Impaired prefrontal synaptic gain in people with psychosis and their relatives during the mismatch negativity.

The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task--for 24 patients with psychosis, 25 of their first-degree unaffected relatives, and 35 controls--and DCM was used to estimate the excitability (modeled as self-inhibition) of (source-specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context-dependent (condition-specific) and context-independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis.

Psychotic Experiences, Working Memory, and the Developing Brain: A Multimodal Neuroimaging Study.

Psychotic experiences (PEs) occur in the general population, especially in children and adolescents, and are associated with poor psychosocial outcomes, impaired cognition, and increased risk of transition to psychosis. It is unknown how the presence and persistence of PEs during early adulthood affects cognition and brain function. The current study assessed working memory as well as brain function and structure in 149 individuals, with and without PEs, drawn from a population cohort. Observer-rated PEs were classified as persistent or transient on the basis of longitudinal assessments. Working memory was assessed using the n-back task during fMRI. Dynamic causal modeling (DCM) was used to characterize frontoparietal network configuration and voxel-based morphometry was utilized to examine gray matter. Those with persistent, but not transient, PEs performed worse on the n-back task, compared with controls, yet showed no significant differences in regional brain activation or brain structure. DCM analyses revealed greater emphasis on frontal connectivity within a frontoparietal network in those with PEs compared with controls. We propose that these findings portray an altered configuration of working memory function in the brain, potentially indicative of an adaptive response to atypical development associated with the manifestation of PEs.

Schizophrenia-like topological changes in the structural connectome of individuals with subclinical psychotic experiences.

Schizophrenia is often regarded as a "dysconnectivity" disorder and recent work using graph theory has been used to better characterize dysconnectivity of the structural connectome in schizophrenia. However, there are still little data on the topology of connectomes in less severe forms of the condition. Such analysis will identify topological markers of less severe disease states and provide potential predictors of further disease development. Individuals with psychotic experiences (PEs) were identified from a population-based cohort without relying on participants presenting to clinical services. Such individuals have an increased risk of developing clinically significant psychosis. 123 individuals with PEs and 125 controls were scanned with diffusion-weighted MRI. Whole-brain structural connectomes were derived and a range of global and local GT-metrics were computed. Global efficiency and density were significantly reduced in individuals with PEs. Local efficiency was reduced in a number of regions, including critical network hubs. Further analysis of functional subnetworks showed differential impairment of the default mode network. An additional analysis of pair-wise connections showed no evidence of differences in individuals with PEs. These results are consistent with previous findings in schizophrenia. Reduced efficiency in critical core hubs suggests the brains of individuals with PEs may be particularly predisposed to dysfunction. The absence of any detectable effects in pair-wise connections illustrates that, at less severe stages of psychosis, white-matter alterations are subtle and only manifest when examining network topology. This study indicates that topology could be a sensitive biomarker for early stages of psychotic illness.

Cerebral metabolism in major depressive disorder: a voxel-based meta-analysis of positron emission tomography studies.

BACKGROUND: Major depressive disorder (MDD) is a common mental illness with high lifetime prevalence close to 20%. Positron emission tomography (PET) studies have reported decreased prefrontal, insular and limbic cerebral glucose metabolism in depressed patients compared with healthy controls. However, the literature has not always been consistent. To evaluate current evidence from PET studies, we conducted a voxel-based meta-analysis of cerebral metabolism in MDD. METHOD: Data were collected from databases including PubMed and Web of Science, with the last report up to April 2013. Voxel-based meta-analyses were performed using the revised activation likelihood estimation (ALE) software. RESULTS: Ten whole-brain-based FDG-PET studies in MDD were included in the meta-analysis, comprising 188 MDD patients and 169 healthy controls. ALE analyses showed the brain metabolism in bilateral insula, left lentiform nucleus putamen and extra-nuclear, right caudate and cingulate gyrus were significantly decreased. However, the brain activity in right thalamus pulvinar and declive of posterior lobe, left culmen of vermis in anterior lobe were significantly increased in MDD patients. CONCLUSION: Our meta-analysis demonstrates the specific brain regions where possible dysfunctions are more consistently reported in MDD patients. Altered metabolism in insula, limbic system, basal ganglia, thalamus, and cerebellum and thus these regions are likely to play a key role in the pathophysiology of depression.

