Journal articles

2023

1. A longitudinal resource for population neuroscience of school-age children and adolescents in China.

   Xue-Ru Fan, Yin-Shan Wang, Da Chang, Ning Yang, Meng-Jie Rong, Zhe Zhang, Ye He, Xiaohui Hou, Quan Zhou, Zhu-Qing Gong, and 40 more authors

   Scientific data, Aug 2023

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   During the past decade, cognitive neuroscience has been calling for population diversity to address the challenge of validity and generalizability, ushering in a new era of population neuroscience. The developing Chinese Color Nest Project (devCCNP, 2013-2022), the first ten-year stage of the lifespan CCNP (2013-2032), is a two-stages project focusing on brain-mind development. The project aims to create and share a large-scale, longitudinal and multimodal dataset of typically developing children and adolescents (ages 6.0-17.9 at enrolment) in the Chinese population. The devCCNP houses not only phenotypes measured by demographic, biophysical, psychological and behavioural, cognitive, affective, and ocular-tracking assessments but also neurotypes measured with magnetic resonance imaging (MRI) of brain morphometry, resting-state function, naturalistic viewing function and diffusion structure. This Data Descriptor introduces the first data release of devCCNP including a total of 864 visits from 479 participants. Herein, we provided details of the experimental design, sampling strategies, and technical validation of the devCCNP resource. We demonstrate and discuss the potential of a multicohort longitudinal design to depict normative brain growth curves from the perspective of developmental population neuroscience. The devCCNP resource is shared as part of the "Chinese Data-sharing Warehouse for In-vivo Imaging Brain" in the Chinese Color Nest Project (CCNP) - Lifespan Brain-Mind Development Data Community ( https://ccnp.scidb.cn ) at the Science Data Bank.

2. Comparison of gut microbiome profile in patients with schizophrenia and healthy controls - A plausible non-invasive biomarker?

   Kuppan Gokulakrishnan, Joyappa Nikhil, Biju Viswanath, Chinnasamy Thirumoorthy, Sandhya Narasimhan, Bharanidharan Devarajan, Ebin Joseph, Arul Kevin Daniel David, Sapna Sharma, Kavitha Vasudevan, and 6 more authors

   Journal of psychiatric research, Jun 2023

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   The human gut microbiome regulates brain function through the microbiome-gut-brain axis and is implicated in several neuropsychiatric disorders. However, the relationship between the gut microbiome and the pathogenesis of schizophrenia (SCZ) is poorly defined, and very few studies have examined the effect of antipsychotic treatment response. We aim to study the differences in the gut microbiota among drug-naïve (DN SCZ) and risperidone-treated SCZ patients (RISP SCZ), compared to healthy controls (HCs). We recruited a total of 60 participants, from the clinical services of a large neuropsychiatric hospital, which included DN SCZ, RISP SCZ and HCs (n = 20 each). Fecal samples were analyzed using 16s rRNA sequencing in this cross-sectional study. No significant differences were found in taxa richness (alpha diversity) but microbial composition differed between SCZ patients (both DN and RISP) and HCs (PERMANOVA, p = 0.02). Linear Discriminant Analysis Effect Size (LEfSe) and Random Forest model identified the top six genera, which significantly differed in abundance between the study groups. A specific genus-level microbial panel of Ruminococcus, UCG005, Clostridium_sensu_stricto_1 and Bifidobacterium could discriminate SCZ patients from HCs with an area under the curve (AUC) of 0.79, HCs vs DN SCZ (AUC: 0.68), HCs vs RISP SCZ (AUC: 0.93) and DN SCZ vs RISP SCZ (AUC: 0.87). Our study identified distinct microbial signatures that could aid in the differentiation of DN SCZ, RISP SCZ, and HCs. Our findings contribute to a better understanding of the role of the gut microbiome in SCZ pathophysiology and suggest potential targeted interventions.

3. Country-level gender inequality is associated with structural differences in the brains of women and men.

   André Zugman, Luz María Alliende, Vicente Medel, Richard A. I. Bethlehem, Jakob Seidlitz, Grace Ringlein, Celso Arango, Aurina Arnatkevičiūtė, Laila Asmal, Mark Bellgrove, and 72 more authors

   Proceedings of the National Academy of Sciences of the United States of America, May 2023

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   Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women’s worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women’s brains and provide initial evidence for neuroscience-informed policies for gender equality.

4. Integrative approach for managing tardive dyskinesia: A case report.

   Kulamarva Kavyashree, Karanth Varsha, Chikkanna Umesh, Bhargav Hemant, Holla Bharath, Ramakrishna Kishore Kumar, Jasti Nishitha, and Varambally Shivarama

   Explore (New York, N.Y.), May 2023

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   Tardive dyskinesia (TD) is a debilitating condition characterized by involuntary movements, often resulting from long-term use of antipsychotic medications. Conventional treatment options for TD are limited, expensive, and show mixed effectiveness. This case report presents successful integrative treatment of TD in a patient with mood disorder using Ayurveda and Yoga therapies. The patient showed significant symptom improvement, with sustained benefits at 8-month follow-up, and without any notable adverse effects. This case highlights the potential of integrative approaches in TD management and emphasizes the need for further research to better understand the underlying mechanisms of such therapies.

5. Neurocognitive Analysis of Low-level Arsenic Exposure and Executive Function Mediated by Brain Anomalies Among Children, Adolescents, and Young Adults in India.

   Nilakshi Vaidya, Bharath Holla, Jon Heron, Eesha Sharma, Yuning Zhang, Gwen Fernandes, Udita Iyengar, Alex Spiers, Anupa Yadav, Surajit Das, and 26 more authors

   JAMA network open, May 2023

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   IMPORTANCE: Arsenic, a contaminant of groundwater and irrigated crops, is a global public health hazard. Exposure to low levels of arsenic through food extends well beyond the areas with high arsenic content in water. OBJECTIVE: To identify cognitive impairments following commonly prevalent low-level arsenic exposure and characterize their underlying brain mechanisms. DESIGN, SETTING, AND PARTICIPANTS: This multicenter population-based cohort study analyzed cross-sectional data of the Indian Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA) cohort, recruited between November 4, 2016, and May 4, 2019. Participants aged 6 to 23 years were characterized using deep phenotyping measures of behavior, neuropsychology, psychopathology, brain neuroimaging, and exposure to developmental adversities and environmental neurotoxins. All analyses were performed between June 1, 2020, and December 31, 2021. EXPOSURE: Arsenic levels were measured in urine as an index of exposure. MAIN OUTCOMES AND MEASURES: Executive function measured using the cVEDA neuropsychological battery, gray matter volume (GMV) from T1-weighted magnetic resonance imaging, and functional network connectivity measures from resting state functional magnetic resonance imaging. RESULTS: A total of 1014 participants aged 6 to 23 years (589 male [58.1%]; mean [SD] age, 14.86 [4.79] years) were included from 5 geographic locations. Sparse-partial least squares analysis was used to describe a negative association of arsenic exposure with executive function (r = -0.12 [P = 5.4 × 10-4]), brain structure (r = -0.20 [P = 1.8 × 10-8]), and functional connectivity (within network, r = -0.12 [P = 7.5 × 10-4]; between network, r = -0.23 [P = 1.8 × 10-10]). Alterations in executive function were partially mediated by GMV (b = -0.004 [95% CI, -0.007 to -0.002]) and within-network functional connectivity (b = -0.004 [95% CI, -0.008 to -0.002]). Socioeconomic status and body mass index moderated the association between arsenic and GMV, such that the association was strongest in participants with lower socioeconomic status and body mass index. CONCLUSIONS AND RELEVANCE: The findings of this cross-sectional study suggest that low-level arsenic exposure was associated with alterations in executive functioning and underlying brain correlates. These results indicate potential detrimental consequences of arsenic exposure that are below the currently recommended guidelines and may extend beyond endemic risk areas. Precision medicine approaches to study global mental health vulnerabilities highlight widespread but potentially modifiable risk factors and a mechanistic understanding of the impact of low-level arsenic exposure on brain development.

6. Risk clustering and psychopathology from a multi-center cohort of Indian children, adolescents, and young adults.

   Debasish Basu, Abhishek Ghosh, Chandrima Naskar, Srinivas Balachander, Gwen Fernandes, Nilakshi Vaidya, Kalyanaraman Kumaran, Murali Krishna, Gareth J. Barker, Eesha Sharma, and 26 more authors

   Development and psychopathology, May 2023

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   Developmental adversities early in life are associated with later psychopathology. Clustering may be a useful approach to group multiple diverse risks together and study their relation with psychopathology. To generate risk clusters of children, adolescents, and young adults, based on adverse environmental exposure and developmental characteristics, and to examine the association of risk clusters with manifest psychopathology. Participants (n = 8300) between 6 and 23 years were recruited from seven sites in India. We administered questionnaires to elicit history of previous exposure to adverse childhood environments, family history of psychiatric disorders in first-degree relatives, and a range of antenatal and postnatal adversities. We used these variables to generate risk clusters. Mini-International Neuropsychiatric Interview-5 was administered to evaluate manifest psychopathology. Two-step cluster analysis revealed two clusters designated as high-risk cluster (HRC) and low-risk cluster (LRC), comprising 4197 (50.5%) and 4103 (49.5%) participants, respectively. HRC had higher frequencies of family history of mental illness, antenatal and neonatal risk factors, developmental delays, history of migration, and exposure to adverse childhood experiences than LRC. There were significantly higher risks of any psychiatric disorder [Relative Risk (RR) = 2.0, 95% CI 1.8-2.3], externalizing (RR = 4.8, 95% CI 3.6-6.4) and internalizing disorders (RR = 2.6, 95% CI 2.2-2.9), and suicidality (2.3, 95% CI 1.8-2.8) in HRC. Social-environmental and developmental factors could classify Indian children, adolescents and young adults into homogeneous clusters at high or low risk of psychopathology. These biopsychosocial determinants of mental health may have practice, policy and research implications for people in low- and middle-income countries.

