Robust determinants of neurocognitive development in children: evidence from the Pune Maternal Nutrition Study.

Neurocognitive development is a dynamic process over the life course and is influenced by intrauterine factors as well as later life environment. Using data from the Pune Maternal Nutrition Study from 1994 to 2008, we investigate the association of in utero, birth, and childhood conditions with offspring neurocognitive development in 686 participants of the cohort, at age 12 years. The life course exposure variables in the analysis include maternal pre-pregnancy size and nutrition during pregnancy, offspring birth measurements, nutrition and physical growth at age 12 years along with parental education and socio-economic status. We used the novel Bayesian Model Averaging (BMA) approach; which has been shown to have better predictive performance over traditional tests of associations. Our study employs eight standard neurocognitive tests that measure intelligence, working memory, visuo-conceptual and verbal learning, and decision-making/attention at 12 years of age. We control for nutritional-metabolic information based on blood measurements from the pregnant mothers and the children at 12 years of age. Our findings highlight the critical role of parental education and socio-economic background in determining child neurocognitive performance. Maternal characteristics (pre-pregnancy BMI, fasting insulin during pregnancy) and child height at 12 years were also robust predictors on the BMA. A range of early factors - such as maternal folate and ferritin concentrations during pregnancy, and child's head circumference at birth - remained important determinants of some dimensions of child's neurocognitive development, but their associations were not robust once we account for model uncertainty. Our results suggest that intrauterine influences on long- term neurocognitive outcomes may be potentially reversible by post-birth remediation. In addition to the current nutritional interventions, public health policy should also consider social interventions in children born into families with low socio-economic status to improve human capital.

Emotional Threat Perception and Its Association with Neurocognition in Social Anxiety Disorder.

Background: The negative appraisal of emotional stimuli is a feature of social anxiety disorder (SAD). People with SAD demonstrate deficits in neurocognitive performance while performing tasks of attention. However, the relationship between attentional control, working memory, and threat perception in SAD has not been studied well. The present study aimed to identify patterns of threat perception in relation to performance on attention and visuospatial working memory tasks in individuals with SAD. Methods: Subjects with SAD (n = 27) and a healthy comparative (HC) group (n = 26) completed tasks of sustained and focused attention, visuospatial working memory, computerized emotion identification, and pictorial emotional Stroop. Results: The SAD group had decreased performance in the domains of sustained (P = 0.001) and focused attention (P = 0.04). They also had an enhanced threat perception as demonstrated by greater reaction time to anger (P = 0.03), lower emotion recognition accuracy (P = 0.05), and higher over-identification of the threat to neutral and nonthreatening faces. However, the Stroop effect was not demonstrated across the groups. No group difference was seen in the performance on the visuospatial working memory tasks. Lower focused attention was significantly correlated with higher emotional threat perception (ETP; P = 0.001) in the SAD group. Conclusion: People with SAD have greater deficits in attention processing and ETP. The attention deficits were associated with enhanced ETP in social anxiety. The link between threat perception and cognitive functions would aid in a better understanding of SAD and in planning appropriate intervention.

Corrigendum: Pre-conceptional Maternal Vitamin B12 Supplementation Improves Offspring Neurodevelopment at 2 Years of Age: PRIYA Trial.

[This corrects the article DOI: 10.3389/fped.2021.755977.].

Pre-conceptional Maternal Vitamin B12 Supplementation Improves Offspring Neurodevelopment at 2 Years of Age: PRIYA Trial.

Background: The first thousand days window does not include the pre-conceptional period. Maternal pre-conceptional health has a profound influence on early embryonic development (implantation, gastrulation, placentation etc). Nutrition provided by B-complex vitamins is important for fetal growth, especially neural development. We report effects of a maternal pre-conceptional vitamin B12 and multi micronutrient (MMN) supplementation on offspring neurodevelopmental performance. Methods: In the Pune Rural Intervention in Young Adolescents trial (PRIYA), adolescents (N = 557, 226 females) were provided with vitamin B12 (2 µg/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayley's Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. Results: Participants had similar baseline B12 levels. The levels improved in the B12 supplemented groups during pre-conception and pregnancy (28 weeks gestation), and were reflected in higher cord blood holotranscobalamin (holo-TC) levels compared to the placebo group. Neurodevelopmental outcomes in the B12 alone group (n = 21) were better than the placebo (n = 27) in cognition (p = 0.044) and language (p = 0.020) domains (adjusted for maternal baseline B12 levels). There was no difference in neurodevelopmental outcomes between the B12 + MMN (n = 26) and placebo group. Cord blood Brain Derived Neurotrophic Factor (BDNF) levels were highest in the B12 alone group, though not significant. Conclusion: Pre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening during pre-conception.

