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Such abnormalities could no significant differences in caudate volume between treat- be owing to aberrations in prenatal programmed cell death ment-naive pediatric OCDpatients and age- and sex-case or postnatal reductions or delays in myelination (84) cheap 0.5mg dutasteride. Localized reductions in putamen volume cent investigation has suggested abnormalities of postnatal associated with OCDsymptom severity but not illness dura- myelination in pediatric OCDpatients (91 order 0.5 mg dutasteride with mastercard,92). Reduced putamen vol- umes have been reported in Tourette syndrome (99), a con- Striatum dition frequently associated with OCDsymptoms. Putami- Despite the striatum being posited as a primary site of pa- nal lesions associated with OCDalso have been reported in thology in OCD(30), structural neuroimaging studies of isolated case reports (100,101) and pediatric OCDpatients the caudate nucleus in adult OCDpatients have revealed have antibodies directed at the putamen at rates significantly contradictory findings. Scarone and colleagues (93) re- greater than in healthy pediatric comparison subjects (102). Four MRI studies have reported no significant differ- OCDor tics associated with group A hemolytic strepto- ences in caudate size between OCDpatients and controls coccal (GABHS) infections and pediatric patients with (79,82,94,95). Investigation of the other components of the Sydenham chorea and associated OCDand tic behaviors basal ganglia, including the putamen and globus pallidus, compared to healthy children. These conditions are now has not demonstrated volumetric differences between adult referred to as pediatric autoimmune neuropsychiatric disor- OCDpatients and controls (84,94,96,97). These studies ders associated with streptococcal infection (PANDAS) were potentially confounded by several factors including (103,104) and may represent discrete subtypes of OCD illness chronicity, past treatments, heterogeneity of OCD, and tic disorders. Increased basal ganglia volumes may be and differences in imaging methodology used. Structural consistent with hypothesized antibody-mediated inflamma- imaging studies in children may prove especially instructive tion of the basal ganglia in poststreptococcal or OCDor because they allow for examination of neurodevelopmental tic disorders (103,104). Giedd and colleagues (24,26), how- factors and repeated studies for longitudinal assessment. Allen and associates (104) OCDpatients is consistent with reductions in striatal vol- observed plasmapheresis to be dramatically effective in ume (information on striatal volumes was not provided). PANDAS patients in reducing OCD and tic symptom se- FIGURE 113. Measurement of putamen in the axial plane using a manual tracing technique (left). Fron- tostriatal measurement in treatment-naive children with ob- sessive-compulsive disorder. Sequential magnetic resonance imaging of basal ganglia volumes in a male adolescent undergo- ingplasma exchangefor infection-relatedobsessive-com- pulsive disorder. Reprinted from Giedd JN, Rapoport JL, Leonard HL,et al. Casestudy: acute basalganglia enlarge- ment and obsessive-compulsive symptoms in an adoles- cent boy. J Am Acad Child Adolesc Psychiatry 1996;3S(7): 913–915. In fact, Giedd and colleagues (25) conducted serial cal volumes have not been found to differ between adult MRI scans and observed a striking relationship among basal OCDpatients and controls (84,85,105). Jenike and associ- ganglia volume, OCDsymptom severity, and treatment ates (84) did observe increased opercular volumes in OCD with plasmapheresis in an adolescent with autoimmune patients. Grachev and co-workers (105) reanalyzed the 10 OCD(PANDAS) (Fig. Recently, Peterson and col- adult female OCDpatients and matched controls studied leagues (27) reported that higher antistreptolysin O anti- by Jenike and associates (84) using a sophisticated topo- body titers were associated with larger basal ganglia volumes graphic parcellation method (106) and found an increase in OCDpatients with chronic or recurrent streptococcal in six right frontal and four left parcellation units in OCD infections. This finding was not specific to OCD; however, patients. Anterior cingulate, orbitofrontal, and opercular as higher antibody titers were also associated with enlarged cortical volumes did not differ significantly between OCD basal ganglia volumes in attention deficit hyperactivity dis- patients and controls. Grachev and associates (105) also order (ADHD) patients with chronic or recurrent strepto- noted a significant correlation between increased volume of coccal infections (Fig. In fact, Peterson right inferior frontal pars triangularis and right midfrontal and colleagues (27) found robust associations