Person:

Stone, William

Background: Recent studies suggest that anhedonia, an inability to experience pleasure, can be measured as an enduring trait in non-clinical samples. In order to examine trait anhedonia in a non-clinical sample, we examined the properties of a range of widely used questionnaires capturing anhedonia. Methods: 887 young adults were recruited from colleges. All of them were administered a set of checklists, including Chapman Scale for Social Anhedonia (CRSAS) and the Chapman Scale for Physical Anhedonia Scale (CPAS), The Temporal Experience of Pleasure Scale (TEPS), and The Schizotypal Personality Questionnaire (SPQ). Results: Males showed significantly higher level of physical (F = 5.09, p<0.001) and social (F = 4.38, p<0.005) anhedonia than females. As expected, individuals with schizotypal personality features also demonstrated significantly higher scores of physical (t = 3.81, p<0.001) and social (t = 7.33, p<0.001) trait anhedonia than individuals without SPD features, but no difference on self-report anticipatory and consummatory pleasure experience. Conclusions: Concerning the comparison on each item of physical and social anhedonia, the results indicated that individuals with SPD feature exhibited higher than individuals without SPD features on more items of social anhedonia than physical anhedonia scale. These preliminary findings suggested that trait anhedonia can be identified a non-clinical sample. Exploring the demographic and clinical correlates of trait anhedonia in the general population may provide clues to the pathogenesis of psychotic disorder.

Difficulties in feeling pleasure and expressing emotions are one of the key features of schizophrenia spectrum conditions, and are significant contributors to constricted interpersonal interactions. The current study examined the experience of pleasure and emotional expression in college students who demonstrated high and low levels of schizotypal personality disorder (SPD) traits on self-report questionnaires. One hundred and seventeen subjects with SPD traits and 116 comparison controls were recruited to participate. Cluster analyses conducted in the SPD group identified negative SPD and positive SPD subgroups. The negative SPD group exhibited deficient emotional expression and anticipatory pleasure, but showed intact consummatory pleasure. The positive SPD group reported significantly greater levels of anticipatory, consummatory and total pleasure compared to the control group. Both SPD groups reported significantly more problems in everyday memory and greater levels of depressive and anxiety-related symptoms.

The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n = 293) or were unaffected first-degree siblings of those probands (n = 382). Paternal age at the time of subjects’ birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 endophenotypes. After controlling for covariates, potential paternal age–endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia.

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.

Abstract Background: In spite of evidence for the premorbid and prodromal onset of cognitive deficits in schizophrenia and related psychotic disorders, there is some limited evidence to suggest that deficits may progress with psychosis onset. Cognitive remediation in youth at risk for psychosis is being touted as an opportunity not only to remediate deficits but to potentially prevent this progression. Yet trajectories of cognitive functioning over time remain poorly understood in youth at risk, including the degree to which age at assessment or illness onset, sociodemographic factors, or symptom progression influence these trajectories. Methods: The North American Prodrome Longitudinal Study (NAPLS) -2 collected data on an extensive battery of neuropsychological (NP) tests at baseline, one year, two years, and post-conversion in a sample of clinical high risk (CHR) youth and healthy comparison (HC) subjects ages 12–35 (N= 960, 92% of the full sample) followed clinically for up to 2 years. NP data were available for 694 at CHR and 265 HC. Linear mixed effects analyses were used to test the effects of group, age, gender, age of onset, maternal education, and clinical outcome on cognitive trajectories. Results: Those who transitioned to a psychotic disorder over the course of follow-up performed significantly below those who did not and well below healthy comparisons. Tasks reliant on attention, visual and auditory working memory, visuospatial and verbal memory, and processing speed best differentiated those who transitioned from those who did not at one year (Cohen’s d from -0.33 to -0.54). Discrepancies from normal functioning on these tests were generally large (Cohen’s d from -0.67 to -1.02) consistent with findings for first episode samples. Although clinical outcome was not associated with a significantly different trajectory over time on any cognitive domain, these are likely due to high rates of conversion in this sample within the first year. Predictors of different trajectories will be presented. Discussion These data from one of the largest CHR studies to date suggest that much of the neuropsychological dysfunction in major psychotic disorders is present early in the course of illness and prior to its full expression. However, trajectories are highly heterogeneous. More frequent assessment prior to and during the onset of illness are needed to fully understand the cognitive correlates of psychosis onset and the implications for early intervention.

