Evaluation of N-400 Evoked Response Potential in schizophrenia: An endophenotype or a disease marker?

N400 evoked response potentials (ERP) reliably map key semantic deficits in schizophrenia. Assessing them as endophenotypes might help in better understanding of schizophrenia risk and their use as biomarkers. We aimed to study N400 as an endophenotype marker by comparing schizophrenia (SCZ), unaffected first-degree relatives (FDR) and healthy controls (HC) and, by assessing its ability to discriminate these groups. Drug naïve or free SCZ probands (n=30), their unaffected FDRs (n=30) and HC (n=30), underwent a 40-channel ERP recording while performing a custom-made, Hindi- sentence context paradigm task, containing congruent and incongruent conditions. Fifteen centro-parietal (CP) leads, further classified into three regions-midline (CPM), right (CPR) and left (CPL) were selected as electrodes-of-interest for assessing N400. During the incongruent condition, compared to both FDRs and HC, SCZ showed significantly longer N400 latency, at CPM, CPR and CPL, and significantly lesser (more negative) amplitude, at CPM; no significant difference was noted between FDR and HC groups. On discriminant functional analysis, significant N400 predictors could accurately classify 73.3% SCZ from HC and 75% of SCZ from FDR. We conclude that N400 deficits, elicited by the incongruent condition of the sentence task, could be potential biomarkers to define disease state in schizophrenia; they may not be endophenotype markers.

Impaired recollection-based episodic memory as a cognitive endophenotype in schizophrenia.

INTRODUCTION: Patients with schizophrenia show impaired recollection but largely preserved familiarity-based episodic memory. This study was done to clarify the endophenotypic nature of recollection and familiarity-based episodic memory in schizophrenia and the role of emotional valence of memoranda and degree of recall confidence in it. METHOD: Twenty-five patients with schizophrenia, one unaffected sibling of each patient, and twenty-three healthy controls completed two tasks assessing recollection and familiarity-based processes in episodic memory. In the first task, participants were asked to remember positive, negative, and neutral emotional valence words in a remember-know paradigm. In the second task, in addition to recollection and familiarity-based responses, participants were asked to make confidence judgments about their responses. RESULTS: Patients with schizophrenia and their first-degree relatives (FDRs) performed poorly on recollection but not familiarity-based responses, compared to healthy controls; performance of first-degree relatives was in between and significantly different from that of both patients and controls. The differences in recollection and familiarity-based responses across the three groups were not moderated by recall confidence judgments or emotional valence of memoranda. Furthermore, there was no correlation between recollection-based memory impairments and duration or severity of illness or current medication exposure. CONCLUSIONS: Impaired recollection-based memory constitutes a potential cognitive endophenotype in schizophrenia. Furthermore, selective impairment of recollection-based, but sparing of familiarity-based, memory in patients and their FDRs supports the distinct nature of recollection and familiarity-based episodic memories.

Artificial intelligence-based classification of schizophrenia: A high density electroencephalographic and support vector machine study.

BACKGROUND: Interview-based schizophrenia (SCZ) diagnostic methods are not completely valid. Moreover, SCZ-the disease entity is very heterogeneous. Supervised-Machine-Learning (sML) application of Artificial-Intelligence holds a tremendous promise in solving these issues. AIMS: To sML-based discriminating validity of resting-state electroencephalographic (EEG) quantitative features in classifying SCZ from healthy and, positive (PS) and negative symptom (NS) subgroups, using a high-density recording. SETTINGS AND DESIGN: Data collected at a tertiary care mental-health institute using a cross-sectional study design and analyzed at a premier Engineering Institute. MATERIALS AND METHODS: Data of 38-SCZ patients and 20-healthy controls were retrieved. The positive-negative subgroup classification was done using Positive and Negative Syndrome Scale operational-criteria. EEG was recorded using 256-channel high-density equipment. Eight priori regions-of-interest were selected. Six-level wavelet decomposition and Kernel-Support Vector Machine (SVM) method were used for feature extraction and data classification. STATISTICAL ANALYSIS: Mann-Whitney test was used for comparison of machine learning-features. Accuracy, sensitivity, specificity, and area under receiver operating characteristics-curve were measured as discriminatory indices of classifications. RESULTS: Accuracy of classifying SCZ from healthy and PS from NS SCZ, were 78.95% and 89.29%, respectively. While beta and gamma frequency related features most accurately classified SCZ from healthy controls, delta and theta frequency related features most accurately classified positive from negative SCZ. Inferior frontal gyrus features most accurately contributed to both the classificatory instances. CONCLUSIONS: SVM-based classification and sub-classification of SCZ using EEG data is optimal and might help in improving the "validity" and reducing the "heterogeneity" in the diagnosis of SCZ. These results might only be generalized to acute and moderately ill male SCZ patients.