Prospective memory in early and established psychosis: An Indian perspective.

Individuals affected by psychosis often have deficits in several neurocognitive functions. Prospective memory (PM), the ability to remember to do things, is crucial for activities of daily living, social and occupational functioning, but very few studies have attempted to examine this domain of functioning in people with psychosis, particularly in India. A total of 71 patients with psychosis, (both early and established psychosis), and 140 age, gender and education-matched healthy controls were assessed using the Positive and Negative Symptom Scale, Hospital Anxiety and Depression scale, and Addenbrooke's Cognitive Examination. PM was assessed using the Cambridge Prospective Memory Test and the Prospective and Retrospective Memory Questionnaire (PRMQ). Group differences were evaluated using Mann-Whitney U-tests. Significantly greater cognitive deficits, higher anxiety and depression were evident in the psychosis group compared with controls. The psychosis group performed significantly poorer on both time- and event-based tests in CAMPROMPT than controls. These differences remained when controlling for age, education, general cognitive functioning and mood. The subjective measure of PM (PRMQ) did not differentiate the two groups. The PM performance of early and established psychosis patients was similar. Comparisons with cross-cultural data (PRMQ UK norms and CAMPROMPT and PRMQ Chinese data) revealed important differences in PM performance. Individuals with psychosis have significant deficits in both time- and event-based PM. CAMPROMPT emerged as a more sensitive PM measure compared with PRMQ. Results from cross-cultural comparisons underscore the need for cultural contextualization of assessments.

Association between hippocampal volume and P300 event related potential in psychosis: support for the Kraepelinian divide.

INTRODUCTION: Abnormalities of the P300 event related potential (ERP) and of hippocampal structure are observed in individuals with psychotic disorders and their unaffected relatives. The understanding and clinical management of psychotic disorders are largely based on the descriptive Kraepelinian distinction between 'dementia praecox' and 'manic depressive psychosis', and not dependant on any well demarcated biological underpinnings. The hippocampus is postulated to be one of the main P300 generators, yet it remains unknown whether hippocampal volume decrements are associated with P300 deficits in psychosis, and whether any association is shared across non-affective and affective psychotic disorders. METHODS: 228 subjects from the Maudsley Family Psychosis Study comprising 55 patients with non-affective psychosis, 23 patients with psychotic bipolar disorder, 98 unaffected relatives, and 52 unrelated controls contributed structural MRI and ERP data. To study the relationship between hippocampal volume and P300 ERP, a seemingly unrelated regression methodology was used, accounting for whole brain volumes, clinical groups, age and gender in the analysis. RESULTS: An association between left hippocampal volume and P300 latency in the combined sample comprising non-affective and affective psychotic patients, their relatives and controls was observed. There was an inverse relationship between brain structure and function in that prolongation of P300 latencies was associated with smaller left hippocampal volumes. On subdividing the sample based on Kraepelinian dichotomy, this association remained significant only for the non-affective psychosis group, comprising patients and their unaffected relatives. CONCLUSIONS: Based on our findings, P300 latency, a measure of the speed of neural transmission, appears to be related to the size of the left hippocampus in schizophrenia, but not in psychotic bipolar disorder. It seems that underlying neuro-biological characteristics could help in unravelling the traditional Kraepelinian differentiation between the two major psychoses. The specificity of this brain structure-function association for schizophrenia opens the scope for further research using integration of multimodal biological data for objective categorisation of psychosis.

COMT gene polymorphism and corpus callosum morphometry in preterm born adults.

