HuiRu Cui

Abnormal white matter microstructure in drug-naive first episode schizophrenia patients before and after eight weeks of antipsychotic treatment

BACKGROUND Abnormal white matter integrity has been reported among first episode schizophrenia patients. However, findings on whether it can be reversed by short-term antipsychotic medications are inconsistent. METHOD Diffusion tensor imaging (DTI) was obtained from 55 drug-naive first episode schizophrenia patients and 61 healthy controls, and was repeated among 25 patients and 31 controls after 8 weeks during which patients were medicated with antipsychotics. White matter integrity is measured using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). These measures showing a group difference by Tract-based spatial statistics (TBSS) at baseline were extracted for longitudinal comparisons. RESULTS At baseline, patients exhibited lower FA, higher MD and higher RD versus controls in forceps, left superior longitudinal fasciculus, inferior fronto-occipital fasciculus, left corticospinal tract, left uncinate fasciculus, left anterior thalamic radiation, and bilateral inferior longitudinal fasciculi. FA values of schizophrenia patients correlated with their negative symptoms (r=-0.412, P=0.002), working memory (r=0.377, P=0.005) and visual learning (r=0.281, P=0.038). The longitudinal changes in DTI indices in these tracts did not differ between patients and controls. However, among the patients the longitudinal changes in FA values in left superior longitudinal fasciculus correlated with the change of positive symptoms (r=-0.560, p=0.004), and the change of processing speed (r=0.469, p=0.018). CONCLUSIONS White matter deficits were validated in the present study by a relatively large sample of medication naïve and first episode schizophrenia patients. They could be associated with negative symptoms and cognitive impairment, whereas improvement in white matter integrity of left superior longitudinal fasciculus correlated with improvement in psychosis and processing speed. Further examination of treatment-related changes in white matter integrity may provide clues to the mechanism of antipsychotic response and provide a biomarker for clinical studies.

Neuropsychological Impairment in Prodromal, First-Episode, and Chronic Psychosis: Assessing RBANS Performance.

Background Cognitive deficits are observed throughout all developmental phases of psychosis. However, prior studies have usually focused on a limited illness period and used a wide variety of cognitive instruments. Therefore, it has been difficult to characterize or highlight cognitive functioning in different stages of psychosis. Method We administered the RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) tests to 4 participant subgroups, including healthy volunteers (controls, HC, n = 28), subjects at high risk for clinical psychosis (prodrome, CHR, n = 27), first-episode schizophrenia patients (FE-Sz, n = 26), and mid-term and long-term chronic schizophrenia patients (Ch-Sz, n =147). Comparison, correlation, and regression analyses of RBANS index scores were assessed among groups. We examined clinical outcomes over 2 years between the CHR and HC subjects, and RBANS domains were used as possible predictors for conversion to psychosis. Results Performance on all RBANS domains was significantly impaired during a post-onset stage of psychosis (FE-Sz and Ch-Sz), and RBANS scores declined along with disease progression. Regression analyses showed that for CHR and HC subjects, baseline impairment in delayed memory (DM) significantly predicted conversion to psychosis. Additionally, partial correlations showed that for FE-Sz and Ch-Sz subjects, DM was the only correlate with a later stage of psychosis. Conclusions Cognitive deficits broadly emerged, and diminished functioning followed along with disease progression. Impairment in DM is perhaps one domain that helps us understand the development of psychosis. A critical need is to monitor and treat memory functioning for psychotic patients throughout all phases of the disease.

Correlation of social cognition and neurocognition on psychotic outcome: a naturalistic follow-up study of subjects with attenuated psychosis syndrome

Neurocognitive decline has been observed in patients with psychosis as well as attenuated psychosis syndrome (APS). We tested the hypothesis that APS increases dependence on neurocognition during the interpretation of others’ mental states and that a combination index of Theory of Mind (ToM) and neurocognition improves the predictive accuracy of psychosis conversion. A sample of 83 APS individuals and 90 healthy controls (HC) were assessed by comprehensive cognitive tests. The cohort also completed a one-year follow-up. In the APS group, ToM was associated with an apparent increase in neurocognition, but this trend was not evident in the HC group. Using the new index of combined neurocognition and ToM scores, the sensitivity for predicting psychosis-proneness was 75% and the specificity was 69%. Our data suggest that the correlations between ToM function and neurocognition in APS subjects were stronger than those in healthy controls. A composite index of neurocognition and ToM could improve the predictive validity of a future conversion to psychosis.