7. Growth trajectories for executive and social cognitive abilities in an Indian population sample: Impact of demographic and psychosocial determinants.

   Eesha Sharma, G. S. Ravi, Keshav Kumar, Kandavel Thennarasu, Jon Heron, Matthew Hickman, Nilakshi Vaidya, Bharath Holla, Madhavi Rangaswamy, Urvakhsh Meherwan Mehta, and 21 more authors

   Asian journal of psychiatry, Apr 2023

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   Cognitive abilities are markers of brain development and psychopathology. Abilities, across executive, and social domains need better characterization over development, including factors that influence developmental change. This study is based on the cVEDA [Consortium on Vulnerability to Externalizing Disorders and Addictions] study, an Indian population based developmental cohort. Verbal working memory, visuo-spatial working memory, response inhibition, set-shifting, and social cognition (faux pas recognition and emotion recognition) were cross-sectionally assessed in \textgreater 8000 individuals over the ages 6-23 years. There was adequate representation across sex, urban-rural background, psychosocial risk (psychopathology, childhood adversity and wealth index, i.e. socio-economic status). Quantile regression was used to model developmental change. Age-based trajectories were generated, along with examination of the impact of determinants (sex, childhood adversity, and wealth index). Development in both executive and social cognitive abilities continued into adulthood. Maturation and stabilization occurred in increasing order of complexity, from working memory to inhibitory control to cognitive flexibility. Age related change was more pronounced for low quantiles in response inhibition (β∼4 versus \textless/=2 for higher quantiles), but for higher quantiles in set-shifting (β \textgreater -1 versus -0.25 for lower quantiles). Wealth index had the largest influence on developmental change across cognitive abilities. Sex differences were prominent in response inhibition, set-shifting and emotion recognition. Childhood adversity had a negative influence on cognitive development. These findings add to the limited literature on patterns and determinants of cognitive development. They have implications for understanding developmental vulnerabilities in young persons, and the need for providing conducive socio-economic environments.

8. Federated Analysis in COINSTAC Reveals Functional Network Connectivity and Spectral Links to Smoking and Alcohol Consumption in Nearly 2,000 Adolescent Brains.

   Harshvardhan Gazula, Kelly Rootes-Murdy, Bharath Holla, Sunitha Basodi, Zuo Zhang, Eric Verner, Ross Kelly, Pratima Murthy, Amit Chakrabarti, Debasish Basu, and 44 more authors

   Neuroinformatics, Apr 2023

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   With the growth of decentralized/federated analysis approaches in neuroimaging, the opportunities to study brain disorders using data from multiple sites has grown multi-fold. One such initiative is the Neuromark, a fully automated spatially constrained independent component analysis (ICA) that is used to link brain network abnormalities among different datasets, studies, and disorders while leveraging subject-specific networks. In this study, we implement the neuromark pipeline in COINSTAC, an open-source neuroimaging framework for collaborative/decentralized analysis. Decentralized exploratory analysis of nearly 2000 resting-state functional magnetic resonance imaging datasets collected at different sites across two cohorts and co-located in different countries was performed to study the resting brain functional network connectivity changes in adolescents who smoke and consume alcohol. Results showed hypoconnectivity across the majority of networks including sensory, default mode, and subcortical domains, more for alcohol than smoking, and decreased low frequency power. These findings suggest that global reduced synchronization is associated with both tobacco and alcohol use. This proof-of-concept work demonstrates the utility and incentives associated with large-scale decentralized collaborations spanning multiple sites.

9. Composition of yoga-philosophy based mental traits (Gunas) in major psychiatric disorders: A trans-diagnostic approach.

   Hemant Bhargav, Najla Eiman, Nishitha Jasti, Pooja More, Vinod Kumar, Bharath Holla, Rashmi Arasappa, Naren P. Rao, Shivarama Varambally, B. N. Gangadhar, and 1 more author

   Frontiers in psychology, Apr 2023

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   Yoga philosophy includes the theory of Tri-guna (three mental traits): sattva (signifies a tendency to ’goodness’), rajas (tendency towards ’activity’), and tamas (tendency towards "inertia"). This cross-sectional study aimed to understand the differences in the expression of gunas in patients suffering from major psychiatric disorders (n = 113, 40 females) and age-gender-education-matched healthy controls (HCs; n = 113, 40 females). Patients were diagnosed by a psychiatrist using DSM 5 criteria and suffered from the following disorders: depression (n = 30), schizophrenia (SCZ; n = 28), obsessive-compulsive disorder (OCD; n = 23), anxiety (n = 16), and bipolar affective disorder (BPAD; n = 16). Tri-gunas were assessed using a validated tool (Vedic Personality Inventory) and symptoms were assessed using standard scales as per the diagnosis. Multi-variate analysis of variance (MANOVA) was used to assess the differences in guna scores between HCs and patients, and between patients with different diagnoses. A two-tailed Pearson correlation was performed between the gunas and psychometric scales. Results revealed that HCs had significantly higher sattva traits as compared to patients (except those with OCD). Each psychiatric diagnosis also showed a specific guna configuration: (1) Anxiety disorders and OCD: High sattva-rajas, low tamas; (2) Depression: High sattva-tamas, low rajas; (3) Psychotic disorders (SCZ/BPAD): High tamo-rajas, low sattva. Significant positive correlations were observed between rajas traits and anxiety/OC/positive psychotic symptoms, negative psychotic symptoms and tamas traits, and sattva traits and OC symptoms. This finding has clinical implications, both to develop ways of predicting outcomes of psychiatric disorders, as well as to develop psycho-therapeutic and lifestyle interventions targeting the gunas.

2022

1. Neurocognition and its association with adverse childhood experiences and familial risk of mental illness.

   Sai Priya Lakkireddy, Srinivas Balachander, Pavithra Dayalamurthy, Mahashweta Bhattacharya, Mino Susan Joseph, Pramod Kumar, Anand Jose Kannampuzha, Sreenivasulu Mallappagari, Shruthi Narayana, Alen Chandy Alexander, and 17 more authors

   Progress in neuro-psychopharmacology & biological psychiatry, Dec 2022

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   Environmental factors such as adverse childhood experiences (ACEs) may affect neurocognition, an endophenotype for several mental illnesses. This study examines the effect of ACEs on neurocognitive performance in first-degree relatives (FDRs) of patients with severe mental illness to determine whether familial risk has a moderating effect on the relationship between ACEs and neurocognition. Unaffected FDRs from multiplex families with severe mental illnesses (schizophrenia, bipolar disorder, obsessive-compulsive disorder, or alcohol use disorder) (n = 324) and healthy controls (with no familial risk) (n = 188) underwent neurocognitive tests for processing speed, new learning, working memory and Theory of Mind. ACEs were measured using the WHO ACE-International Questionnaire (ACE-IQ). Regression models were done to predict each neurocognitive domain by the effect of familial risk, ACE-IQ Score and their interaction (familial risk*ACE-IQ score). The main effect of familial risk predicted poor performance in all domains of neurocognition (p \textless 0.01), and the interaction had a negative association with global neurocognition (β = -0.093, p = 0.009), processing speed (β = -0.109, p = 0.003) and working memory (β = -0.092, p = 0.01). Among the ACEs sub-domains, only maltreatment (specifically the main effect of physical neglect and the interaction effect of sexual abuse with familial risk) predicted poorer neurocognition. In FDRs of schizophrenia and bipolar disorder, only the main effects of familial risk were significantly associated with poorer neurocognition. We conclude that there is a relationship between ACEs (especially maltreatment) and neurocognitive functioning, which is moderated by the familial risk of mental illnesses. Genetic/familial vulnerability may have a stronger association with neurocognition in schizophrenia and bipolar disorder.

2. Whole exome sequencing in dense families suggests genetic pleiotropy amongst Mendelian and complex neuropsychiatric syndromes.

   Suhas Ganesh, Alekhya Vemula, Samsiddhi Bhattacharjee, Kezia Mathew, Dhruva Ithal, Karthick Navin, Ravi Kumar Nadella, Biju Viswanath, Patrick F. Sullivan, Sanjeev Jain, and 1 more author

   Scientific reports, Dec 2022

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   Whole Exome Sequencing (WES) studies provide important insights into the genetic architecture of serious mental illness (SMI). Genes that are central to the shared biology of SMIs may be identified by WES in families with multiple affected individuals with diverse SMI (F-SMI). We performed WES in 220 individuals from 75 F-SMI families and 60 unrelated controls. Within pedigree prioritization employed criteria of rarity, functional consequence, and sharing by ≥ 3 affected members. Across the sample, gene and gene-set-wide case-control association analysis was performed with Sequence Kernel Association Test (SKAT). In 14/16 families with ≥ 3 sequenced affected individuals, we identified a total of 78 rare predicted deleterious variants in 78 unique genes shared by ≥ 3 members with SMI. Twenty (25%) genes were implicated in monogenic CNS syndromes in OMIM (OMIM-CNS), a fraction that is a significant overrepresentation (Fisher’s Exact test OR = 2.47, p = 0.001). In gene-set SKAT, statistically significant association was noted for OMIM-CNS gene-set (SKAT-p = 0.005) but not the synaptic gene-set (SKAT-p = 0.17). In this WES study in F-SMI, we identify private, rare, protein altering variants in genes previously implicated in Mendelian neuropsychiatric syndromes; suggesting pleiotropic influences in neurodevelopment between complex and Mendelian syndromes.

3. Sample size requirement for achieving multisite harmonization using structural brain MRI features.

   Pravesh Parekh, Gaurav Vivek Bhalerao, John P. John, and G. Venkatasubramanian

   NeuroImage, Dec 2022

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   When data is pooled across multiple sites, the extracted features are confounded by site effects. Harmonization methods attempt to correct these site effects while preserving the biological variability within the features. However, little is known about the sample size requirement for effectively learning the harmonization parameters and their relationship with the increasing number of sites. In this study, we performed experiments to find the minimum sample size required to achieve multisite harmonization (using neuroHarmonize) using volumetric and surface features by leveraging the concept of learning curves. Our first two experiments show that site-effects are effectively removed in a univariate and multivariate manner; however, it is essential to regress the effect of covariates from the harmonized data additionally. Our following two experiments with actual and simulated data showed that the minimum sample size required for achieving harmonization grows with the increasing average Mahalanobis distances between the sites and their reference distribution. We conclude by positing a general framework to understand the site effects using the Mahalanobis distance. Further, we provide insights on the various factors in a cross-validation design to achieve optimal inter-site harmonization.

