Person:

Keshavan, Matcheri

Abstract Background: While the etiology of schizophrenia (SZ) is still unclear, it has been characterized as a neurodevelopmental disorder because patients exhibit deviations from normal maturational trajectories that are evident prior to the onset of psychotic symptoms. White matter (WM) has been purported to play a central role in the development of SZ, however, the timing and nature of WM changes in SZ is still poorly understood. This study uses diffusion imaging from three independent Genetic High Risk (GHR) populations spanning the developmental timeline from infancy to young adulthood. The aim of this study is to understand the extent and the time-course of WM maturational pathologies as a function of age and genetic risk for psychosis. Methods: Two datasets of 3T diffusion-weighted images of children aged 7 to 12 (24 HC and 16 at GHR) and young adults aged 19 to 29 (26 HC and 43 GHR) were collected at the Massachusetts Institute of Technology. The third dataset of 3T images of infants aged 2 years (35 HC and 18 GHR) was collected at the University of North Carolina – Chapel Hill. Whole brain two-tensor tractography was performed and 4 bilateral WM tracts (arcuate fasciculus (AF); inferior longitudinal fasciculus (ILF); cingulum bundle (CB); superior longitudinal fasciculus-ii (SLF-ii)), were extracted utilizing an atlas-guided fiber clustering algorithm. The fractional anisotropy of the tissue (FA-t) was obtained. We carried out group comparisons of FA-t between GHR and HCs utilizing Mann-Whitney-U tests and Cohen’s d effect sizes for each WM tract. Results: Preliminary analyses reveal significant reductions in FAt between GHR and HC in the right CB (p = 0.013) in the child GHR population. This is mirrored by medium to large effect sizes in the bilateral CB in GHR children (CB-left, d = 0.51; CB-right, d = 0.79). Reductions in FAt in the adult GHR population within the right CB was the largest effect observed in the adult analysis (CB-right, d = 0.46). Effect sizes in the bilateral CB were minimal in the infant GHR population (CB-left, d = 0.14, CB-right, d = 0.11). Significant decreases were also seen in the right SLF-ii in the adult GHR population (p = 0.012), but not in the infant or child GHR populations, though the reductions in FAt in the child GHR population exhibited a small effect (d = 0.35). All other white matter tracts in the adult analysis showed minor effects ranging from d = 0.033 (ILF-right) to 0.28 (ILF-left). The children and infant population also exhibited small effect sizes for all other tracts, with the child GHR dataset ranging from 0.036 (ILF-left) to 0.41 (ILF-right) and the infant GHR dataset ranging from d = 0.038 (SLF-left) to 0.34 (ILF-left). Discussion Our preliminary results suggest that abnormal WM maturation may occur in the right CB and right SLF-ii in individuals with increased genetic risk for SZ, specifically after early childhood (7 to 12 years) and into adulthood (19 to 29 years). The CB and SLF-ii are highly implicated in working memory performance, an ability that retrospective studies have shown begins to decline during the peripubertal period in those that develop SZ (~7 to 9 years). The lack of structural findings in GHR infants, may suggest that WM alterations are more likely to arise later in development, thereby possibly identifying childhood as a vulnerable period. Taken together, the preliminary results of this study provide possible evidence of subtle divergences from a healthy WM maturational trajectory in the right CB and right SLF-ii in early to late childhood that may persist into adulthood and these deviations may contribute to cognitive phenotypes described in other studies.