between diag- cortical volumes and poor cognitive performance on non- nosis of ADHD and titers of antistreptolysin O and antide- verbal immediate recall testing. More recent investigation oxyribonuclease B titers, whereas no such association was (107) found localized reduced bilateral orbital frontal vol- seen between antibody titers and a diagnosis of OCDor umes in OCDpatients versus healthy comparison subjects. We also do not know the impact of Superior frontal gyrus and anterior cingulate volumes did chronic or recurrent strepto- not differ between OCDpatients and controls. Further leagues (87) reported no significant differences between study is clearly warranted. It also illustrates how function, neurobehavioral response inhibition, with no ab- brain imaging is exploiting advances in developmental normalities in working memory (delayed response) or pre- neurobiology with important implications for neurodiag- paratory set (Fig. Monkey studies and human clini- nostic assessment and treatment development. A neurode- cal studies suggest that ventral prefrontal cortex plays a velopmental perspective is equally critical as illustrated in critical role in mediating the suppression of context inappro- the following.

Le Heuzey JY dutasteride 0.5mg fast delivery, De Ferrari GM order 0.5 mg dutasteride fast delivery, Radzik D, et randomized comparison of left atrial and al. A short-term, randomized, double-blind, biatrial radiofrequency ablation in the parallel-group study to evaluate the efficacy treatment of atrial fibrillation. Eur J and safety of dronedarone versus Cardiothorac Surg. J Circumferential pulmonary vein ablation Cardiovasc Electrophysiol. Circ Arrhythm vena cava in addition to pulmonary vein Electrophysiol. J Cardiovasc Comparison of antiarrhythmic drug therapy Electrophysiol. PMID: and radiofrequency catheter ablation in 19732237. J Improvements in symptoms and quality of Cardiovasc Electrophysiol. A prospective randomized multicenter Impact of rate versus rhythm control on comparison on health-related quality of life: quality of life in patients with persistent the value of add-on arrhythmia surgery in atrial fibrillation. Results from a prospective patients with paroxysmal, permanent or randomized study. Reduction of Atrial Fibrillation (STAR AF): Eur Heart J. PMID: a randomized, multicentre, international 12042011. Van Gelder IC, Hagens VE, Bosker HA, et PMID: 20215126. Results from the Rate Control Versus Randomized ablation strategies for the Electrical Cardioversion (RACE) Study. J treatment of persistent atrial fibrillation: Am Coll Cardiol. Boersma LV, Castella M, van Boven W, et death in patients with persistent atrial al. Atrial fibrillation catheter ablation versus fibrillation in the rate control versus surgical ablation treatment (FAST): a 2- electrical cardioversion (RACE) study. Hagens VE, Van Veldhuisen DJ, Kamp O, Pulmonary venous isolation versus et al. Effect of rate and rhythm control on additional substrate modification as left ventricular function and cardiac treatment for paroxysmal atrial fibrillation. J dimensions in patients with persistent atrial Interv Card Electrophysiol. Rienstra M, Van Veldhuisen DJ, Crijns HJ, paroxysmal atrial fibrillation? PMID: Rhythm or rate control in atrial fibrillation— 17272359. Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Gender-related differences in Analysis of cause-specific mortality in the rhythm control treatment in persistent atrial Atrial Fibrillation Follow-up Investigation fibrillation: data of the Rate Control Versus of Rhythm Management (AFFIRM) study. A Randomized trial of rate-control versus comparison of rate control and rhythm rhythm-control in persistent atrial control in patients with atrial fibrillation. N fibrillation: the Strategies of Treatment of Engl J Med. Confounding factors in Hispanics and Caucasians: clinical features rate versus rhythm control trials in patients and outcomes from the AFFIRM trial. J Natl with atrial fibrillation: lessons from the Med Assoc. PMID: strategies of treatment of atrial fibrillation 16573295. Comparison control strategies for atrial fibrillation: of rate and rhythm control in patients with results of the Atrial Fibrillation Follow-Up atrial fibrillation and nonischemic heart Investigation of Rhythm Management failure. Sinus rhythm patients with persistent atrial fibrillation. The cost comparison of rhythm and rate Quality of life in atrial fibrillation: the Atrial control strategies in persistent atrial Fibrillation Follow-up Investigation of fibrillation. Investigation of Sinus Rhythm Management 2006;13(4):331-7. Control of heart rate versus rhythm in rheumatic atrial fibrillation: a randomized study. Control of rate versus rhythm in rheumatic atrial fibrillation: a randomized study.