4. Familial risk of psychosis in obsessive-compulsive disorder: Impact on clinical characteristics, comorbidity and treatment response.

   Srinivas Balachander, Navya Spurthi Thatikonda, Anand Jose Kannampuzha, Mahashweta Bhattacharya, Sweta Sheth, Vinutha Ramesh, Alen Chandy Alexander, Moorthy Muthukumaran, Mino Susan Joseph, Sowmya Selvaraj, and 7 more authors

   Journal of psychiatric research, Dec 2022

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   BACKGROUND: Family studies in obsessive-compulsive disorder (OCD) indicate higher rates of psychosis among their first-degree relatives (FDRs). However, the etiological and clinical relationships between the two disorders remain unclear. We compared the clinical characteristics and pharmacological treatment response in patients diagnosed with OCD with a family history of psychosis (OCD-FHP), with a family history of OCD (OCD-FHO) and those with sporadic OCD (OCD-S). METHODS: A total of 226 patients who met DSM-IV criteria for OCD (OCD-FHP = 59, OCD-FHO = 112, OCD-S = 55) were included for analysis. All patients were evaluated using the Mini International Neuropsychiatric Interview (MINI 6.0.0), Yale-Brown Obsessive-Compulsive Scale (YBOCS), and the Family Interview for Genetic Studies (FIGS). Treatment response was characterized over naturalistic follow-up. RESULTS: The three groups did not differ across any demographic or clinical variables other than treatment response. Patients in the OCD-FHP group were found to have received a greater number of trials with serotonin reuptake inhibitors (SRI) [F (2,223) = 7.99, p \textless 0.001], were more likely to have failed ≥2 trials of SRIs (χ(2) = 8.45, p = 0.014), and less likely to have attained remission (χ(2) = 6.57, p = 0.037) CONCLUSIONS: We observed that having a relative with psychosis may predispose to treatment resistance in OCD. Further research on the influence of genetic liability to psychosis on treatment response in OCD may offer novel translational leads.

5. Title of the study: Practice and attitude of doctors towards patients with substance use: A study from south India.

   Venkata Lakshmi Narasimha, Banavaram Anniappan Arvind, Bharath Holla, Ramana Tadepalli, Arun Kandasamy, and Pratima Murthy

   Asian journal of psychiatry, Nov 2022

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   AIM: To evaluate the practice and attitude of doctors towards substance use disorders (SUD) and their management. METHODS: Following stratified proportionate random sampling, selected doctors in the south zone of Bengaluru, India, were interviewed face-to-face using a structured questionnaire. RESULTS: 150 doctors were interviewed. In their practice, a quarter of patients (median of 27.5 (IQR: 11.45-45) use one or other form of Alcohol, Tobacco or Other Drugs of abuse (ATOD). Doctors, in general, enquire about substance use but do not actively intervene. They have mixed attitudes (both positive and negative) towards persons with SUD. A significant positive correlation was noted between the number of years of experience (post-MBBS) with practices related to "brief-intervention" (p = 0.014) and "concerned and sympathetic" attitudes (p \textless 0.001). However, a significant negative correlation was observed between the number of years of experience and "substance-specific management" practices (p \textless 0.001). Further, there was a positive correlation between "brief-interventions" practices with the attitude of being "concerned and sympathetic" (p \textless 0.001). A mediation analysis revealed that nearly a third of the overall effect of the number of years of experience on brief-interventions practices was mediated by a concerned and sympathetic attitude. CONCLUSIONS: Serious efforts must be made to train doctors in the effective management of SUD. Attitudes of the doctors influence practices such as brief interventions. Programs directed towards changing the attitudes of doctors can bring changes in their practices.

6. Abnormalities in the migration of neural precursor cells in familial bipolar disorder.

   Salil K. Sukumaran, Pradip Paul, Vishwesha Guttal, Bharath Holla, Alekhya Vemula, Harsimar Bhatt, Piyush Bisht, Kezia Mathew, Ravi K. Nadella, Anu Mary Varghese, and 6 more authors

   Disease models & mechanisms, Oct 2022

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   Cellular migration is a ubiquitous feature that brings brain cells into appropriate spatial relationships over time; and it helps in the formation of a functional brain. We studied the migration patterns of induced pluripotent stem cell-derived neural precursor cells (NPCs) from individuals with familial bipolar disorder (BD) in comparison with healthy controls. The BD patients also had morphological brain abnormalities evident on magnetic resonance imaging. Time-lapse analysis of migrating cells was performed, through which we were able to identify several parameters that were abnormal in cellular migration, including the speed and directionality of NPCs. We also performed transcriptomic analysis to probe the mechanisms behind the aberrant cellular phenotype identified. Our analysis showed the downregulation of a network of genes, centering on EGF/ERBB proteins. The present findings indicate that collective, systemic dysregulation may produce the aberrant cellular phenotype, which could contribute to the functional and structural changes in the brain reported for bipolar disorder. This article has an associated First Person interview with the first author of the paper.

7. Resting-state network connectivity in cannabis-induced psychosis: Is it different from first episode schizophrenia with heavy cannabis use?

   Fareed Oomer, Abhishek Ghosh, Chirag K. Ahuja, Debasish Basu, Bharath Holla, and Ajit Avasthi

   Asian journal of psychiatry, Sep 2022
8. Yoga and Integrative Healthcare: Lessons from the National Institute of Mental Health and Neurosciences (NIMHANS) in India.

   Hemant Bhargav, Bharath Holla, Kishore Kumar Ramakrishna, Venkataram Shivakumar, K. Gokulakrishnan, Shivarama Varambally, and B. N. Gangadhar

   International journal of yoga, Aug 2022

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   BACKGROUND: There is growing evidence and increasing interest for systemic integration of medicine (synergistic and evidence-based combination of different systems along with conventional biomedicine). The National Institute of Mental Health and Neurosciences (NIMHANS), an Institute of National Importance and a tertiary mental and neurological healthcare hospital situated in Bengaluru, India, has established one such integrative model. The present manuscript traces the history and describes the important steps followed in this integrative approach. METHODOLOGY: The NIMHANS model followed a stage-wise two-step approach: (1) First stage - Starting with Integration of Yoga: The process began more than a decade ago, with integrating yoga into a clinical department (rather than an exclusive research-based approach) of the institute which had relatively high clinical service load (For example, Department of Psychiatry in NIMHANS). Yoga was gradually formalized into academic and clinical activities (outpatient and inpatient services) by appointing a Yoga faculty with a medical background with an MD/PhD in Yoga. The research was primarily directed by the clinical observations of patients receiving yoga therapy. (2) Second stage: Adding an appropriate and compatible discipline from Ayurveda, Yoga and Naturopathy, Unani, Siddha, and Homeopathy (AYUSH) system (Ayurveda in this case): The center for yoga gradually evolved into the Department of Integrative Medicine with the appointment of faculty from the Ayurveda stream. In this model, specialists from each discipline provide clinical inputs after simultaneous consultation with the patient through systemic integration in clinical, academic, and research domains rather than mere co-location of AYUSH services with mainstream medicine. CONCLUSION: The NIMHANS model of integration suggests the application of yoga into mainstream clinical service as the first step toward integration. Yoga should be added as a formalized clinical discipline with systemic integration. Gradually, other feasible systems of traditional medicine from AYUSH can be integrated at a later stage in a step-by-step manner based on clinical practice and evidence.

9. Systematic evaluation of the impact of defacing on quality and volumetric assessments on T1-weighted MR-images.

   Gaurav Vivek Bhalerao, Pravesh Parekh, Jitender Saini, Ganesan Venkatasubramanian, and John P. John

   Journal of neuroradiology = Journal de neuroradiologie, May 2022

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   BACKGROUND AND PURPOSE: Facial features can be potentially reconstructed from structural magnetic resonance images, thereby compromising the confidentiality of study participants. Defacing methods can be applied to MRI images to ensure privacy of study participants. These methods remove facial features, thereby rendering the image unidentifiable. It is commonly assumed that defacing would not have any impact on quantitative assessments of the brain. In this study, we have assessed the impact of different defacing methods on quality and volumetric estimates. MATERIALS AND METHODS: We performed SPM-, Freesurfer-, pydeface, and FSL-based defacing on 30 T1-weighted images. We statistically compared the change in quality measurements (from MRIQC) and volumes (from SPM, CAT, and Freesurfer) between non-defaced and defaced images. We also calculated the Dice coefficient of each tissue class between non-defaced and defaced images. RESULTS: Almost all quality measurements and tissue volumes changed after defacing, irrespective of the method used. All tissue volumes decreased post-defacing for CAT, but no such consistent trend was seen for SPM and Freesurfer. Dice coefficients indicated that segmentations are relatively robust; however, partial volumes might be affected leading to changed volumetric estimates. CONCLUSION: In this study, we demonstrated that volumes and quality measurements get affected differently by defacing methods. It is likely that this will have a significant impact on the reproducibility of experiments. We provide suggestions on ways to minimize the impact of defacing on outcome measurements. Our results warrant the need for robust handling of defaced images at different steps of image processing.