Abstract Background: The present study aims to validate the predictive accuracy of the NAPLS-2 psychosis risk calculator in a clinical high-risk (CHR) sample from the SHARP (ShangHai At Risk for Psychosis) program in Shanghai, China using comparable inclusion/exclusion criteria and assessments. Methods: Three hundred CHR individuals were identified by the Chinese version of the Structured Interview for Prodromal Symptoms. Of these, 228 (76.0%) completed neuro-cognitive assessments at baseline and 199 (66.3%) had at least a one-year follow-up assessment. The latter group was used in risk calculation. Six key predictors (baseline age, unusual thoughts and suspiciousness, symbol coding and verbal learning test performance, functional decline and family history of psychosis) were entered into the NAPLS-2 model to generate a psychosis risk estimate for each case. The area under the receiver operating characteristic curve (AUC) was used to test the effectiveness of this discrimination. Results: The NAPLS risk calculator showed moderate discrimination of subsequent transition to psychosis in the SHARP sample with an AUC of 0.631 (p = 0.007). Whether discriminating either transition or poor treatment/clinical outcomes, the AUC of the model increased to 0.754 (p < 0.001). A risk estimate of 30% or higher had moderate sensitivity (53%) and excellent specificity (86%) for prediction of poor treatment/clinical outcome. Discussion The NAPLS-2 risk calculator largely generalizes to a Shanghai CHR sample but is meaningfully improved when predicting an individual’s poor clinical outcome as well as conversion. Our findings provide a critical step in the implementation of CHR risk calculation in China.

Abstract Background: Frontal and temporal lobes abnormalities are often reported in schizophrenia. In the present study, we tested whether or not these abnormalities exist in individuals at clinical high risk for psychosis (CHR), and whether they distinguish between those CHR who convert to psychosis versus those who do not convert to psychosis at one year. We analyzed both cortical thickness (CT) and surface area (SA) given the fact that CT and SA develop along different developmental genetically mediated pathways. Since CHR individuals also experience a deterioration of cognitive functions and sub-threshold psychotic symptoms, we also explored the relationship between cognition and symptomatology and the two brain regions. Methods: Magnetic resonance images, clinical and cognitive data were acquired in 130 CHR who did not convert to psychosis (CHR-NC), 22 CHR who converted to psychosis (CHR-C) and 92 healthy controls (HC) at the Shanghai Mental Health Center, in Shanghai, China, who were tested as part of a NIH funded China and Harvard Medical School collaboration. An internal pipeline developed at the Psychiatry Neuroimaging Laboratory (PNL), Brigham and Women’s Hospital, Harvard Medical School, was used to process the scans. The pipeline includes several quality control steps and FreeSurfer 5.3 (FS) processing, the latter modified to include an automated PNL developed masking methodology, the MABS. FS output was 9 temporal and 11 frontal regions in the left and right hemisphere. All data were Z-scored to the mean and standard deviation of HC. Gender and group differences were investigated using multivariate analyses, and Spearman’s correlations were employed to investigate the relationship between brain measures and cognitive and clinical measures. Results: SA analysis of the frontal and temporal lobes showed no significant differences among the three groups, while specific and significant group differences were found in CT. More specifically, for the temporal lobe a main effect of Group (p=0.021) and a significant interaction of Region x Group (p=0.01) were found. Post hoc analyses showed that CT of Heschl’s gyrus and of the posterior region of the superior temporal sulcus distinguished CHR-C from CHR-NC (p=0.027) and from NC (p=0.002), with CT of CHR <CHR-NC=NC. For the middle temporal gyrus (MTG) CT was also significantly smaller in CHR-C than in NC (p=0.004) and at trend level in CHR-NC (p=0.098). With respect to the frontal lobe, no significant main effect of Group was found but a significant region X Group interaction was identified. Post hoc analyses showed smaller CT of the pars triangularis in CHR-C with CHR-C<CHR-NC (p=0.02) and NC (p=0.012). The CT of the pars opercularis was smaller in CHR-C compared to NC (p=0.036). In CHR-C, the CT of MTG was significantly and positively correlated with the Verbal Learning test and with the Hopkins Verbal Learning test (rho= 0.64; p=0.002), with strength of correlation decreasing with task repetition. Further CT of MTG was correlated with the Brief Visual Memory Test (rho=0.6, p=0.004). A significant and positive correlation was also found between CT of the pars opercularis (rho=0.7; p=0.002) and the Brief Visual Memory test. The same correlation was also present with the pars triangularis. None of these correlations were present in NC or CHR-NC. Discussion These results indicate that specific CT abnormalities in circumscribed areas of the frontal and temporal lobes at baseline distinguish between CHR individuals who convert to psychosis versus those who do not at one-year follow-up. The brain regions involved belong to language circuits and their CT abnormalities correlate with verbal learning suggesting that these brain circuits are among the first affected by processes leading to frank psychosis.