Predictors of chronicity in alcohol use disorder: an evoked response potential study.

INTRODUCTION: Evoked response potentials (ERP) can reliably map key neurocognitive processes which are putatively responsible for chronic alcohol use disorder (AUD). Aim of the present study was to study P300 auditory odd ball and N400 visual semantic incongruity paradigm mapping executive functions rubric as a potential biomarker predicting chronicity in AUDs. Methodology: 60 right handed 18 to 54 years age subjects were divided into chronic "CAD" and non chronic alcohol dependence "NAD" in addition to healthy control "HC" (N = 30). Subjects were assessed by Addiction Severity Index (ASI), P300 auditory odd ball paradigm in midline region and visual N400 semantic incongruity task in centro-parietal region in a cross sectional design. Results: All the three groups differed significantly for P300 and N400 amplitude in all the leads with maximum attenuation seen in CAD. On discriminant function analysis (DFA), P300 Pz and N 400 C2 amplitude values could accurately classified 78.3% subjects. Composite sensitivity and specificity of the two predictor variables differentiating CAD subjects from NAD were 79.31 and 77.41%. receiver operating characteristic curve generated an area under the curve of .758 and .847 i.e., "fair to good" ability to predict CAD from NAD. Conclusion: We conclude that specific ERP paradigm can be used as a state marker to map the cognitive deficits and as a biomarker to detect chronic AUDs.

Lower P300 amplitudes for internally-generated events in patients with schizophrenia.

BACKGROUND: Patients with schizophrenia demonstrate difficulty differentiating internally-generated from externally-generated events. An excessive deployment of attention to external events as well as poor processing of self-generated events has been proposed to explain this misattribution. This study was done to understand the neurophysiological basis of source monitoring bias in schizophrenia. METHODS: Seventeen patients and fourteen healthy controls completed a two-stage source monitoring task involving solving a three-letter jumbled word either by the participant or a computer following which they had to identify the correct source of the word - solved by self (internal source monitoring, ISM) or by computer (external source monitoring, ESM) - while EEG was recorded. P300 amplitude and latency were computed separately for ISM and ESM conditions. RESULTS: P300 amplitude for ISM condition was lower in patients with schizophrenia compared to controls over right and left parietal regions. Additionally, P300 amplitude for ISM condition was lower compared to ESM condition in patients over right and left parietal regions. However, P300 amplitude for ESM condition did not differ significantly between the groups. In contrast to P300 amplitude, there was no significant difference in P300 latency in ISM or ESM condition within or between the groups. CONCLUSION: P300 amplitude was lower for internally-generated but not externally-generated events in patients with schizophrenia. These findings suggest that patients allocate less attentional resources to internally generated events resulting in poorer processing and consequent misattribution of their source of origin. This study provides the first specific electrophysiological evidence of impaired source monitoring in schizophrenia.

Effect of Olanzapine on Clinical and Polysomnography Profiles in Patients with Schizophrenia.