10. Altered Intestinal Permeability Biomarkers in Schizophrenia: A Possible Link with Subclinical Inflammation.

    Kuppan Gokulakrishnan, Joyappa Nikhil, Sreeraj Vs, Bharath Holla, Chinnasamy Thirumoorthy, Narasimhan Sandhya, Sonika Nichenametla, Harsh Pathak, Venkataram Shivakumar, Monojit Debnath, and 2 more authors

    Annals of neurosciences, Apr 2022

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    BACKGROUND AND PURPOSE: Emerging studies have shown that gut-derived endotoxins might play a role in intestinal and systemic inflammation. Although the significance of intestinal permeability in modulating the pathogenesis of Schizophrenia (SCZ) is recognized, not much data on the specific role of intestinal permeability biomarkers, viz., zonulin, lipopolysaccharide-binding protein (LBP), and intestinal alkaline phosphatase (IAP) in SCZ is available. Therefore, we measured the plasma levels of zonulin, LBP, and IAP and its correlation with neutrophil-to-lymphocyte ratio (NLR); a marker of systemic inflammation in patients with SCZ. METHODS: We recruited 60 individuals, patients with SCZ (n = 40) and healthy controls (n = 20), from a large tertiary neuropsychiatry center. Plasma levels of zonulin, IAP, and LBP were quantified by enzyme-linked immunosorbent assay. RESULTS: Plasma levels of both LBP and zonulin were significantly increased (P \textless0.05), whereas the IAP levels (P \textless0.05) were significantly decreased in patients with SCZ compared to healthy controls. Pearson correlation analysis revealed that zonulin and LBP had a significant positive correlation with NLR, and IAP negatively correlated with NLR. Individuals with SCZ had higher independent odds of zonulin [odds ratio (OR): 10.32, 95% CI: 1.85-57.12], LBP [OR: 1.039, 95% CI: 1.02-1.07], and IAP [OR: 0.643, 95% CI: 0.471-0.879], even after adjusting for potential confounders. CONCLUSION: Our study demonstrates an association of zonulin, LBP, and IAP in Asian Indian SCZ patients and correlates with NLR. Our results indicate that low-grade inflammation induced by metabolic endotoxemia might be implicated in the pathoetiology of SCZ.

11. Brain charts for the human lifespan.

    R. A. I. Bethlehem, J. Seidlitz, S. R. White, J. W. Vogel, K. M. Anderson, C. Adamson, S. Adler, G. S. Alexopoulos, E. Anagnostou, A. Areces-Gonzalez, and 192 more authors

    Nature, Apr 2022

    Abs

    Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight(1). Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories(2) of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones(3), showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

2021

1. Heavy Metals in Indian Traditional Systems of Medicine: A Systematic Scoping Review and Recommendations for Integrative Medicine Practice.

   Sanchari Mukhopadhyay, Shalu Elizabeth Abraham, Bharath Holla, Kishore Kr Ramakrishna, Kamala Lakshmi Gopalakrishna, Akhila Soman, Umesh C. Chikkanna, Muchukunte Mukunda Srinivas Bharath, Hemant Bhargav, Shivarama Varambally, and 1 more author

   Journal of alternative and complementary medicine (New York, N.Y.), Nov 2021

   Abs

   Introduction: Ayurveda and Siddha are two important components of the traditional Indian medicine (TIM). The regulatory mechanisms have been insufficient, and heavy metal toxicity with TIM preparations continues to be a public health nuisance, putting integrated medicine practice in jeopardy. The current study was undertaken to review the potential health hazards of the heavy metal content in the TIM and formulate patient-safety recommendations for integrative medical practice. Materials and Methods: Systematic MEDLINE searches were performed using a combination of relevant MeSH terms and keywords, and case report/series of Ayurveda or Siddha-induced heavy metal toxicity, published in the previous two decades, were included. Risk of bias was assessed with the tool by Murad et al. Results: A total of 220 cases (51 case reports and 14 case series) were found (lead, n = 156; arsenic, n = 11; mercury, n = 47; thallium, n = 1; gold, n = 1; combination of heavy metals, n = 4) after screening for the inclusion and exclusion criteria. Among them, 169 (76.8%) had a low risk of bias, 113 (out of 135 [83.7%] analyzed) contained higher-than-permissible heavy metal content in the drug samples, and the majority showed elevated biological levels of the heavy metals in the body. Conclusion: The heavy metals in TIM are often the result of adulteration or improper manufacturing and prescribing practices, despite national and international guidelines recommending quality standards and protocols for preparing and dispensing TIM. We thus propose multipronged approaches and provide recommendations at various levels, including individual, institutional, national policy decisions essential to establish patient safety of TIM.

2. Analysis of whole exome sequencing in severe mental illness hints at selection of brain development and immune related genes.

   Jayant Mahadevan, Ajai Kumar Pathak, Alekhya Vemula, Ravi Kumar Nadella, Biju Viswanath, Sanjeev Jain, Meera Purushottam, and Mayukh Mondal

   Scientific reports, Oct 2021

   Abs

   Evolutionary trends may underlie some aspects of the risk for common, non-communicable disorders, including psychiatric disease. We analyzed whole exome sequencing data from 80 unique individuals from India coming from families with two or more individuals with severe mental illness. We used Population Branch Statistics (PBS) to identify variants and genes under positive selection and identified 74 genes as candidates for positive selection. Of these, 20 were previously associated with Schizophrenia, Alzheimer’s disease and cognitive abilities in genome wide association studies. We then checked whether any of these 74 genes were involved in common biological pathways or related to specific cellular or molecular functions. We found that immune related pathways and functions related to innate immunity such as antigen binding were over-represented. We also evaluated for the presence of Neanderthal introgressed segments in these genes and found Neanderthal introgression in a single gene out of the 74 candidate genes. However, the introgression pattern indicates the region is unlikely to be the source for selection. Our findings hint at how selection pressures in individuals from families with a history of severe mental illness may diverge from the general population. Further, it also provides insights into the genetic architecture of severe mental illness, such as schizophrenia and its link to immune factors.

3. Adverse childhood experiences and substance misuse in young people in India: results from the multisite cVEDA cohort.

   G. S. Fernandes, A. Spiers, N. Vaidya, Y. Zhang, E. Sharma, B. Holla, J. Heron, M. Hickman, P. Murthy, A. Chakrabarti, and 18 more authors

   BMC public health, Oct 2021

   Abs

   BACKGROUND: Adverse childhood experiences (ACEs) increases vulnerability to externalising disorders such as substance misuse. The study aims to determine the prevalence of ACEs and its association with substance misuse. METHODS: Data from the Consortium on Vulnerability to Externalising Disorders and Addictions (cVEDA) in India was used (n = 9010). ACEs were evaluated using the World Health Organisation (WHO) Adverse Childhood Experiences International Questionnaire whilst substance misuse was assessed using the WHO Alcohol, Smoking and Substance Involvement Screening Test. A random-effects, two-stage individual patient data meta-analysis explained the associations between ACEs and substance misuse with adjustments for confounders such as sex and family structure. RESULTS: 1 in 2 participants reported child maltreatment ACEs and family level ACEs. Except for sexual abuse, males report more of every individual childhood adversity and are more likely to report misusing substances compared with females (87.3% vs. 12.7%). In adolescents, family level ACEs (adj OR 4.2, 95% CI 1.5-11.7) and collective level ACEs (adj OR 6.6, 95% CI 1.4-31.1) show associations with substance misuse whilst in young adults, child level ACEs such as maltreatment show similar strong associations (adj OR 2.0, 95% CI 1.1-3.5). CONCLUSION: ACEs such as abuse and domestic violence are strongly associated with substance misuse, most commonly tobacco, in adolescent and young adult males in India. The results suggest enhancing current ACE resilience programmes and ’trauma-informed’ approaches to tackling longer-term impact of ACEs in India. FUNDING: Newton Bhabha Grant jointly funded by the Medical Research Council, UK (MR/N000390/1) and the Indian Council of Medical Research (ICMR/MRC-UK/3/M/2015-NCD-I).

4. Cross-diagnostic evaluation of minor physical anomalies in psychiatric disorders.

   Vanteemar S. Sreeraj, Joan C. Puzhakkal, Bharath Holla, Ravi Kumar Nadella, Sweta Sheth, Srinivas Balachander, Dhruva Ithal, Furkhan Ali, Biju Viswanath, Kesavan Muralidharan, and 7 more authors

   Journal of psychiatric research, Oct 2021

   Abs

   BACKGROUND: Minor physical anomalies (MPA) are markers of impaired neurodevelopment during the prenatal stage. Assessing MPA across psychiatric disorders may help understand their shared nature. In addition, MPA in family members would indicate a shared liability and endophenotype potential. We examined familial aggregation of MPA and their role as transdiagnostic and disorder-specific markers of 5 major psychiatric/neuropsychiatric conditions (schizophrenia, bipolar disorder, substance dependence, obsessive-compulsive disorder, and Alzheimer’s dementia). METHODS: Modified Waldrop’s MPA scale was applied on 1321 individuals from 439 transdiagnostic multiplex families and 125 healthy population controls (HC). Stage of fetal development (morphogenetic/phenogenetic)- and anatomical location (craniofacial/peripheral)-based sub-scores were calculated. Familiality and endophenotypic potential of MPA were analyzed with serial negative binomial mixed-effect regression. Cross-diagnostic differences and the effect of family history density (FHD) of each diagnosis on MPA were assessed. Mixed-effects Cox models estimated the influence of MPA on age-at-onset of illness (AAO). RESULTS: MPA were found to be heritable in families with psychiatric disorders, with a familiality of 0.52. MPA were higher in psychotic disorders after controlling for effects of sex and intrafamilial correlation. Morphogenetic variant MPA was noted to be lower in dementia in comparison to HC. FHD of schizophrenia and bipolar disorder predicted higher, and that of dementia and substance dependence predicted lower MPA. MPA brought forward the AAO [HR:1.07 (1.03-1.11)], and this was more apparent in psychotic disorders. CONCLUSION: MPA are transmissible in families, are specifically related to the risk of developing psychoses, and predict an earlier age at onset. Neurodevelopmentally informed classification of MPA has the potential to enhance the etiopathogenic and translational understanding of psychiatric disorders.

5. Decentralized Multisite VBM Analysis During Adolescence Shows Structural Changes Linked to Age, Body Mass Index, and Smoking: a COINSTAC Analysis.