INTRODUCTION: Preterm birth is associated with a range of neurodevelopmental deficits, including corpus callosum (CC) abnormalities, which persist into late adolescence and early adulthood. A common single-nucleotide polymorphism in the catechol-o-methyl transferase (COMT) gene (Val158Met) is associated with cognition and brain structure and may play a role in neurodevelopment. It is not known whether this polymorphism is associated with CC morphometry in individuals born preterm. METHODS: Structural MRI scans were acquired in 33 adults born very preterm (before 33 weeks' gestation) and 29 healthy controls. DNA was collected and COMT Val158Met polymorphism status determined using standard available assays. The mid-sagittal area of four antero-posterior subdivisions of the CC was measured. The effect of COMT Val158Met polymorphism on cross-sectional CC areas was studied using multivariate analysis and generalised linear models, adjusted for the effects of the clinical sample group (preterm vs. control), age and sex. RESULTS: The COMT Val/Val homozygous genotype was observed to be significantly associated with reduced size of the total corpus callosum, and this relationship was present for the anterior, midposterior and posterior quarters of the CC. CONCLUSIONS: The COMT Val158Met polymorphism possibly influences the morphometry of the corpus callosum associated with very preterm births. Further studies with larger sample sizes are warranted to conclusively establish the effects of individual genotypes of the COMT gene on corpus callosum in preterm born adults.

Volumetric, relaxometric and diffusometric correlates of psychotic experiences in a non-clinical sample of young adults.

BACKGROUND: Grey matter (GM) abnormalities are robust features of schizophrenia and of people at ultra high-risk for psychosis. However the extent to which neuroanatomical alterations are evident in non-clinical subjects with isolated psychotic experiences is less clear. METHODS: Individuals (mean age 20 years) with (n = 123) or without (n = 125) psychotic experiences (PEs) were identified from a population-based cohort. All underwent T1-weighted structural, diffusion and quantitative T1 relaxometry MRI, to characterise GM macrostructure, microstructure and myelination respectively. Differences in quantitative GM structure were assessed using voxel-based morphometry (VBM). Binary and ordinal models of PEs were tested. Correlations between socioeconomic and other risk factors for psychosis with cortical GM measures were also computed. RESULTS: GM volume in the left supra-marginal gyrus was reduced in individuals with PEs relative to those with no PEs. The greater the severity of PEs, the greater the reduction in T1 relaxation rate (R1) across left temporoparietal and right pre-frontal cortices. In these regions, R1 was positively correlated with maternal education and inversely correlated with general psychopathology. CONCLUSIONS: PEs in non-clinical subjects were associated with regional reductions in grey-matter volume reduction and T1 relaxation rate. The alterations in T1 relaxation rate were also linked to the level of general psychopathology. Follow up of these subjects should clarify whether these alterations predict the later development of an ultra high-risk state or a psychotic disorder.

Mediation of Developmental Risk Factors for Psychosis by White Matter Microstructure in Young Adults With Psychotic Experiences.