Reduced γ-Aminobutyric Acid and Glutamate+Glutamine Levels in Drug-Naïve Patients with First-Episode Schizophrenia but Not in Those at Ultrahigh Risk.

Altered γ-aminobutyric acid (GABA), glutamate (Glu) levels, and an imbalance between GABAergic and glutamatergic neurotransmissions have been involved in the pathophysiology of schizophrenia. However, it remains unclear how these abnormalities impact the onset and course of psychosis. In the present study, 21 drug-naïve subjects at ultrahigh risk for psychosis (UHR), 16 drug-naïve patients with first-episode schizophrenia (FES), and 23 healthy controls (HC) were enrolled. In vivo GABA and glutamate+glutamine (Glx) levels in the medial prefrontal cortex were measured using proton magnetic resonance spectroscopy. Medial prefrontal GABA and Glx levels in FES patients were significantly lower than those in HC and UHR, respectively. GABA and Glx levels in UHR were comparable with those in HC. In each group, there was a positive correlation between GABA and Glx levels. Reduced medial prefrontal GABA and Glx levels thus may play an important role in the early stages of schizophrenia.

Theory of Mind impairments in youth at Clinical High-Risk of Psychosis

Objective: The normal maturational processes of theory of mind (ToM) capacity are ongoing during adolescence and even early adulthood. However, research has shown that ToM ability also declines among adults suffering from prodromal psychotic experiences. The goal of this study was to investigate the characteristics of ToM performance in youth with clinical high risk (CHR) of psychosis. Methods: The Reading Mind in Eyes Task (RMET), including own-race and other-race eyes, was administered to 40 CHR youth; 42 age-, gender-, and education-matched healthy controls (HCs); and 62 adult patients with schizophrenia (SZ). Nine-month follow-up data were collected from 31 CHR subjects, of whom 7 (22.6%) had made the transition to psychosis. Results: CHR youth showed significant impairment in RMET performance compared to HC youth but performed better than did SZ patients. Moreover, they were significantly slower than were HC youth in responding to the RMET, with a response time similar to that of SZ patients. In particular, they had significantly poorer accuracy in interpreting positive and neutral eye expressions compared to the HC group, but not in interpreting negative eye expressions. Preliminary follow-up data showed a trend toward significance (p = 0.079) for RMET performance between those who transitioned to psychosis and those who did not. Conclusions: Our findings illustrate that deficits in ToM capacity, specifically the ability to interpret people’s mental state from eye expressions, occur early on in prodromal psychosis in youth. Early interventions for CHR youth focusing on ToM enhancement may halt progress toward psychosis.

Progressive decline of cognition during the conversion from prodrome to psychosis with a characteristic pattern of the theory of mind compensated by neurocognition

The association between neurocognition and the theory of mind (ToM) abilities during the progression of psychosis is unclear. This study included 83 individuals with attenuated psychosis syndrome (APS), from which 26 converted to psychosis (converters) after a follow up period of 18months. Comprehensive cognitive tests (including MATRICS Consensus Cognitive Battery, Faux-Pas Task, and Reading-Mind-in-Eyes Tasks) were administered at baseline. A structural equation modeling (SEM) analysis was conducted to estimate the effects of neurocognition on the ToM functioning in both APS and healthy controls (HC) datasets. At baseline, the converters and non-converters groups differed significantly on several domains of cognitive performance. The SEM analysis demonstrated that the path from neurocognition to ToM was statistically significant in the APS dataset (p<0.001). However, in the HC dataset, the result of the same analysis was not significant (p=0.117). Positive correlations between neurocognition and ToM were observed, and the most obvious correlations were found in the converters group compared with the non-converters group (p=0.064) and compared with the HC group (p=0.002). The correlation between ToM abilities and neurocognition may be increased during the progression of the condition, especially for individuals who convert to psychosis after a short period.

