects discount 120 mg isoptin visa. Krings Yet a different technologic problem in this new area revolves et al. In two patients, they also performed cern, the early combinational studies used imaging tech- direct cortical stimulation, finding good correspondence niques in which TMS was delivered in a location other than among all three methods. This probabilistic technique is that where the actual brain imaging was performed (54, more or less acceptable, depending on how consistently 55). Both FDG PET and perfusion SPECT allow one to from one subject to the next a function is located within administer TMS and deliver the radiopharmaceutical agent identifiable anatomic structures, and on how the shapes of away from the scanner. The tracer crosses the blood–brain those structures vary. Thus, this technique still entails the barrier and then settles into active regions. The subject can problem that function does not strictly map to the same then be transported to the scanner for image acquisition. Because of radiation dose limits and slow time resolution, neither of these techniques (FDG PET and perfusion Placement Based on Function SPECT) is suited for thoroughly examining circuits and behavior with the combination of TMS and imaging. For A different approach is to use TMS, electromyography, or this purpose, it is much better to have the TMS coil directly functional imaging to determine the regions activated dur- within the scanner. However, one then has to understand ing a behavior and then position the coil directly over the to what extent, if any, the TMS coil interferes with the functioning region. For behaviors like movement or phos- acquisition of the functional images. Ob- this spot throughout an imaging study (functional behavioral viously, solid core coils are not suited for this type of combi- approach to placement). With fMRI, the TMS coil can produce motor and vision areas, TMS does not produce easily viewed both static and dynamic artifacts. Although it may be possi- effects, so that this direct functional approach becomes im- ble to correct for the static effects, as in PET, some groups possible. The movement elicited by the TMS a train of pulses (56). Both mechanical and pneumatic sys- is a reassuring, if somewhat imprecise, way of being certain tems have been developed to do this. Although it minimizes that one is in the correct area. However, even with compara- the potential impact of the artifact, mechanically moving ble visible movement, one can be on one side or the other the TMS coil produces shimming and alignment issues on of the target area, and it is difficult to know how much or its own and does not allow for true interleaved imaging in how little additional stimulation is occurring. The dynamic artifacts produced by TMS within method reliably causes activation in large corticospinal cir- an fMRI scanner are both more complicated and more diffi- cuits, we have used the functional behavioral approach for cult to account for (see Fig. Substantial progress has been made, so that this cortex (51,52). Whichever method of locating the site of stimulation is used, it is important that the TMS coil be positioned accu- rately and repeatably, and then held securely in place so Integration of Temporal Domains of the that its position relative to the brain is maintained through- Scanner and Transcranial Magnetic out the stimulation. Each group seems to have developed Stimulation its own mounting systems. We have developed a system for accurately and repeatably positioning the TMS coil within The final picture produced by each of the functional imag- an MRI scanner (53). Both structural and functionally ing tools represents summed brain activity over a measure 30: Measuring Brain Connectivity 399 A TMS pulse Fat saturation pulse 90˚ Excitation pulse Read gradient x 100 Ringdown x 100 B C FIGURE 30. Researchers at the Medical University of South Carolina have recently developed the technique of performing transcranial magnetic stimulation (TMS) within the bore of a conven- tional 1. This process produces dynamic TMS-induced eddy currents (B) and static TMS-induced eddy currents (C). As seen in (B), these dynamic eddy currents are approximately twice as strong as the read gradient for about 20 milliseconds, and then drop to approximately the same size as the read gradient for another 20 milliseconds. Although the major eddy currents have died out by 40 to 50 milliseconds after the TMS pulse, some longer, low-level currents are still present that cause significant image artifact (C). The averaged time domain ranges from 20 to 30 Steady State minutes for FDG PET, to 40 to 60 seconds for 15O PET Inthismodel,researchersperformTMSthroughoutanentire and perfusion SPECT, to 2 to 3 seconds for BOLD fMRI, scan and then compare results with those of another scan in to milliseconds for EEG and electromyography. The actual which all conditions are the same except for the TMS.

