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    The ability of the previous neutral buy generic levitra extra dosage 40mg on-line, Similar results have been obtained in an operant runway drug-paired stimulus to maintain responding in the absence task (57) 40mg levitra extra dosage with amex. It is also apparent that environmental stimuli of drug injections provides a measure of the reinforcing predictive of cocaine self-administration reliably elicit drug- value of these stimuli. This procedure provides a stringent seeking behavior in experimental animals and that respond- test for the conditioned incentive effects of drugs because ing for these stimuli is highly resistant to extinction (39, responding for drug-associated stimuli occurs under extinc- 87,97). It also provides an animal model of drug craving because the incentive moti- Reinstatement of Extinguished Drug- vational effects of a stimulus are examined in the absence Seeking Behavior in an Animal Model of of drug taking. Relapse: Use of Discriminative Stimuli Rat models of 'relapse' induced by drug-related stimuli Second-Order Schedules also can involve the use of a drug-predictive discriminative Second-order schedules also can be used to evaluate the stimulus (S? This stimulus is paired with response-contin- conditioned reinforcing effects of drugs. To assess the effects gent presentation of a stimulus that has been contiguously of conditioned reinforcement, the number of responses with paired with drug presentations (i. For example, substitu- lever after prior extinction of alcohol-seeking behavior. Dis- tion of drug-paired stimuli with nondrug-paired stimuli ac- criminative stimuli signal the availability of a reinforcer, tually can decrease response rates (43). This maintenance and thereby provide motivation to engage in behavior that of performance with drug-paired stimuli appears to be anal- brings the organism into contact with the reinforcer. A con- ogous to the maintenance and reinstatement of drug seeking dition often associated with drug craving in humans is cog- in humans with the presentation of drug-paired stimuli nitive awareness of drug availability (63). In rats, a decrease in responding and an increase in stimuli, therefore, may have a prominent role in craving the latency to initiate responding occurs in response to with- and the resumption of drug-seeking behavior in abstinent holding a stimulus paired with cocaine self-administration individuals. The schedule can be repeated several times during a as a conditioned reinforcer, may contribute to the mainte- test session, resulting in multiple infusions of drug. How- nance of subsequent drug-seeking behavior once initiated. Associated with Intravenous Drug To investigate the role of drug-associated stimuli in the Self-Administration motivational effects of a history of cocaine self-administra- Extinction procedures provide measures of the incentive or tion, rats were trained to associate discriminative stimuli motivational effects of drugs by assessing the persistence of (S ) with response-contingent availability of intravenous drug-seeking behavior in the absence of response–contin- cocaine versus saline (97) (Fig. In this paradigm, subjects first are subjected to repeated extinction sessions during which co- trained to self-administer a drug until stable self-administra- caine, saline, and the respective S were withheld until the tion patterns are exhibited. Extinction sessions are identical rats reached extinction. Subsequent re-exposure to the co- to training sessions except that no drug is delivered after caine S , but not the nonreward S , produced strong re- the completion of the response requirement. 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. The probability ward S showed complete recovery of responding when of reinstating responding under extinction conditions with subsequently presented with the cocaine S , but rats that drug-paired stimuli or even stimuli previously paired with had shown robust reinstatement ceased responding when drug withdrawal can be examined. 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 (31,55). 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.

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    When they achieve ences in the clinical symptoms of 15 outpatients with OCD such perfection generic 40mg levitra extra dosage visa, they describe a curious sensation that they but not tics and 12 adult patients with Tourette syndrome can compare to no other feeling purchase 60 mg levitra extra dosage mastercard. All patients with OCD reported that some sional brief appearance of sublime ecstasy. In contrast, all patients with Tourette syndrome reported Feelings of going exactly through the middle of a door, that sensory phenomena preceded their repetitive behaviors; of having both shoelaces tied to exactly the same tension, no OCDpatients reported such sensations (97). Most of us can relate to In the study of Thiel et al. But for the obsessive, this feeling of OCDin a sample of 16-year-old girls in whom anorexia becomes attached to an action that would hold little signifi- nervosa had been diagnosed. The most commonly encountered Patients with trichotillomania or Tourette syndrome also diagnoses are dependent, avoidant, passive–aggressive, and describe a feeling of incompleteness with continued tension compulsive. Schizotypal, paranoid, and borderline personal- until they have finished pulling out an entire patch of hair ities are found less commonly in OCDbut appear to be or completed a sequence of tics to their satisfaction. The core features appear to relate both to the clinical RELATIONSHIP OF HETEROGENEITY TO features of OCDand to the comorbid disorders. In patients COMORBIDITY with abnormal risk