Maternal vitamin B12, folate during pregnancy and neurocognitive outcomes in young adults of the Pune Maternal Nutrition Study (PMNS) prospective birth cohort: study protocol.

INTRODUCTION: The Developmental Origins of Health and Disease (DOHaD) hypothesis proposes that intrauterine and early life exposures significantly influence fetal development and risk for disease in later life. Evidence from prospective birth cohorts suggests a role for maternal B12 and folate in influencing neurocognitive outcomes in the offspring. In the Indian setting, B12 deficiency is common during the pregnancy while rates of folate deficiency are lower. The long-term influences of maternal nutrition during the pregnancy on adult neurocognitive outcomes have not been examined. The Pune Maternal Nutrition Study (PMNS) is a preconceptional birth cohort into its 24th year and is considered a unique resource to study the DOHaD hypothesis. We found an association between maternal B12 status in pregnancy and child's neurocognitive status at 9 years of age. We now plan to assess neurocognitive function and MRI measurements of brain structural-functional connectivity at young adult age to study its association with maternal nutritional exposures during the pregnancy. METHODS AND ANALYSIS: As part of ongoing prospective follow-up in young adults of the PMNS at the Diabetes Unit, KEM Hospital Research Center, Pune India, the following measurements will be done: neurocognitive performance (Standardised Tests of Intelligence, Verbal and Visual Memory, Attention and Executive Functions), temperament (Adult Temperament Questionnaire), psychopathology (Brief Symptom Inventory and Clinical Interview on Mini Neuropsychiatric Interview 7.0). Brain MRI for structural T1, resting-state functional connectivity and diffusion tensor imaging will be performed on a subset of the cohort (selected based on exposure to a lower or higher maternal B12 status at 18 weeks of pregnancy). ETHICS AND DISSEMINATION: The study is approved by Institutional ethics committee of KEM Hospital Research Center, Pune. The results will be shared at national and international scientific conferences and published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT03096028.

Facial emotion recognition and its association with quality of life and socio-occupational functioning in patients with bipolar disorder and their first-degree relatives.

INTRODUCTION: Facial emotion recognition deficits (FERD) are common even in the remitted phase of bipolar disorder (BD). Research regarding FERD in first-degree relatives is inconclusive. This study aimed to assess the facial emotion recognition in remitted patients of bipolar disorder and first-degree relatives(FDR) in comparison with healthy controls. Correlation between FERD and quality of life and socio-occupational functioning was also assessed. METHODS: It was an observational, cross-sectional study done at a tertiary hospital in India. Study population (n = 75) included remitted patients of bipolar disorder (n = 27), first-degree relatives of BD patients (FDR) (n = 20) and healthy controls (HC) (n = 28). Facial emotion recognition, social and occupational functioning, and quality of life (QoL) was measured using Tool for Recognition of Emotions in Neuropsychiatric Disorders, Social & Occupational Functioning Assessment Scale and World Health Organization Quality of Life-Bref, respectively, in all the participants. RESULTS: The BD group did significantly worse in facial emotion recognition in comparison to FDR and HC groups (p < 0.001). Emotion recognition of fear, anger, surprise, and happy were most affected. FDR did not vary significantly from HC in facial emotion recognition. Lower scores on facial emotion recognition were associated with lower QoL in the social domain(p = 0.006) and poorer socio- occupational functioning scores (p = 0.01), but it was not significant within the BD group. CONCLUSION: FERD is seen in remitted patients of bipolar disorder but not in the first -degree relatives. FERD affects social quality of life and functioning. Poorer social functioning in remitted patients of bipolar disorder might be multifactorial and cannot be attributed solely to FERD.

Thought Disorder on Object Sorting Test Is Associated with Executive Dysfunction in Schizophrenia.