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Am J on brain activation patterns in postmenopausal women during Psychiatry 1998;155:910–913 generic 40 mg isoptin with mastercard. In vivo measurement spinal fluid content of neurosteroids in patients with unipolar of dopamine receptors in human brain by positron emission major depression who are receiving fluoxetine or fluvoxamine purchase 120 mg isoptin mastercard. Ann NY Acad Sci 1988; Proc Natl Acad Sci USA 1998;95:3239–3244 purchase 120 mg isoptin otc. Ar- one is associated with increases in cortical allopregnanolone and chives of Neurology and Psychiatry 1931;26:1053–1057 generic isoptin 120mg with visa. Premenstrual syndromes: over- hydroxy-5 [ ]-pregnan-20-one: endogenous metabolites of view from a methodologic perspective order 40 mg isoptin fast delivery. Am J Psychiatry 1984; progesterone that are active at the GABA receptor. Anxiolytic activity assessment of menstrually related mood disorders. Am J Psychia- of the progesterone metabolite 5 -pregnan-3 -ol-one. Stress-induced ual of mental disorders, third edition, revised. Washington, DC: elevations of gamma-aminobutyric acid type A receptor-active American Psychiatric Association, 1987. Selective serotonin reuptake inhibitors menstrually related mood disorder and in control subjects. Am directly alter activity of neurosteroidogenic enzymes. Patients with pre- mones, and the menstrual cycle: II. Hormone levels and their menstrual syndrome have a different sensitivity to a neuroactive Chapter 80: Hormonal and Gender Influences on Mood Regulation 1177 steroid during the menstrual cycle compared to control subjects. Interperson strual syndrome have reduced sensitivity to midazolam com- variability but intraperson stability of baseline plasma cortisol pared to control subjects. Neuropsychopharmacology 1997;17: concentrations, and its relation to feedback sensitivity of the 370–381. J Clin Endocrinol Metab 1998;83: lite allopregnanolone in women with premenstrual syndrome. Circulating levels repeat within the androgen receptor gene and its relationship of anxiolytic steroids in the luteal phase in women with premen- to prostate cancer. Proc Natl Acad Sci USA 1997;94:3320– strual syndrome and in control subjects. Reproducibility of varies according to CAG repeat number within the normal regional brain metabolic responses to lorazepam. In: Proceedings of the 81st annual meeting of the Endocrine 1996;37:1609–1613. Neonatal exposure to sensitivity in patients with premenstrual syndrome: an open diethylstilbestrol permanently alters the basal and 17 beta-estra- trial. Mol Cell Endocrinol 1997;126:133– steroids in modulating mood in premenstrual syndrome. Proceedings of the 51st annual meeting of the Society of Biological 213. Lack of effect of with and without depression as compared with controls. Maturi- induced menses on symptoms in women with premenstrual tas 1996;23:91–105. Psychol Med 1996;26: syndrome: effects of 'medical ovariectomy. Lasting response to nous levels of dehydroepiandrosterone sulfate, but not other sex ovariectomy in severe intractable premenstrual syndrome. Am hormones, are associated with depressed mood in older women: J Obstet Gynecol 1990;162:99–105. N Engl J Med 1998;338: gonadotropin secretion in depressive and normothymic phases 209–216.

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The behavioral sig- degree of resistance to extinction and include the duration nificance of the cocaine S was further confirmed by the of extinction responding and the total number of responses fact that the rats initially tested in the presence of the nonre- emitted during the entire extinction session purchase isoptin 40 mg line. The probability ward S showed complete recovery of responding when of reinstating responding under extinction conditions with subsequently presented with the cocaine S isoptin 240mg lowest price, but rats that drug-paired stimuli or even stimuli previously paired with had shown robust reinstatement ceased responding when drug withdrawal can be examined purchase 120 mg isoptin free shipping. These results Both stimulant and opiate self-administration have been support the hypothesis that learned responses to drug- consistently reinstated following priming injections of drug related environmental stimuli can be important factors in (31 40mg isoptin with mastercard,55) discount 120mg isoptin overnight delivery. Responding during extinction is greater in the pres- the reinstatement of drug-seeking in animals and provide 1392 Neuropsychopharmacology: The Fifth Generation of Progress ity in human alcoholics, the motivating effects of alcohol- related stimuli are highly resistant to extinction in that they retain their efficacy in eliciting alcohol-seeking behavior over more than 1 month of repeated testing (96). Place Conditioning Place conditioning procedures can be modified to serve as a model of relapse. Place aversions to opiate withdrawal last for over 8weeks (94) and are resistant to extinction. At- tempts to modify such conditioned effects could hypotheti- cally contribute to knowledge of the factors that contribute to relapse or 