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

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.

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

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.

Feasibility and Clinical Utility of High-definition Transcranial Direct Current Stimulation in the Treatment of Persistent Hallucinations in Schizophrenia.

Persistent auditory verbal hallucination is a clinically significant problem in schizophrenia. Recent studies suggest a promising role for add-on transcranial direct current stimulation (tDCS) in treatment. An optimised version of tDCS, namely high-definition tDCS (HD-tDCS), uses smaller electrodes arranged in a 4x1 ring configuration and may offer more focal and predictable neuromodulation than conventional tDCS. This case report illustrates the feasibility and clinical utility of add-on HD-tDCS over the left temporoparietal junction in a 4x1 ring configuration to treat persistent auditory verbal hallucination in schizophrenia.

Prevalence of metabolic syndrome and its clinical correlates among patients with bipolar disorder.

OBJECTIVE: To assess the prevalence of metabolic syndrome (MetS) in patients with bipolar disorder (BD) and examine the clinical correlates of MetS. METHODS: Sixty-seven patients with BD were evaluated for presence for MetS. The consensus definition was used to define MetS. The clinical variables were recorded on the basis of information provided by the patients, accompanying caregivers and review of treatment records. The symptoms severity of present depressive and manic episode was assessed by using Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) respectively. RESULTS: The prevalence of MetS was 53.7%. Patients with MetS were older than the patients with BD alone (P=0.001). Increased waist circumference was the most common abnormal parameter (74.6%) followed by low high density lipoprotein (HDL) (71.6%) and raised triglycerides (64.2%). High blood pressures were recorded in 35.8% with high fasting blood glucose levels were seen in 33.3%. MetS was associated with greater number of life time episodes (p=0.010), longer duration of illness (p=0.010), greater numbers of lifetime depressive episodes (p<0.001). Substance use (alcohol and nicotine) associated with significantly higher prevalence of high blood pressure among MetS patients (p<0.001) while abnormal triglyceride level shown associated with substance use (p=0.010). Age of the patients, number of lifetime depressive episodes and use of Olanzapine were found to predictive of the development of MetS. CONCLUSIONS: Patients with BD have high prevalence of MetS and its presence correlates with clinical variables.

Regulatory Considerations for the Clinical and Research Use of Transcranial Direct Current Stimulation (tDCS): review and recommendations from an expert panel.

The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. We therefore convened a group of research and clinician experts on tDCS to review the research and clinical use of tDCS. In this report, we review the regulatory status of tDCS, and we summarize the results according to research, off-label and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan and United States. Research use, off label treatment and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.

Yoga increases the volume of the hippocampus in elderly subjects.

CONTEXT: The neurobiological effect of yoga on the cortical structures in the elderly is as yet unknown. MATERIALS AND METHODS: Seven healthy elderly subjects received yoga intervention as an add-on life-style practice. Magnetic resonance imaging scans were obtained before and 6 months later. Voxel-based-morphometric analyses compared the brains before and after the yoga. RESULTS: Yoga group was found to have increases in hippocampal, but not in occipital gray matter. CONCLUSION: Yoga has potential to reduce neuro-senescence. Small sample size and absence of the control group prevent generalization of the findings limiting its translational value.

Effect of yoga therapy on plasma oxytocin and facial emotion recognition deficits in patients of schizophrenia.

