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Objective: Causes of placebo effects in antidepressant trials have been inferred from observational studies and meta-analyses, but their mechanisms have not been directly established. The goal of this study was to examine in a prospective, randomized controlled trial whether patient expectancy mediates placebo effects in antidepressant studies.Method: Adult outpatients with major depressive disorder were randomly assigned to open or placebo-controlled citalopram treatment. Following measurement of pre- and postrandomization expectancy, participants were treated with citalopram or placebo for 8 weeks. Independent samples t tests determined whether patient expectancy differed between the open and placebo-controlled groups, and mixed-effects models assessed group effects on Hamilton Depression Rating Scale (HAM-D) scores over time while controlling for treatment assignment. Finally, mediation analyses tested whether between-group differences in patient expectancy mediated the group effect on HAM-D scores.Results: Postrandomization expectancy scores were significantly higher in the open group (mean=12.1 [SD=2.1]) compared with the placebo-controlled group (mean=11.0 [SD=2.0]). Mixed-effects modeling revealed a significant week-by-group interaction, indicating that HAM-D scores for citalopram-treated participants declined at a faster rate in the open group compared with the placebo-controlled group. Patient expectations postrandomization partially mediated group effects on week 8 HAM-D.Conclusions: Patient expectancy is a significant mediator of placebo effects in antidepressant trials. Expectancy-related interventions should be investigated as a means of controlling placebo responses in antidepressant clinical trials and improving patient outcome in clinical treatment. [ABSTRACT FROM AUTHOR]

Objective: The authors assessed the functioning of mesolimbic and striatal areas involved in reward-based spatial learning in unmedicated adults with obsessive-compulsive disorder (OCD).Method: Functional MRI blood-oxygen-level-dependent response was compared in 33 unmedicated adults with OCD and 33 healthy, age-matched comparison subjects during a reward-based learning task that required learning to use extramaze cues to navigate a virtual eight-arm radial maze to find hidden rewards. The groups were compared in their patterns of brain activation associated with reward-based spatial learning versus a control condition in which rewards were unexpected because they were allotted pseudorandomly to experimentally prevent learning.Results: Both groups learned to navigate the maze to find hidden rewards, but group differences in neural activity during navigation and reward processing were detected in mesolimbic and striatal areas. During navigation, the OCD group, unlike the healthy comparison group, exhibited activation in the left posterior hippocampus. Unlike healthy subjects, participants in the OCD group did not show activation in the left ventral putamen and amygdala when anticipating rewards or in the left hippocampus, amygdala, and ventral putamen when receiving unexpected rewards (control condition). Signal in these regions decreased relative to baseline during unexpected reward receipt among those in the OCD group, and the degree of activation was inversely associated with doubt/checking symptoms.Conclusions: Participants in the OCD group displayed abnormal recruitment of mesolimbic and ventral striatal circuitry during reward-based spatial learning. Whereas healthy comparison subjects exhibited activation in this circuitry in response to the violation of reward expectations, unmedicated OCD participants did not and instead over-relied on the posterior hippocampus during learning. Thus, dopaminergic innervation of reward circuitry may be altered, and future study of anterior/posterior hippocampal dysfunction in OCD is warranted. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine neural activity and connectivity within cortico-striato-thalamo-cortical circuits and to reveal circuit-based neural mechanisms that govern tic generation in Tourette's syndrome. Method: Functional magnetic resonance imaging data were acquired from 13 individuals with Tourette's syndrome and 21 healthy comparison subjects during spontaneous or simulated tics. Independent component analysis with hierarchical partner matching was used to isolate neural activity within functionally distinct regions of cortico-striato-thalamo-cortical circuits. Granger causality was used to investigate causal interactions among these regions. Results: The Tourette's syndrome group exhibited stronger neural activity and interregional causality than healthy comparison subjects throughout all portions of the motor pathway, including the sensorimotor cortex, putamen, pallidum, and substantia nigra. Activity in these areas correlated positively with the severity of tic symptoms. Activity within the Tourette's syndrome group was stronger during spontaneous tics than during voluntary tics in the somatosensory and posterior parietal cortices, putamen, and amygdala/hippocampus complex, suggesting that activity in these regions may represent features of the premonitory urges that generate spontaneous tic behaviors. In contrast, activity was weaker in the Tourette's syndrome group than in the healthy comparison group within portions of cortico-striato-thalamo-cortical circuits that exert top-down control over motor pathways (the caudate and anterior cingulate cortex), and progressively less activity in these regions accompanied more severe tic symptoms, suggesting that faulty activity in these circuits may result in their failure to control tic behaviors or the premonitory urges that generate them. Conclusions: Our findings, taken together, suggest that tics are caused by the combined effects of excessive activity in motor pathways and reduced activation in control portions of cortico-striato-thalamo-cortical circuits. [ABSTRACT FROM AUTHOR]