Increased resting-state global functional connectivity density of default mode network in schizophrenia subjects treated with electroconvulsive therapy

Modified electroconvulsive therapy (MECT) has been widely applied to help treat schizophrenia patients who are treatment-resistant to pharmaceutical therapy. Although the technique is increasingly prevalent, the underlying neural mechanisms have not been well clarified. We conducted a longitudinal study to investigate the alteration of global functional connectivity density (gFCD) in schizophrenia patients undergoing MECT using resting state fMRI (functional magnetic resonance imaging). Two groups of schizophrenia inpatients were recruited. One group received a four-week MECT together with antipsychotic drugs (ECT+Drug, n=21); the other group only received antipsychotic drugs (Drug, n=21). Both groups were compared to a sample of healthy controls (HC, n=23). fMRI scans were obtained from the schizophrenia patients twice at baseline (t1) and after 4-week treatment (t2), and from healthy controls at baseline. gFCD was computed using resting state fMRI. Repeated ANCOVA showed a significant interaction effect of group×time in the schizophrenia patients in left precuneus (Pcu), ventral medial prefrontal cortex (vMPFC), and dorsal medial prefrontal cortex (dMPFC) (GRF-corrected P<0.05), which are mainly located within the default mode network (DMN). Post-hoc analysis revealed that compared with baseline (t1), an increased gFCD was found in the ECT+Drug group in the dMPFC (t=3.87, p=0.00095), vMPFC (t=3.95, p=0.00079) and left Pcu (t=3.33, p=0.0034), but no significant effect was identified in the Drug group. The results suggested that increased global functional connectivity density within the DMN might be one important neural mechanism of MECT in schizophrenia.

Isolated hallucination is less predictive than thought disorder in psychosis: Insight from a longitudinal study in a clinical population at high risk for psychosis

Perceptual abnormalities (PAs) such as auditory hallucinations are one of the most common symptoms of psychotic patients. However, it remains unclear whether symptoms of sub-clinical PAs also play a key role in predicting psychosis. In an ongoing prospective follow-up study of individuals at a clinical high risk (CHR) of psychosis, we evaluated the potential of first-time experience of PAs and/or thought content disorders (TCDs) to predict psychosis. Conversion to psychosis was the major focus of this follow-up study. A total of 511 CHRs were recruited, of whom 443 (86.7%) completed the clinical follow-up of at least 6 months and up to 2 years. CHRs were divided into four groups according to the presence of PAs and/or TCDs. At the follow-up endpoint, 39 (19.9%) CHRs in the “TCDs-only” group, 2 (8.3%) in the “PAs-only” group, 45 (17.0%) in the “TCDs-and-PAs” group, and 1 (3.8%) in the “None” group converted to psychosis. Survival analysis revealed a higher conversion rate in CHRs with TCDs compared with those with PAs only. CHRs with isolated PAs had shown a higher level of dysphoric mood at baseline compared with those with TCDs. About 89% TCDs contents were related with their experienced PAs. Compared with TCDs, the isolated PAs are not strongly associated with increased susceptibility to psychosis.

Identification and prediction of clinical high risk of psychosis in Chinese outpatients using two-stage screening

Two-stage screening, involving a self-rating report, followed by a structured interview, has been proposed for identifying clinical high risk of psychosis (CHR) for nearly two decades. This study used PRIME Screen-Revised (PS-R) and Structured Interview for Prodromal Syndromes (SIPS) to investigate the predictive validity of the two-stage screening. Of 566 participants who completed two-stage screening in this study, 192 were PS-R(-) and 374 were PS-R(+). After being interviewed with SIPS, 112 were rated as CHR(+), 109 were diagnosed with psychosis, and the other 345 individuals were CHR(-). Those who were rated through SIPS as CHR(+) and CHR(-) were followed up within 2 years to observe their clinical outcome. Ninety one (81.3%) CHR(+) and 171 (49.6%) CHR(-) individuals completed the investigation at baseline and the two-year follow-up. The cumulative conversion rate to psychosis was 27.5% in CHR(+) group, but only 1.7% in CHR(-) group, with a significant difference between the two groups (log-rank test, χ2 = 30.07, p < 0.001). In terms of two-stage screening, PS-R(-)/CHR(-), PS-R(-)/CHR(+), and PS-R(+)/CHR(-) groups were viewed as expected negative (EN), and the PS-R(+)/CHR(+) group as expected positive (EP), and the sensitivity and specificity was 64.3% and 79.1%, respectively. Furthermore, Kaplan-Meyer survival analysis showed that EP group were more likely to convert to psychosis than EN group (log-rank test, χ2 = 16.702, p < 0.001). Two-stage screening indeed saves much time and alleviates the workload, but may exclude some target individuals. Optimizing self-report scale, and forming a nurse-doctor-interviewer coalition are likely to improve the use of self-rating report and structured interview.

F14. REDUCED DURATION MISMATCH NEGATIVITY ASSOCIATED WITH DECREASED GLUTAMATE+GLUTAMINE LEVEL IN SUBJECTS AT CLINICAL HIGH-RISK FOR PSYCHOSIS

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.