CONTEXT: Yoga therapy has been demonstrated to be useful in treatment of negative symptoms and improving the socio-occupational functioning and emotion recognition deficits in antipsychotic-stabilized schizophrenia patients. Oxytocin has been recently implicated in social cognition deficits in schizophrenia. The effect of yoga therapy on oxytocin levels in schizophrenia has not been studied. AIMS: This study aimed to assess the effect of yoga therapy on symptoms, socio-occupational functioning, facial emotion recognition deficits and plasma oxytocin levels in antipsychotic stabilized schizophrenia patients. SETTINGS AND DESIGN: Randomized controlled study on 43 consenting, medication stabilized patients with schizophrenia in a tertiary psychiatric center using yoga intervention and waitlisted groups. MATERIALS AND METHODS: A total of 43 schizophrenia patients were randomized to yoga group (n=15) or waitlist group (n=28). Patients in the yoga group received training in a specific yoga therapy module for schizophrenia. Patients in both groups were continued on stable antipsychotic medication. Assessments included scale for assessment of positive symptoms, scale for assessment of negative symptoms, socio-occupational functioning scale and tool for recognition of emotions in neuropsychiatric disorders (TRENDS) and plasma oxytocin levels; performed at baseline and at the end of 1 month. RESULTS: A total of 15 patients in the yoga group and 12 in waitlist group completed the study. The yoga therapy group showed a significant improvement in socio-occupational functioning, performance on TRENDS (P<0.001) and plasma increase in oxytocin levels (P=0.01) as compared with the waitlist group. CONCLUSION: The study supported the role of add-on yoga therapy in management of schizophrenia and demonstrated an improvement in endogenous plasma oxytocin levels in schizophrenia patients receiving yoga therapy.

Therapeutic efficacy of add-on yogasana intervention in stabilized outpatient schizophrenia: Randomized controlled comparison with exercise and waitlist.

BACKGROUND: Schizophrenia is a highly disabling illness. Previous studies have shown yoga to be a feasible add-on therapy in schizophrenia. AIMS: The current study aimed to test the efficacy of yoga as an add-on treatment in outpatients with schizophrenia. SETTINGS AND DESIGN: The study done at a tertiary psychiatry center used a single blind randomized controlled design with active control and waitlist groups. MATERIALS AND METHODS: Consenting patients with schizophrenia were randomized into yoga, exercise, or waitlist group. They continued to receive pharmacological therapy that was unchanged during the study. Patients in the yoga or exercise group were offered supervised daily procedures for one month. All patients were assessed by a blind rater at the start of the intervention and at the end of 4 months. RESULTS: Kendall tau, a nonparametric statistical test, showed that significantly more patients in the yoga group improved in Positive and Negative Syndrome Scale (PANSS) negative and total PANSS scores as well as social functioning scores compared with the exercise and waitlist group. Odds ratio analysis showed that the likelihood of improvement in yoga group in terms of negative symptoms was about five times greater than either the exercise or waitlist groups. CONCLUSION: In schizophrenia patients with several years of illness and on stabilized pharmacological therapy, one-month training followed by three months of home practices of yoga as an add-on treatment offered significant advantage over exercise or treatment as usual. Yoga holds promise as a complementary intervention in the management of schizophrenia.

A six-to-ten weeks' follow-up study on the effects of olanzapine on abdominal fat and other metabolic parameters in patients with psychoses--an imaging-based study with controls.

OBJECTIVES: To measure the changes in subcutaneous and intra-abdominal fat and other metabolic parameters in patients with psychotic disorders, who were newly started on olanzapine treatment and in drug-free controls. The correlation between changes in visceral fat and other metabolic parameters were also studied. METHODS: Using a longitudinal open-label design, the 2 studied groups included patients with psychoses (n = 23) [diagnosed as per the 10th edition of the International Classification of Diseases criteria] and drug-free controls (n = 11). Fasting sugar, lipid profile and glycosylated haemoglobin levels were collected at baseline and follow-up. Computed tomographic scans were used to determine changes in the various abdominal fat parameters. RESULTS: The patients were significantly younger than the controls, and the former had higher mean subcutaneous fat at baseline. There were statistically significant increases in the subcutaneous fat, intraabdominal fat, weight, waist circumference, hip circumference and body mass index in patients but not in controls. The mean dose of olanzapine (mg/day) correlated significantly with change of intraabdominal fat at follow-up. The change in intra-abdominal fat did not correlate significantly with any of the metabolic parameters studied. CONCLUSIONS: Olanzapine produced significant increase in weight and fat parameters. This increase correlated with the dose of olanzapine.

Effect of yoga therapy on facial emotion recognition deficits, symptoms and functioning in patients with schizophrenia.

