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1.  Transcriptome Profiling of Peripheral Blood in 22q11.2 Deletion Syndrome Reveals Functional Pathways Related to Psychosis and Autism Spectrum Disorder 
PLoS ONE  2015;10(7):e0132542.
22q11.2 Deletion Syndrome (22q11DS) represents one of the greatest known genetic risk factors for the development of psychotic illness, and is also associated with high rates of autistic spectrum disorders (ASD) in childhood. We performed integrated genomic analyses of 22q11DS to identify genes and pathways related to specific phenotypes.
We used a high-resolution aCGH array to precisely characterize deletion breakpoints. Using peripheral blood, we examined differential expression (DE) and networks of co-expressed genes related to phenotypic variation within 22q11DS patients. Whole-genome transcriptional profiling was performed using Illumina Human HT-12 microarrays. Data mining techniques were used to validate our results against independent samples of both peripheral blood and brain tissue from idiopathic psychosis and ASD cases.
Eighty-five percent of 22q11DS individuals (N = 39) carried the typical 3 Mb deletion, with significant variability in deletion characteristics in the remainder of the sample (N = 7). DE analysis and weighted gene co-expression network analysis (WGCNA) identified expression changes related to psychotic symptoms in patients, including a module of co-expressed genes which was associated with psychosis in 22q11DS and involved in pathways associated with transcriptional regulation. This module was enriched for brain-expressed genes, was not related to antipsychotic medication use, and significantly overlapped with transcriptional changes in idiopathic schizophrenia. In 22q11DS-ASD, both DE and WGCNA analyses implicated dysregulation of immune response pathways. The ASD-associated module showed significant overlap with genes previously associated with idiopathic ASD.
These findings further support the use of peripheral tissue in the study of major mutational models of diseases affecting the brain, and point towards specific pathways dysregulated in 22q11DS carriers with psychosis and ASD.
PMCID: PMC4511766  PMID: 26201030
2.  Reciprocal social behavior in youths with psychotic illness and those at clinical high risk 
Development and psychopathology  2013;25(4 0 1):1187-1197.
Youths at clinical high risk (CHR) for psychosis typically exhibit significant social dysfunction. However, the specific social behaviors associated with psychosis risk have not been well characterized. We administer the Social Responsiveness Scale (SRS), a measure of autistic traits that examines reciprocal social behavior, to the parents of 117 adolescents (61 CHR individuals, 20 age-matched adolescents with a psychotic disorder [AOP], and 36 healthy controls) participating in a longitudinal study of psychosis risk. AOP and CHR individuals have significantly elevated SRS scores relative to healthy controls, indicating more severe social deficits. Mean scores for AOP and CHR youths are typical of scores obtained in individuals with high functioning autism (Constantino & Gruber, 2005). SRS scores are significantly associated with concurrent real-world social functioning in both clinical groups. Finally, baseline SRS scores significantly predict social functioning at follow-up (an average of 7.2 months later) in CHR individuals, over and above baseline social functioning measures ( p < .009). These findings provide novel information regarding impairments in domains critical for adolescent social development, because CHR individuals and those with overt psychosis show marked deficits in reciprocal social behavior. Further, the SRS predicts subsequent real-world social functioning in CHR youth, suggesting that this measure may be useful for identifying targets of treatment in psychosocial interventions.
PMCID: PMC4416482  PMID: 24229557
3.  Multi-system Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees 
JAMA psychiatry  2014;71(4):375-387.
Genetic factors contribute to risk for bipolar disorder (BP), yet its pathogenesis remains poorly understood. A focus on measuring multi-system quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that impact on BP as well as its component phenotypes.
To identify quantitative neurocognitive, temperament-related, and neuroanatomic phenotypes that appear heritable and associated with severe bipolar disorder (BP-I), and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk.
Multi-generational pedigree study in two closely related, genetically isolated populations: the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT).
738 individuals, all from CVCR and ANT pedigrees, of whom 181 are affected with BP-I.
Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) phenotypes.
Seventy-five percent (126) of the phenotypes investigated were significantly heritable, and 31% (53) were associated with BP-I. About 1/4 of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions, and volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture.
This is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I-association within families that is consistent with expectations from case-control studies. Together these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.
PMCID: PMC4045237  PMID: 24522887
4.  The 22q11.2 Deletion Syndrome as a Window into Complex Neuropsychiatric Disorders Over the Lifespan 
Biological psychiatry  2013;75(5):351-360.