Acute and short-term administration of olanzapine has a favorable effect on sleep in schizophrenia patients. This study aimed to clarify the effect of olanzapine on polysomnographic profiles of schizophrenia patients during the acute phase of illness after controlling for previous drug exposure. Twenty-five drug-naïve or drug-free schizophrenia patients were assessed at baseline and after six weeks of olanzapine treatment on Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), and Udvalg for Kliniske Undersogelser (UKU) side-effect rating scale and a whole-night polysomnography; fifteen patients completed the study. There was a significant reduction in all psychopathological variables with maximum reduction in PANSS total, BPRS total, and PANSS positive scores. A significant increase in total sleep time (TST), sleep efficiency (SE), nonrapid eye movement (NREM) stage 1 duration, stage 3 duration, stage 4 duration, and stage 4 percentage of TST, number of rapid eye movement (REM) periods, REM duration, and REM percentage of TST was observed. REM latency at baseline inversely predicted the reduction in BPRS total and PANSS total and positive scores. In summary, short-term treatment with olanzapine produced significant improvement in clinical and polysomnography profiles of patients with schizophrenia with shorter REM latency predicting a good clinical response.

Auditory P300 event-related potential: Normative data in the Indian population.

OBJECTIVE: To generate the normative data of auditory P300 event-related potential for various age groups in the Indian population. MATERIALS AND METHODS: Auditory P300 event-related potentials, using the oddball paradigm, of healthy control participants in studies carried out at our institute were included to generate normative data in the age range of 10-50 years. The amplitude and latency of P300 for Fz, Cz, and Pz were selected for analysis. RESULTS: For P300 amplitude, overall multivariate analysis of variance (MANOVA) was significant [Pillai's Trace F (9/453) = 3.46, P < 0.001]. Follow-up ANOVA showed significant difference across age groups at Fz, Cz, and Pz. For P300 latency, there was a trend towards significance for overall MANOVA [Pillai's Trace F (9/453) = 1.68, P = 0.09]. Follow-up ANOVA showed a trend towards significant difference across age groups at Fz only. CONCLUSION: Our study generated a P300 amplitude and frequency normative database at Fz, Cz, and Pz, which will serve as a reference for future studies attempting to define P300 abnormalities in various psychiatric disorders in Indian population.

Social anhedonia and gamma band abnormalities as a composite/multivariate endophenotype for schizophrenia: a dense array EEG study.

AIM: Social anhedonia and gamma band oscillations are proposed as a promising endophenotype for schizophrenia (SZ). The aim was to assess whether social anhedonia and spontaneous gamma band oscillations could be used as multivariate/composite endophenotypic measures for SZ. METHODS: Sixty consented subjects, of which 20 remitted SZ patients, 20 unaffected siblings of patients with schizophrenia (US) and 20 healthy controls (HC) were recruited for the study. The Revised Social Anhedonia Scale, Temporal Experience of Pleasure Scale and the Schizotypal Personality Questionnaire assessed social anhedonia, temporal experience of pleasure and schizotypal features. All participants underwent awake, resting state 192-channel dense array electroencephalographic recording. Gamma spectral power and coherence were calculated. We performed chi-square test, one-way analysis of variance, Pearsons correlation coefficient and step-by-step linear discriminant functional analysis. RESULTS: Social anhedonia was significantly higher and anticipatory aspects of pleasure were significantly lower in both SZ and US compared with HC. US scored significantly higher than HC in the Schizotypal Personality Questionnaire. Spectral power of high gamma band (>70 Hz) was significantly lower over the right temporo-parietal and midline regions in both SZ and US than HC. We accurately classified (85%) three groups when social anhedonia, high gamma band spectral power of midline, right frontal and right fronto-temporal interhemispheric gamma coherence were considered as composite measures rather than each variable representing independently. CONCLUSION: We propose region-specific high gamma spectral 'power and coherence' and social anhedonia as composite/multivariate measures could be a useful measure in distinguishing schizophrenia patients and unaffected siblings from healthy controls.

Sleep architecture and EEG power spectra in recently detoxified alcohol dependent patients.

