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1.  Effect of Schizophrenia on Frontotemporal Activity During Word Encoding and Recognition: A PET Cerebral Blood Flow Study 
The American journal of psychiatry  2001;158(7):1114-1125.
Objective
Neuropsychological studies have shown that deficits in verbal episodic memory in schizophrenia occur primarily during encoding and retrieval stages of information processing. The current study used positron emission tomography to examine the effect of schizophrenia on change in cerebral blood flow (CBF) during these memory stages.
Method
CBF was measured in 23 healthy comparison subjects and 23 patients with schizophrenia during four conditions: resting baseline, motor baseline, word encoding, and word recognition. The motor baseline was used as a reference that was subtracted from encoding and recognition conditions by using statistical parametric mapping.
Results
Patients’ performance was similar to that of healthy comparison subjects. During word encoding, patients showed reduced activation of left prefrontal and superior temporal regions. Reduced left prefrontal activation in patients was also seen during word recognition, and additional differences were found in the left anterior cingulate, left mesial temporal lobe, and right thalamus. Although patients’ performance was similar to that of healthy comparison subjects, left inferior prefrontal activation was associated with better performance only in the comparison subjects.
Conclusions
Left frontotemporal activation during episodic encoding and retrieval, which is associated with better recognition in healthy people, is disrupted in schizophrenia despite relatively intact recognition performance and right prefrontal function. This may reflect impaired strategic use of semantic information to organize encoding and facilitate retrieval.
PMCID: PMC4332582  PMID: 11431234
2.  Levels-of-Processing Effect on Frontotemporal Function in Schizophrenia During Word Encoding and Recognition 
The American journal of psychiatry  2005;162(10):1840-1848.
Objective
Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function.
Method
Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects.
Results
Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response.
Conclusions
Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.
doi:10.1176/appi.ajp.162.10.1840
PMCID: PMC4332803  PMID: 16199830
3.  Event-Related fMRI of Frontotemporal Activity During Word Encoding and Recognition in Schizophrenia 
The American journal of psychiatry  2004;161(6):1004-1015.
Objective
Neuropsychological studies have demonstrated verbal episodic memory deficits in schizophrenia during word encoding and retrieval. This study examined neural substrates of memory in an analysis that controlled for successful retrieval.
Method
Event-related blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation during word encoding and recognition in 14 patients with schizophrenia and 15 healthy comparison subjects. An unbiased multiple linear regression procedure was used to model the BOLD response, and task effects were detected by contrasting the signal before and after stimulus onset.
Results
Patients attended during encoding and had unimpaired reaction times and normal response biases during recognition, but they had lower recognition discriminability scores, compared with the healthy subjects. Analysis of contrasts was restricted to correct items. Previous findings of a deficit in bilateral prefrontal cortex activation during encoding in patients were reproduced, but patients showed greater parahippocampal activation rather than deficits in temporal lobe activation. During recognition, left dorsolateral pre-frontal cortex activation was lower in the patients and right anterior prefrontal cortex activation was preserved, as in the authors’ previous study using positron emission tomography. Successful retrieval was associated with greater right dorsolateral prefrontal cortex activation in the comparison subjects, whereas orbitofrontal, superior frontal, mesial temporal, middle temporal, and inferior parietal regions were more active in the patients during successful retrieval.
Conclusions
The pattern of prefrontal cortex underactivation and parahippocampal overactivation in the patients suggests that functional connectivity of dorsolateral prefrontal and temporal-limbic structures is disrupted by schizophrenia. This disruption may be reflected in the memory strategies of patients with schizophrenia, which include reliance on rote rehearsal rather than associative semantic processing.
PMCID: PMC4332807  PMID: 15169688
4.  [No title available] 
PMCID: PMC3927993  PMID: 24077613
5.  [No title available] 
PMCID: PMC3946310  PMID: 24030200
6.  [No title available] 
PMCID: PMC4295823  PMID: 20080981
7.  [No title available] 
PMCID: PMC4290854  PMID: 23545795
8.  [No title available] 
PMCID: PMC4291021  PMID: 16741197
9.  Neuropsychological Near Normality and Brain Structure Abnormality in Schizophrenia 
The American journal of psychiatry  2008;166(2):189-195.