Evidence is rapidly accumulating that rare, recurrent copy number variants (CNVs) represent large effect risk factors for neuropsychiatric disorders. 22q11.2 Deletion Syndrome (22q11DS; Velo-Cardio-Facial Syndrome (VCFS) or DiGeorge Syndrome) is the most common known contiguous gene deletion syndrome, and is associated with diverse neuropsychiatric disorders across the lifespan. One of the most intriguing aspects of the syndrome is the variability in clinical and cognitive presentation: children with 22q11DS have high prevalence of autism spectrum (ASD), attention deficit, and anxiety disorders, as well as psychotic-like features, and up to 30% of adolescents and adults develop schizophrenia-like psychosis. Recently, cases of early-onset Parkinson’s Disease in adults have been reported, collectively suggesting a role for disrupted dopaminergic neurotransmission in the observed neuropsychiatric phenotypes. There is also some evidence that 22q11DS-associated ASD and schizophrenia represent two unrelated phenotypic manifestations, consistent with a neuropsychiatric pleiotropy model. This genetic lesion thus provides a unique model for the discovery of specific genomic risk and (potentially) protective factors for neuropsychiatric disease. Here we provide an overview of neuropsychiatric findings to date, which highlight the value of this syndrome in mapping the developmental trajectory of dimensional phenotypes that traverse multiple diagnostic categories. Potential sources of genetic variability that may contribute to the disorder’s heterogeneous presentation are reviewed. Because of its known genetic etiology, animal models can readily be developed that recapitulate specific aspects of the syndrome. Future research directions involve translational models and potential for drug screenable targets in the context of this human model system.
PMCID: PMC3875621  PMID: 23992925
Velocardiofacial/Di George Syndrome; schizophrenia; copy number variant; pleiotropy; neurodevelopment; dopamine
5.  Reliability of an fMRI Paradigm for Emotional Processing in a Multisite Longitudinal Study 
Human brain mapping  2015;36(7):2558-2579.
Multisite neuroimaging studies can facilitate the investigation of brain-related changes in many contexts, including patient groups that are relatively rare in the general population. Though multisite studies have characterized the reliability of brain activation during working memory and motor functional magnetic resonance imaging tasks, emotion processing tasks, pertinent to many clinical populations, remain less explored. A traveling participants study was conducted with eight healthy volunteers scanned twice on consecutive days at each of the eight North American Longitudinal Prodrome Study sites. Tests derived from generalizability theory showed excellent reliability in the amygdala (Eρ2=0.82), inferior frontal gyrus (IFG;Eρ2=0.83), anterior cingulate cortex (ACC;Eρ2=0.76), insula (Eρ2=0.85), and fusiform gyrus (Eρ2=0.91) for maximum activation and fair to excellent reliability in the amygdala (Eρ2=0.44), IFG (Eρ2=0.48), ACC (Eρ2=0.55), insula (Eρ2=0.42), and fusiform gyrus (Eρ2=0.83) for mean activation across sites and test days. For the amygdala, habituation (Eρ2=0.71) was more stable than mean activation. In a second investigation, data from 111 healthy individuals across sites were aggregated in a voxelwise, quantitative meta-analysis. When compared with a mixed effects model controlling for site, both approaches identified robust activation in regions consistent with expected results based on prior single-site research. Overall, regions central to emotion processing showed strong reliability in the traveling participants study and robust activation in the aggregation study. These results support the reliability of blood oxygen level-dependent signal in emotion processing areas across different sites and scanners and may inform future efforts to increase efficiency and enhance knowledge of rare conditions in the population through multisite neuroimaging paradigms.
PMCID: PMC4478164  PMID: 25821147
fMRI; reliability; multisite; emotion; meta-analysis; amygdale
6.  Identification and Treatment of a Pineal Gland Tumor in an Adolescent with Prodromal Psychotic Symptoms 
The American journal of psychiatry  2010;167(9):1033-1037.
An adolescent male patient originally presented to a prodromal clinical research program with severe obsessive-compulsive behaviors and subthreshold symptoms of psychosis, which eventually developed into Schneiderian first-rank psychotic symptoms. The patient was followed over a two-year period. His symptoms did not respond to psychotherapy or pharmacological interventions. However, when a pineal gland tumor was discovered and treated with chemotherapy and autologous stem cell rescue, both psychotic symptoms and psychosocial functioning reverted towards baseline. Although subcortical brain structures have been implicated in the pathophysiology of idiopathic psychosis, reports of psychiatric sequelae of treatment of subcortical tumors are extremely rare. Etiological pathways that may have played a role in symptom development are of particular interest, as understanding these mechanisms may shed light on the pathophysiology of psychotic disorders more generally.