   Harshvardhan Gazula, Bharath Holla, Zuo Zhang, Jiayuan Xu, Eric Verner, Ross Kelly, Sanjeev Jain, Rose Dawn Bharath, Gareth J. Barker, Debasish Basu, and 12 more authors

   Neuroinformatics, Oct 2021

   Abs

   There has been an upward trend in developing frameworks that enable neuroimaging researchers to address challenging questions by leveraging data across multiple sites all over the world. One such open-source framework is the Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation (COINSTAC) that works on Windows, macOS, and Linux operating systems and leverages containerized analysis pipelines to analyze neuroimaging data stored locally across multiple physical locations without the need for pooling the data at any point during the analysis. In this paper, the COINSTAC team partnered with a data collection consortium to implement the first-ever decentralized voxelwise analysis of brain imaging data performed outside the COINSTAC development group. Decentralized voxel-based morphometry analysis of over 2000 structural magnetic resonance imaging data sets collected at 14 different sites across two cohorts and co-located in different countries was performed to study the structural changes in brain gray matter which linked to age, body mass index (BMI), and smoking. Results produced by the decentralized analysis were consistent with and extended previous findings in the literature. In particular, a widespread cortical gray matter reduction (resembling a ’default mode network’ pattern) and hippocampal increase with age, bilateral increases in the hypothalamus and basal ganglia with BMI, and cingulate and thalamic decreases with smoking. This work provides a critical real-world test of the COINSTAC framework in a "Large-N" study. It showcases the potential benefits of performing multivoxel and multivariate analyses of large-scale neuroimaging data located at multiple sites.

6. An instrument for visual cue associated craving of HEroin (IV-CACHE): A preliminary functional neuroimaging-based study of validity and reliability.

   Shantanu Shukla, Abhishek Ghosh, Chirag Kamal Ahuja, Debasish Basu, and Bharath Holla

   Indian journal of psychiatry, Oct 2021

   Abs

   BACKGROUND: Craving is the subjective experience of desire for specific drugs. Lack of reliability and untested construct validity are limiting factors for the existing questionnaires to assess craving. AIM: The aim of the study was to design and test the validity and reliability of an instrument to assess visual cue-induced craving for heroin dependence. MATERIALS AND METHODS: In the first stage of the study, a set of forty images (twenty each of heroin and neutral cues-) were captured and validated by expert consensus. Thirty male participants with heroin dependence rated their cue-induced craving on a six-point Likert scale while viewing this image-set. In the next stage, putative construct validity was examined using a pilot cue-reactivity functional magnetic resonance imaging paradigm with ten additional heroin-dependent patients. RESULTS: Cronbach’s alpha for the instrument for visual cue-associated craving of HEroin (IV-CACHE) was 0.9, suggestive of high internal consistency. There were modest and significant correlations of IV-CACHE with the drug desire questionnaire (r = 0.43), and obsessive-compulsive drug use scale (r = 0.37), supporting concurrent validity. Patients with heroin dependence exhibited cue reactivity in the left fusiform area, right lingual gyrus, right precuneus region, right inferior frontal, inferior temporal gyri, and middle occipital gyri. The activated brain areas were largely aligned to the underlying neurobiological substrates of craving but might also have depicted nondrug-specific factors (aberrant face processing and attentional bias). CONCLUSION: The present cue-task is a promising tool for the examination of cue-related craving for heroin in the Indian setting.

7. Protocol for magnetic resonance imaging acquisition, quality assurance, and quality check for the Accelerator program for Discovery in Brain disorders using Stem cells.

   Pravesh Parekh, Gaurav V. Bhalerao, Rashmi Rao, Vanteemar S. Sreeraj, Bharath Holla, Jitender Saini, Ganesan Venkatasubramanian, John P. John, and Sanjeev Jain

   International journal of methods in psychiatric research, Sep 2021

   Abs

   OBJECTIVE: The Accelerator program for Discovery in Brain disorders using Stem cells (ADBS) is a longitudinal study on five cohorts of patients with major psychiatric disorders from genetically high-risk families, their unaffected first-degree relatives, and healthy subjects. We describe the ADBS protocols for acquisition, quality assurance (QA), and quality check (QC) for multimodal magnetic resonance brain imaging studies. METHODS: We describe the acquisition and QC protocols for structural, functional, and diffusion images. For QA, we acquire proton density and functional images on phantoms, along with repeated scans on human volunteer. We describe the analysis of phantom data and test-retest reliability of volumetric and diffusion measures. RESULTS: Analysis of acquired phantom data shows linearity of proton density signal with increasing proton fraction, and an overall stability of various spatial and temporal QA measures. Examination of dice coefficient and statistical analyses of coefficient of variation in test-retest data on the human volunteer showed consistency of volumetric and diffusivity measures at whole-brain, regional, and voxel-level. CONCLUSION: The described acquisition and QA-QC procedures can yield consistent and reliable quantitative measures. It is expected that this longitudinal neuroimaging dataset will, upon its release, serve the scientific community well and pave the way for interesting discoveries.

8. Prevalence of child maltreatment in India and its association with gender, urbanisation and policy: a rapid review and meta-analysis protocol.

   Gwen Fernandes, Megan Fernandes, Nilakshi Vaidya, Philip De Souza, Evgeniya Plotnikova, Rosemary Geddes, Bharath Holla, Eesha Sharma, Vivek Benegal, and Vikas Choudhry

   BMJ open, Aug 2021

   Abs

   INTRODUCTION: India is home to 20% of the world’s children and yet, little is known on the magnitude and trends of child maltreatment nationwide. The aims of this review are to provide a prevalence of child maltreatment in India with considerations for any effects of gender; urbanisation (eg, urban vs rural) and legislation (Protection of Children from Sexual Offences (POCSO) Act 2012). METHODS AND ANALYSIS: A rapid review will be undertaken of all quantitative peer-reviewed studies on child maltreatment in India between 2005 and 2020. Four electronic databases will be systematically searched: PubMed, EMBASE, Cochrane and PsychInfo. The primary outcomes will include all aspects of child maltreatment: physical abuse, sexual abuse, emotional abuse, emotional neglect and physical neglect. Study participants will be between 0 and 18 years and will have reported maltreatment experiences using validated, reliable tools such as the Adverse Childhood Experiences Questionnaire as well as child self-reports and clinician reports. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the methodological appraisal of the studies will be assessed by the Newcastle-Ottawa Quality assessment scale. A narrative synthesis will be conducted for all included studies. Also, if sufficient data are available, a meta-analysis will be conducted. Effect sizes will be determined from random-effects models stratified by gender, urbanisation and the pre-2012 and post-2012 POCSO Act cut-off. I(2) statistics will be used to assess heterogeneity and identify their potential sources and τ(2) statistics will indicate any between-study variance. ETHICS AND DISSEMINATION: As this is a rapid review, minimal ethical risks are expected. The protocol and level 1 self-audit checklist were submitted and approved by the Usher Research Ethics Group panel in the Usher Institute (School of Medicine and Veterinary Sciences) at the University of Edinburgh (Reference B126255). Findings from this review will be disseminated widely through peer-reviewed publications and in various media, for example, conferences, congresses or symposia. PROSPERO REGISTRATION NUMBER: CRD42019150403.

9. A Neural Substrate for Mirror Agnosia and Mirror Image Agnosia - Is it a Network disorder?

   Sumanth Sivaram, Sadanandavalli Retnaswami Chandra, G. Venkatasubramanian, Bharath Holla, and Maya Bhat

   Neurology India, Aug 2021

   Abs

   BACKGROUND: Reflected image processing is a unique brain function and its abnormalities result in problems of localizing, recognizing the images, and utilizing this information in everyday life. OBJECTIVES: The aim of this study was to characterize clinical and neuropsychological profiles and to identify the probable neural substrate for this phenomenon in major cognitive disorder. MATERIALS AND METHODS: We conducted a prospective study from February 2015 to May 2017 in patients with Major Cognitive Disorder (MCD, DSM-5 criteria). All patients were tested for problems in reflected image processing using the detailed protocol after ethical approval of the institute and consent. They also underwent a detailed neuropsychological evaluation, biochemical tests and neuroimaging (structural, diffusion, and resting-state functional MRI) as per established protocol. RESULTS: Of the 18 patients, 11 had mirror agnosia (MA), 5 had mirror image agnosia (MIA) and 2 had both. MRI of MA patients showed parietal atrophy and whereas diffuse pattern of atrophy was seen with MIA. In the MA group, the left superior longitudinal fasciculus showed significantly greater fractional anisotropy and the left angular gyrus showed increased functional connectivity with left anterior cingulate, left dorsolateral prefrontal and bilateral posterior cingulate regions. CONCLUSION: Mirror image processing defects were not related to the type of MCD, severity or pattern of neuropsychological dysfunction. There are structural and functional alterations in localized regions as well as both hemispheres. Therefore, it is more likely to be a network disorder, irrespective of the MCD type or severity.

10. Are There Familial Patterns of Symptom Dimensions in Obsessive-Compulsive Disorder?

    Srinivas Balachander, Sandra Meier, Manuel Matthiesen, Furkhan Ali, Anand Jose Kannampuzha, Mahashweta Bhattacharya, Ravi Kumar Nadella, Vanteemar S. Sreeraj, Dhruva Ithal, Bharath Holla, and 5 more authors

    Frontiers in psychiatry, Aug 2021

    Abs

    Background: Obsessive-compulsive disorder (OCD) is a heterogeneous illness, and emerging evidence suggests that different symptom dimensions may have distinct underlying neurobiological mechanisms. We aimed to look for familial patterns in the occurrence of these symptom dimensions in a sample of families with at least two individuals affected with OCD. Methods: Data from 153 families (total number of individuals diagnosed with DSM-5 OCD = 330) recruited as part of the Accelerator Program for Discovery in Brain Disorders using Stem Cells (ADBS) was used for the current analysis. Multidimensional Item Response Theory (IRT) was used to extract dimensional scores from the Yale-Brown Obsessive-Compulsive Scale (YBOCS) checklist data. Using linear mixed-effects regression models, intra-class correlation coefficients (ICC), for each symptom dimension, and within each relationship type were estimated. Results: IRT yielded a four-factor solution with Factor 1 (Sexual/Religious/Aggressive), Factor 2 (Doubts/Checking), Factor 3 (Symmetry/Arranging), and Factor 4 (Contamination/Washing). All except for Factor 1 were found to have significant ICCs, highest for Factor 3 (0.41) followed by Factor 4 (0.29) and then Factor 2 (0.27). Sex-concordant dyads were found to have higher ICC values than discordant ones, for all the symptom dimensions. No major differences in the ICC values between parent-offspring and sib-pairs were seen. Conclusions: Our findings indicate that there is a high concordance of OCD symptom dimensions within multiplex families. Symptom dimensions of OCD might thus have significant heritability. In view of this, future genetic and neurobiological studies in OCD should include symptom dimensions as a key parameter in their analyses.