Objective : The authors examined functional activity in the frontostriatal systems that mediate self-regulatory capacities and conflict resolution in adolescents with bulimia nervosa. Method : Functional magnetic resonance imaging was used to compare bloodoxygen- level-dependent response in 18 female adolescents with bulimia nervosa and 18 healthy female age-matched subjects during performance on a Simon spatial incompatibility task. Bayesian analyses were used to compare the two groups on patterns of brain activation during correct responses to conflict stimuli and to explore the effects of antecedent stimulus context on group differences in self-regulation and conflict resolution. Results : Adolescents with and without bulimia nervosa performed similarly on the task. During correct responses in conflict trials, frontostriatal circuits-including the right inferolateral and dorsolateral prefrontal cortices and putamen-failed to activate to the same degree in adolescents with bulimia nervosa as in healthy comparison subjects. Instead, deactivation was seen in the left inferior frontal gyrus as well as a neural system encompassing the posterior cingulate cortex and superior frontal gyrus. Group differences in cortical and striatal regions were driven by the differential responses to stimuli preceded by conflict and nonconflict stimuli, respectively. Conclusions : When engaging the selfregulatory control processes necessary to resolve conflict, adolescents with bulimia nervosa displayed abnormal patterns of activation in frontostriatal and defaultmode systems. Their abnormal processing of the antecedent stimulus context conditioned their brain response to conflict differently from that of healthy comparison subjects, specifically in frontal regions. It is suspected that functional disturbances in frontal portions of frontostriatal systems may release feeding behaviors from regulatory control, thereby perpetuating the conflicting desires to consume fattening foods and avoid weight gain that characterize bulimia nervosa. [ABSTRACT FROM AUTHOR]

Objective: Disturbances in the basal ganglia portions of cortico-striato-thalamocortical circuits likely contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The authors examined the morphologic features of the basal ganglia nuclei (caudate, putamen, and globus pallidus) in children with ADHD. Method: A total of 104 individuals (combined-type ADHD patients: N=47; healthy comparison subjects: N=57), aged 7 to 18 years, were examined in a cross-sectional case-control study using anatomical magnetic resonance imaging. Conventional volumes and the surface morphology for the basal ganglia were measured. Results: Overall volumes were significantly smaller only in the putamen. Analysis of the morphological surfaces revealed significant inward deformations in each of the three nuclei, localized primarily in portions of these nuclei that are components of limbic, associative, and sensorimotor pathways in the corticostriato-thalamo-cortical circuits in which these nuclei reside. The more prominent these inward deformations were in the patient group, the more severe the ADHD symptoms. Surface analyses also demonstrated significant outward deformations of all basal ganglia nuclei in the ADHD children treated with stimulants compared with those ADHD youth who were untreated. These stimulant-associated enlargements were in locations similar to the reduced volumes detected in the ADHD group relative to the comparison group. The outward deformations associated with stimulant medications attenuated the statistical effects of the primary group comparisons. Conclusions: These findings potentially represent evidence of anatomical dysregulation in the circuitry of the basal ganglia in children with ADHD and suggest that stimulants may normalize morphological features of the basal ganglia in children with the disorder. [ABSTRACT FROM AUTHOR]