PMCID: PMC4414088  PMID: 20826854
7.  Hippocampal Morphology in Lithium and Non-Lithium-Treated Bipolar I Disorder Patients, Non-Bipolar Co-Twins, and Control Twins 
Human brain mapping  2011;33(3):501-510.
Bipolar I disorder is a highly heritable psychiatric illness with undetermined predisposing genetic and environmental risk factors. We examined familial contributions to hippocampal morphology in bipolar disorder, using a population-based twin cohort design.
We acquired high-resolution brain MRI scans from 18 adult patients with bipolar I disorder [BPI; mean age 45.6 ± 8.69 (SD); 10 lithium-treated], 14 non-bipolar co-twins, and 32 demographically matched healthy comparison twins. We used three-dimensional radial distance mapping techniques to visualize hippocampal shape differences between groups.
Lithium-treated BPI patients had significantly larger global hippocampal volume compared to both healthy controls (9%) and non-bipolar co-twins (12%), and trend-level larger volumes relative to non-lithium-treated BPI patients (8%). In contrast, hippocampal volumes in non-lithium-treated BPI patients did not differ from those of non-bipolar co-twins and control twins. 3D surface maps revealed thicker hippocampi in lithium-treated BPI probands compared with control twins across the entire anterior-to-posterior extent of the cornu ammonis (CA1 and 2) regions, and the anterior part of the subiculum. Unexpectedly, co-twins also showed significantly thicker hippocampi compared with control twins in regions that partially overlapped those showing effects in the lithium treated BPI probands.
These findings suggest that regionally thickened hippocampi in bipolar I disorder may be partly due to familial factors and partly due to lithium-induced neurotrophy, neurogenesis, or neuroprotection. Unlike schizophrenia, hippocampal alterations in co-twins of bipolar I disorder probands are likely to manifest as subtle volume excess rather than deficit, perhaps indicating protective rather than risk effects.
PMCID: PMC4383766  PMID: 21455943
bipolar disorder; magnetic resonance imaging; hippocampus; shape; volume; mood disorders; twin; morphology
8.  A cognitive decline precedes the onset of psychosis in patients with the 22q11.2 deletion syndrome 
JAMA psychiatry  2015;72(4):377-385.
Patients with 22q11.2 deletion syndrome (22q11DS) have an elevated (25%) risk for developing schizophrenia. Recent reports have suggested that a subgroup of children with 22q11DS display a substantial decline in cognitive abilities, starting at a young age.
To determine whether early cognitive decline is associated with risk of psychotic disorder in 22q11DS.
Design, setting and participants
As part of an international research consortium initiative, we used the largest dataset of intelligence (IQ) measurements in subjects with 22q11DS reported to date in order to investigate longitudinal IQ trajectories and the risk of subsequent psychotic illness. A total of 829 subjects with a confirmed hemizygous 22q11.2 deletion, recruited through 12 international clinical research sites, were included. Both psychiatric assessment and longitudinal IQ measurements were available for a subset of 411 subjects (388 with ≥1 assessment at age 8 to 24 years).
Main outcome measures
Diagnosis of a psychotic disorder, longitudinal IQ trajectory and initial IQ, as well as timing of the last psychiatric assessment with respect to the last IQ test.
On average, children with 22q11DS showed a mild decline in full scale IQ (7 points) with increasing age, particularly in the domain of verbal IQ (9 points). In those who developed psychotic illness (47/388) this decline was significantly steeper (p<0.0001). Those with a negative deviation from the average cognitive trajectory observed in 22q11DS were at significantly increased risk for the development of a psychotic disorder (OR=2.49, 95% CI 1.24–5.00, p=0.01). The divergence of verbal IQ trajectories between those who subsequently developed a psychotic disorder and those who did not was distinguishable from the age of 11 years onwards.
Conclusions and relevance
In 22q11DS early cognitive decline is a robust indicator of the risk of developing a psychotic illness. These findings mirror those observed in idiopathic schizophrenia. The results provide further support for investigations of 22q11DS as a genetic model for elucidating neurobiological mechanisms underlying the development of psychosis.
