Alterations of neurometabolism in the dorsolateral prefrontal cortex and thalamus in transition to psychosis patients change under treatment as usual - A two years follow-up 1H/31P-MR-spectroscopy study.

BACKGROUND: The ultra-high risk (UHR) paradigm allows early contact with patients developing acute psychosis and the study of treatment effects on the underlying pathology. METHODS: 29 patients with first acute psychosis according to CAARMS criteria (transition patients, TP) (T0) and thereof 22 patients after two-year follow-up (mean 788 d) (T1) underwent 1H-/31P-MR spectroscopy of the prefrontal (DLPFC) and anterior midcingulate (aMCC) cortices and the thalamus. N-acetylaspartate (NAA), glutamate (Glu, Glx), energy (PCr, ATP) and phospholipid metabolites (PME, PDE) were compared to 27 healthy controls by ANCOVA and correlated with patients' symptom ratings (BPRS-E, SCL-90R). For longitudinal analysis, linear mixed model (LMM) and ANCOVA for repeated measures were used. RESULTS: DLPFC: In patients, NAA and PME were decreased bilaterally and Glu on the left side at T0. Left-sided Glu and NAA (trend) and bilateral Glx increased during follow-up. Thalamus: In TP, bilateral NAA, left-sided Glu and right-sided Glx were decreased at T0; bilateral NAA and left-sided Glx increased during follow-up. aMCC: In TP, bilateral NAA, right-sided Glu, and bilateral PME and PDE were decreased, while left-sided PCr was increased at T0. No changes were observed during follow-up. CONCLUSION: Regardless of the long-term diagnosis, the psychotic state of illness includes disturbed neuronal function in the DLPFC, thalamus and aMCC. Treatment-as-usual (TAU), including antipsychotic/antidepressant medication and supportive psychotherapy, had an effect on the thalamo-frontal area but not or less pronounced on the neurometabolic deficits of the aMCC.

Prefrontal glutamatergic emotion regulation is disturbed in cluster B and C personality disorders - A combined 1H/31P-MR spectroscopic study.

BACKGROUND: Personality disorders (PD) belong to the most common and most serious mental disorders as regards social dysfunction, inability to work, occurrence of comorbidity and suicidal risk. PDs also crucially influence the incidence, clinical course and treatment response of mental disorders with high suicidal risk, such as depression or substance abuse. One key issue of PD concerns the regulation of emotions. METHODS: Both 1H-/31P-Chemical Shift Imaging (CSI) was applied in a single session to assess neurochemical markers of glutamate function (NAA, Glu) and local energy metabolism (PCr, ATP) in two patient cohorts encompassing 22 cluster B (CB) and 21 cluster C (CC) PD patients, whereby 10 patients of each group were on low-dose antidepressants, and in 60 healthy controls (HC). Non-parametric statistical tests and correlation analyses were performed to assess disease effects on the metabolites and their relation to symptomatology as assessed by SCL-90R self-ratings. RESULTS: Overall comparison including Bonferroni correction revealed significant differences of Glu across all groups in the dorsolateral prefrontal cortex (DLPFC). The following uncorrected results of pairwise tests were obtained: (i) Glu was bilaterally increased in the DLPFC in CB patients, whereas it was - together with NAA - bilaterally decreased in the DLPFC in CC patients and accompanied by increased PCr in the left DLPFC. (ii) NAA and Glu, accompanied by increased PCr, were significantly decreased in the dorsomedial prefrontal cortex (DMPFC) in CC patients. (iii) NAA was decreased in the right anterior cingulate cortex (ACC) in CB patients, and in the left ACC in CC patients with PCr being increased bilaterally. (iv) No associations were observed between metabolites and psychopathology measures. CONCLUSION: The observations in the DLPFC may reflect a neurobiochemical correlate of disturbed cognitive control function in CB and CC PD. While the alterations in CB patients suggest increased basal activity, the observed patterns in CC patients likely reflect decreased or inhibited activity. The alterations of NAA and Glu levels in the ACC and DMPFC indirectly support the assumption of disturbed neuronal function in regions involved in social cognition and mentalizing abilities in both CB and CC PD. Further studies should include the investigation of metabolites of neuronal inhibition (GABA) and the examination of treatment effects.