Objective: The role of the thalamus in the genesis of attention deficit hyperactivity disorder (ADHD) remains poorly understood. The authors used anatomical MRI to examine the morphology of the thalamus in youths with ADHD and healthy comparison youths. Method: The authors examined 46 youths with ADHD and 59 comparison youths 8-18 years of age in a cross-sectional case-control study. Conventional volumes and measures of surface morphology of the thalamus served as the main outcome measures. Results: A mixed-effects model comparing whole thalamic volumes revealed no significant differences between groups. Maps of the thalamic surface revealed significantly smaller regional volumes bilaterally in the pulvinar in youths with ADHD relative to comparison subjects. Post hoc analyses showed that ADHD patients who received stimulants (N=31) had larger conventional thalamic volumes than untreated youths with ADHD, and maps of the thalamic surface showed enlargement over the pulvinar in those receiving stimulants. Smaller regional volumes in the right lateral and left posterior thalamic surfaces were associated with more severe hyperactivity symptoms, whereas larger regional volumes in the right medial thalamic surfaces were associated with more severe symptoms of inattention. Conclusion: These findings demonstrate reduced pulvinar volumes in youths with ADHD and indicate that this same area is relatively enlarged in patients treated with stimulants compared to those untreated. Associations of hyperactivity scores with smaller regional volumes on the lateral thalamic surface and inattention scores with larger regional volumes on the medial thalamic surface suggest the differential involvement of thalamic subcircuits in the pathogenesis of differing ADHD symptoms. [ABSTRACT FROM AUTHOR]

Objective: The authors examined the effect of psychostimulants on brain activity in children and adolescents with ADHD performing the Stroop Color and Word Test. Method: The authors acquired 52 functional MRI scans in 16 youths with ADHD who were known responders to stimulant medication and 20 healthy comparison youths. Participants with ADHD were scanned on and off medication in a counterbalanced design, and comparison subjects were scanned once without medication. Results: Stimulant medication significantly improved suppression of default-mode activity in the ventral anterior cingulate cortex in the ADHD group. When off medication, youths with ADHD were unable to suppress default-mode activity to the same degree as comparison subjects, whereas when on medication, they suppressed this activity to comparison group levels. Greater activation of the lateral prefrontal cortex when off medication predicted a greater reduction in ADHD symptoms when on medication. Granger causality analyses demonstrated that activity in the lateral prefrontal and ventral anterior cingulate cortices mutually influenced one another but that the influence of the ventral anterior cingulate cortex on the lateral prefrontal cortex was significantly reduced in youths with ADHD off medication relative to comparison subjects and increased significantly to normal levels when ADHD youths were on medication. Conclusions: Psychostimulants in youths with ADHD improved suppression of default-mode activity in the ventral anterior cingulate and posterior cingulate cortices, components of a circuit in which activity has been shown to correlate with the degree of mind-wandering during attentional tasks. Stimulants seem to improve symptoms in youths with ADHD by normalizing activity within this circuit and improving its functional interactions with the lateral prefrontal cortex. [ABSTRACT FROM AUTHOR]

Objective: Neuroimaging studies of healthy individuals inform us about the normative maturation of the frontostriatal circuits that subserve self-regulatory control processes. Findings from these studies can be used as a reference frame against which to compare the aberrant development of these processes in individuals across a wide range of childhood psycho-pathologies. Method: The authors reviewed extensive neuroimaging evidence for the presence of abnormalities in frontostriatal circuits in children and adults with Tourette's syndrome and obsessive-compulsive disorder (OCD) as well as a more limited number of imaging studies of adolescents and adults with anorexia nervosa or bulimia nervosa that, together, implicate dysregulation of frontostriatal control systems in the pathogenesis of these eating disorders. Results: The presence of an impaired capacity for self-regulatory control that derives from abnormal development of frontostriatal circuits likely interacts in similar ways with normally occurring somatic sensations and motor urges, intrusive thoughts, sensations of hunger, and preoccupation with body shape and weight to contribute, respectively, to the development of the tics of Tourette's syndrome, the obsessions of OCD, the binge eating behaviors of bulimia, and the self-starvation of anorexia. Conclusions: Analogous brain mechanisms in parallel frontostriatal circuits, or even in differing portions of the same frontostriatal circuit, may underlie the differing behavioral disturbances in these multiple disorders, although further research is needed to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Objective: Cognitive deficits are prominent in schizophrenia. Patients have an average score one standard deviation below normal on a broad spectrum of cognitive tests. It has been repeatedly noted, however, that 20%-25% of patients differ from this general pattern and score close to normal on neuropsychological testing. This study used brain morphometry to 1) identify brain abnormalities associated with more severe cognitive deficits and 2) help determine whether cognitively relatively intact patients perform better because they have less severe illness or because they have a different illness. Method: Patients were assigned to a neuropsychologically near normal (N21) sub-group if they scored within 0.5 standard deviation of healthy comparison subjects (N=30) on four tests of attention and verbal and nonverbal working memory, and to a neuropsychologically impaired (N= 54) group if they scored at least 1.0 standard deviation below that of comparison subjects. Subgroup assignments were confirmed with the California Verbal Learning Test and degraded-stimulus Continuous Performance Test. Volumes of ventricular compartments, hippocampus, amygdala, thalamus, cerebellum, and regional cortical gray and white matter were dependent variables. Differences among groups were evaluated by using linear mixed-model multivariate analyses with gender, age, and height as covariates. Results: Both neuropsychologically near normal and neuropsychologically impaired patients had markedly smaller gray matter and larger third ventricle volumes than healthy comparison subjects. Only neuropsychologically impaired patients, however, had significantly smaller white matter and larger lateral ventricle volumes than healthy comparison subjects. Conclusions: Although both neuropsychologically impaired and neuropsychologically near normal patients have marked nedropathology in their gray matter, the relative absence of white matter pathology in the neuropsychologically near normal group suggests the possibility of differences in the disease process. [ABSTRACT FROM AUTHOR]