BACKGROUND: Thought disorder is considered to be central to the core disturbances in schizophrenia and was described by Goldstein as aberrant "concept formation." Executive dysfunction is another core deficit in schizophrenia. With a greater emphasis on psychopathology in nosological systems, the classical thought disorder receives less prominence. The present study aimed to understand the association between classical thought disorder (aberrant concept formation and concrete abstraction) and executive dysfunction. METHODS: Thirty patients with schizophrenia and thirty healthy subjects, matched on age, gender, education, and socioeconomic status, were screened using MINI 5.0, following which they were assessed on object sorting test (OST) and selected tests for executive functions (EFs). RESULTS: Individuals with schizophrenia were found to have significantly decreased performance on all domains of EFs and OST. Total peculiar scores on OST were significantly associated with mental speed, focused attention, and divided attention. Total impoverished scores on OST was significantly associated with focused attention, sustained attention, planning, set shifting, perseveration, and concept formation. CONCLUSION: Several correlations, among performance on OST and neuropsychological tests, suggest that patterns of responses on OST can point to underlying executive dysfunction. Both thought disorder and executive dysfunction mirror similar constructs. This similarity represents a conceptual bridge between the classical and contemporary descriptions of the core deficits in schizophrenia.

A combined stimuli presentation for assessing facial emotion related N170, N250 and visual mismatch negativity in neuropsychiatric disorders.

Event-related potential (ERP) is a useful approach to assess the neurophysiological correlates of facial emotion processing. Previous studies examined the facial emotion recognition (FER) related ERPs (N170, N250, visual MisMatch Negativity) individually using ERP specific paradigms. This approach can be time-consuming and may not resemble real-life scenarios where an individual must process multiple stimuli simultaneously. The aim of the study was to assess the utility of a combined paradigm when compared to individual paradigms to measure N170, N250 and visual MisMatch Negativity (vMMN) in healthy controls (HC), utilizing emotion stimuli standardized in the Indian population. Further, the combined paradigm was examined in patients with schizophrenia (SCZ) to detect the differences in ERPs compared to HC. Within paradigms, ERPs showed higher amplitudes for emotion compared to neutral stimuli suggesting that the paradigms were able to detect valence associated with emotional stimuli. The combined paradigm was able to elicit decipherable peaks of N170, N250 and vMMN similar to individual paradigms. ERP data quality as assessed by analytic Standardized Measurement Error (aSME) showed a satisfactory aggregate score of above 2 for all the three paradigms. Combined paradigm approaches to record ERPs in neuropsychiatric conditions has the advantage of reducing the time required for task administration, avoiding practice effects, better subject cooperation and participation.

Maternal Vitamin B12 Status During Pregnancy and Its Association With Outcomes of Pregnancy and Health of the Offspring: A Systematic Review and Implications for Policy in India.

Background: Vitamins B12 and folate participate in the one-carbon metabolism cycle and hence regulate fetal growth. Though vitamin B12 deficiency is widely prevalent, the current public health policy in India is to supplement only iron and folic acid for the prevention of anaemia. Prompted by our research findings of the importance of maternal vitamin B12 status for a healthy pregnancy, birth and offspring health outcomes, we evaluated available literature evidence using a systematic review approach, to inform policy. Methods: A systematic search was performed for relevant Indian studies in the MEDLINE/PubMed and IndMed databases. We selected studies reporting maternal vitamin B12 status (dietary intake or blood concentrations), and/or metabolic markers of vitamin B12 deficiency (homocysteine, methylmalonic acid) or haematological indices during pregnancy and their associations with outcomes of pregnancy, infancy or in later life. Intervention trials of vitamin B12 during pregnancy were also included. Quality of evidence was assessed on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Of the 635 articles identified, 46 studies met the inclusion criteria (cohort studies-26, case-control studies-13, RCT's -7). There is a high prevalence of vitamin B12 deficiency in Indian women during pregnancy (40-70%) (3 studies). Observational studies support associations (adjusted for potential sociodemographic confounders, maternal body size, postnatal factors) of lower maternal B12, higher homocysteine or an imbalance between vitamin B12-folate status with a higher risk of NTDs (6 studies), pregnancy complications (recurrent pregnancy losses, gestational diabetes, pre-eclampsia) (9 studies), lower birth weight (10 studies) and adverse longer-term health outcomes in the offspring (cognitive functions, adiposity, insulin resistance) (11 studies). Vitamin B12 supplementation (7 RCT's) in pregnancy showed a beneficial effect on offspring neurocognitive development and an effect on birth weight was inconclusive. There is a high quality evidence to support the role of low maternal vitamin B12 in higher risk for NTD and low birth weight and moderate-quality evidence for higher risk of gestational diabetes and later life adverse health outcomes (cognitive functions, risk for diabetes) in offspring. Conclusion: In the Indian population low maternal vitaminB12 status, is associated with adverse maternal and child health outcomes. The level of evidence supports adding vitamin B12 to existing nutritional programs in India for extended benefits on outcomes in pregnancy and offspring health besides control of anaemia. Systematic Review Registration: [website], identifier [registration number].