PMCID: PMC4383767  PMID: 25715178
This article presents some of the earliest evidence of visuospatial and numerical cognitive deficits in children with the chromosome 22q11.2 deletion syndrome; a common but ill-understood genetic disorder resulting in medical complications, cognitive impairment, and brain morphologic changes. Relative to a group of typically developing controls, deleted children performed more poorly on tests of visual attentional orienting, visual enumeration and relative numerical magnitude judgment. Results showed that performance deficits in children with the deletion could not be explained by a global deficit in psychomotor speed. Instead, our findings are supportive of the hypothesis that visuospatial and numerical deficits in children with the chromosome 22q11.2 deletion are due, at least in part, to posterior parietal dysfunction.
PMCID: PMC4318636  PMID: 15714897
child; chromosome 22q11.2; VCFS; parietal lobe; attention; enumeration; magnitude; judgment
11.  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.
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.
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.
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.
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.
PMCID: PMC4285461  PMID: 24577245
12.  Autism traits in the RASopathies 
Journal of medical genetics  2013;51(1):10-20.
Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.
We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).
Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.
Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.
PMCID: PMC4230531  PMID: 24101678
13.  Altered white matter microstructure is associated with social cognition and psychotic symptoms in 22q11.2 microdeletion syndrome 
22q11.2 Microdeletion Syndrome (22q11DS) is a highly penetrant genetic mutation associated with a significantly increased risk for psychosis. Aberrant neurodevelopment may lead to inappropriate neural circuit formation and cerebral dysconnectivity in 22q11DS, which may contribute to symptom development. Here we examined: (1) differences between 22q11DS participants and typically developing controls in diffusion tensor imaging (DTI) measures within white matter tracts; (2) whether there is an altered age-related trajectory of white matter pathways in 22q11DS; and (3) relationships between DTI measures, social cognition task performance, and positive symptoms of psychosis in 22q11DS and typically developing controls. Sixty-four direction diffusion weighted imaging data were acquired on 65 participants (36 22q11DS, 29 controls). We examined differences between 22q11DS vs. controls in measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD), using both a voxel-based and region of interest approach. Social cognition domains assessed were: Theory of Mind and emotion recognition. Positive symptoms were assessed using the Structured Interview for Prodromal Syndromes. Compared to typically developing controls, 22q11DS participants showed significantly lower AD and RD in multiple white matter tracts, with effects of greatest magnitude for AD in the superior longitudinal fasciculus. Additionally, 22q11DS participants failed to show typical age-associated changes in FA and RD in the left inferior longitudinal fasciculus. Higher AD in the left inferior fronto-occipital fasciculus (IFO) and left uncinate fasciculus was associated with better social cognition in 22q11DS and controls. In contrast, greater severity of positive symptoms was associated with lower AD in bilateral regions of the IFO in 22q11DS. White matter microstructure in tracts relevant to social cognition is disrupted in 22q11DS, and may contribute to psychosis risk.
PMCID: PMC4227518  PMID: 25426042
DTI; theory of mind; psychosis; schizophrenia; velocardiofacial syndrome; axial diffusivity; radial diffusivity; prodromal
14.  Deficits in Mental State Attributions in Individuals with 22q11.2 Deletion Syndrome (Velo-Cardio-Facial Syndrome) 
Velo-cardio-facial syndrome (VCFS; 22q11.2 deletion syndrome) results from a genetic mutation that increases risk for Autism Spectrum Disorder (ASD). We compared Theory of Mind (ToM) skills in 63 individuals with VCFS (25% with an ASD diagnosis) and 43 typically-developing controls, and investigated the relationship of ToM to reciprocal social behavior. We administered a video-based task to assess mentalizing at two sites (UCLA and SUNY Upstate Medical University). The videos depicted interactions representing complex mental states (ToM condition), or simple movements (Random condition). Verbal descriptions of the videos were rated for Intentionality (i.e., mentalizing) and Appropriateness. Using Repeated Measures ANOVA, we assessed the effects of VCFS and ASD on Intentionality and Appropriateness, and the relationship of mentalizing to Social Responsiveness Scale (SRS) scores. Results indicated that individuals with VCFS overall had lower Intentionality and Appropriateness scores than controls for ToM, but not for Random scenes. In the SUNY sample, individuals with VCFS, both with and without ASD, performed more poorly than controls on the ToM condition; however, in the UCLA sample, only individuals with VCFS without ASD performed significantly worse than controls on the ToM condition. Controlling for site and age, performance on the ToM condition was significantly correlated with SRS scores. Individuals with VCFS, regardless of an ASD diagnosis, showed impairments in the spontaneous attribution of mental states to abstract visual stimuli, which may underlie real-life problems with social interactions. A better understanding of the social deficits in VCFS is essential for the development of targeted behavioral interventions.