Objective: Disturbances in the maturation of neural systems that mediate self-regulatory processes may contribute to the development of Tourette's syndrome by releasing motor and vocal tics from regulatory control. The purpose of this study was to examine the age correlates of functional activity in neural circuits that subserve self-regulatory control in children and adults with Tourette's syndrome.Method: The participants were 136 children and adults, which included 66 Tourette's syndrome patients and 70 healthy comparison subjects. During performance of the Stroop interference task, the authors compared the functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent response in patients with Tourette's syndrome with that of healthy comparison subjects. General linear modeling of Stroop-related activations was used to compare the differential effects of age and behavioral performance on changes in self-regulatory control between the two diagnostic groups.Results: Although the correlations of age with behavioral performance on the Stroop task were similar between patients with Tourette's syndrome and healthy comparison subjects, the two groups differed significantly in their correlations of age with the magnitude of regional brain activation during the task. Interactions of age with diagnosis were detected in the ventral prefrontal (Brodmann's areas 10 and 24) and posterior cingulate cortices (Brodmann's area 31), and post hoc analyses indicated that subjects with Tourette's syndrome deactivated these regions less with advancing age. Greater activation of bilateral frontostriatal regions (Brodmann's areas 9/46, 45/46; lenticular nucleus; and thalamus) accompanied poorer performance in the patient group, which-in the presence of normal behavioral performance on the Stroop task-suggests that greater activation of the frontostriatal systems helps to maintain task performance in individuals with Tourette's syndrome.Conclusions: Normative developmental correlates of activity in frontostriatal circuits that subserve self-regulatory control are disturbed in persons with Tourette's syndrome. These aberrant developmental correlates are likely a consequence of greater anatomical and functional disturbances in these circuits in adults with Tourette's syndrome, which leads to impaired regulation of tic behaviors. Reduced default-mode processing in ventral prefrontal and posterior cingulate cortices in adults with Tourette's syndrome suggests the presence of greater difficulty in engaging mental processes that become active when freed from the demands of more challenging cognitive tasks. However, individuals with Tourette's syndrome appear to co-opt normal developmental processes in circuits that subserve age-related improvement in self-regulatory control while presumably struggling to maintain adequate task performance. [ABSTRACT FROM AUTHOR]