'craving. Reliability and Predictability Each of the techniques described has reliability and predic- tive validity. Presentation of stimuli associated with drug injection induces drug craving in humans and maintains responding in the conditioned reinforcement, second-order schedule, and extinction paradigms. The presence or ab- sence of cues associated with drug administration alters the reinstatement of extinguished drug-seeking behavior in pre- FIGURE 97. Lever-press responses during self-administration dictable ways. Training phase: cocaine-reinforced re- sponses during the final 3 days of the self-administration phase in rats (n 15) trained to associate S? No differences were observed between responses during the first and second daily hour of cocaine availability, and responses for cocaine or saline Although it is very difficult to find an animal model of any between rats designated for testing under S versus S condi- psychiatric disorder that mimics the entire syndrome, one tions during the initial 3 days of the reinstatement phase. The data were, therefore, collapsed across groups and daily cocaine can reasonably validate animal models for different symp- sessions for the purpose of this illustration. Extinction phase: ex- toms of mental disorders (32). In the realm of addiction tinction responses at criterion. The extinction criterion ( 4 re- research, the observation that animals readily self-administer sponses per session over 3 consecutive days) was reached within 16. Although intra- the S versus S condition during the reinstatement phase). Rein- venous drug self-administration meets the criteria of reliabil- statement phase: responses under the S (n 7) and S (n 8) ity, predictability, and face validity, it does not represent reinstatement conditions. Exposure to the S elicited significant recovery of responding in the absence of further drug availability. Other Responding in the presence of the S remained at extinction lev- aspects of the addiction syndrome can indeed be modeled, els. Taken with permission from Weiss F, Maldonado-Vlaar CS, but again, it is incorrect to consider any one of these an Parsons LH, et al. Control of cocaine-seeking behavior by drug- associated stimuli in rats: effects on recovery of extinguished op- animal model of addiction. The DSM-IV criteria for sub- erant-responding and extracellular dopamine levels in amygdala stance dependence and animal models relevant to their and nucleus accumbens. Proc Natl Acad Sci USA 2000;97: study are summarized in Table 97. Tolerance (criterion 1) and withdrawal (criterion 2) no longer define addiction, as illustrated by the change in crite- ria outlined in DSM-III versus DSM-IIIR and DSM-IV (5–7); however, evidence is accumulating to suggest that a a powerful model for elucidating the neuropharmacologic common element associated with addiction is a motiva- basis for such effects that are related to the human concepts tional form of withdrawal that is reflected in a compromised of relapse and craving (97). This not only reaf- Cues associated with oral self-administration and avail- firms the importance of withdrawal in addiction (e. In addition, and the dimension of a persistent motivational change that may consistent with the well-established conditioned cue reactiv- be reflected in criteria 7 of the DSM-IV: 'continued use Chapter 97: Recent Advances in Animal Models of Drug Addiction 1393 TABLE 97. ANIMAL MODELS FOR THE CRITERIA OF DSM-IV DSM-IV Animal Models A. A maladaptive pattern of substance use, leading to clinically significant impairment or distress as occurring at any time in the same 12-month period: (1) Need for markedly increased amounts of substance to achieve (1) Tolerance to reinforcing effects: intoxication or desired effect; or markedly diminished effect with Cocaine continued use of the same amount of substance Opiates (2) The characteristic withdrawal syndrome for substance; or substance (2) Increased: (or closely related substance) is taken to relieve or avoid withdrawal Reward thresholds Anxiety-like responses symptoms Cocaine Cocaine Opiates Opiates Alcohol Alcohol Nicotine Tetrahydrocannabinol Tetrahydrocannabinol (3) Persistent desire or one or more unsuccessful efforts to cut down (3) Conditional positive reinforcing effects: or control substance use Cocaine Opiates Alcohol (4) Substance used in larger amounts or over a longer period than (4) Cocaine binge the person intended Opiate intake (dependent animals) Alcohol intake (dependent animals) Alcohol Deprivation Effect (5) Important social, occupational, or recreational activities given up (5) Choice paradigms or reduced because of substance use Behavioral economics—loss of elasticity (6) A great deal of time spent in activities necessary to obtain (6) Opiate self-administration during withdrawal substance, to use substance, or to recover from its effect Alcohol self-administration during withdrawal Progressive-ratio responding (7) Continued substance use despite knowledge of having a (7) Cocaine binge toxicity persistent problem that is likely to be caused or exacerbated by substance use From: American Psychiatric Association, 1994.