Brain structural correlates of schizotypy and psychosis proneness in a non-clinical healthy volunteer sample.

Schizotypal traits are phenotypic risk factors for schizophrenia, associated with biological changes across a putative schizophrenia spectrum. In this study, we tested the hypothesis that brain structural changes in key brain areas relevant to this spectrum (esp. medial and lateral prefrontal cortex) would vary across different degrees of schizotypal trait expression and/or phenotypic markers of psychosis proneness in healthy non-clinical volunteers. We analysed high-resolution 3Tesla magnetic resonance images (MRI) of 59 healthy volunteers using voxel-based morphometry (VBM), correlating grey matter values to the positive and negative symptom factors of the schizotypal personality questionnaire (SPQ, German version) and a measure of psychosis proneness (community assessment of psychic experiences, CAPE). We found positive correlations between positive SPQ dimension and bilateral inferior and right superior frontal cortices, and positive CAPE dimension and left inferior frontal cortex, as well as CAPE negative dimension and right supplementary motor area (SMA) and left inferior parietal cortex. However, only the positive correlation of the right precuneus with negative schizotypy scores was significant after FWE correction for multiple comparisons. Our findings confirm an effect of schizotypal traits and psychosis proneness on brain structure in healthy subjects, providing further support to a biological continuum model.

Associations of hippocampal metabolism and regional brain grey matter in neuroleptic-naïve ultra-high-risk subjects and first-episode schizophrenia.

Hippocampal pathology has been shown to be central to the pathophysiology of schizophrenia and a putative risk marker for developing psychosis. We applied both (1)H MRS (proton magnetic resonance spectroscopy) at 3Tesla and voxel-based morphometry (VBM) of high-resolution brain structural images in order to study the association of the metabolites glutamate (Glu) and N-acetyl-aspartate (NAA) in the hippocampus with whole-brain morphometry in 31 persons at ultra-high-risk for psychosis (UHR), 18 first-episode schizophrenia patients (Sz), and 42 healthy controls (all subjects being neuroleptic-naïve). Significantly diverging associations emerged for UHR subjects hippocampal glutamate showed positive correlation with the left superior frontal cortex, not seen in Sz or controls, while in first-episode schizophrenia patients a negative correlation was significant between glutamate and a left prefrontal area. For NAA, we observed different associations for left prefrontal and caudate clusters bilaterally for both high-risk and first-episode schizophrenia subjects, diverging from the pattern seen in healthy subjects. Our results suggest that associations of hippocampal metabolites in key areas of schizophrenia might vary due to liability to or onset of the disorder.

Brain structure in people at ultra-high risk of psychosis, patients with first-episode schizophrenia, and healthy controls: a VBM study.

Early intervention research in schizophrenia has suggested that brain structural alterations might be present in subjects at high risk of developing psychosis. The heterogeneity of regional effects of these changes, which is established in schizophrenia, however, has not been explored in prodromal or high-risk populations. We used high-resolution MRI and voxel-based morphometry (VBM8) to analyze grey matter differences in 43 ultra high-risk subjects for psychosis (meeting ARMS criteria, identified through CAARMS interviews), 24 antipsychotic-naïve first-episode schizophrenia patients and 49 healthy controls (groups matched for age and gender). Compared to healthy controls, resp., first-episode schizophrenia patients had reduced regional grey matter in left prefrontal, insula, right parietal and left temporal cortices, while the high-risk group showed reductions in right middle temporal and left anterior frontal cortices. When dividing the ultra-high-risk group in those with a genetic risk vs. those with attenuated psychotic symptoms, the former showed left anterior frontal, right caudate, as well as a smaller right hippocampus, and amygdala reduction, while the latter subgroup showed right middle temporal cortical reductions (each compared to healthy controls). Our findings in a clinical psychosis high-risk cohort demonstrate variability of brain structural changes according to subgroup and background of elevated risk, suggesting frontal and possibly also hippocampal/amygdala changes in individuals with genetic susceptibility. Heterogeneity of structural brain changes (as seen in schizophrenia) appears evident even at high-risk stage, prior to potential onset of psychosis.