Objective: A previous small study showed lower serum ferritin levels in subjects with Tourette's syndrome than in healthy subjects. The authors measured peripheral iron indices in a large group of Tourette's syndrome and comparison subjects and explored associations of ferritin levels with regional brain volumes.Method: Ferritin was measured in 107 children and adults (63 Tourette's syndrome, 44 comparison); serum iron was measured in 73 (41 Tourette's syndrome, 32 comparison). Magnetic resonance imaging scans were used to measure volumes of the basal ganglia and cortical gray matter.Results: Ferritin and serum iron were significantly lower in the Tourette's syndrome subjects, although still within the normal range. No association was found between tic severity and either iron index. In the Tourette's syndrome subjects, ferritin did not correlate significantly with caudate volume but did correlate positively with putamen volume. In the comparison subjects, ferritin correlated inversely with caudate volume but did not correlate significantly with putamen volume. Irrespective of diagnosis, ferritin correlated positively with volumes of the sensorimotor, midtemporal, and subgenual cortices.Conclusions: The lower peripheral ferritin and iron levels in persons with Tourette's syndrome are consistent with findings in other movement disorders and suggest that lower iron availability may have a causal role in the pathophysiology of tic disorders. Lower iron stores may contribute to hypoplasia of the caudate and putamen, increasing vulnerability to developing tics or to having more severe tics. Lower iron stores may also contribute to smaller cortical volumes and consequently to reduced inhibitory control of tics. [ABSTRACT FROM AUTHOR]

Objective: The purpose of the study was to examine adaptive, emotional, and family functioning in a well-characterized group of children and adolescents with obsessive-compulsive disorder (OCD) and to evaluate the influence of comorbid attention deficit hyperactivity disorder (ADHD) on the levels of impairment in various functional domains. Method: The study group included 287 children and adolescents (191 boys, 96 girls) ages 7-18 years. Fifty-six subjects had a diagnosis of OCD only, 43 had both OCD and ADHD, 95 had ADHD, and 93 were unaffected comparison children. Best estimate DSM-IV diagnoses were assigned on the basis of structured inter- views and clinical ratings. The children's functioning was evaluated with a comprehensive battery of well-established, standardized measures, including the Vine- land Adaptive Behavior Scales, parents' ratings of social and family functioning, and children's self-reports of emotional adjustment. Results: The children with OCD only were more impaired than were unaffected comparison subjects in most areas of adaptive functioning and emotional adjustment. Children with OCD plus ADHD had additional difficulties in social functioning, school problems, and self-reported depression. Impairment in daily living skills, reduced number of activities, and self-reported anxiety were uniquely associated with the diagnosis of OCD. Family dysfunction was associated with ADHD but not with ocD. Conclusions: Children and adolescents with OCD are impaired in multiple domains of adaptive and emotional functioning. When comorbid ADHD is present, there is an additional burden on social, school, and family functioning. [ABSTRACT FROM AUTHOR]

Objective: The corpus callosum is the major commissure connecting the cerebral hemispheres. Prior evidence suggests involvement of the corpus callosum in the pathophysiology of Tourette's disorder. The authors assessed corpus callosum size and anatomical connectivity across the cerebral hemispheres in persons with Tourette's disorder. Method: The size of the corpus callosum was determined on the true midsagittal slices of reformatted, high-resolution magnetic resonance imaging scans and compared across groups in a cross-sectional case-control study of 158 subjects with Tourette's disorder and 121 healthy comparison subjects, ages 5-65 years. Results: In the context of increasing midsagittal corpus callosum area from childhood to age 30 years, children with Tourette's disorder had smaller overall corpus callosum size, whereas adults with Tourette's disorder on average had larger corpus callosum size, yielding a prominent interaction of diagnosis with age. Corpus callosum size correlated positively with tic severity. Corpus callosum size also correlated inversely with dorsolateral prefrontal and orbitofrontal cortical volumes in both the subjects with Tourette's disorder and the comparison subjects, but the magnitudes of the correlations were significantly greater in the group with Tourette's disorder. The effects of medication and comorbid illnesses had no appreciable influence on the findings. Conclusions: Given prior evidence for the role of prefrontal hypertrophy in the regulation of tic symptoms, the current findings suggest that neural plasticity may contribute to smaller corpus callosum size in persons with Tourette's disorder, which thereby limits neuronal trafficking across the cerebral hemispheres and reduces in- put to cortical inhibitory interneurons within the prefrontal cortices. Reduced inhibitory input may in turn enhance prefrontal excitation, thus helping to control tics and possibly contributing to the cortical hyperexcitatibility reported previously in patients with Tourette's disorder. [ABSTRACT FROM AUTHOR]