PMCID: PMC3528795  PMID: 22962003
22q11.2 deletion syndrome; Velo-cardio-facial syndrome; Theory of Mind; Autism Spectrum Disorders; reciprocal social behavior; social cognition
15.  Social Cognition in 22q11.2 Microdeletion Syndrome: Relevance to Psychosis 
Schizophrenia research  2012;142(0):99-107.
22q11.2 deletion syndrome (22qDS) represents one of the largest known genetic risk factors for schizophrenia. Approximately 30% of individuals with 22qDS develop psychotic illness in adolescence or young adulthood. Given that deficits in social cognition are increasingly viewed as a central aspect of idiopathic schizophrenia, we sought to investigate abilities in this domain as a predictor of psychotic symptoms in 22qDS participants. We assessed multiple domains of social and non-social cognition in 22qDS youth to: 1) characterize performance across these domains in 22qDS, and identify whether 22qDS participants fail to show expected patterns of age-related improvements on these tasks; and 2) determine whether social cognition better predicts positive and negative symptoms than does non-social cognition. Task domains assessed were: emotion recognition and differentiation, Theory of Mind (ToM), verbal knowledge, abstract reasoning, working memory, and processing speed. Positive and negative symptoms were measured using scores obtained from the Structured Interview for Prodromal Symptoms (SIPS). 22qDS participants (N=31, mean age: 15.9) showed the largest impairment, relative to healthy controls (N=31, mean age: 15.6), on measures of ToM and processing speed. In contrast to controls, 22qDS participants did not show age-related improvements on measures of working memory and verbal knowledge. Notably, ToM performance was the best predictor of positive symptoms in 22qDS, accounting for 39% of the variance in symptom severity. Processing speed emerged as the best predictor of negative symptoms, accounting for 37% of the variance in symptoms. Given that ToM was a robust predictor of positive symptoms in our sample, these findings suggest that social cognition may be a valuable intermediate trait for predicting the development of psychosis.
PMCID: PMC3714207  PMID: 23122739
22q11.2 Microdeletion Syndrome; social cognition; schizophrenia; prodromal; psychosis
16.  Conceptualizing impulsivity and risk taking in bipolar disorder: importance of history of alcohol abuse 
Bipolar disorders  2009;11(1):33-40.
Elevated levels of impulsivity and increased risk taking are thought to be core features of both bipolar disorder (BD) and addictive disorders. Given the high rates of comorbid alcohol abuse in BD, alcohol addiction may exacerbate impulsive behavior and risk-taking propensity in BD. Here we examine multiple dimensions of impulsivity and risk taking, using cognitive tasks and self-report measures, in BD patients with and without a history of alcohol abuse.
Thirty-one BD subjects with a prior history of alcohol abuse or dependence (BD-A), 24 BD subjects with no history of alcohol abuse / dependence (BD-N), and 25 healthy control subjects (HC) were assessed with the Barratt Impulsiveness Scale (BIS) and the computerized Balloon Analogue Risk Task (BART).
Both BD groups scored significantly higher than controls on the BIS. In contrast, only the BD-A group showed impaired performance on the BART. BD-A subjects popped significantly more balloons than the BD-N and HC groups. In addition, subjects in the BD-A group failed to adjust their performance after popping balloons. Severity of mood symptomatology was not associated with performance on either task.
The current study supports a primary role of prior alcohol abuse in risk-taking propensity among patients with bipolar disorder. In addition, findings suggest that impulsivity and risky behavior, as operationalized by self-report and experimental cognitive probes, respectively, are separable constructs that tap distinct aspects of the bipolar phenotype.
PMCID: PMC4187105  PMID: 19133964
alcohol abuse; bipolar disorder; impulsivity; risk taking
17.  Association of clinical symptoms and neurocognitive performance in bipolar disorder: a longitudinal study 
Bipolar disorders  2011;13(1):118-123.
Despite evidence that individuals with bipolar disorder have neurocognitive impairment that persists during euthymia, the impact of changes in affective symptoms on cognitive function has not been well established. Here, we sought to determine whether specific neurocognitive functions are sensitive to mood changes in individuals with bipolar disorder assessed three months apart without changes in treatment regimen.