A physiological dose of oral vitamin B-12 improves hematological, biochemical-metabolic indices and peripheral nerve function in B-12 deficient Indian adolescent women.

BACKGROUND: Vitamin B-12 deficiency is often considered synonymous with pernicious anemia, a rare condition in which severe malabsorption of the vitamin requires high-dose parenteral treatment. In developing countries such as India, inadequate dietary intake of B-12 due to socio-cultural factors leads to widely prevalent asymptomatic low B-12 status. In this scenario, lower doses of oral B-12 may be effective, safer and more affordable. OBJECTIVE: To examine the effects of oral B-12 treatment at physiological doses on hematological and biochemical indices and peripheral nerve function in B-12 deficient rural Indian adolescent women. METHODS: Thirty-nine women with B-12 deficiency who were excluded from a community based B-12 supplementation trial (Pune Rural Intervention in Young Adolescents (PRIYA)) received oral B-12 2µg/day, either alone (n = 19) or with multiple micronutrients (UNIMAPP formula + 20gm milk powder, n = 20) for 11 months. Hematological indices, nutrients (B-12, folate), metabolites (homocysteine) and peripheral nerve function (SUDOSCAN, Impetomedical, Paris and sensory nerve conduction velocity (NCV) of median and sural nerves) were assessed at baseline and after 11 months of B-12 treatment. RESULTS: Results were similar in the two treatment allocation groups, which were therefore combined. At baseline, all women had B-12 concentration <100pmol/L, 79% were anemic and 33% had macrocytosis, but none had neuropathy. After 11 months of treatment, B-12 levels increased, while folate did not change. The prevalence of anemia fell to 59% and mean corpuscular volume (MCV) and plasma homocysteine concentrations decreased. Sudomotor nerve function in the feet improved by an average of 14.7%, and sensory conduction velocity in median and sural nerves increased by 16.2% and 29.4% respectively. CONCLUSION: We document clinically beneficial effects of supplementation with a physiological dose of oral B-12 in asymptomatic rural Indian adolescent women with very low B-12 status. These findings support a public health approach to tackle the widely prevalent low B-12 status in young Indians.

Developmental undernutrition, offspring obesity and type 2 diabetes.

The Developmental Origins of Health and Disease (DOHaD) paradigm posits that a mismatch between circumstances at or around conception and in later life leads to metabolic dysregulation and the development of obesity and diabetes. In this review we highlight three strands of evidence: prospective studies of patterns of growth from birth to adulthood, historical studies of exposure to famine at defined points during gestation and early life, and nutrition intervention studies. We conclude that, while much is still unknown, it is becoming clearer that the combination of early-life undernutrition and later development of obesity is associated with increased risk of diabetes. There is a need to support public health programmes aimed at intergenerational (primordial) prevention of diabetes and other non-communicable disease.

Facial emotion recognition, socio-occupational functioning and expressed emotions in schizophrenia versus bipolar disorder.

Facial emotion recognition deficits have been consistently demonstrated in patients with severe mental disorders. Expressed emotion is found to be an important predictor of relapse. However, the relationship between facial emotion recognition abilities and expressed emotions and its influence on socio-occupational functioning in schizophrenia versus bipolar disorder has not been studied. In this study we examined 91 patients with schizophrenia and 71 with bipolar disorder for psychopathology, socio occupational functioning and emotion recognition abilities. Primary caregivers of 62 patients with schizophrenia and 49 with bipolar disorder were assessed on Family Attitude Questionnaire to assess their expressed emotions. Patients of schizophrenia and bipolar disorder performed similarly on the emotion recognition task. Patients with schizophrenia group experienced higher critical comments and had a poorer socio-occupational functioning as compared to patients with bipolar disorder. Poorer socio-occupational functioning in patients with schizophrenia was significantly associated with greater dissatisfaction in their caregivers. In patients with bipolar disorder, poorer emotion recognition scores significantly correlated with poorer adaptive living skills and greater hostility and dissatisfaction in their caregivers. The findings of our study suggest that emotion recognition abilities in patients with bipolar disorder are associated with negative expressed emotions leading to problems in adaptive living skills.

Social cognition intervention in schizophrenia: Description of the training of affect recognition program - Indian version.