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 (N=21) subgroup 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 neuropsycho-logically near normal patients have marked neuropathology 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.
doi:10.1176/appi.ajp.2008.08020258
PMCID: PMC4288572  PMID: 18765481
10.  Psychiatric Disorders From Childhood to Adulthood in 22q11.2 Deletion Syndrome: Results From the International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome 
The American journal of psychiatry  2014;171(6):627-639.
Objective
Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants.
Method
The 1,402 participants with 22q11.2 deletion syndrome, ages 6–68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years.
Results
Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills.
Conclusions
To the authors' knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.
doi:10.1176/appi.ajp.2013.13070864
PMCID: PMC4285461  PMID: 24577245
11.  Emotional dysregulation and Attention-Deficit/Hyperactivity Disorder 
The American journal of psychiatry  2014;171(3):276-293.
It has long been recognized that many individuals with ADHD also have difficulties with emotion regulation but lack of consensus on how to conceptualize this clinically challenging domain renders a review timely. The authors examine the current literature using both quantitative and qualitative methods. Three key findings emerge. First, emotion dysregulation is prevalent in ADHD throughout the lifespan and is a major contributor to impairment. Second, emotion dysregulation in ADHD may arise from deficits in orienting towards, recognizing and/or allocating attention to emotional stimuli; these deficits that implicate dysfunction within a striato-amygdalo-medial prefrontal cortical network. Third, while current treatments for ADHD often also ameliorate emotion dysregulation, a focus on this combination of symptoms reframes clinical questions and could stimulate novel therapeutic approaches. Three models to explain the overlap between emotion dysregulation and ADHD are considered: emotion dysregulation and ADHD are correlated but distinct dimensions; emotion dysregulation is a core, diagnostic feature of ADHD; and the combination constitutes a nosological entity, distinct from both ADHD and emotion dysreguation alone. The differing predictions from each model can guide future research into this much-neglected population.
doi:10.1176/appi.ajp.2013.13070966
PMCID: PMC4282137  PMID: 24480998
Attention Deficit hyperactivity disorder; emotion; affect; irritability; cognition; meta-analysis
12.  Morphological Abnormalities of the Thalamus in Youths With Attention Deficit Hyperactivity Disorder 
The American journal of psychiatry  2010;167(4):397-408.
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.
doi:10.1176/appi.ajp.2009.09030398
PMCID: PMC4282161  PMID: 20123910
13.  Neuropsychological Decline in Schizophrenia from the Premorbid to Post-Onset Period: Evidence from a Population-Representative Longitudinal Study 
Objective
Despite widespread belief that neuropsychological decline is a cardinal feature of the progression from the premorbid to the chronic form of schizophrenia, few longitudinal studies have examined change in neuropsychological functioning from before to after the onset of schizophrenia. We addressed the following unresolved questions: Is neuropsychological decline generalized versus confined to particular mental functions? Is neuropsychological decline unique to schizophrenia? Do individuals with schizophrenia also have cognitive problems in everyday life?
Method
Participants were members of a representative cohort of 1,037 individuals born in Dunedin, New Zealand between 1972-73 and followed prospectively to age 38, with 95% retention. Assessment of IQ and other specific neuropsychological functions was conducted at ages 7-13, before the onset of schizophrenia, and again at age 38. Informants also reported on cognitive problems at age 38.
Results
Individuals with schizophrenia showed decline in IQ as well as a range of different mental functions, particularly those tapping processing speed, learning, executive functioning, and motor functioning. There was little evidence of decline in verbal abilities or delayed memory, however, and the developmental progression of deficits in schizophrenia differed across mental functions. Processing speed deficits increased gradually from childhood to beyond the early teen years, whereas verbal deficits emerged early but remained static through midlife. Neuropsychological decline was specific to schizophrenia, as no evidence of decline was apparent among individuals with persistent depression, children with mild cognitive impairment, individuals matched on childhood risk factors for schizophrenia, and psychiatrically healthy individuals. Informants also reported cognitive problems for individuals diagnosed with schizophrenia.