OBJECTIVE: Facial emotion recognition deficits have been consistently demonstrated in schizophrenia and can impair socio-occupational functioning in these patients. Treatments to improve these deficits in antipsychotic-stabilized patients have not been well studied. Yoga therapy has been described to improve functioning in various domains in schizophrenia; however, its effect on FERD is not known. METHOD: Antipsychotic-stabilized patients randomized to receive Yoga (n=27), Exercise (n=17) or Waitlist group (n=22) were assessed at baseline, 2nd month, and 4th month of follow-up by raters blind to group status. Assessments included Positive and Negative Syndrome Scale (PANSS), Socio-Occupational Functioning Scale (SOFS), and Tool for Recognition of Emotions in Neuropsychiatric DisorderS (TRENDS). RESULTS: There was a significant positive correlation between baseline FERD and socio-occupational functioning (r=0.3, P=0.01). Paired samples t test showed significant improvement in positive and negative symptoms, socio-occupational functioning and performance on TRENDS (P<0.05) in the Yoga group, but not in the other two groups. Maximum improvement occurred at the end of 2 months, and improvement in positive and negative symptoms persisted at the end of 4 months. CONCLUSION: Yoga therapy can be a useful add-on treatment to improve psychopathology, FERD, and socio-occupational functioning in antipsychotic-stabilized patients with schizophrenia.

Prospective comparison of course of disability in antipsychotic-treated and untreated schizophrenia patients.

OBJECTIVE: To compare the course of disability in schizophrenia patients receiving antipsychotics and those remaining untreated in a rural community. METHOD: Of 215 schizophrenia patients identified in a rural south Indian community, 58% were not receiving antipsychotics. Trained raters assessed the disability in 190 of these at baseline and after 1 year. The course of disability in those who remained untreated was compared with that in those who received antipsychotics. RESULTS: Mean disability scores remained virtually unchanged in those who remained untreated, but showed a significant decline (indicating decrement in disability) in those who continued to receive antipsychotics and in those in whom antipsychotic treatment was initiated (P < 0.001; group x occasion effect). The proportion of patients classified as 'disabled' declined significantly in the treated group (P < 0.01), but remained the same in the untreated group. CONCLUSION: Disability in untreated schizophrenia patients remains unchanged over time. Treatment with antipsychotics in the community results in a considerable reduction in disability.

Automated MRI parcellation study of regional volume and thickness of prefrontal cortex (PFC) in antipsychotic-naïve schizophrenia.

OBJECTIVE: Prefrontal cortical dysfunction is considered to be critical in the pathogenesis of schizophrenia. However, structural magnetic resonance imaging (MRI) studies on the PFC have yielded inconsistent results because of various confounding factors. METHOD: In this study we examined the volume and thickness abnormalities of the PFC in antipsychotic-naïve schizophrenia patients (n = 51) in comparison with age-, sex-, and handedness-matched (as a group) healthy comparison subjects (n = 47) using a newly described automated MRI parcellation analysis. RESULTS: Schizophrenia patients showed i) significant volume deficits in bilateral lateral orbitofrontal and left medial orbitofrontal cortices as well as bilateral pars triangularis; and ii) significant thickness deficit in bilateral medial orbitofrontal cortices. Negative syndrome score had a significant negative correlation with the thickness of the left medial orbitofrontal cortex. CONCLUSION: The study findings emphasize that prefrontal deficit in schizophrenia is differential and involves primarily the regions essential for 'social cognition'.

MRI volumetric and 31P MRS metabolic correlates of caudate nucleus in antipsychotic-naïve schizophrenia.