assessment, high levels of anxiety are associated with symptoms. They are also likely to have com- We have become increasingly interested in developing a orbid axis I generalized anxiety disorder or social phobia, model for subtyping patients with OCDaccording to what avoidant and dependent personality features, and a family we see as the three core features of the disorder: abnormal history of an anxiety disorder. In contrast, patients with risk assessment, pathologic doubt, and incompleteness. These patients are also in a million chance that the elevator cable will snap, the more likely to exhibit incompleteness. In the same way, many of the thoughts of the 107 patients with OCDwho completed the Y-BOC Symp- patient with OCDare dominated by improbable events that tom Checklist and examined the correlations between the most of us would not think twice about. Many checkers factor scores and the presence of comorbid tic or personality suffer from 'what if? Three factors, symmetry/hoarding, contamina- Chapter 111: Obsessive-Compulsive Disorder 1605 tion/cleaning, and pure obsessions, best explained the vari- incomplete remission that permits normal social function- ance. Only the first factor was significantly related to OCPD ing. Although the results of studies varied considerably in (obsessive-compulsive personality disorder) or a lifetime his- regard to the percentage of patients in each category, the tory of Tourette syndrome. These figures are consistent COMMENT with our own study of patients meeting DSM-III criteria for OCD(Table 111. Although previous descriptive studies During the past 15 years, significant advances have revolu- found a chronic waxing and waning course in 85% of pa- tionized the way we conceptualize and treat OCD. Epide- tients, no attempt was made in previous studies to subdivide miologic studies have confirmed that OCDis an underrec- the waxing and waning course into predictable patterns or ognized common major psychiatric disorder with a lifetime subtypes. More recent studies in which a prospective design prevalence of 2% to 3% in the general population, and and standardized criteria were used have shown that the they have been instrumental in focusing the attention of episodic form of this disorder (clear periods of remission researchers, clinicians, and the media on OCD. Studies of while the patient is off medication) is uncommon. The peri- the clinical features and course of the disorder and associated odicity, duration, and severity of episodes in patients with comorbid conditions have appeared in the literature since OCDvary considerably. Once established, obsessions and the turn of the twentieth century and have been the subject compulsions usually persist, although the content, intensity, of numerous prospective and retrospective studies of its and frequency of the symptoms change over time. The introduction of the SSRIs has led to a significantly Finally, future studies will continue to benefit from fur- improved prognosis for patients with OCDduring the last ther refinement of our thinking about the heterogeneity decade. The identification of an OCD–tic subtype has tion, 64% had a decrease of more than 50% in Y-BOCS already led to important new genetic and biological studies score, and 33% had a decrease of more than 75% in Y- and has been directly relevant to treatment. These results are at odds with fort to characterize pediatric autoimmune neuropsychiatric those of two other prospective longitudinal observational disorders and their relationship to genetic vulnerability to studies of the course of OCDthat have recently been initi- streptococcal infection offers a promising lead for furthering ated at our site. It is compulsive outpatients evaluated at the Yale–Brown clinics possible that we will increase our understanding of predic- and followed them prospectively during a 2-year period. Of tions of remission and relapse related to possible homogene- the 51 patients who started the study meeting full criteria, ous subtypes of illness. A review of these studies suggests 57% still met full criteria after 2 years. Survival analysis that the course of OCD, long thought to be chronic, may revealed a 47% probability of achieving at least partial re- be more episodic than previously believed, particularly in mission during the 2-year study period.

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    A time course series of axial images (matrix size 96 96 buy 60mg levitra extra dosage visa, field of view 20 cm order 40mg levitra extra dosage, echo time 40 ms, repetition time 500 ms, flip angle 80 degrees) through the motor cortex was obtained. Bilateral finger tapping was performed for 2 s, followed by 18 s of rest. These figures demonstrate that the upper temporal resolution is determined by the variability of the signal change in time and space. A: Time course of the signal elicited by tapping fingers for 2 s. The standard deviation at each point is in the range of 1% to 2%. The standard deviation of the hemodynamic change, in time, is in the range of 450 to 650 ms. B: Map of the dot product (a measure of the activation-induced signal change magni- tude) and the relative latencies or delays of the reference function (the plot in A was used as the reference function) at which the corre- lation coefficient was maximized. The spatial distribution of hemo- dynamicdelayshasastandarddeviation ofabout900ms. Thelongest delays approximately match the regions that show the highest dot product and the area where veins are shown as dark lines in the T2*- weighted anatomic image. The third source of variabilityis the la- maybe almost fullydiluted back to resting state oxygena- tencyspread over space. Again, work is ongoing to characterize this correlation analysis and