IMPORTANCE: White matter (WM) abnormalities have been identified in schizophrenia at the earliest stages of the disorder. Individuals in the general population with psychotic experiences (PEs) may show similar changes, suggesting dysfunction due to aberrant neurodevelopment. Studying such people is a powerful means of understanding the nature of neurodevelopmental problems without the confound of clinical management and allows other potential risk factors associated with the schizophrenia spectrum to be taken into account. OBJECTIVES: To compare WM microstructure and myelination in young adults with and without PEs identified from a population-based cohort using diffusion and relaxometry magnetic resonance imaging and to quantify potential mediating effects of WM on several known risk factors for psychosis. DESIGN, SETTING, AND PARTICIPANTS: In this case-control study, participants were drawn from the UK Avon Longitudinal Study of Parents and Children. Psychotic experiences were assessed using a semistructured interview. Magnetic resonance imaging was carried out at age 20 years in 123 participants who had PEs and 124 individuals serving as controls. Participants with PEs were subdivided into those with operationally defined suspected PEs, definite PEs, and psychotic disorder. MAIN OUTCOMES AND MEASURES: Diffusion tensor magnetic resonance imaging and relaxometry-derived myelin water fractions were used to measure WM microstructure and myelination, respectively. Differences in quantitative WM indices were assessed using tract-based spatial statistics. A binary model and a continuum-like ordinal model of PEs were tested. RESULTS: Among the 123 participants who had PEs (mean [SE] age, 20.01 [0.004] years), 37 were male and 86 were female. Among the 124 controls (mean [SE] age, 20.11 [0.004] years), 49 were male and 76 were female. Fractional anisotropy in left frontomedial WM was significantly reduced in individuals with PEs (Montreal Neurological Institute [MNI] coordinates, -18, 37, -2; P = .0046). The ordinal model identified a similar but more widespread effect, with a corresponding increase in radial diffusivity (MNI coordinates, -15, 29, 21; P = .0042). Low birth weight (ρ = -0.155; P = .015) and childhood IQ (ρ = -0.188; P = .003) were associated with the presence of PEs. Results of mediation analysis were consistent with the association between birth weight (21.1% mediation effect; P = 6.20 × 10-3) and childhood IQ (7.9% mediation effect; P = .041) and by PEs being mediated by fractional anisotropy changes in these regions. CONCLUSIONS AND RELEVANCE: The results of the study imply the presence of abnormal WM microstructure in young adults with PEs. The results are consistent with the hypothesis that neurodevelopmental factors cause alterations in the cellular composition of WM circuits critical to higher cognitive function. Such alterations may first manifest in childhood as reduced IQ and later contribute to PEs in early adulthood.

Perceived ethnic discrimination and persecutory paranoia in individuals at ultra-high risk for psychosis.

Despite a consensus that psychosocial adversity plays a role in the onset of psychosis, the nature of this role in relation to persecutory paranoia remains unclear. This study examined the complex relationship between perceived ethnic discrimination and paranoid ideation in individuals at Ultra High Risk (UHR) for psychosis using a virtual reality paradigm to objectively measure paranoia. Data from 64 UHR participants and 43 healthy volunteers were analysed to investigate the relationship between perceived ethnic discrimination and persecutory ideation in a virtual reality environment. Perceived ethnic discrimination was higher in young adults at UHR in comparison to healthy controls. A positive correlation was observed between perceived ethnic discrimination and paranoid persecutory ideation in the whole sample. Perceived ethnic discrimination was not a significant predictor of paranoid persecutory ideation in the VR environment. Elevated levels of perceived ethnic discrimination are present in individuals at UHR and are consistent with current biopsychosocial models in which psychosocial adversity plays a key role in the development of psychosis and attenuated symptomatology.

Exploring neural dysfunction in 'clinical high risk' for psychosis: a quantitative review of fMRI studies.

Individuals at clinical high risk (CHR) of developing psychosis present with widespread functional abnormalities in the brain. Cognitive deficits, including working memory (WM) problems, as commonly elicited by n-back tasks, are observed in CHR individuals. However, functional MRI (fMRI) studies, comprising a heterogeneous cluster of general and social cognition paradigms, have not necessarily demonstrated consistent and conclusive results in this population. Hence, a comprehensive review of fMRI studies, spanning almost one decade, was carried out to observe for general trends with respect to brain regions and cognitive systems most likely to be dysfunctional in CHR individuals. 32 studies were included for this review, out of which 22 met the criteria for quantitative analysis using activation likelihood estimation (ALE). Task related contrast activations were firstly analysed by comparing CHR and healthy control participants in the total pooled sample, followed by a comparison of general cognitive function studies (excluding social cognition paradigms), and finally by only looking at n-back working memory task based studies. Findings from the ALE implicated four key dysfunctional and distinct neural regions in the CHR group, namely the right inferior parietal lobule (rIPL), the left medial frontal gyrus (lmFG), the left superior temporal gyrus (lSTG) and the right fronto-polar cortex (rFPC) of the superior frontal gyrus (SFG). Narrowing down to relatively few significant dysfunctional neural regions is a step forward in reducing the apparent ambiguity of overall findings, which would help to target specific neural regions and pathways of interest for future research in CHR populations.

Sensory gating deficits in the attenuated psychosis syndrome.