Abstract Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC’s impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

Abstract Background: Abnormal mismatch negativity (MMN), thought to be a putative marker of glutamatergic function, has been reported in non-Asian, first episode schizophrenia and clinical high-risk for psychosis (CHR) individuals as indicative of impairments in pre-attentive processes. However, reports of abnormal MMN in Asian populations are sparse, as well as its relationships to glutamate and γ–aminobutyric acid (GABA) levels in medial prefrontal cortex. The present longitudinal study explored MMN differences between CHR subjects who will and who will not remit, and its relationships with prefrontal glutamate and GABA levels. Methods: All subjects participated in the ShangHai At-Risk for Psychosis (SHARP) program. CHR subjects met the criteria defined by the Chinese version of the Structural Interview for Prodromal Syndromes (SIPS). From the SHARP sample, 76 CHR subjects (41 male, age 18.63 ± 5.02 years) and 53 HC (31 male, age 17.72 ± 3.18 years) completed both MMN test and proton magnetic resonance spectroscopy (1H MRS) scans using a MEGA-PRESS sequence at their initial visit. CHR subjects were divided into remitted (37) and non-remitted (34) individuals based on their clinical symptoms and functional scores at a one-year follow up. Duration MMN amplitude was measured at electrodes F1/2, Fz, FC1/2, FCz, C1/2 and Cz. Concentrations of glutamate+glutamine (Glx) and GABA in the medial prefrontal cortex (mPFC) were quantified using the LCModel software (version 6.3-0I). Repeated measures analysis of variance (ANOVA) with group (remitted CHR, non-remitted CHR and HC) as the between-group factor and electrodes (Fz, FCz and Cz) as the within-group factor were performed for the midline sites, and the ANOVA using F1/2, FC1/2 and C1/C2 with laterality (left and right hemisphere) as an additional within-group factor was performed for the lateral sites. Correlations of the dMMN amplitude (averaged over the 9 electrodes) and Glx and GABA concentrations were assessed by Pearson correlation tests for each group. Results: There was a significant main effect of group (F(2,121)=3.14, p<0.05) for the midline fronto-central dMMN amplitude. Post-hoc tests showed that non-remitted CHR subjects had lower baseline dMMN amplitude (-4.75 ± 0.37μv) than HC (-5.92 ± 0.30μv, p<0.05), whereas dMMN in remitted CHR (-5.22 ± 0.36μv, p=0.41) was comparable to dMMN in HC. The main effect of group was marginally significant at lateral sites (F(2,121)=2.83, p=0.06). DMMN amplitude in non-remitted CHR (-4.67 ± 0.37μv) tended to be lower than those in HC (-5.76 ± 0.29μv, p<0.1), while remitted CHR had dMMN amplitude (-5.11 ± 0.35μv, p=0.47) comparable to HC. There was no significant main effect of laterality or interaction of group × laterality. In non-remitted CHR subjects, dMMN amplitude was significantly correlated with Glx level (r=-0.47, p<0.01) and with GABA level (r=-0.38, p<0.05) in the mPFC. However, the correlation of dMMN amplitude with Glx or GABA levels was not significant among either HC or remitted CHR. Discussion In line with previous studies, reduced dMMN amplitude distinguished between remitted and non-remitted CHR subjects, with remitted CHR not different from HCs. Our finding further supports the idea that reduced dMMN amplitude could be a candidate biomarker for predicting outcome in CHR. More importantly, we linked the reduced dMMN amplitude in non-remitted CHR to their Glx and GABA levels in mPFC, the region identified as one of dMMN sources (responsible for attention switching) thus supporting the idea that NMDA-mediated disruptions may play a key role in predicting psychosis and functional outcome.