Social cognition refers to mental operations involved in processing of social cues and includes the domains of emotion processing, Theory of Mind (ToM), social perception, social knowledge and attributional bias. Significant deficits in ToM, emotion perception and social perception have been demonstrated in schizophrenia which can have an impact on socio-occupational functioning. Intervention modules for social cognition have demonstrated moderate effect sizes for improving emotion identification and discrimination. We describe the Indian version of the Training of Affect Recognition (TAR) program and a pilot study to demonstrate the feasibility of administering this intervention program in the Indian population. We also discuss the cultural sensibilities in adopting an intervention program for the Indian setting. To the best of our knowledge this is the first intervention program for social cognition for use in persons with schizophrenia in India.

Clozapine-induced Supraventricular Tachycardia and its Treatment with Verapamil.

Clozapine is known to be an effective antipsychotic for schizophrenia. Cardiovascular complications associated with initiation of clozapine include tachycardia, postural hypotension, and myocarditis. Factors associated with development of cardiovascular adverse events are not clearly known, and dose titration has been described to be one among the associated risk factors. We report a case of a 45-year-old man with treatment resistant schizophrenia who developed supraventricular tachycardia during initiation of clozapine and discuss the role of verapamil in its successful management.

Factors Affecting Well-being and Socio-occupational Functioning in Schizophrenia Patients Following an Acute Exacerbation: A Hospital Based Observational Study.

BACKGROUND: Improving functioning levels are an important goal of treatment in schizophrenia. Most studies have described long-term course and outcome in schizophrenia. However, understanding factors influencing functioning in the immediate recovery period following an acute exacerbation may be of important clinical relevance. AIM: The aim of this study is to assess the factors that influence well-being and socio-occupational functioning following an acute exacerbation in schizophrenia patients. MATERIALS AND METHODS: The study included 40 patients during the period from June 2013 to June 2014. The possible effect of gender, duration of illness, duration of untreated psychosis, premorbid adjustment, cognitive impairment, facial affect perception and treatment compliance on well-being, and socio-occupational functioning was examined. RESULTS: About 45% of the individuals experienced below average well-being. On logistic regression analysis poor compliance with medication and poorer cognitive functioning significantly differentiated the patient group with below average well-being from those with an above average well-being. Male gender, poor premorbid adjustment, poor compliance to treatment, poor cognitive functioning, and greater duration of untreated psychosis were found to be associated with a poorer socio-occupational functioning. CONCLUSION: Clinical interventions focusing on improving cognitive impairment and compliance to treatment could play a role in improving well-being, and socio-occupational functioning in schizophrenia patients following an acute exacerbation.

Mirtazapine for antipsychotic-induced acute akathisia: a systematic review and meta-analysis of randomized placebo-controlled trials.

OBJECTIVE: To conduct a systematic review and meta-analysis of randomized placebo-controlled trials of mirtazapine for the treatment of antipsychotic-induced acute akathisia (AIAA). METHODS: Studies were identified using online searches of PUBMED/MEDLINE and Cochrane database (CENTRAL), along with websites recording trial information such as www.clinicaltrials.gov, www.controlled-trials.com, and www.clinicalstudyresults.org. The study eligibility criteria were randomized, double-blind clinical trials comparing mirtazapine with placebo for AIAA with standardized rating for akathisia as outcome measure. The methodological quality of included trials was assessed using the Jadad Scale. Separate meta-analyses were undertaken for each outcome (response rate and complete remission) and treatment effects were expressed as Mantel-Haenszel risk ratio (RR). Fixed-effect meta-analysis was performed as heterogeneity was not significant. Number need to treat (NNT) as a measure of relative treatment effectiveness was calculated. RESULTS: A systematic review of the literature revealed six studies that had assessed mirtazapine for the treatment of AIAA. Of these, two studies (n = 86) met the review inclusion criteria and were included in the final analysis. A meta-analysis was performed to see the effect size of response rate and complete remission. For response rate, RR was 6.67 [95% confidence interval (CI) 2.14-20.78], favoring mirtazapine compared with placebo, and the overall effect was significant (p = 0.001, NNT 4, 95% CI 2.6-8.6). For complete remission, RR was 6.20 (95% CI 1.74-22.08), favoring mirtazapine compared with placebo, and the overall effect was significant (p = 0.005, NNT 5, 95% CI 2.9-11.6). CONCLUSIONS: Although limited to only two studies and small sample, existing data support the efficacy of mirtazapine for the treatment of AIAA, with one in four patients showing partial response and one in five patients showing complete remission.