Conclusion
There is substantial neuropsychological decline in schizophrenia from the premorbid to post-onset period, but the extent and developmental progression of decline varies across mental functions. Findings suggest that different pathophysiological mechanisms might underlie deficits in different mental functions.
doi:10.1176/appi.ajp.2013.12111438
PMCID: PMC3947263  PMID: 24030246
14.  Lower Gene Expression for KCNS3 Potassium Channel Subunit in Parvalbumin-Containing Neurons in the Prefrontal Cortex in Schizophrenia 
Objective
In schizophrenia, alterations in markers of cortical GABA neurotransmission are prominent in parvalbumin-containing neurons. Parvalbumin neurons selectively express KCNS3, the gene encoding the Kv9.3 potassium channel α-subunit. Kv9.3 subunits are present in voltage-gated potassium channels that contribute to the precise detection of coincident excitatory synaptic inputs to parvalbumin neurons. This distinctive feature of parvalbumin neurons appears important for the synchronization of cortical neural networks in γ-oscillations. Because impaired prefrontal cortical γ-oscillations are thought to underlie the cognitive impairments in schizophrenia, the authors investigated whether KCNS3 mRNA levels are altered in the prefrontal cortex of schizophrenia subjects.
Method
KCNS3 mRNA expression was evaluated by in situ hybridization in 22 matched pairs of schizophrenia and comparison subjects and by microarray analyses of pooled samples of individually dissected neurons that were labeled with Vicia villosa agglutinin (VVA), a parvalbumin neuron-selective marker, in a separate cohort of 14 pairs. Effects of chronic antipsychotic treatments on KCNS3 expression were tested in the prefrontal cortex of antipsychotic-exposed monkeys.
Results
By in situ hybridization, KCNS3 mRNA levels were 23% lower in schizophrenia subjects. At the cellular level, both KCNS3 mRNA-expressing neuron density and KCNS3 mRNA level per neuron were significantly lower. By microarray, KCNS3 mRNA levels were lower by 40% in VVA-labeled neurons from schizophrenia subjects. KCNS3 mRNA levels were not altered in antipsychotic-exposed monkeys.
Conclusions
These findings reveal lower KCNS3 expression in prefrontal cortical parvalbumin neurons in schizophrenia, providing a molecular basis for compromised detection of coincident synaptic inputs to parvalbumin neurons that could contribute to altered γ-oscillations and impaired cognition in schizophrenia.
doi:10.1176/appi.ajp.2013.13040468
PMCID: PMC3947279  PMID: 24170294
15.  The Neural Correlates of Anomalous Habituation to Negative Emotional Pictures in Borderline and Avoidant Personality Disorder Patients 
Objective
Extreme emotional reactivity is a defining feature of borderline personality disorder, yet the neural-behavioral mechanisms underlying this affective instability are poorly understood. One possible contributor would be diminished ability to engage the mechanism of emotional habituation. We tested this hypothesis by examining behavioral and neural correlates of habituation in borderline patients, healthy controls, and a psychopathological control group of avoidant personality disorder patients.
Method
During fMRI scan acquisition, borderline patients, healthy controls and avoidant personality disorder patients viewed novel and repeated pictures, providing valence ratings at each presentation. Statistical parametric maps of the contrasts of activation during repeat versus novel negative picture viewing were compared between groups. Psychophysiological interaction analysis was employed to examine functional connectivity differences between groups.
Results
Unlike healthy controls, neither borderline nor avoidant personality disorder participants showed increased activity in dorsal anterior cingulate cortex when viewing repeat versus novel pictures. This failure to increase dorsal anterior cingulate activity was associated with greater affective instability in borderline participants. In addition, borderline and avoidant participants showed smaller insula-amygdala connectivity increases than healthy participants and did not show habituation in ratings of the emotional intensity of the images as did healthy participants. Borderline patients differed from avoidant patients in insula-ventral anterior cingulate connectivity during habituation.