A total of 29 individuals with DSM-IV bipolar disorder and 30 healthy controls participated in the study. All participants received a comprehensive neuropsychological assessment and ratings of depressive [Hamilton Depression Rating Scale (HAMD)] and manic [Young Mania Rating Scale (YMRS)] symptoms at baseline and follow-up. Changes in symptoms over time were calculated and were examined in relation to changes in neurocognitive performance.
At baseline, clinically stable but symptomatic patients were impaired on measures of speed of processing and attention. Over the three-month follow-up period, HAMD scores changed by 6 points on average [range: −10 to +18] and YMRS scores changed by 5.31 points on average [range −11 to +15]. Changes in depressive symptoms were correlated with poorer verbal fluency, while no relationship between manic symptoms and neuropsychological performance was detected.
Individuals with bipolar disorder showed consistent impairment on speed of processing and attention over time, despite significant changes in mood.
PMCID: PMC4180262  PMID: 21320259
bipolar disorder; cognition; depression; mania; neuropsychology
18.  Fronto-temporal dysregulation in remitted bipolar patients: an fMRI delayed-non-match-to-sample (DNMS) study 
Bipolar disorders  2009;11(4):351-360.
Bipolar disorder is associated with working memory (WM) impairments that persist during periods of symptomatic remission. However, the neural underpinnings of these deficits are not well understood.
Fifteen clinically remitted bipolar patients and 15 demographically matched healthy controls underwent functional magnetic resonance imaging while performing a novel delayed-non-match-to-sample (DNMS) task. This nonverbal DNMS task involves two conditions, one requiring the organization of existing memory traces (‘familiarity’), and one involving the formation of new memory traces (‘novelty’). These processes are thought to differentially engage the prefrontal cortex and medial temporal lobe, respectively.
Although behavioral performance did not differ between groups, bipolar patients and controls exhibited significantly different patterns of neural activity during task performance. Patients showed relative hyperactivation in the right prefrontal gyrus and relative hypoactivation in visual processing regions compared to healthy subjects across both task conditions. During the novelty condition, patients showed a pattern of hypoactivation relative to controls in medial temporal regions, with relative hyperactivation in the anterior cingulate.
These findings suggest that disruption in fronto-temporal neural circuitry may underlie memory difficulties frequently observed in patients with bipolar disorder.
PMCID: PMC4180290  PMID: 19500088
bipolar disorder; cognition; euthymia; medial temporal lobe; prefrontal cortex; working memory
19.  Towards a Psychosis Risk Blood Diagnostic for Persons Experiencing High-Risk Symptoms: Preliminary Results From the NAPLS Project 
Schizophrenia Bulletin  2014;41(2):419-428.
Introduction: A barrier to preventative treatments for psychosis is the absence of accurate identification of persons at highest risk. A blood test that could substantially increase diagnostic accuracy would enhance development of psychosis prevention interventions. Methods: The North American Prodrome Longitudinal Study project is a multisite endeavor that aims to better understand predictors and mechanisms for the development of psychosis. In this study, we measured expression of plasma analytes reflecting inflammation, oxidative stress, hormones, and metabolism. A “greedy algorithm” selected analytes that best distinguished persons with clinical high-risk symptoms who developed psychosis (CHR-P; n = 32) from unaffected comparison (UC) subjects (n = 35) and from those who did not develop psychosis during a 2-year follow-up (CHR-NP; n = 40). Results: The classifier included 15 analytes (selected from 117), with an area under the receiver operating curve for CHR-P vs UC of 0.91 and CHR-P vs CHR-NP of 0.88. Randomly scrambled group membership followed by reconstructions of the entire classifier method yielded consistently weak classifiers, indicating that the true classifier is highly unlikely to be a chance occurrence. Such randomization methods robustly imply the assays contain consistent information distinguishing the groups which was not obscured by the data normalization method and was revealed by classifier construction. These results support the hypothesis that inflammation, oxidative stress, and dysregulation of hypothalamic-pituitary axes may be prominent in the earliest stages of psychosis. Conclusion: If confirmed in other groups of persons at elevated risk of psychosis, a multiplex blood assay has the potential for high clinical utility.