11. Estimating the familial risk of psychiatric illnesses: A review of family history scores.

    Furkhan Ali, Vanteemar S. Sreeraj, Ravi Kumar Nadella, Bharath Holla, Jayant Mahadevan, Dhruva Ithal, Srinivas Balachander, Biju Viswanath, Ganesan Venkatasubramanian, John P. John, and 2 more authors

    Asian journal of psychiatry, Feb 2021

    Abs

    A history of psychiatric illnesses in family members of those diagnosed to have an illness has been of significant interest both in research and in clinical practice. Almost all of the major psychiatric illnesses have a familial component to them, perhaps influenced by genetics and a shared environment or their combination. Systematic attempts have been made to quantify these familial risks, as obtained from family history (FH) of psychiatric illnesses. The methods range from a simple dichotomous or count scores to those quantifying as weighted risks such as the Family history density (FHD) measures. This article reviews the available literature on such FH methods and discusses their advantages and limitations. Validation studies have shown that FHD measures may be preferred over dichotomous measures as indicators of familial risk. However, the FHD method has certain limitations, like mostly relying on categorical diagnosis and ignoring other familial risk factors. By critically analysing various existing density measures based on ’ideal characteristics’, we suggest a modified version of FHD that would benefit psychiatric research.

12. Psychiatric symptoms and syndromes transcending diagnostic boundaries in Indian multiplex families: The cohort of ADBS study.

    Vanteemar S. Sreeraj, Bharath Holla, Dhruva Ithal, Ravi Kumar Nadella, Jayant Mahadevan, Srinivas Balachander, Furkhan Ali, Sweta Sheth, Janardhanan C. Narayanaswamy, Ganesan Venkatasubramanian, and 6 more authors

    Psychiatry research, Feb 2021

    Place: Ireland

    Abs

    Syndromes of schizophrenia, bipolar disorder, obsessive-compulsive disorder, substance use disorders and Alzheimer’s dementia are highly heritable. About 10-20% of subjects have another affected first degree relative (FDR), and thus represent a ’greater’ genetic susceptibility. We screened 3583 families to identify 481 families with multiple affected members, assessed 1406 individuals in person, and collected information systematically about other relatives. Within the selected families, a third of all FDRs were affected with serious mental illness. Although similar diagnoses aggregated within families, 62% of the families also had members with other syndromes. Moreover, 15% of affected individuals met criteria for co-occurrence of two or more syndromes, across their lifetime. Using dimensional assessments, we detected a range of symptom clusters in both affected and unaffected individuals, and across diagnostic categories. Our findings suggest that in multiplex families, there is considerable heterogeneity of clinical syndromes, as well as sub-threshold symptoms. These families would help provide an opportunity for further research using both genetic analyses and biomarkers.

2020

1. 

   A series of five population-specific Indian brain templates and atlases spanning ages 6-60 years.

   Bharath Holla, Paul A. Taylor, Daniel R. Glen, John A. Lee, Nilakshi Vaidya, Urvakhsh Meherwan Mehta, Ganesan Venkatasubramanian, Pramod Kumar Pal, Jitender Saini, Naren P. Rao, and 12 more authors

   Human brain mapping, Dec 2020

   Abs

   Anatomical brain templates are commonly used as references in neurological MRI studies, for bringing data into a common space for group-level statistics and coordinate reporting. Given the inherent variability in brain morphology across age and geography, it is important to have templates that are as representative as possible for both age and population. A representative-template increases the accuracy of alignment, decreases distortions as well as potential biases in final coordinate reports. In this study, we developed and validated a new set of T1w Indian brain templates (IBT) from a large number of brain scans (total n = 466) acquired across different locations and multiple 3T MRI scanners in India. A new tool in AFNI, make_template_dask.py, was created to efficiently make five age-specific IBTs (ages 6-60 years) as well as maximum probability map (MPM) atlases for each template; for each age-group’s template-atlas pair, there is both a "population-average" and a "typical" version. Validation experiments on an independent Indian structural and functional-MRI dataset show the appropriateness of IBTs for spatial normalization of Indian brains. The results indicate significant structural differences when comparing the IBTs and MNI template, with these differences being maximal along the Anterior-Posterior and Inferior-Superior axes, but minimal Left-Right. For each age-group, the MPM brain atlases provide reasonably good representation of the native-space volumes in the IBT space, except in a few regions with high intersubject variability. These findings provide evidence to support the use of age and population-specific templates in human brain mapping studies.

2. Population normative models of human brain growth across development.

   Bharath Holla, Jakob Seidlitz, Richard A. I. Bethlehem, and Gunter Schumann

   Science bulletin, Nov 2020
3. Adverse childhood experiences in families with multiple members diagnosed to have psychiatric illnesses.

   Amala Someshwar, Bharath Holla, Preeti Pansari Agarwal, Anza Thomas, Anand Jose, Boban Joseph, Birudu Raju, Hariprasad Karle, M. Muthukumaran, Prabhath G. Kodancha, and 15 more authors

   The Australian and New Zealand journal of psychiatry, Nov 2020

   Abs

   OBJECTIVE: Adverse childhood experiences are linked to the development of a number of psychiatric illnesses in adulthood. Our study examined the pattern of adverse childhood experiences and their relation to the age of onset of major psychiatric conditions in individuals from families that had ⩾2 first-degree relatives with major psychiatric conditions (multiplex families), identified as part of an ongoing longitudinal study. METHODS: Our sample consisted of 509 individuals from 215 families. Of these, 268 were affected, i.e., diagnosed with bipolar disorder (n = 61), obsessive-compulsive disorder (n = 58), schizophrenia (n = 52), substance dependence (n = 59) or co-occurring diagnoses (n = 38), while 241 were at-risk first-degree relatives who were either unaffected (n = 210) or had other depressive or anxiety disorders (n = 31). All individuals were evaluated using the Adverse Childhood Experiences - International Questionnaire and total adverse childhood experiences exposure and severity scores were calculated. RESULTS: It was seen that affected males, as a group, had the greatest adverse childhood experiences exposure and severity scores in our sample. A Cox mixed effects model fit by gender revealed that a higher total adverse childhood experiences severity score was associated with significantly increased risk for an earlier age of onset of psychiatric diagnoses in males. A similar model that evaluated the interaction of diagnosis revealed an earlier age of onset in obsessive-compulsive disorder and substance dependence, but not in schizophrenia and bipolar disorder. CONCLUSION: Our study indicates that adverse childhood experiences were associated with an earlier onset of major psychiatric conditions in men and individuals diagnosed with obsessive-compulsive disorder and substance dependence. Ongoing longitudinal assessments in first-degree relatives from these families are expected to identify mechanisms underlying this relationship.

4. Effect of prefrontal tDCS on resting brain fMRI graph measures in Alcohol Use Disorders: A randomized, double-blind, sham-controlled study.

   Bharath Holla, Jitendriya Biswal, Vinutha Ramesh, Venkataram Shivakumar, Rose Dawn Bharath, Vivek Benegal, Ganesan Venkatasubramanian, Prabhat Kumar Chand, and Pratima Murthy

   Progress in neuro-psychopharmacology & biological psychiatry, Aug 2020

   Abs

   OBJECTIVES: Transcranial Direct Current Stimulation (tDCS) is a promising new adjuvant approach in the treatment of Alcohol Use Disorders (AUDs) that has the potential to ameliorate the aberrations secondary to chronic alcohol use. In this study, using a randomized, double-blind, sham-controlled, parallel-arm design, we examined the effects of prefrontal tDCS on resting-state functional magnetic resonance imaging (rsfMRI) and its correlates with impulsivity and time to first lapse in subjects with AUDs. METHODS: Patients with AUD as per DSM-5 criteria were randomly allocated to receive a five-day course of either verum-tDCS (n = 12) or sham-tDCS (n = 12). Of them, 21 patients (verum/sham = 11/10) participated in both baseline and post-intervention 10-min rsfMRI sessions. Outside the scanner, subjects also performed the Stop-Signal Task at two time-points (baseline and post-intervention), which provided a measure of changes in impulsivity following tDCS. After completion of the post-intervention scan, all subjects were discharged and were followed-up for 90 days post-discharge or until lapse to first alcohol use. RESULTS: Graph theoretical analysis of rsfMRI data revealed that verum-tDCS (but not sham) resulted in a significant increase in the global efficiency of brain networks with a concurrent significant reduction in global clustering; network-based statistical analysis identified a significant increase in the functional connectivity of a specific sub-network involving prefrontal regions. Furthermore, increased global efficiency of brain networks following verum tDCS predicted a significantly reduced likelihood of relapse. In addition, a reduction in the global clustering had a significant positive correlation with a reduction in the measure of impulsivity. CONCLUSIONS: The present study adds further support to the increasing evidence base for the clinical utility of tDCS in AUDs. Importantly, we observed improvement in both whole-brain network efficiency as well as inter-regional connectivity within a specific local prefrontal sub-network that is relevant to the neurobiology of AUDs. Replication and extension of these promising leads from the present study can facilitate clinical translation of tDCS, given its advantages (i.e. safety, cost-effectiveness, administration ease with potential for remotely-supervised / home-based application) for treating patients with AUDs.

5. The Consortium on Vulnerability to Externalizing Disorders and Addictions (c-VEDA): an accelerated longitudinal cohort of children and adolescents in India.

