Pranav Nanda

Local gyrification index in Probands with psychotic disorders and their first-degree relatives

BACKGROUND Psychotic disorders are characterized by aberrant neural connectivity. Alterations in gyrification, the pattern and degree of cortical folding, may be related to the early development of connectivity. Past gyrification studies have relatively small sample sizes, yield mixed results for schizophrenia, and are scant for psychotic bipolar and schizoaffective (SZA) disorders and for relatives of these conditions. Here, we examine gyrification in psychotic disorder patients and their first-degree relatives as a possible endophenotype. METHODS Regional local gyrification index (LGI) values, as measured by FreeSurfer software, were compared between 243 control subjects, 388 psychotic disorder probands, and 300 of their first-degree relatives. For patients, LGI values were examined grouped across psychotic diagnoses and then separately for schizophrenia, SZA, and bipolar disorder. Familiality (heritability) values and correlations with clinical measures were also calculated for regional LGI values. RESULTS Probands exhibited significant hypogyria compared with control subjects in three brain regions and relatives with Axis II cluster A disorders showed nearly significant hypogyria in these same regions. Local gyrification index values in these locations were significantly heritable and uncorrelated with any clinical measure. Observations of significant hypogyria were most widespread in SZA. CONCLUSIONS Psychotic disorders appear to be characterized by significant regionally localized hypogyria, particularly in cingulate cortex. This abnormality may be a structural endophenotype marking risk for psychotic illness and it may help elucidate etiological underpinnings of psychotic disorders.

Polygenic risk for type 2 diabetes mellitus among individuals with psychosis and their relatives

BACKGROUND An elevated prevalence of Type 2 diabetes (T2D) has been observed in people with psychotic disorders and their relatives compared to the general population. It is not known whether this population also has increased genetic risk for T2D. METHODS Subjects included probands with schizophrenia, schizoaffective disorder, or psychotic bipolar I disorder, their first-degree relatives without psychotic disorders, and healthy controls, who participated in the Bipolar Schizophrenia Network for Intermediate Phenotypes study. We constructed sets of polygenic risk scores for T2D (PGRST2D) and schizophrenia (PGRSSCHIZ) using publicly available data from genome-wide association studies. We then explored the correlation of PGRST2D with psychiatric proband or relative status, and with self-reported diabetes. Caucasians and African-Americans were analyzed separately. We also evaluated correlations between PGRSSCHIZ and diabetes mellitus among Caucasian probands and their relatives. RESULTS In Caucasians, PGRST2D was correlated with self-reported diabetes mellitus within probands, but was not correlated with proband or relative status in the whole sample. In African-Americans, a PGRST2D based on selected risk alleles for T2D in this population did not correlate with proband or relative status. PGRSSCHIZ was not correlated with self-reported diabetes within Caucasian probands. CONCLUSION Differences in polygenic risk for T2D do not explain the increased prevalence of diabetes mellitus observed in psychosis probands and their relatives.

Novel gene-brain structure relationships in psychotic disorder revealed using parallel independent component analyses

BACKGROUND Schizophrenia, schizoaffective disorder, and psychotic bipolar disorder overlap with regard to symptoms, structural and functional brain abnormalities, and genetic risk factors. Neurobiological pathways connecting genes to clinical phenotypes across the spectrum from schizophrenia to psychotic bipolar disorder remain largely unknown. METHODS We examined the relationship between structural brain changes and risk alleles across the psychosis spectrum in the multi-site Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) cohort. Regional MRI brain volumes were examined in 389 subjects with a psychotic disorder (139 schizophrenia, 90 schizoaffective disorder, and 160 psychotic bipolar disorder) and 123 healthy controls. 451,701 single-nucleotide polymorphisms were screened and processed using parallel independent component analysis (para-ICA) to assess associations between genes and structural brain abnormalities in probands. RESULTS 482 subjects were included after quality control (364 individuals with psychotic disorder and 118 healthy controls). Para-ICA identified four genetic components including several risk genes already known to contribute to schizophrenia and bipolar disorder and revealed three structural components that showed overlapping relationships with the disease risk genes across the three psychotic disorders. Functional ontologies representing these gene clusters included physiological pathways involved in brain development, synaptic transmission, and ion channel activity. CONCLUSIONS Heritable brain structural findings such as reduced cortical thickness and surface area in probands across the psychosis spectrum were associated with somewhat distinct genes related to putative disease pathways implicated in psychotic disorders. This suggests that brain structural alterations might represent discrete psychosis intermediate phenotypes along common neurobiological pathways underlying disease expression across the psychosis spectrum.

Evolving applications, technological challenges and future opportunities in neuromodulation: Proceedings of the fifth annual deep brain stimulation think tank

The annual Deep Brain Stimulation (DBS) Think Tank provides a focal opportunity for a multidisciplinary ensemble of experts in the field of neuromodulation to discuss advancements and forthcoming opportunities and challenges in the field. The proceedings of the fifth Think Tank summarize progress in neuromodulation neurotechnology and techniques for the treatment of a range of neuropsychiatric conditions including Parkinsons disease, dystonia, essential tremor, Tourette syndrome, obsessive compulsive disorder, epilepsy and cognitive, and motor disorders. Each section of this overview of the meeting provides insight to the critical elements of discussion, current challenges, and identified future directions of scientific and technological development and application. The report addresses key issues in developing, and emphasizes major innovations that have occurred during the past year. Specifically, this years meeting focused on technical developments in DBS, design considerations for DBS electrodes, improved sensors, neuronal signal processing, advancements in development and uses of responsive DBS (closed-loop systems), updates on National Institutes of Health and DARPA DBS programs of the BRAIN initiative, and neuroethical and policy issues arising in and from DBS research and applications in practice.