Conclusions
Borderline patients fail to habituate to negative pictures as do healthy participants and differ from both healthy controls and avoidant patients in neural activity during habituation. A failure to effectively engage emotional habituation processes may contribute to affective instability in borderline patients.
doi:10.1176/appi.ajp.2013.13070852
PMCID: PMC3947284  PMID: 24275960
borderline personality disorder; avoidant personality disorder; affective instability; fMRI; functional connectivity
16.  Job Performance Deficits Due to Depression 
The American journal of psychiatry  2006;163(9):1569-1576.
Objective
This study assessed the relationship between depression severity and job performance among employed primary care patients.
Method
In a 2001–2004 longitudinal observational study of depression’s affect on work productivity, 286 patients with DSM-IV major depressive disorder and/or dysthymia were compared to 93 individuals with rheumatoid arthritis, a condition associated with work disability, and 193 depression-free healthy control subjects. Participants were employed at least 15 hours per week, did not plan to stop working, and had no major medical co-morbidities. Measures at baseline, six, 12, and 18 months included the Work Limitations Questionnaire for work outcomes, and the Patient Health Questionnaire-9 for depression.
Results
At baseline and each follow-up, the depression group had significantly greater deficits in managing mental-interpersonal, time, and output tasks, as measured by the Work Limitations Questionnaire: The rheumatoid arthritis group’s deficits in managing physical job demands surpassed those of either the depression or comparison groups. Improvements in job performance were predicted by symptom severity. However, the job performance of even the “clinically improved” subset of depressed patients remained consistently worse than the control groups.
Conclusions
Multiple dimensions of job performance are impaired by depression. This impact persisted after symptoms have improved. Efforts to reduce work-impairment secondary to depression are needed.
doi:10.1176/appi.ajp.163.9.1569
PMCID: PMC4269259  PMID: 16946182
17.  Risk of Mortality Among Individual Antipsychotics in Patients with Dementia 
Objective
The use of antipsychotics to treat the behavioral symptoms of dementia is associated with increased mortality. However, there remains limited information regarding individual agents’ risks.
Method
This was a retrospective cohort study using national data from the US Department of Veterans Affairs (fiscal years 1999–2008) for patients ≥65 years old with dementia, beginning outpatient treatment with an antipsychotic (risperidone, olanzapine, quetiapine, and haloperidol) or valproic acid and its derivatives (as a non-antipsychotic comparison). The total sample included 33,604 patients. Individual drug groups were compared for 180-day mortality rates. Potential confounding was addressed using multivariate models and propensity adjustments.
Results
In covariate-adjusted intent to treat analyses, haloperidol users had the highest mortality rates (relative risk 1.54, 95% confidence interval 1.38–1.73) followed by risperidone (reference), olanzapine (RR 0.99, 95% CI 0.89–1.10), valproic acid and its derivatives (RR 0.91, 95% CI 0.78–1.06) and quetiapine (RR 0.73, 95% CI 0.67–0.80). Propensity-stratified and propensity-weighted models as well as analyses controlling for site of care and medication dosage showed similar patterns. Haloperidol risk was highest in the first 30 days and then significantly and sharply decreased. Among the other agents, mortality risk differences were most significant in the first 120 days and declined in the subsequent 60 days during 180-day follow-up.
Conclusions
There may be differences in mortality risks among individual antipsychotic agents. Further, the use of valproic acid and its derivatives as alternative agents to address the neuropsychiatric symptoms of dementia may carry associated risks as well.
doi:10.1176/appi.ajp.2011.11030347
PMCID: PMC4269551  PMID: 22193526
18.  Basal Ganglia Surface Morphology and the Effects of Stimulant Medications in Youth with Attention-Deficit/Hyperactivity Disorder 
The American journal of psychiatry  2010;167(8):977-986.