   Yuning Zhang, Nilakshi Vaidya, Udita Iyengar, Eesha Sharma, Bharath Holla, Chirag K. Ahuja, Gareth J. Barker, Debasish Basu, Rose Dawn Bharath, Amit Chakrabarti, and 29 more authors

   Molecular psychiatry, Aug 2020

   Abs

   The global burden of disease attributable to externalizing disorders such as alcohol misuse calls urgently for effective prevention and intervention. As our current knowledge is mainly derived from high-income countries such in Europe and North-America, it is difficult to address the wider socio-cultural, psychosocial context, and genetic factors in which risk and resilience are embedded in low- and medium-income countries. c-VEDA was established as the first and largest India-based multi-site cohort investigating the vulnerabilities for the development of externalizing disorders, addictions, and other mental health problems. Using a harmonised data collection plan coordinated with multiple cohorts in China, USA, and Europe, baseline data were collected from seven study sites between November 2016 and May 2019. Nine thousand and ten participants between the ages of 6 and 23 were assessed during this time, amongst which 1278 participants underwent more intensive assessments including MRI scans. Both waves of follow-ups have started according to the accelerated cohort structure with planned missingness design. Here, we present descriptive statistics on several key domains of assessments, and the full baseline dataset will be made accessible for researchers outside the consortium in September 2019. More details can be found on our website [cveda.org].

6. Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA): A developmental cohort study protocol.

   Eesha Sharma, Nilakshi Vaidya, Udita Iyengar, Yuning Zhang, Bharath Holla, Meera Purushottam, Amit Chakrabarti, Gwen Sascha Fernandes, Jon Heron, Matthew Hickman, and 27 more authors

   BMC psychiatry, Jan 2020

   Abs

   BACKGROUND: Low and middle-income countries like India with a large youth population experience a different environment from that of high-income countries. The Consortium on Vulnerability to Externalizing Disorders and Addictions (cVEDA), based in India, aims to examine environmental influences on genomic variations, neurodevelopmental trajectories and vulnerability to psychopathology, with a focus on externalizing disorders. METHODS: cVEDA is a longitudinal cohort study, with planned missingness design for yearly follow-up. Participants have been recruited from multi-site tertiary care mental health settings, local communities, schools and colleges. 10,000 individuals between 6 and 23 years of age, of all genders, representing five geographically, ethnically, and socio-culturally distinct regions in India, and exposures to variations in early life adversity (psychosocial, nutritional, toxic exposures, slum-habitats, socio-political conflicts, urban/rural living, mental illness in the family) have been assessed using age-appropriate instruments to capture socio-demographic information, temperament, environmental exposures, parenting, psychiatric morbidity, and neuropsychological functioning. Blood/saliva and urine samples have been collected for genetic, epigenetic and toxicological (heavy metals, volatile organic compounds) studies. Structural (T1, T2, DTI) and functional (resting state fMRI) MRI brain scans have been performed on approximately 15% of the individuals. All data and biological samples are maintained in a databank and biobank, respectively. DISCUSSION: The cVEDA has established the largest neurodevelopmental database in India, comparable to global datasets, with detailed environmental characterization. This should permit identification of environmental and genetic vulnerabilities to psychopathology within a developmental framework. Neuroimaging and neuropsychological data from this study are already yielding insights on brain growth and maturation patterns.

2019

1. Altered brain cortical maturation is found in adolescents with a family history of alcoholism.

   Bharath Holla, Rose Dawn Bharath, Ganesan Venkatasubramanian, and Vivek Benegal

   Addiction biology, Jul 2019

   Abs

   Substance-naïve offspring from high-density alcohol use disorder (AUD) families exhibit altered subcortical brain volumes structurally and altered executive-functioning and emotion-processing functionally, compared with their peers. However, there is a dearth of literature exploring alterations of cortical thickness (CTh) in this population. T1-weighted structural brain MRI was acquired in 75 substance-naïve male offspring of treatment-seeking early onset (\textless25 years) AUD patients with high familial loading of AUDs (≥2 affected relatives) (FHP) and 65 age-matched substance-naïve male controls with negative family history from the community. Surface-based CTh reconstruction was done using FreeSurfer. Univariate general linear models were implemented at each vertex using SurfStat, controlling for age (linear and quadratic effects), and head size, to examine the main effect of familial AUD risk on CTh and its relationship with externalizing symptom score (ESS). A Johnson-Neyman procedure revealed that the main effect of familial AUD risk on CTh was seen during adolescence, where the FHP group had thicker cortices involving bilateral precentral gyri, left caudal middle frontal gyrus (MFG), bilateral temporo-parietal junction, left inferior-frontal gyrus and right inferior-temporal gyrus. Thicker cortices in left MFG and inferior-parietal lobule were also associated with greater ESS within both groups. More importantly, these group differences diminished with age by young adulthood. Familial AUD risk is associated with age-related differences in maturation of several higher order association cortices that are critical to ongoing development in executive function, emotion regulation and social cognition during adolescence. Early supportive intervention for a delay in alcohol initiation during this critical phase may be crucial for this at-risk population.

2018

1. Brain Functional Magnetic Resonance Imaging Cue-reactivity Can Predict Baclofen Response in Alcohol Use Disorders.

   Bharath Holla, Sheshachala Karthik, Jitendriya Biswal, Biju Viswanath, Deepak Jayarajan, Rose Dawn Bharath, Ganesan Venkatasubramanian, and Vivek Benegal

   Clinical Psychopharmacology and Neuroscience, Aug 2018

   Abs

   OBJECTIVE: Baclofen is a promising treatment for alcohol use disorders (AUD), although its clinical response in humans is mixed. The present study aimed at investigating the impact of baclofen treatment on cue-induced brain activation pattern and its relationship with relapse outcomes. METHODS: Twenty-three inpatients with AUD underwent a functional magnetic resonance imaging cue-reactivity task before beginning medication with baclofen and 2 weeks later. Twelve additional inpatients with AUD, who did not receive any anticraving medications, formed the control group. All subjects were prospectively followed up for 90 days post-discharge or until lapse to first alcohol use. RESULTS: Whole-brain linear mixed effects analysis revealed a significant group-by-time interaction with greater activation of the bilateral dorsolateral pre-frontal cortex and right anterior cingulate cortex (ACC) following baclofen treatment in comparison with the control group. Further, cox regression analysis revealed that increased activation of ACC and deactivation of insular cortex (IC) was associated with longer time to first alcohol use only in the baclofen treatment group but not in the control group. CONCLUSION: This study provides preliminary evidence for the neural predictors of baclofen treatment response in AUD. Baclofen treatment in AUD was associated with changes in cue-reactivity at critical brain regions within the incentive-salience network. Importantly, baclofen treatment-related specific activation of regions involved in cognitive control (ACC) and deactivation of regions involved in reward anticipation (IC) prolonged the time to first alcohol drink.

2017

1. Disrupted resting brain graph measures in individuals at high risk for alcoholism.

   Bharath Holla, Rajanikant Panda, Ganesan Venkatasubramanian, Bharat Biswal, Rose Dawn Bharath, and Vivek Benegal

   Psychiatry research. Neuroimaging, Jul 2017

   Abs

   Familial susceptibility to alcoholism is likely to be linked to the externalizing diathesis seen in high-risk offspring from high-density alcohol use disorder (AUD) families. The present study aimed at comparing resting brain functional connectivity and their association with externalizing symptoms and alcoholism familial density in 40 substance-naive high-risk (HR) male offspring from high-density AUD families and 30 matched healthy low-risk (LR) males without a family history of substance dependence using graph theory-based network analysis. The HR subjects from high-density AUD families compared with LR, showed significantly reduced clustering, small-worldness, and local network efficiency. The frontoparietal, cingulo-opercular, sensorimotor and cerebellar networks exhibited significantly reduced functional segregation. These disruptions exhibited independent incremental value in predicting the externalizing symptoms over and above the demographic variables. The reduction of functional segregation in HR subjects was significant across both the younger and older age groups and was proportional to the family loading of AUDs. Detection and estimation of these developmentally relevant disruptions in small-world architecture at critical brain regions sub-serving cognitive, affective, and sensorimotor processes are vital for understanding the familial risk for early onset alcoholism as well as for understanding the pathophysiological mechanism of externalizing behaviors.

2015

1. High doses of Baclofen as suicide attempt in patients with alcohol use disorders - A serious concern.

   Bharath Holla, Guru S. Gowda, Lokesh Prabhu, Sojan Baby, Biju Viswanath, Prabhat Chand, and Pratima Murthy

   Asian journal of psychiatry, Oct 2015

   Abs

   Baclofen is increasingly being used as an off label anti-craving agent in alcohol use disorders in various parts of the world. The lack of proper recommendations regarding the dosage has important implications for safety in clinical management. In this context, we report two patients who were started with Baclofen as an anti-craving agent, and later developed serious complications following acute self inflicted overdose. We also highlight the important mechanisms of such complications and precautions that needs to be exerted while prescribing.

2. Course and outcome of schizophrenia in asian countries: review of research in the past three decades.

   Bharath Holla, and Jagadisha Thirthalli

   Asian journal of psychiatry, Apr 2015

   Abs

   Considerable variation has been observed in the course and outcome of schizophrenia. With regard to epidemiology of schizophrenia, papers from different Asian countries have reported findings which are in contrast with literature from the western countries. In this background we undertook a narrative review of literature regarding course and outcome of schizophrenia in Asian countries. We conducted Medline search for English-language papers on long-term course and outcome of schizophrenia conducted in Asia in the past 3 decades. We also reviewed data pertaining to Asian countries from the World Health Organization’s International Study of Schizophrenia (ISoS). In addition to ISoS, we retrieved 14 reports from 9 Asian countries. While ISoS used comparable methodology across the countries, non-ISoS studies differed substantially in their aims, sampling, follow-up rates and assessment tools used for studying the course and outcome. Overall, the percentage of patients who experienced clinical and functional outcome in the Asian countries were largely comparable to those in the western studies. We observed significant variations in the long-term outcome and mortality in schizophrenia even among the Asian countries. In conclusion, there is substantial variation in the long-term course and outcome and mortality across different Asian countries. The reason for this remains unexplored. Cross-national studies exploring biological and cultural explanations for this variation may provide clues, which may have heuristic, translational and public-health significance.