allowed to shift 2 s. The spread in As previouslydiscussed, the magnitude of the fMRI signal latencies is more than 4 s. Making a com- latency; the regions showing the longest latency roughly plete and direct correlation between neuronal activityand correspond to the regions that show the largest signal fMRI signal change magnitude in a single experiment will changes. Although these largest signal changes are likely remain impossible until all the variables can be characterized downstream draining veins, it is important to note that this on a voxel-related basis. Because of these primarilyphysio- approximate correlation between latencyand magnitude is logic variables, the magnitude of BOLD signal changes on extremelyweak. Manyverysmall signal changes show very brain activation maps typically ranges from 1% to 5% [at, long latencies. It is also interesting to note that the inverse, say, 1. This implies that manydownstream vessels years, considerable progress has been made in characterizing 348 Neuropsychopharmacology: The Fifth Generation of Progress the magnitude of the fMRI signal changes with underlying would be present in the voxel. The same could applyif the time constant of the neuronal area corresponding to specific, well-characterized oxidative metabolic rate were slightlyslower than that of tasks. Second, inferred neuronal modulation was carried out flow and volume changes. Evidence for an increased oxida- by systematically varying some aspect of the task. Clear cor- tive metabolic rate after 2 min of activation is given by relations between BOLD signal change magnitude and vis- Frahm et al. This parametric seconds longer than the flow increase time constant—as experimental design represented a significant advance in the would be required to be applicable onlyto relativelyhigh- manner in which fMRI experiments were performed, en- amplitude single-event responses. These hemodynamics, abling more precise inferences, not about the BOLD signal which mayalso differ on a voxel-related basis, remain to be change with task modulation. Recently, several more intriguing studies have emerged SCANNER-RELATED ISSUES correlating measured neuronal firing rate with well-known stimuli in animals (51) and humans (52,53) and demon- A complete discussion of all scanner-related issues and po- strating a remarkablyhigh correlation between BOLD sig- tential solutions is beyond the scope of this chapter. Most practitioners of functional MRI typically undergo a Linearity painful, frustrating, and prolonged period of learning about Related to the topic of signal change magnitude is that of all scanner-related limitations and issues. This learn- that it behaves as a linear system (54,55). This greater than ing process also applies to understanding the physiology of expected BOLD signal change is generallyspecific to stimu- the signal, but typically the greatest anguish arises in the lus durations below 3 s. Reasons for nonlinearities in the context of MRI pulse sequences and hardware.

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    Neuropsychological studies of and magnetic resonance imaging cheap levitra extra dosage 60mg online. Ann Intern Med 1987;107: asymptomatic human immunodeficiency virus-type 1 infected 828–836 levitra extra dosage 60 mg. Do asymptomatic HIV- psychological manifestations of human immunodeficiency virus seropositive individuals show cognitive deficit? AIDS 1995;9: infection in intravenous drug users without acquired immuno- 1211–1220. Early neuropsychological change in neuropsychological functioning: a cluster analysis approach. Working memory in nous drug users in AIDS stages of HIV infection. Cognition and im- Clin Exp Neuropsychol 1992;14:857–868. Psychopharmacology: the fourth generation of progress. New predictors of medication adherence in HIV/AIDS: a preliminary York: Raven Press, 1995:1545–1558. London: Erl- performance in HIV-1-infected homosexual men: The Multi- baum, 1990. Introduction: methodologies and models in the study 197–203. Apathy, depression, healthy HIV-1 infected individuals: results from the Multicenter and cognitive performance in HIV-1 infection. Working memory and nervous system abnormalities among a cohort of intrave- deficits in HIV-seropositive drug users. Delayed recognition 1296 Neuropsychopharmacology: The Fifth Generation of Progress memory span in HIV-1 infection. J Int Neuropsychol Soc 1995; HIV patients: a clinical perspective. Prevalence of psychiatric in tests of executive function in asymptomatic and symptomatic disorders among men infected with human immunodeficiency HIV-1 seropositive men. Mood disorders in associated minor cognitive/motor disorder exhibit a 'subcorti- HIV infection: prevalence and risk factors in a non-epicenter cal' memory profile? Evidence using the California Verbal of the AIDS epidemic. Neuropsychological test per- Int Rev Psychiatry 1996;8:157–166. Proceedings of the National Conference on Women and HIV human immunodeficiency virus (HIV) infection using the Beck 1997;[P1. Depression Inventory: disease processes and other potential con- 53. Computerized and conventional formance among African-American men impacted by HIV/ neuropsychological assessment of HIV-1 infected homosexual AIDS. Mortality risks in gay men Appl Neuropsychol 1998;5:74–84. Mild cognitive im- infection: a case–control study of the evolution of dementia. Variable progression havioral Research Center Group. The AIDS dementia complex: Neuropsychol Soc 1997;3:457–464. World Health Organization con- not explain neuropsychological deficits in HIV-infected per- sultation on the neuropsychiatric aspects of HIV-1 infection. Nomenclature and research and neuropsychological impairment in HIV-1 infection.

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