Higher genetic risk of schizophrenia is associated with lower cognitive performance in healthy individuals

Psychotic disorders including schizophrenia are commonly accompanied by cognitive deficits. Recent studies have reported negative genetic correlations between schizophrenia and indicators of cognitive ability such as general intelligence and processing speed. Here we compare the effect of the genetic risk of schizophrenia (PRSSCZ) on measures that differ in their relationships with psychosis onset: a measure of current cognitive abilities (the Brief Assessment of Cognition in Schizophrenia, BACS) that is greatly reduced in psychosis patients; a measure of premorbid intelligence that is minimally affected by psychosis (the Wide-Range Achievement Test, WRAT); and educational attainment (EY), which covaries with both BACS and WRAT. Using genome-wide SNP data from 314 psychotic and 423 healthy research participants in the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Consortium, we investigated the association of PRSSCZ with BACS, WRAT and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRSSCZ) was associated with lower BACS scores (r = −0.19, p = 1 × 10−4 at PT = 1 × 10−4) but did not associate with WRAT or EY, suggesting that these areas of cognition vary in their etiologic relationships with schizophrenia. Among individuals with psychosis, PRSSCZ did not associate with variation in cognitive performance. These findings suggest that the same cognitive abilities that are disrupted in psychotic disorders are also associated with schizophrenia genetic risk in the general population. Specific cognitive phenotypes, independent of education or general intelligence, could be more deeply studied for insight into the specific processes affected by the genetic influences on psychosis. Significance Psychotic disorders such as schizophrenia often involve profound cognitive deficits, the genetic underpinnings of which remain to be elucidated. Poor educational performance early in life is a well-known risk factor for future psychotic illness, potentially reflecting either shared genetic influences or other risk factors that are epidemiologically correlated. Here we show that, in apparently healthy individuals, common genetic risk factors for schizophrenia associate with lower performance in areas of cognition that are impaired in psychotic disorders but do not associate independently with educational attainment or more general measures of intelligence. These results suggest that specific cognitive phenotypes – independent of education or general intelligence – could be more deeply studied for insight into the processes affected by the genetic influences on psychosis.

Connectivity-based parcellation of the anterior limb of the internal capsule

The anterior limb of the internal capsule (ALIC) is an important locus of frontal‐subcortical fiber tracts involved in cognitive and limbic feedback loops. However, the structural organization of its component fiber tracts remains unclear. Therefore, although the ALIC is a promising target for various neurosurgical procedures for psychiatric disorders, more precise understanding of its organization is required to optimize target localization. Using diffusion tensor imaging (DTI) collected on healthy subjects by the Human Connectome Project (HCP), we generated parcellations of the ALIC by dividing it according to structural connectivity to various frontal regions. We then compared individuals’ parcellations to evaluate the ALICs structural consistency. All 40 included subjects demonstrated a posterior–superior to anterior–inferior axis of tract organization in the ALIC. Nonetheless, subdivisions of the ALIC were found to vary substantially, as voxels in the average parcellation were accurately assigned for a mean of only 66.2% of subjects. There were, however, some loci of consistency, most notably in the region maximally connected to orbitofrontal cortex. These findings clarify the highly variable organization of the ALIC and may represent a tool for patient‐specific targeting of neuromodulation. Hum Brain Mapp 38:6107–6117, 2017.

205 Tractography Characterizing Lesions Differentiating Responders to Stereotactic Capsulotomy for Obsessive-Compulsive Disorder.

INTRODUCTION: It has been increasingly recognized that the insular cortex plays an important role in frontotemporal epilepsy (FTE) in children. The insula, however, cannot properly by monitored with conventional subdural grids, and open surgical resection of the insula is technically difficult and often associated with significant morbidity. Stereotactically placed insular depth electrodes allow direct and comprehensive monitoring of this region, and can easily be replaced with a laser applicator for minimally invasive treatment via thermo-ablation.

Polygenic risk for schizophrenia and measured domains of cognition in individuals with psychosis and controls.

Psychotic disorders including schizophrenia are commonly accompanied by cognitive deficits. Recent studies have reported negative genetic correlations between schizophrenia and indicators of cognitive ability such as general intelligence and processing speed. Here we compare the effect of polygenetic risk for schizophrenia (PRSSCZ) on measures that differ in their relationships with psychosis onset: a measure of current cognitive abilities (the Brief Assessment of Cognition in Schizophrenia, BACS) that is greatly reduced in psychotic disorder patients, a measure of premorbid intelligence that is minimally affected by psychosis onset (the Wide-Range Achievement Test, WRAT); and educational attainment (EY), which covaries with both BACS and WRAT. Using genome-wide single nucleotide polymorphism (SNP) data from 314 psychotic and 423 healthy research participants in the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) Consortium, we investigated the association of PRSSCZ with BACS, WRAT, and EY. Among apparently healthy individuals, greater genetic risk for schizophrenia (PRSSCZ) was significantly associated with lower BACS scores (r = −0.17, p = 6.6 × 10−4 at PT = 1 × 10−4), but not with WRAT or EY. Among individuals with psychosis, PRSSCZ did not associate with variations in any of these three phenotypes. We further investigated the association between PRSSCZ and WRAT in more than 4500 healthy subjects from the Philadelphia Neurodevelopmental Cohort. The association was again null (p > 0.3, N = 4511), suggesting that different cognitive phenotypes vary in their etiologic relationship with schizophrenia.