PMCID: PMC4332942  PMID: 25103207
clinical high risk; psychosis; prodrome;  multiplex; risk prediction; malondialdehyde-modified low-density lipoprotein (MDA-LDL); immune; inflammation; oxidative stress
20.  Processing Speed and Neurodevelopment in Adolescent-Onset Psychosis: Cognitive Slowing Predicts Social Function 
Onset of psychosis may be associated with abnormal adolescent neurodevelopment. Here we examined the neurocognitive profile of first-episode, adolescent onset psychosis (AOP) as compared to typically developing adolescents, and asked whether neurocognitive performance varied differentially as a function of age in the cases compared with controls. A comprehensive neuropsychological battery was administered to 35 patients experiencing a first-episode of a DSM-IV psychotic disorder and to 31 matched controls. Clinicians also rated subjects’ social and role functioning, both at the time of neuropsychological assessment and 1 year later. Although patients displayed a wide range of impairments relative to controls, their most pronounced deficits included verbal memory, sensorimotor dexterity and cognitive processing speed. Among these, only processing speed showed a significant group-by-age interaction, consistent with an aberrant developmental course among AOP patients. Processing speed also accounted for substantial variance in other areas of deficit, and predicted social functioning 1 year later. AOP patients fail to show normal age-related increases in processing speed, which in turn predicts poorer functional outcomes. This pattern is consistent with the view that adolescent brain developmental processes, such as myelination, may be disrupted in these patients.
PMCID: PMC4119229  PMID: 22134489
Schizophrenia; Adolescence; Neurodevelopment; Outcome; Cognitive processing speed
21.  Psychotropic Medication Use in Youth at High Risk for Psychosis: Comparison of Baseline Data from Two Research Cohorts 1998-2005 and 2008-2011 
Schizophrenia research  2013;148(0):10.1016/j.schres.2013.05.019.
Antipsychotic medication use rates have generally been rising among youth with psychiatric disorders, but little is known about use rates of antipsychotics or other psychotropic medications in patients at high risk for psychosis.
Baseline psychotropic medication use rates were compared in two research cohorts of patients at high risk for psychosis that enrolled between 1998-2005 (n=391) and 2008-2011 (n=346). Treatment durations and antipsychotic doses were described for cohort 2.
Median age was 17 years in cohort 1 and 18 years in cohort 2. The rate of prescription of any psychotropic at baseline was roughly 40% for each cohort. Antipsychotic prescription rates were 24% among sites that permitted baseline antipsychotic use in cohort 1 and 18% in the cohort 2; the decline did not quite reach statistical significance (p=0.064). In cohort 2 the mean±sd baseline chlorpromazine-equivalent dose was 121±108 mg/d, and lifetime duration of antipsychotic treatment was 3.8±5.9 months.
Although the rate of antipsychotic prescription among high-risk youth may have fallen slightly, the nearly one-in-five rate in the second cohort still constitutes a significant exposure. Mitigating factors were that doses and durations of treatment were low. As for other nonpsychotic conditions, it is incumbent on our field to develop alternative treatments for high-risk patients and to generate additional evidence for or against the efficacy of antipsychotics to help define their appropriate role if alternative treatments fail.
PMCID: PMC3867209  PMID: 23787224
psychosis; high risk; risk syndrome; psychotropic medication; antipsychotic medication
22.  Obstetric complications and risk for conversion to psychosis among individuals at high clinical risk 
Early intervention in psychiatry  2009;3(3):226-230.
Examining risk factors among high-risk populations stands to inform treatment and to elucidate our understanding of the pathophysiology of schizophrenia. Despite substantial evidence implicating the incidence of obstetric complications (OCs) as a risk factor for schizophrenia, little is known about the relationship between OCs and risk for conversion among high-risk individuals.
We prospectively followed individuals at high-risk for developing psychotic disorders for a 2-year period to determine if a history of OCs is associated with conversion.
Individuals who converted to psychosis had significantly more OCs when compared to non-converting participants; a history of OCs was associated with increased odds of conversion (OR=4.90, CI:1.04/22.20). OCs were positively associated with prodromal symptomatology.
To date, this report represents the first empirical evidence suggesting that OCs confer increased risk of conversion to psychosis. It is possible that OCs interact with brain maturational processes in the pathophysiology of schizophrenia and can serve as a risk marker.