In an animal prepara- using [18F]fluorodeoxyglucose carried out at the end of each tion buy dutasteride 0.5 mg with amex, Abercrombie and DeBoer demonstrated the principle treatment period (35) discount dutasteride 0.5 mg with mastercard. Regional cerebral metabolic rates of that a pharmacologic perturbation delivered to a restricted glucose, calculated using the usual analytic techniques, were region in the basal ganglia (e. Haloperidol neurochemical and functional effects (1). The model of significantly activated neuronal activity in the basal ganglia antipsychotic drug action we propose suggests that a pri- (caudate and putamen) and thalamus, whereas the frontal mary effect of dopamine-receptor blockade occurs in the cortex (especially the middle and inferior regions) and the caudate and putamen with antipsychotic drug treatment, anterior cingulate cortex demonstrated a reduction in re- and the transmission of this primary action through the gional cerebral metabolic rates of glucose with haloperidol basal ganglia thalamocortical pathway to limbic and neocor- (Fig. Activational differences between the on-drug tex mediates antipsychotic and motor aspect of the drug and off-drug conditions were surprisingly restricted to these actions in humans. The full mechanism of antidopami- areas, despite the systemic manner of drug delivery and nergic actions therefore could include altered GABAergic steady-state kinetic conditions at testing. The striatal transmission in the globus pallidus (GP), which alters activ- changes had been previously reported (6,68). Subsequent ity in the basal ganglia output nuclei; these changes then evaluation of haloperidol action using regional cerebral modify GABAergic transmission from substantia nigra pars blood flow analysis pharmacodynamically verified these re- reticulata (SNR) to the thalamus, inhibit thalamic nuclei, gional actions. These observations suggest the hypothesis that the whose activity is perturbed by haloperidol, are the same same basal ganglia thalamocortical circuits that mediate 1834 Neuropsychopharmacology: The Fifth Generation of Progress basal ganglia modulatory influence on prefrontal cortex may models of the condition have been developed in nonhuman also mediate the therapeutic effect of antidopaminergic anti- primates and in small animals using long-term administra- psychotic compounds in schizophrenia. We have reasoned tion of antipsychotics and applied to the study of TD mech- that a drug-induced regional change, occurring over time anisms. The structural and functional brain characteristics within this basal ganglia–thalamocortical pathway, associ- of nonhuman primates are reasonably similar to those of ated with a regional increase in the thalamocortical signal human primates; hence, primate preparations may make could be associated with TD. Yet, it is the reality of nonhuman primate models that many treatment years are required for ROLE OF THE BASAL GANGLIA dyskinesia development (2 to 6 years), and monkey care is THALAMOCORTICAL PATHWAY IN involved and expensive. Alternatively, putative rat models MEDIATING AND TRANSMITTING THE have also been proposed; rat oral dyskinesias develop faster ANTIDOPAMINERGIC ACTION IN with chronic treatment (6 to 12 months), yet they retain STRIATUM TO CORTEX many phenomenologic and pharmacologic characteristics of human TD (61,70). These models often provide a more Basal ganglia and thalamic structures modulate functions realistic experimental platform, even if not more valid, than of the frontal cortex through parallel segregated circuits, a the nonhuman primate for developing hypotheses about process that has been most fully studied for motor function. For the Animal models of all human diseases have been sought CNS motor system, specific areas of primary motor cortex, for pursuing pathophysiologic hypotheses and for identify- primary sensory cortex, and supplementary motor cortex ing new therapeutics. Investigators have