Objective: Function of the ventromedial prefrontal cortex has been implicated in impulse control. The authors used the Stroop paradigm to test attention and response inhibition during the presentation of congruent and incongruent stimuli in male pathological gamblers and a group of comparison subjects. Method: Event-related functional magnetic resonance imaging was used to examine ventromedial prefrontal cortex function during Stroop performance. Results: In response to infrequent incongruent stimuli, pathological gamblers demonstrated decreased activity in the left ventromedial prefrontal cortex relative to the comparison subjects. Both groups demonstrated similar activity changes in multiple brain regions, including activation of the dorsal anterior cingulate and dorsolateral frontal cortex. Conclusions: Pathological gamblers share many neural correlates of Stroop task performance with healthy subjects but differ in a brain region previously implicated in disorders characterized by poor impulse control. [ABSTRACT FROM AUTHOR]

Investigates the autoimmune etiology of Tourette's syndrome. Infusion of sera into the ventrolateral striatum of rats; Sources of the infused sera; Effect of sera on oral stereotypies of rats.

Objective: To investigate whether cerebral hyperintensities on T2-weighted magnetic resonance images (MRI) are associated with childhood neuropsychiatric disorders. Method: The authors compared the frequency of cortical and subcortical cerebral hyperintensities in 100 children and adolescents with Tourette's syndrome, obsessive-compulsive disorder (OCD), or attention deficit hyperactivity disorder (ADHD) and 32 healthy comparison subjects. Results: The frequency of cerebral hyperintensities was significantly higher in subjects with Tourette's syndrome, OCD, or ADHD than in healthy comparison subjects; each diagnostic group seemed to contribute to this effect. Among the patient groups, the likelihood of detecting cerebral hyperintensities in the subcortex (primarily the basal ganglia and thalamus) was significantly greater than in the cortex. Conclusions: A childhood diagnosis of Tourette's syndrome, OCD, or ADHD significantly increased the likelihood of detecting cerebral hyperintensities, particularly in the subcortex, supporting the notion that subcortical injury may play a role in the pathophysiology of these conditions. [ABSTRACT FROM AUTHOR]

Objective: This study investigated whether the functional abnormalities in prefrontal systems observed in adult bipolar disorder are manifested in adolescents with this illness. Method: Ten adolescents with bipolar disorder and 10 healthy comparison subjects participated in a color-naming Stroop task during event-related functional magnetic resonance imaging. Results: Signal increases in the left putamen and thalamus were significantly greater in the bipolar disorder group than in the healthy group. Age correlated positively with signal increases in the bilateral rostroventral prefrontal cortex and the striatum in the healthy group but not in the bipolar disorder group. In the bipolar disorder subjects, depressive symptoms correlated positively with signal increases in the ventral striatum. Conclusions: These findings suggest the presence of dysfunction in the subcortical portions of the frontostriatal circuits in adolescents with bipolar disorder. The absence of the prefrontal abnormalities that were observed previously in adults and the absence of the age-related increases in prefrontal activity observed in normal comparison subjects suggest that a developmental disturbance in prefrontal function may emerge in bipolar disorder over the course of adolescence. [ABSTRACT FROM AUTHOR]

Objective: The authors sought to study activity in neural circuits that subserve the inhibition of a semi-involuntary motor behavior, eye blinking, in children and adults with Tourette syndrome and in healthy comparison subjects. Method: Functional magnetic resonance imaging was used to scan 120 participants (51 with Tourette syndrome and 69 comparison subjects) as they either blinked normally or successfully inhibited eye blinking. The authors compared the blood-oxygen-level dependent signal during these two conditions across the Tourette and comparison groups. Results: Results: Relative to comparison subjects, patients with Tourette syndrome activated more strongly the frontal cortex and striatum during eye blink inhibition. Activation increased more with age in the dorsolateral and inferolateral prefrontal cortex and caudate nucleus in the Tourette group relative to comparison subjects. In addition, the Tourette group more strongly activated the middle frontal gyrus, dorsal anterior cingulate, and temporal cortices. The severity of tic symptoms in the Tourette group correlated inversely with activation in the putamen and inferolateral prefrontal cortex. Conclusions: Conclusions: Frontostriatal activity is increased in persons with Tourette syndrome during the inhibition of eye blinks. Activation of frontostriatal circuits in this population may help to maintain regulatory control over semi-involuntary behaviors, whether these are tics or eye blinks. [ABSTRACT FROM AUTHOR]