PMCID: PMC4090059  PMID: 22640387
Obstetric Complications; Prodromal; Conversion; Schizophrenia; Psychosis
23.  The Learning Disabilities Network (LeaDNet): Using Neurofibromatosis Type 1 (NF1) as a Paradigm for Translational Research 
Learning disabilities and other cognitive disorders represent one of the most important unmet medical needs and a significant source of lifelong disability. To accelerate progress in this area, an international consortium of researchers and clinicians, the Learning Disabilities Network (LeaDNet), was established in 2006. Initially, LeaDNet focused on neurofibromatosis type 1 (NF1), a common single gene disorder with a frequency of 1:3,000. Although NF1 is best recognized as an inherited tumor predisposition syndrome, learning, cognitive, and neurobehavioral deficits account for significant morbidity in this condition and can have a profound impact on the quality of life of affected individuals. Recently, there have been groundbreaking advances in our understanding of the molecular, cellular, and neural systems underpinnings of NF1-associated learning deficits in animal models, which precipitated clinical trials using a molecularly targeted treatment for these deficits. However, much remains to be learned about the spectrum of cognitive, neurological, and psychiatric phenotypes associated with the NF1 clinical syndrome. In addition, there is a pressing need to accelerate the identification of specific clinical targets and treatments for thesephenotypes. The successeswith NF1 have allowed LeaDNet investigators to broaden their initial focus to other genetic disorders characterized by learning disabilities and cognitive deficits including other RASopathies (caused by changes in the Ras signaling pathway). The ultimate mission of LeaDNet is to leverage an international translational consortium of clinicians and neuroscientists to integrate bench-to-bedside knowledge across a broad range of cognitive genetic disorders, with the goal of accelerating the development of rational and biologically based treatments.
PMCID: PMC4074877  PMID: 22821737
neurofibromatosis type 1; learning disabilities; RAS/MAPK pathway; neurodevelopmental disorders; Learning Disabilities Network
24.  Youth-caregiver Agreement on Clinical High-risk Symptoms of Psychosis 
Early identification of individuals who will go on to develop schizophrenia is a difficult endeavor. The variety of symptoms experienced by clinical high-risk youth make it difficult to identify who will eventually develop schizophrenia in the future. Efforts are being made, therefore, to more accurately identify at-risk individuals and factors that predict conversion to psychosis. As in most assessments of children and adolescents, however, both youth and parental report of symptomatology and resulting dysfunction are important to assess. The goals of the current study were to assess the extent of cross-informant agreement on the Structured Interview for Prodromal Symptoms (SIPS), a widely-used tool employed to determine clinical high-risk status. A total of 84 youth-caregiver pairs participated. Youth and caregiver raters displayed moderate overall agreement on SIPS-rated symptoms. Both youth and caregiver ratings of youth symptomatology contributed significantly to predicting conversion to psychosis. In addition, youth age and quality of youth-caregiver relationships appear to be related to cross-informant symptom ratings. Despite differences on individual SIPS domains, the majority of dyads agreed on youth clinical high-risk status. Results highlight the potential clinical utility of using caregiver informants to determine youth psychosis risk.
PMCID: PMC4074879  PMID: 24092494
CHR; Clinical high risk; Assessment; Psychosis; Adolescents; Cross-informant agreement
25.  Greater Cortical Gray Matter Density in Lithium-Treated Patients with Bipolar Disorder 
Biological psychiatry  2007;62(1):7-16.
The neurobiological underpinnings of bipolar disorder are not well understood. Previous neuroimaging findings have been inconsistent; however, new methods for three-dimensional (3-D) computational image analysis may better characterize neuroanatomic changes than standard volumetric measures.
We used high-resolution magnetic resonance imaging and cortical pattern matching methods to map gray matter differences in 28 adults with bipolar disorder, 70% of whom were lithium-treated (mean age = 36.1 ± 10.5; 13 female subject), and 28 healthy control subjects (mean age = 35.9 ± 8.5; 11 female subjects). Detailed spatial analyses of gray matter density (GMD) were conducted by measuring local proportions of gray matter at thousands of homologous cortical locations.
Gray matter density was significantly greater in bipolar patients relative to control subjects in diffuse cortical regions. Greatest differences were found in bilateral cingulate and paralimbic cortices, brain regions critical for attentional, motivational, and emotional modulation. Secondary region of interest (ROI) analyses indicated significantly greater GMD in the right anterior cingulate among lithium-treated bipolar patients (n = 20) relative to those not taking lithium (n = 8).
These brain maps are consistent with previous voxel-based morphometry reports of greater GMD in portions of the anterior limbic network in bipolar patients and suggest neurotrophic effects of lithium as a possible etiology of these neuroanatomic differences.
PMCID: PMC3586797  PMID: 17240360
Bipolar disorder; cortical pattern matching; lithium; magnetic resonance imaging; mood disorders; neuroprotection

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