Angiotensin antagonists (ACEIs and Administer receptor antagonists) are also effective; their use requires close Intervention fails to antihypertensive agent monitoring of renal function generic isoptin 120mg on-line, serum potassium levels trusted isoptin 40 mg, and hematocrit normalize BP (CA discount 120mg isoptin amex, ACEI isoptin 40 mg with mastercard, or other) levels discount 240 mg isoptin otc. Diuretics frequently are useful adjuncts to therapy in recipients owing to the salt retention that often accom panies cyclosporine M ultidrug regimen: Adequate response add agents of different use. O ther antihypertensive m edications offer no particular benefits to therapy? No classes as necessary or drawbacks and can be em ployed as needed. The rationale of Yes m ultidrug therapy is to em ploy agents that block hypertensive responses via interruption of differing pathogenetic pathways. As antihypertensive drugs are added, this consideration should Yes rem ain param ount [31,32]. GFR— glom erular filtration rate; Yes No TRAS— transplanted renal artery stenosis. Continue Re-evaluate allograft antihypertensive therapy function and drug therapy Reassess periodically Consider TRAS FIGURE 13-19 Transplant renal artery stenosis (TRAS). TRAS accounts for less than 5% of cases of hypertension after transplantation. N onetheless, TRAS should always be considered in patients with refractory hypertension who develop renal insufficiency after addition of an ACEI to the therapeutic regim en. Although noninvasive studies (such as a renal scan with captopril) m ay be helpful in diagnosing TRAS, angiography rem ains the gold standard for diagnosis. Revascularization of the allograft by either surgical or angioplastic techniques m ay im prove renal function and am eliorate hypertension [33,34]. Both tacrolim us and m ycophenolate m ofetil (M M F) cause bloating, nausea, vom iting, and diarrhea in a dose-dependent m anner, particularly when used Nausea and in combination [15,16,25]. Some authors have noted that this rather nonspecific GI toxicity occurs m ore com m only with N eoral® than Drug vomiting Diarrhea Other complications with Sandim m une® (both from Sandoz Pharm aceuticals, East Cyclosporine 4 3 Hepatotoxicity, constipation H anover, N J). Tacrolimus 30 32 Hepatotoxicity, constipation MMF 20 31 Constipation, dyspepsia Azathioprine 12 Rare Hepatotoxicity, pancreatitis FIGURE 13-21 (See Color Plate) Endoscopic image of candida esophagitis with diffuse white exudate (panel A) and colitis induced by cytomegalovirus infection with submucosal hemorrhage, ulcers, and diffuse mucosal edema (panel B). The avail- ability and common use of effective prophy- laxis against acid-peptic disease (eg, H2 block- ers, omeprazole, and antacids) have signifi- cantly reduced the frequency of upper gastrointestinal bleeding. However, infectious agents such as cytomegalovirus and candida continue to be problematic, particularly in the setting of the more intense immunosup- pression afforded by drugs such as mycophe- A B nolate mofetil (M M F) and tacrolimus. FIGURE 13-22 H istologic im age of chronic active hepatitis secondary to infection with the hepatitis C virus (H CV). N ote the periportal distribution of the lymphocytic infiltrate. Recent identification of HCV has caused intense reevaluation of the causes, frequency, and natural history of liver disease in renal allograft recipients. As the percentage of patients with end-stage renal disease who are infected with the hepatitis B virus has diminished, HCV has become the most problematic cause of liver disease. In recipients with H CV antibodies, im m unosup- pressive therapy m ay potentiate liver injury from the virus and accelerate the course of tim e over which cirrhosis develops. Nonetheless, in patients who desire transplantation and have well- preserved liver function, little evidence exists of better longevity on dialysis. HCV can be transmitted easily from donor to recipient in solid organ transplantation. Because kidney transplantation is not a life-saving procedure, m ost transplant centers choose not to use kidneys from donors who are infected with H CV. Previously, liver disease was thought to be a com m on cause of death in renal allograft recipients. As blood transfusions have becom e less com m on in the dialysis population and hepatitis B virus less prevalent, the risk of death owing to hepatic disease seems to have diminished. Unfortunately, therapies for HCV-related hepatitis (interferon- ) have proved to be of questionable efficacy and m ay stim ulate rejection of the renal allograft [35–37]. Bone densitom etry M agnetic resonance imaging of osteonecrosis. H ere, a renal transplant fem oral head but can affect any weight- early after transplantation.

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