OBJECTIVES: Persistent sleep abnormalities during abstinence are a harbinger for relapse in patients with chronic alcohol dependence. The present study aimed to compare polysomnography (PSG) data between 'recently detoxified' patients with chronic alcohol dependence and healthy controls. METHODS: Both conventional sleep architectural and power spectral analyses were conducted. Twenty subjects in each of the groups were enrolled. A 2 nights' sleep (first-habituation and second-experimental) PSG data was collected. Computer assisted scoring supplemented by manual method using the Rechtschaffen and Kales criteria were used for sleep staging. Twenty eight channels were used for the EEG recording. Spectral power across early NREM (Non-rapid-eye-movement), Slow Wave Sleep and REM was computed using the Welch's averaged periodogram method. RESULTS: Results on conventional sleep staging showed that patients had significantly lesser total sleep time, sleep efficiency and stage shifts and longer sleep onset latency; while duration of each NREM stages were significantly lower, and latency of stage 2 NREM was significantly longer in patients. After controlling for multiple comparisons, spectral power analysis revealed significant differences only during REM sleep and specifically in high frequency (beta and gamma) bands. CONCLUSIONS: Stating the mutually complementary role of conventional and spectral analyses of polysomnography EEG data, we conclude that sleep abnormalities are fairly evident in recently detoxified alcohol dependent patients.

Twelve-month prevalence and treatment gap for common mental disorders: Findings from a large-scale epidemiological survey in India.

BACKGROUND: Common mental disorders, such as mood, anxiety, and substance use disorders, are significant contributors to disability globally, including India. Available research is, however, limited by methodological issues and heterogeneities. AIM: The present paper focuses on the 12-month prevalence and 12-month treatment for anxiety, mood, and substance use disorders in India. MATERIALS AND METHODS: As part of the World Health Organization World Mental Health (WMH) Survey Initiative, in India, the study was conducted at eleven sites. However, the current study focuses on the household sample of 24,371 adults (≥18 years) of eight districts of different states, covering rural and urban areas. Respondents were interviewed face-to-face using the WMH Composite International Diagnostic Interview after translation and country-specific adaptations. Diagnoses were generated as per the International Classification of Diseases, 10th edition, Diagnostic Criteria for Research. RESULTS: Nearly 49.3% of the sample included males. The 12-month prevalence of common mental disorders was 5.52% - anxiety disorders (3.41%), mood disorders (1.44%), and substance use disorders (1.18%). Females had a relatively higher prevalence of anxiety and mood disorders, and lower prevalence of substance use disorders than males. The 12-month treatment for people with common mental disorders was 5.09% (range 1.66%-11.55% for individual disorders). The survey revealed a huge treatment gap of 95%, with only 5 out of 100 individuals with common mental disorders receiving any treatment over the past year. CONCLUSION: The survey provides valuable data to understand the mental health needs and treatment gaps in the Indian population. Despite the 12-month prevalence study being restricted to selected mental disorders, these estimates are likely to be conservative due to under-reporting or inadequate detection due to cultural factors.

Safety and Efficacy of Adjunctive Θ Burst Repetitive Transcranial Magnetic Stimulation to Right Inferior Parietal Lobule in Schizophrenia Patients With First-Rank Symptoms: A Pilot, Exploratory Study.

BACKGROUND: First-rank symptoms (FRS) in schizophrenia have been found to be associated with various cognitive and biological markers. Repetitive transcranial magnetic stimulation (rTMS) has been shown to modulate such factors. We hypothesized that rTMS adjunctive to antipsychotics will be safe and effective in treatment of FRS in schizophrenia. METHODS: Schizophrenia patients with FRS randomly received either active or sham-magnetic resonance imaging navigated continuous Θ burst stimulation (cTBS)-rTMS to right inferior parietal lobule for 2 weeks; assessments were repeated. While primary outcome variables were safety profile, FRS and overall psychopathology; secondary outcomes were γ oscillatory activity, brain-derived neurotrophic factor levels, and self-monitoring function. RESULTS: No significant adverse events were reported in either group. None of the outcome measures showed sufficient power on the time by group analysis. CONCLUSIONS: This study fails to demonstrate whether or not adjunctive cTBS to right inferior parietal lobule could significantly alleviate FRS. We also fail to provide evidence for whether this protocol has any effect on brain-derived neurotrophic factor levels, self-monitoring function, and right hemispheric γ oscillations.