Abstract Background: The first episode of schizophrenia is typically preceded by a prodromal phase characterized by sub-threshold symptoms and declining functioning. Elucidating the neurobiological substrate of prodromal symptoms that progress into overt psychotic illness is crucial to the development of early detection and intervention strategies for schizophrenia. In this study, we performed a functional connectome analysis in a large group of adolescents and young adults at Clinical High Risk (CHR) for schizophrenia. We aim to assess whether, and if so how, baseline connectome organization distinguishes CHR youth that go on to develop psychosis. Methods: This study comprises a total of 251 subjects, including 158 psychotropically-naïve CHR subjects (CHRs) and 93 healthy controls (HCs), who were matched to CHRs on age, gender, and level of education. Prodromal symptoms and cognition were assessed using the SIPS structured interview and MATRICS cognitive battery. Anatomical T1 MRI and resting-state fMRI scans were collected at baseline and processed using Freesurfer v6.0 and CONN v17.d software. For each subject, a functional connectome map was reconstructed consisting of 162 nodes representing 148 cortical regions from the Destrieux atlas and 14 subcortical structures. Functional connectomes were analyzed in terms of modular topology using the Louvain community detection method. Modular network partitions of individual CHRs were compared to a group-averaged HC network using the rand similarity coefficient (SR), providing a measure of the level of (ab)normality of the CHRs’ modular partitions. Analysis of covariance (correcting for age- and gender) was used to compare SR levels between CHRs who developed psychosis during follow-up (CHR+; N = 23) as compared to CHRs who did not develop psychosis (CHR-; N = 135). Kaplan-Meier analysis was used to estimate psychosis-free survival functions for CHRs with below- versus above-average SR, which were compared using log-rank tests. Cox regression analysis was used to assess how baseline connectome organization and clinical measures (i.e., demographics, symptoms, IQ) predicted time to conversion. Results: Modular community detection in HCs yielded five major modules including a posterior ‘visual’, central ‘sensorimotor’, medial frontoparietal ‘default-mode’, lateral frontoparietal ‘central-executive’, and inferior ‘limbic’ module. Modular connectome organization of CHR+ was significantly less similar to HCs than CHR- (F(1,154) = 7.14, p = 0.008). A region-specific analysis to identify which regions contributed most to aberrant modular connectome organization in CHR+ showed that superior temporal (including STG), medial temporal (including amygdala), and ventromedial prefrontal regions were most abnormal in terms of their modular assignment. Psychosis-free survival functions of CHRs with low versus high SR were significantly different (z = 2.5, p = 0.013), with a Hazard ratio of 3.3 indicating an over 3-fold relative event rate (i.e., conversion to psychosis) in CHRs with abnormal baseline connectome organization. Cox regression analysis indicated that baseline connectome organization (z = -2.3, p = 0.019), IQ (z = -2.7, p = 0.007), and gender (z = 2.0, p = 0.048) predicted time to conversion. Discussion This study indicates that abnormalities in functional connectome organization precede the first psychotic episode. Conversion to psychosis was found to be over three times more likely in CHRs with abnormal modular organization of the functional connectome at baseline. Our results suggest that functional connectome reorganization may underlie the gradual manifestation of prodromal symptoms. These findings may contribute to early diagnosis and intervention in schizophrenia.

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: In 2010, the “ShangHai At Risk for Psychosis (SHARP)” study was launched at the Shanghai Mental Health Center (SMHC), the largest outpatient mental health clinic in China. The Chinese SHARP research was led by Dr. Larry Seidman, who was also the PI of the Harvard site of the NAPLS project. He had implemented methods very similar to those used in NAPLS for the identification of clinical high risk (CHR) individuals in Mainland China in studies jointly funded by the United States National Institute of Mental Health and Chinese funding agencies. Methods: Dr. Seidman began a collaboration with the SMHC by advising us in carrying out an epidemiological study and then received joint funding for an R21 MH093294 (Fogarty/NIH, “Broadening the Investigation of Psychosis Prodrome to Different Cultural Groups”) designed to implement a variety of clinical, neurocognitive and event related potential (ERP) measures in a preliminary study of CHR. That study, which began in April 2012 and ended in March 2015, aimed to build research capacity at the SMHC. He guide us provided 4 in-person research and clinical skills trainings (2 in SMHC, 2 in Boston), translated a widely used CHR diagnostic instrument (the Structured Interview for Prodromal Symptoms/SIPS), and trained China partners to conduct a preliminary study of 100 CHR individuals. Building upon the R21 project, and the North American Prodrome Longitudinal Studies (NAPLS) model, the same group of researchers led by Dr. Seidman is collaborating on an NIMH R01 101052-01 project (2013 to 2016) to examine biomarkers of CHR with 1 year follow-up. The R21 and R01 collaborations between Harvard Medical School (HMS), MIT, Florida A&M University (FAMU), and SMHC investigators have capitalized on the resources and experiences of the Harvard researchers as members of NAPLS, MIT researchers’ leading role in functional magnetic resonance imaging (fMRI), and FAMU researchers’ expertise in bridging western and Chinese cultures to enhance the existing capacity of Chinese researchers studying the biopsychosocial aspects of CHR. Finally, a stratified cohort of 300 CHR participants was recruited between 2012–2015, and followed up for at least 1 year. Results: With the hope of Dr. Seidman, the SHARP project is ongoing and getting better, larger and stronger. Of the total 417 CHR participants (previous epidemiological survey [CHR, n = 117], R21 [CHR, n = 100], R01 [CHR, n =200]), 349 completed at least a year of follow-up (until August 30, 2017; the longest follow-up case was six and a half years), in which 83 converted to psychosis, and 68 were lost. Preliminary data showed about 20% CHR converted to a psychotic disorder over the course of follow-up, several clinical factors such as 1) functional decline; 2) selected positive symptoms(unusual thoughts and suspiciousness); 3) selected negative symptoms(social anhedonia, expression of emotion, and ideational richness); biological factors such as the P300 auditory ERP; fMRI: Reduced anti-correlation between the bilateral parietal lobule and left dorsolateral prefrontal cortex; Structural MRI: superior temporal gyrus. et al. are account for increasing the risk of conversion to full psychosis. Discussion This is the first, well-implemented, longitudinal study of CHR in a low and middle-income country to comprehensively investigate clinical and biological factors in predicting psychosis conversion and illness progression. Dr. Seidman provide a critical step in the implementation of CHR concept in China, just as an obvious need and urgency for prevention and early intervention for Chinese patients with schizophrenia.

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 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.