Objective
Disturbances in the basal ganglia portions of Cortico-Striato-Thalamo-Cortical (CSTC) circuits likely contribute to the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). This study examines the morphologic features of the basal ganglia nuclei (caudate, putamen, and globus pallidus) in children with ADHD.
Design
We examined 104 individuals (47 with combined-type ADHD and 57 controls) aged 7 to 18 years, in a cross-sectional case-control study using anatomical magnetic resonance imaging. We measured conventional volumes and the surface morphology for the basal ganglia.
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 that were localized primarily in portions of these nuclei that are components of limbic, associative, and sensorimotor pathways in the CSTC circuits in which these nuclei reside. The more prominent these inward deformations were in the patient group, the more severe were their ADHD symptoms. Surface analyses also demonstrated significant outward deformations of all basal ganglia nuclei in the ADHD children treated with stimulants compared to those with ADHD who were untreated. These stimulant-associated enlargements were in locations similar to the reduced volumes detected in the ADHD group relative to controls. The outward deformations associated with stimulant medications attenuated the statistical effects of the primary group comparisons.
Conclusion
These findings potentially represent evidence of anatomical dysregulation in the circuitry of the basal ganglia of children with ADHD and suggest that stimulants may “normalize” morphological features of the basal ganglia in children with ADHD.
doi:10.1176/appi.ajp.2010.09091259
PMCID: PMC4254769  PMID: 20595414
19.  Microvascular Abnormality in Schizophrenia as Shown by Retinal Imaging  
The American journal of psychiatry  2013;170(12):10.1176/appi.ajp.2013.13020234.
Objective
Retinal and cerebral microvessels are structurally and functionally homologous, but, unlike cerebral microvessels, retinal microvessels can be noninvasively measured in vivo via retinal imaging. Here we test the hypothesis that individuals with schizophrenia show microvascular abnormality and evaluate the utility of retinal imaging as a tool for future schizophrenia research.
Methods
Participants were members of the Dunedin Study, a population-representative cohort followed from birth with 95% retention. Study members underwent retinal imaging at age 38 years. We assessed retinal arteriolar and venular caliber for all members of the cohort, including individuals who developed schizophrenia.
Results
Study members who developed schizophrenia were distinguished by wider retinal venules, suggesting microvascular abnormality reflective of insufficient brain oxygen supply. Analyses that controlled for confounding health conditions suggested that wider retinal venules are not simply an artifact of co-occurring health problems in schizophrenia patients. Wider venules were also associated with a dimensional measure of adult psychosis symptoms and with psychosis symptoms reported in childhood.
Conclusions
Findings provide initial support for the hypothesis that individuals with schizophrenia show microvascular abnormality. Moreover, results suggest that the same vascular mechanisms underlie subthreshold symptoms and clinical disorder and that these associations may begin early in life. These findings highlight the promise of retinal imaging as a tool for understanding the pathogenesis of schizophrenia.
doi:10.1176/appi.ajp.2013.13020234
PMCID: PMC3857729  PMID: 24030514
20.  Should Mental Health Interventions Be Locally Grown or Factory-Farmed? 
The American journal of psychiatry  2013;170(4):362-365.
doi:10.1176/appi.ajp.2013.13010043
PMCID: PMC4249622  PMID: 23545790
21.  The Neural Circuits that Generate Tics in Gilles de la Tourette Syndrome 
The American journal of psychiatry  2011;168(12):1326-1337.
Objective
To study neural activity and connectivity within cortico-striato-thalamo-cortical circuits and to reveal circuit-based neural mechanisms that govern tic generation in Tourette syndrome.
Method
We acquired fMRI data from 13 participants with Tourette syndrome and 21 controls during spontaneous or simulated tics. We used independent component analysis with hierarchical partner matching to isolate neural activity within functionally distinct regions of cortico-striato-thalamo-cortical circuits. We used Granger causality to investigate causal interactions among these regions.