OBJECTIVE: To examine the volumetric and metabolic correlates of caudate nucleus in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. METHOD: Twelve antipsychotic-naïve schizophrenia patients and 13 healthy controls underwent (31)P magnetic resonance spectroscopy of basal ganglia. Magnetic resonance imaging volume of caudate nuclei was measured using scion image software. RESULTS: Patients had significantly smaller caudate volume than healthy controls. Phosphocreatine (PCr)/total phosphorous and PCr/total adenosine tri-phosphate ratios of both caudate nuclei were significantly lower in patients than controls. Significant negative correlation was found between the left caudate volume and left PCr/total phosphorus ratio in the patients. Age at onset of psychosis had i) significant negative correlation with right and left caudate volumes and ii) significant positive correlation with left PCr/total phosphorus ratio. CONCLUSION: The metabolic and volumetric abnormalities of caudate nucleus in antipsychotic-naïve schizophrenia patients support neurodevelopmental etiopathogenesis.

Cerebellar and other neurological soft signs in antipsychotic-naïve schizophrenia.

OBJECTIVE: Cerebellar neurological abnormalities in schizophrenia have been associated with severe negative symptoms, cognitive deficits, and smaller cerebellar volume. This study assessed the comparative discriminant validity between Cerebellar Soft Signs (CSS) vs. other neurological soft signs (ONSS) [in discriminating between schizophrenia patients and healthy controls] as well as the relationship between the soft signs and psychopathology. METHOD: Antipsychotic-naïve schizophrenia patients (n = 32) and healthy subjects (n = 32) were examined using International Co-Operative Ataxia Rating Scale and Neurological Evaluation Scale. RESULTS: Mean CSS scores, ONSS total score, and Sensory Integration Signs sub-score were significantly higher in patients. Discriminant analysis revealed two CSS sub-scores (but none of the ONSS scores) to be significant (P < 0.0001) accounting for 78% of classification. CSS total score, Posture sub-score, and Oculomotor sub-score had significant positive correlation with negative syndrome score. CONCLUSION: Findings support intrinsic cerebellar dysfunction in schizophrenia. The observations are discussed in relationship with cognitive dysmetria.

Measuring the corpus callosum in schizophrenia: a technique with neuroanatomical and cytoarchtectural basis.

BACKGROUND: Corpus Callosum (CC) abnormalities have been described in schizophrenia. Review of CC measurement methods in schizophrenia reveals inconsistency and lack of neuroanatomical basis. AIMS: The aims of the study are to describe a new CC measurement method with valid a neuroanatomical and cytoarchitectural basis and to demonstrate inter-rater reliability for the same. SETTINGS AND DESIGN: The study was performed in the National Institute of Mental Health & Neurosciences, Bangalore, India. Ours is a cross-sectional study in which both the first author and senior neuroradiologist were blind to clinical details. MATERIAL AND METHODS: We report a reliable, semi-automated CC measuring technique with a neuroanatomical and cytoarchitectural basis tested in a group of 16 never-treated schizophrenia patients using 1-mm thick, objectively defined midsagittal MRI section. Measurement on coded slices using scion image software ensured elimination of rater bias. STATISTICAL ANALYSIS USED: The statistical analysis used for assessing inter-rater reliability is intraclass correlation coefficient analysis. RESULTS: The intraclass correlation coefficients for the CC measurements were as follows: CC Area = 0.93; Anterior CC area = 0.84; Area of body of the CC = 0.83; Area of CC isthmus = 0.65; Area of CC splenium = 0.88; maximum antero-posterior distance of CC = 0.96. CONCLUSION: Measurements showed good inter-rater reliability. The methodology demonstrated in our study is simple, relevant, reliable and can be used for future schizophrenia research.

Neurological soft signs in never-treated schizophrenia.

OBJECTIVE: Studies of Neurological Soft Signs (NSS) in schizophrenia are confounded by handedness, inconsistent methodology, and prior treatment with neuroleptics. The study objective is to examine NSS in never-treated schizophrenia. METHOD: We examined the NSS in treatment-naïve schizophrenia patients (n = 21) and age, sex, education, and handedness matched normal controls (n = 21) using the modified Neurological Evaluation Scale with good inter-rater reliability. RESULTS: Schizophrenia patients had significantly more NSS than normals. No significant correlation was found between illness duration and NSS. CONCLUSION: Higher neurological signs in never-treated patients and their lack of association with illness duration suggest neurodevelopmental etiopathogenesis of schizophrenia.