2014

1. Visual Image-Induced Craving for Ethanol (VICE): Development, Validation, and a Pilot fMRI Study.

   Bharath Holla, Biju Viswanath, Sri Mahavir Agarwal, Sunil Vasu Kalmady, Ami Sebastian Maroky, Deepak Jayarajan, Rose Dawn Bharath, Ganesan Venkatasubramanian, and Vivek Benegal

   Indian journal of psychological medicine, Apr 2014

   Abs

   BACKGROUND: Craving induction in a controlled environment is helpful in the research of craving mechanism and its role in development of alcohol dependence (AD). We describe a novel tool Visual Image-induced Craving for Ethanol (VICE) and its effects on brain activation with pilot functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: Alcohol-related visual cues (ARCs) in 5 scenarios were photographed, which included pictures of bars, alcoholic beverage bottles, pouring of alcohol into glasses, glasses filled with alcohol, and scenes of people sipping alcohol, counterbalanced with neutral pictures (involving water, milk etc.,). Craving scores were obtained from 15 hospitalized patients with AD to validate this tool. In the pilot fMRI (3-Tesla) study, 5 patients were examined using VICE in a symptom provocation model. Group level-fixed effect analysis of brain activation differences was done using SPM8. RESULTS: VICE showed a high internal consistency with Cronbach’s α coefficient of 0.86, which confirmed its reliability. Concurrent validity of VICE was demonstrated via its convergence with the Penn Alcohol Craving Scale. ARCs had significantly greater mean craving scores than neutral cues in all the 5 scenarios (intentional validity). In the pilot fMRI, patients were found to have greater activation while viewing ARCs compared to the neutral cues in right insular cortex and deficient activation in right orbitofrontal cortex. CONCLUSIONS: The VICE is a reliable and valid measure of alcohol craving with promising clinical and translational research implications. Preliminary fMRI findings indicate it can be used as a symptom provocation tool for fMRI experiments.

2. Profile of male forensic psychiatric inpatients in South India.

   Dayachandra Kumar, Biju Viswanath, Ami Sebestian, Bharath Holla, Reddema Konduru, Chanapatna Rajannachar Chandrashekar, and Suresh Bada Math

   The International journal of social psychiatry, Feb 2014

   Abs

   AIM: The study explored the socio-demographic, clinical and legal profile of forensic psychiatric inpatients in an attempt to improve the existing mental health services for prisoners within the prison and in psychiatric hospitals. METHOD: ology: A chart review of 135 forensic psychiatric inpatients admitted between January 2005 and December 2009 was done. A structured data-extraction tool was used for data collection and a descriptive approach for analyses. RESULTS: Subjects were referred either directly from prison (62.2%) or from court (37.8%) for diagnosis, treatment or certification. References to the Mental Health Act 1987, charges and inclusion of first investigation report and behavioural observation report was lacking in most. The majority of prisoners (85.7%) were under trial, murder being the most common charge. Psychiatric diagnosis was made in 90.3%, the most common being psychosis. Substance use (nicotine, alcohol, cannabis) and high-risk behaviours were also common. CONCLUSION: There is a need to streamline the procedure of referral and to sensitize the referral authorities about the Mental Health Act and mental illnesses, and the need to enclose first investigation reports and behavioural observation reports. De-addiction services and facilities need to be established within prison premises so that the inmates get the benefit of treatment at the earliest opportunity.

2013

1. Modafinil for the treatment of antipsychotic-induced excessive daytime sedation: does it exacerbate tics?

   Gayatri Saraf, Biju Viswanath, Janardhanan C. Narayanaswamy, Bharath Holla, and Suresh Bada Math

   The Journal of neuropsychiatry and clinical neurosciences, Feb 2013
2. Karnataka state telemedicine project: utilization pattern, current, and future challenges.

   Bharath Holla, Biju Viswanath, Shanthaveeranna Neelaveni, T. Harish, Channaveerachari Naveen Kumar, and Suresh Bada Math

   Indian journal of psychological medicine, Jul 2013

   Abs

   BACKGROUND: The Telemedicine Network Project in the state of Karnataka was introduced in the year 2001. This is a value added service from the health department of the government of Karnataka. There is no data on its utilization pattern or its future challenges. This study was conducted from a nodal center in order to understand the above two issues. MATERIALS AND METHODS: We used a 51-item survey questionnaire that captured data on infrastructure, technical aspects, and connectivity parameters, tele-consultations including emergency services, human resources, and coordination aspects both at the client as well as the nodal centers. RESULTS: Services are operational in 25 district hospitals across the state for the past 3.3 (2.1) years. Space was ear-marked across all the client centers. Back-up power supply was present only in 10 (40%) of the client centers. Quality of satellite connection was acceptable in 18 (72%) centers. Approximately, 3.0 (1.8) phone calls had to be made to the nodal centers to obtain one appointment. Monthly maximum and minimum cases done over the past 2 year period were reported as 58.2 (66.2) and 13.5 (16.2) respectively. Each consultation lasted for 26.1 (13.9) min. Tele-consultation advices from nodal centers were carried out completely in only 9 (36%) centers. Only in 13 (52%) client centers, did doctors keep up with appointment regularly. All technicians reported that the training they received was inadequate. 16 (64%) technicians were asked to do works that were not pertaining to telemedicine. 19 (76%) technicians had frequently felt insecurities about their jobs. CONCLUSIONS: The telemedicine service has been largely under-utilized and has failed to deliver the promise in Karnataka state. At present, the obstacles reflect both inherent limitations in the technology and also improper use of human resources. Successful implementation of the given recommendations may in the long run help optimal utilization and reach all end-users.

3. Piracetam treatment in patients with cognitive impairment.

   Mukund G. Rao, Bharath Holla, Shivarama Varambally, Dhanya Raveendranathan, Ganesan Venkatasubramanian, and Bangalore N. Gangadhar

   General hospital psychiatry, Aug 2013

   Abs

   Piracetam is a cognitive-enhancing agent that is used for the treatment of cognitive impairments of various etiologies. Little is known about its side effect profile, especially in those with psychiatric illness. We herewith present two cases with cognitive impairment who had contrasting responses to piracetam. One of them with organic amnestic syndrome had significant improvement, whereas the other who had an organic personality change as well as a family history of mental illness had significant worsening of behavioral problems after piracetam was introduced. This report highlights the need for caution in the use of piracetam, especially in those with past or family history of psychiatric illness.

4. Effectiveness of electroconvulsive therapy for drug-induced parkinsonism in the elderly.

   Suneetha K. Sadananda, Bharath Holla, Biju Viswanath, Aniruddh Narasimha, Ami Sebastian, Suresh B. Math, and Channapatna R. Chandrashekar

   The journal of ECT, Mar 2013
5. Reversible dementia in young persons due to cobalamin deficiency.

   Sunil Kumar, Aniruddh Narasimha, Bharath Holla, Biju Viswanath, Janardhanan C. Narayanaswamy, Suresh Bada Math, and C. R. Chandrashekar

   The Journal of neuropsychiatry and clinical neurosciences, Mar 2013

Conference Proceedings

2023

1. Neuroimaging in Clinical Psychiatry – Recent Advances

   B. Holla

   2023
2. Challenges and opportunities for developing a career in mental health research in India

   B. Holla

   2023
3. Neuroimaging and Yoga

   B. Holla

   2023

2022

1. Evidence for Shared Neurocognitive Deficits in Major Psychiatric Illnesses – Cross-Disorder Evaluation of Bifactor Model

   B. Holla, and  others

   2022
2. Grant writing and funding opportunities

   B. Holla

   2022
3. Young physician leaders Panel Discussion on Effective Leaders for Effective Health Systems – Bridging the digital health gap

   B. Holla

   2022

2021

1. Gene-Environment Interaction and Brain Networks in the Pathophysiology of Externalizing Behaviors and Substance Use Risk

   B. Holla, and  others

   2021

   Awarded with Early Career Investigator Award / ECIP Travel Fellowship for 2022 WCPG
2. Grant writing and funding opportunities

   B. Holla

   2021
3. Population Neuroscience to Precision Psychiatry

   B. Holla

   2021

2020

1. Clinical Correlates of Yoga Based Personality Traits (Sattva, Rajas And Tamas) in Patients with Common Psychiatric Disorders

   L. N. Jasti, and  others

   2020
2. Ayurveda and Neurobiology of psychiatric disorders - Intersections and possibilities

   B. Holla

   2020
3. India Brain Template

   B. Holla

   2020

2019

1. A series of five population-specific Indian brain templates and atlases for ages 6 to 60 years

   B. Holla, and  others

   2019
2. Search for trans-diagnostic neuropsychological endophenotypes in severe mental illness – preliminary data from a family-based study

   B. Holla, and  others

   2019

   Hugh Gurling Award Finalist
3. Tracking deviations in neurodevelopmental trajectories to predict adult psychopathology

   B. Holla, and  others

   2019
4. Discovering the biology of neuropsychiatric syndromes

   B. Holla, and  others

   2019
5. A transdiagnostic approach with multiplex families for genetic studies in psychiatric disorders

   V. S. Sreeraj, and  others

   2019
6. Impact of family history density and adverse childhood experiences on age of onset of psychiatric illness in multiplex families

   J. Mahadevan, and  others

   2019
7. The Effect of Acamprosate Treatment on Cue Reactivity and Central Glutamate Activity in Recently Abstinent Alcohol Dependent Patients: A fMRI and MRS Study

   P. Khadse, and  others

   2019
8. To explore the relationship of age at onset of illness with adverse childhood life experiences in an Indian population

   P. P. Agarwal, and  others

   2019
9. Global Brain Research Initiatives in Biological Psychiatry

   B. Holla

   2019