suggested the char- project topographically to the putamen. These projections acteristics of good animal models for an expressed human are thought to remain segregated but parallel throughout illness as similarities in (a) origin, (b) phenomenology, (c) the full course of the circuit, but they are subject to basal biochemical characteristics, and (d) pharmacology (45,73). Investi- Similarities of these features provide greater validation of gators have proposed a family of these frontal circuits whose the model. Across all the TD models, both primate and pathways originate in specific frontal cortex areas, course rodent, origin and phenomenology approximate character- through the basal ganglia and thalamus, and return to the istics of human TD. Biochemical determinants are un- same areas of cortex, to modulate regional frontal cortical known for the TD models as well as for the disease itself. For the motor system, these subcortical struc- However, extensive similarities exist in pharmacologic re- tures appear to contribute to the planning and execution sponse between the human illness (TD) and the model of body movements; for other frontal systems, these same preparations. Because rodent models are more practical to subcortical structures may contribute to maintenance and pursue, their pharmacology has been more broadly de- switching of behaviors and aspects of cognition (2,26). It would be obvious to The thalamus exerts an excitatory effect on frontal cortex suggest that the use of both rat and monkey models would pyramidal cell activity, partially delivered within each fron- be ideal, as the efficiency and specificity of the questions tal region by the paired parallel segregated circuit. These inhibitory output nuclei Nonhuman Primate Models stimuli are, in turn, regulated by two parallel but opposing pathways from the caudate and putamen, one excitatory Antipsychotic treatment in the nonhuman primate has been and the other inhibitory. The primary cortical signal to basal studied to define the mechanism of acute drug-induced par- ganglia is mediated by an excitatory glutamatergic pathway. It would be rational to suspect some role of these parallel Gunne et al. This idea correlated with the known clinical phar- The cause of TD in antipsychotic drug–treated patients macology of TD, namely, that GABA agonist treatment can is, by definition, long-term drug treatment. Thus, putative improve drug-induced dyskinesias (65). Chapter 126: Tardive Dyskinesia 1835 Rodent Models transmission in nonhuman primate basal ganglia directly affected the output nuclei, and from there, the thalamic and Results from many laboratories suggested that rats treated frontal regions associated with the segregated motor circuit. In comparison, the newer antipsychotics, often called vacuous chewing movements (13,16,18,23,27,30, including clozapine, olanzapine, sertindole, and low-dose 56,61). The phenomenology of CMs resembles TD, in that risperidone, failed to induce the rat 'syndrome' of CMs movements have a gradual onset (61), partial penetrance (21,39). Can these preparations contribute to knowledge (34), and a delayed offset, and they are sensitive to stress of TD pathophysiology? However, the movements in rats remain limited to mation to the mechanism of antipsychotic drug action? The Comparison of several different animal treatment groups pharmacology of CMs resembles that of TD: CMs are sup- has been useful in addressing these questions: (a) haloperi- pressed by antipsychotics, but not by anticholinergics (52); dol-treated rats, with versus without rat CMs and (b) halo- they are reduced by GABAmimetics (20), and they are at- peridol-treated rats versus newer antipsychotic drug–treated tenuated with benzodiazepines. Antipsychotic drugs block advance the onset and severity of the rat CMs (24). The the inhibitory D2 receptor and disinhibit the medium spiny similarities across phenomenology and pharmacology are neuronal projections to the GP.