Results
We found that the Tourette group exhibited stronger neural activity and interregional causality than controls throughout all portions of the motor pathway including sensorimotor cortex, putamen, pallidum, and substania nigra. Activity in these areas correlated positively with the severity of tic symptoms. Activity within the Tourette group was stronger during spontaneous tics than during voluntary tics in 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 group than in controls within portions of cortico-striato-thalamo-cortical circuits that exert top-down control over motor pathways (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 fail 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.
doi:10.1176/appi.ajp.2011.09111692
PMCID: PMC4246702  PMID: 21955933
22.  Association of enhanced limbic response to threat with decreased cortical facial recognition memory response in schizophrenia 
The American journal of psychiatry  2010;167(4):418-426.
Objective
Recognition memory of faces is impaired in patients with schizophrenia, as is the neural processing of threat-related signals, but how these deficits interact to produce symptoms is unclear. Here we used an affective face recognition paradigm to examine possible interactions between cognitive and affective neural systems in schizophrenia.
Methods
fMRI (3T) BOLD response was examined in 21 controls and 16 patients during a two-choice recognition task using images of human faces. Each target face had previously been displayed with a threatening or non-threatening affect, but here were displayed with neutral affect. Responses to successful recognition and for the effect of previously threatening vs. non-threatening affect were evaluated, and correlations with total BPRS examined. Functional connectivity analyses examined the relationship between activation in the amygdala and cortical regions involved in recognition memory.
Results
Patients performed the task more slowly than controls. Controls recruited the expected cortical regions to a greater degree than patients, and patients with more severe symptoms demonstrated proportionally less recruitment. Increased symptoms were also correlated with augmented amygdala and orbitofrontal cortex response to threatening faces. Controls exhibited a negative correlation between activity in the amygdala and cortical regions involved in cognition, while patients showed a weakening of that relationship.
Conclusions
Increased symptoms were related to an enhanced threat response in limbic regions and a diminished recognition memory response in cortical regions, supporting a link between two brain systems often examined in isolation. This finding suggests that abnormal processing of threat-related signals in the environment may exacerbate cognitive impairment in schizophrenia.
doi:10.1176/appi.ajp.2009.09060808
PMCID: PMC4243460  PMID: 20194482
23.  A randomized controlled trial of contingency management for psycho-stimulant use in community mental health outpatients with co-occurring serious mental illness 
Objective
The primary objective of this study was to determine if contingency management was associated with increased stimulant drug abstinence in community mental health outpatients with serious mental illness and stimulant dependence. Secondary objectives were to determine if contingency management was associated with reductions in use of other substances, psychiatric symptoms, HIV-risk behavior, and inpatient service utilization.
Method
A randomized controlled design compared outcomes of 176 outpatients with serious mental illness and stimulant dependence. Participants were randomized to three months of contingency management for stimulant abstinence plus treatment-as-usual or treatment-as-usual with reinforcement for study participation only. Urine drug tests, self-report, clinician-report, and service utilization outcomes were assessed during three-month treatment and three-month follow-up periods.
Results
While participants in the contingency management condition were less likely to complete the treatment period (n=38; 42%) than those assigned to the control condition (n=55; 65%), X2(1)=9.8, p=0.02; those assigned to the contingency management condition were 2.4 (CI=1.9-3.0) times more likely to submit a stimulant-negative urine test during treatment. Participants assigned to contingency management experienced significantly lower levels of alcohol use, injection drug use, psychiatric symptoms, and were five times less likely than those assigned to the control condition to be admitted for psychiatric hospitalization, X2(1)=5.4, p=0.02. Contingency management participants reported significantly fewer days of stimulant drug use, relative to controls during the three-month follow-up.
Conclusions
When added to treatment-as-usual, contingency management is associated with large reductions in stimulant, injection drug, and alcohol use. Reductions in psychiatric symptoms and hospitalizations were important secondary benefits.
doi:10.1176/appi.ajp.2012.11121831
PMCID: PMC4242089  PMID: 23138961
24.  Varenicline, Smoking Cessation and Neuropsychiatric Adverse Events 
The American journal of psychiatry  2013;170(12):1460-1467.