BACKGROUND: Individuals with an "Attenuated Psychosis Syndrome" (APS) have a 20-40% chance of developing a psychotic disorder within two years; however it is difficult to predict which of them will become ill on the basis of their clinical symptoms alone. We examined whether P50 gating deficits could help to discriminate individuals with APS and also those who are particularly likely to make a transition to psychosis. METHOD: 36 cases meeting PACE (Personal Assessment and Crisis Evaluation) criteria for the APS, all free of antipsychotics, and 60 controls performed an auditory conditioning-testing experiment while their electroencephalogram was recorded. The P50 ratio and its C-T difference were compared between groups. Subjects received follow-up for up to 2 years to determine their clinical outcome. RESULTS: The P50 ratio was significantly higher and C-T difference lower in the APS group compared to controls. Of the individuals with APS who completed the follow-up (n=36), nine (25%) developed psychosis. P50 ratio and the C-T difference did not significantly differ between those individuals who developed psychosis and those who did not within the APS group. CONCLUSION: P50 deficits appear to be associated with the pre-clinical phase of psychosis. However, due to the limitations of the study and its sample size, replication in an independent cohort is necessary, to clarify the role of P50 deficits in illness progression and whether this inexpensive and non-invasive EEG marker could be of clinical value in the prediction of psychosis outcomes amongst populations at risk.

Resting EEG in psychosis and at-risk populations--a possible endophenotype?

BACKGROUND: Finding reliable endophenotypes for psychosis could lead to an improved understanding of aetiology, and provide useful alternative phenotypes for genetic association studies. Resting quantitative electroencephalography (QEEG) activity has been shown to be heritable and reliable over time. However, QEEG research in patients with psychosis has shown inconsistent and even contradictory findings, and studies of at-risk populations are scarce. Hence, this study aimed to investigate whether resting QEEG activity represents a candidate endophenotype for psychosis. METHOD: QEEG activity at rest was compared in four frequency bands (delta, theta, alpha, and beta), between chronic patients with psychosis (N=48), first episode patients (N=46), at-risk populations ("at risk mental state", N=33; healthy relatives of patients, N=45), and healthy controls (N=107). RESULTS: Results showed that chronic patients had significantly increased resting QEEG amplitudes in delta and theta frequencies compared to healthy controls. However, first episode patients and at-risk populations did not differ from controls in these frequency bands. There were no group differences in alpha or beta frequency bands. CONCLUSION: Since no abnormalities were found in first episode patients, ARMS, or healthy relatives, resting QEEG activity in the frequency bands examined is unlikely to be related to genetic predisposition to psychosis. Rather than endophenotypes, the low frequency abnormalities observed in chronic patients are probably related to illness progression and/or to the long-term effects of treatments.

Effect of DISC1 on the P300 waveform in psychosis.

INTRODUCTION: Abnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-Schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia. METHODS: We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis. RESULTS: Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies. DISCUSSION: The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.

Reduced mismatch negativity predates the onset of psychosis.

BACKGROUND: Individuals with an "At Risk Mental State" have a 20-30% chance of developing a psychotic disorder within two years; however it is difficult to predict which individuals will become ill on the basis of their clinical symptoms alone. We examined whether mismatch negativity (MMN) could help to identify those who are particularly likely to make a transition to psychosis. METHOD: 41 cases meeting PACE criteria for the At Risk Mental State (ARMS) and 50 controls performed a duration-deviant passive auditory oddball task whilst their electroencephalogram was recorded. The amplitude of the MMN wave was compared between groups using linear regression. The ARMS subjects were then followed for 2 years to determine their clinical outcome. RESULTS: The MMN amplitude was significantly reduced in the ARMS group compared to controls. Of the at-risk subjects who completed followed up (n=41), ten (24% of baseline sample) subsequently developed psychosis. The MMN amplitude in this subgroup was significantly smaller across all three recording sites (FZ, F3 and F4) than in the ARMS individuals who did not become psychotic. CONCLUSION: Among those with the ARMS, MMN amplitude reduction is associated with an increased likelihood of developing frank psychosis.