Resting state theta band source distribution and functional connectivity in remitted schizophrenia.

Increased resting theta activity is one consistent observation occurring during all the phases of schizophrenia. However, the resting theta oscillations during the remission phase are yet unclear. We studied resting theta current source density and functional connectivity in remitted schizophrenia and compared with healthy controls. Significantly increased current source density was found in the dominant anterior cingulate cortex. Increased connectivity between the inferior parietal lobe bilaterally and between the left inferior parietal lobe and right middle frontal gyrus was also found. It may be concluded that schizophrenia patients have aberrant regional theta band current source density and functional connectivity even during remission.

Sources of mu activity and their functional connectivity in perceiving complexities in reciprocal social interactive motion: An exploratory study using the 'Namaste' task.

Cognitive processes underlying reciprocal social interactions are understood by the mechanism of embodiment, which is closely related to the mirror neuron system. Electroencephalographic (EEG) mu activity is a neural marker of the mirror neuron system. This study investigated the mu activity, localization of its sources and functional connectivity, which was induced while watching reciprocal social interactive motion across various degrees of complexity. Eighteen healthy participants underwent high-resolution EEG recording using 256-channels while they watched a specifically designed, culture specific, video task that showed two persons interacting socially using body gestures. Task complexity was determined by (1) whether there was an identical gestural response or a non-identical one; (2) whether the participant watched two persons interacting or was virtually involved in the interaction. Source localization and functional connectivity analysis was conducted for mu activity across various tasks. We also correlated mu activity and functional connectivity measures with serum BDNF. We found that spectral densities in various brain sources of mu activity and their increased functional connectivity distinguished identical and non-identical reciprocal expression observations, while mu suppression alone did not discriminate various degrees of complexities. These findings might have important implications in the understanding of mechanisms underlying mirror neuron dysfunction in various psychiatric disorders.

Comparing mirror neuron system activity between sporadic and familial cases of schizophrenia.

Schizophrenia is a heterogenous disorder, and has often been subtyped on the basis of family history of psychotic disorders. Compared to those without, a positive family history is associated with an earlier age of onset, greater structural brain abnormalities and poorer clinical course. Given recent emphasis on mirror neuron system (MNS) in attempting to explain psychopathology in schizophrenia; present analysis tried to tease out differences in MNS functioning between these two groups. With ethical approval, 10 consenting right-handed patients with schizophrenia (ICD-10-DCR; M=8; Drug-naïve=2) were recruited and divided into two groups of five each (M=4, F=1): those with (age 29.40±5.85 years, duration of illness 50.80±30.84 months) and without (age 29.60±5.77 years, duration of illness 43.20±43.76 months) family history of schizophrenic illness (group difference p>0.05). MNS activity was assessed using event-related desynchronization of EEG Mu waves in response to biological motion on 192-channel EEG Neurofax EEG-1100K. On comparison, while patients had significantly lower mu suppression compared to controls (p<0.001); two schizophrenia groups did not differ between themselves, neither on MNS activity nor on psychopathology (p>0.05). Present study replicates finding of a dysfunctional MNS in schizophrenia patients, and represents a preliminary attempt at comparing two groups of symptomatic schizophrenia patients. In both these groups, MNS dysfunctions were comparable, and commensurate with respect to psychopathology. Thus, MNS dysfunction in schizophrenia might either be inherited or acquired. However, this abnormality forms a common base, and ultimate vulnerability marker, for development of psychopathology during active disease states.

Cerebral Hemodynamics With rTMS in Alcohol Dependence: A Randomized, Sham-Controlled Study.