Objective
In 2009 FDA issued a black box warning for varenicline and neuropsychiatric events. We studied efficacy (smoking cessation) of varenicline, and safety (neuropsychiatric events) in both randomized clinical trials (RCTs) and a large observational study. The observational study was included to determine the generalizability of the RCT findings to the general population.
Method
RCTs: Re-analysis of all 17 placebo controlled RCTs (n=8027) of varenicline conducted by Pfizer using complete intent-to-treat person-level longitudinal data.
Observational Study
Analysis of Department of Defense collected adverse neuropsychiatric adverse event data in inpatients and outpatients taking varenicline versus nicotine replacement therapy (NRT) (n=35,800). The primary endpoints for the RCTs were smoking abstinence and adverse event reports of suicidal thoughts and behavior, depression, aggression/agitation, and nausea. The effect of varenicline in patients with (n=1004) and without (n=7023) psychiatric disorders was examined. The primary endpoints for the observational study were anxiety, depression, drug induced mental disorder, episodic and mood disorder, other psychiatric disorder, post traumatic stress disorder, schizophrenia, suicide attempt, transient mental disorder.
Results
RCTs: Varenicline did not increase rates of suicidal events, depression, or aggression/agitation. Varenicline increased risk of nausea (OR=3.69, 95% CI = (3.03, 4.48), p<0.0001). Varenicline increased rate of abstinence by 124% compared to placebo (p<0.0001), and 22% compared to bupropion (p<0.0001). While having a current psychiatric disorder or history of psychiatric illness increased the risk of neuropsychiatric events, it did so equally in treated and control patients.
Observational Study
Following propensity score matching, overall rate of neuropsychiatric disorders was lower for varenicline versus NRT (2.28% versus 3.16%, p<0.0001).
Conclusions
In the RCTs, varenicline revealed no increased risk of neuropsychiatric adverse events relative to placebo. Varenicline provided greater benefit in terms of smoking cessation relative to both placebo and bupropion. The same results were observed in patients with and without a current psychiatric disorder or history of psychiatric illness. In the observational study, the overall rate of neuropsychiatric disorders was lower in patients treated with varenicline relative to NRT, revealing that the finding of no increased risk of neuropsychiatric adverse events in RCTs generalizes to the population of patients engaging in treatment with varenicline.
doi:10.1176/appi.ajp.2013.12121599
PMCID: PMC4238282  PMID: 24030388
25.  Brain Activity in Adolescent Major Depressive Disorder Before and After Fluoxetine Treatment 
The American journal of psychiatry  2012;169(4):381-388.
Objective
Major depression in adolescents is a significant public health concern because of its frequency and severity. To examine the neurobiological basis of depression in this population, the authors studied functional activation characteristics of the brain before and after antidepressant treatment in antidepressant-naive depressed adolescents and healthy comparison subjects.
Method
Depressed (N=19) and healthy (N=21) adolescents, ages 11 to 18 years, underwent functional MRI assessment while viewing fearful and neutral facial expressions at baseline and again 8 weeks later. The depressed adolescents received 8 weeks of open-label fluoxetine treatment after their baseline scan.
Results
Voxel-wise whole brain analyses showed that depressed youths have exaggerated brain activation compared with healthy comparison subjects in multiple regions, including the frontal, temporal, and limbic cortices. The 8 weeks of fluoxetine treatment normalized most of these regions of hyperactivity in the depressed group. Region-of-interest analyses of the areas involved in emotion processing indicated that before treatment, depressed youths had significantly greater activations to fearful relative to neutral facial expressions than did healthy comparison subjects in the amygdala, orbitofrontal cortex, and subgenual anterior cingulate cortex bilaterally. Fluoxetine treatment decreased activations in all three regions, as compared with the repeat scans of healthy comparison subjects.
Conclusions
While effective treatments are available, the impact of depression and its treatment on the brain in adolescents is understudied. This study confirms increases in brain activation in untreated depressed adolescents and demonstrates reductions in these aberrant activations with treatment.
doi:10.1176/appi.ajp.2011.11040615
PMCID: PMC4225078  PMID: 22267183

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