The authors studied cerebral hemodynamics in alcohol dependence and evaluated their changes with application of high-frequency rTMS. A prospective, single-blind, randomized, parallel-group, sham-controlled clinical study was conducted with patients with alcohol dependence (DSM-IV-TR). The study population comprised 25 subjects each in active rTMS, sham rTMS, and healthy control groups. At baseline, cerebral hemodynamic indices were measured with transcranial Doppler sonography. Subjects in the active rTMS group received 10 sessions of rTMS daily; the sham group was administered sham rTMS with the same parameters. Cerebral hemodynamic parameters were repeated 5 minutes after the last rTMS session. At baseline, mean velocity (MV) of both middle cerebral artery (MCA; R-MCA: p=0.003; L-MCA: p=0.002) and anterior cerebral artery (ACA; R-ACA: p=0.003; L-ACA: p=.001) was significantly reduced. Pulsatility index (PI) of MCA (p<0.001) and resistance index (RI) of ACA (R-ACA: p=0.009; L-ACA: p=0.008) were increased in alcohol-dependent subjects in comparison with healthy controls. In the active rTMS group, except L-MCA PI, significant differences were observed in values of MV, PI, and RI of both MCA and ACA following rTMS intervention; such changes were not evident in the sham rTMS group. The changes in mean difference in MV of L-MCA (p=0.006) and L-ACA (p=0.015) were statistically significant in the active rTMS group, in comparison with the sham group. Significant differences were also observed between the two groups postintervention, in RI of L-MCA (p=0.001) and ACA (R-ACA: p=0.010; L-ACA: p=0.015). Alcohol dependence may result in altered cerebral hemodynamic parameters, which can be improved with high-frequency rTMS application.

Schneiderian first rank symptoms in schizophrenia: A developmental neuroscience evaluation.

INTRODUCTION: Self disorders in schizophrenia have been suggested to have distinct neurobiological underpinnings. Using comprehensive neuro-scientific assessments including a neurophysiological, a neurochemical and a neuropsychological marker, this study assesses disordered-"self" in schizophrenia. METHODS: Twenty schizophrenia patients with first rank symptoms (FRS;FRS+), 20 patients without FRS (FRS-) and 20 healthy controls (HC) were assessed for psychopathology, especially on specially designed FRS score sheets with a narrow and a broad definition. Resting state electroencephalography was acquired using 256-electrodes; gamma spectral-power was measured in 8 regions of interest. Serum BDNF and self-monitoring were also assessed. Comparative and correlation analysis were conducted in addition to a step-wise discriminant function analysis. RESULTS: FRS+ group with greater positive symptom score and a lower negative symptom score, showed significantly increased gamma spectral power, especially on right hemispheric regions, along with lower BDNF levels and lower scores on self-monitoring compared to FRS- and HC. Serum BDNF levels and gamma spectral power in the region corresponding right inferior parietal lobule were identified as predictors that most accurately classified the defined groups. CONCLUSIONS: Schizophrenia patients satisfying the criteria of presence of first rank symptoms represent a distinct neurodevelopmental subgroup with associated features of predominantly positive symptoms, significantly lower neurotrophin levels, aberrant resting state brain activity in the heteromodal association cortex and performing poorer on self-monitoring tasks.

Negative symptoms in schizophrenia.

The negative symptoms have been described in association with schizophrenia since the early days of it being recognized as an entity. However, their elusive nature kept them unacknowledged until there was a revival of interest in them following the development of specific quantifying measures. Over the past three decades, there has been a tremendous surge in research on their types, measurements, status in the present classificatory system, and their implications. The developments in modern investigatory methods have provided the researchers with fresh insights into the underlying mechanisms, and a distributed functioning of the neuronal networks has emerged as the major abnormality. Accordingly, a variety of pharmacological and other treatment modalities have been developed which go beyond the traditional. Nevertheless, a lot remain unanswered. The present paper summarizes important concepts with regard to negative symptoms in schizophrenia.