• Aberrant anterior cingulate processing of anticipated threat as a mechanism for psychosis

      Kvarta, Mark D; Chiappelli, Joshua; West, Jeffrey; Goldwaser, Eric L; Bruce, Heather A; Ma, Yizhou; Kochunov, Peter; Hatch, Kathryn; Gao, Si; Jones, Aaron; et al. (Elsevier B.V., 2021-05-12)
      Stress and abnormal stress response are associated with schizophrenia spectrum disorder (SSD), but the brain mechanisms linking stress to symptomatology remain unclear. In this study, we used a stress-based functional neuroimaging task, reverse-translated from preclinical studies, to test the hypothesis that abnormal corticolimbic processing of stressful threat anticipation is associated with psychosis and affective symptoms in SSD. Participants underwent an MRI-compatible ankle-shock task (AST) in which the threat of mild electrical shock was anticipated. We compared functional brain activations during anticipatory threat periods from N = 18 participants with SSD (10 M/8F) to those from N = 12 community controls (9 M/3F). After family-wise error correction, only one region, the ventral anterior cingulate cortex (vACC), showed significantly reduced activation compared with controls. vACC activation significantly correlated with clinical symptoms measured by the Brief Psychiatric Rating Scale total score (r = 0.54) and the psychosis subscale (r = 0.71), and inversely correlated with trait depression measured by the Maryland Trait and State Depression scale (r=-0.48). Deficient activation in vACC under stress of anticipated threat may lead to aberrant interpretation of such threat, contributing to psychosis and mood symptoms in SSD. This experimental paradigm has translational potential and may identify circuitry-level mechanisms of stress-related mental illness, leading to more targeted treatment.
    • Assessment of brain cholesterol metabolism biomarker 24S-hydroxycholesterol in schizophrenia

      Chiappelli, Joshua; Quinton, Maria S; Volfson, Dmitri; Cwik, Michael; Marshall, Wyatt; Bruce, Heather; Goldwaser, Eric; Kvarta, Mark; Summerfelt, Ann; Kochunov, Peter; et al. (Springer Nature, 2020-11-20)
      Plasma 24S-hydroxycholesterol mostly originates in brain tissue and likely reflects the turnover of cholesterol in the central nervous system. As cholesterol is disproportionally enriched in many key brain structures, 24S-hydroxycholesterol is a promising biomarker for psychiatric and neurologic disorders that impact brain structure. We hypothesized that, as schizophrenia patients have widely reported gray and white matter deficits, they would have abnormal levels of plasma 24S-hydroxycholesterol, and that plasma levels of 24S-hydroxycholesterol would be associated with brain structural and functional biomarkers for schizophrenia. Plasma levels of 24S-hydroxycholesterol were measured in 226 individuals with schizophrenia and 204 healthy controls. The results showed that levels of 24S-hydroxycholesterol were not significantly different between patients and controls. Age was significantly and negatively correlated with 24S-hydroxycholesterol in both groups, and in both groups, females had significantly higher levels of 24S-hydroxycholesterol compared to males. Levels of 24S-hydroxycholesterol were not related to average fractional anisotropy of white matter or cortical thickness, or to cognitive deficits in schizophrenia. Based on these results from a large sample and using multiple brain biomarkers, we conclude there is little to no value of plasma 24S-hydroxycholesterol as a brain metabolite biomarker for schizophrenia.
    • Effects of neuroactive metabolites of the tryptophan pathway on working memory and cortical thickness in schizophrenia

      Huang, Junchao; Tong, Jinghui; Zhang, Ping; Zhou, Yanfang; Cui, Yimin; Tan, Shuping; Wang, Zhiren; Yang, Fude; Kochunov, Peter; Chiappelli, Joshua; et al. (Springer Nature, 2021-04-01)
      A number of tryptophan metabolites known to be neuroactive have been examined for their potential associations with cognitive deficits in schizophrenia. Among these metabolites, kynurenic acid (KYNA), 5-hydroxyindole (5-HI), and quinolinic acid (QUIN) are documented in their diverse effects on α-7 nicotinic acetylcholine receptor (α7nAChR) and/or N-methyl-D-aspartate receptor (NMDAR), two of the receptor types thought to contribute to cognitive impairment in schizophrenia. In this study, serum levels of KYNA, 5-HI, and QUIN were measured in 195 patients with schizophrenia and in 70 healthy controls using liquid chromatography-tandem mass spectrometry; cognitive performance in MATRICS Consensus Cognitive Battery and cortical thickness measured by magnetic resonance imaging were obtained. Patients with schizophrenia had significantly lower serum KYNA (p < 0.001) and QUIN (p = 0.02) levels, and increased 5-HI/KYNA (p < 0.001) and QUIN/KYNA ratios (p < 0.001) compared with healthy controls. Multiple linear regression showed that working memory was positively correlated with serum 5-HI levels (t = 2.10, p = 0.04), but inversely correlated with KYNA concentrations (t = -2.01, p = 0.05) in patients. Patients with high 5-HI and low KYNA had better working memory than other subgroups (p = 0.01). Higher 5-HI levels were associated with thicker left lateral orbitofrontal cortex (t = 3.71, p = 2.94 × 10-4) in patients. The different effects of 5-HI and KYNA on working memory may appear consistent with their opposite receptor level mechanisms. Our findings appear to provide a new insight into the dynamic roles of tryptophan pathway metabolites on cognition, which may benefit novel therapeutic development that targets cognitive impairment in schizophrenia.
    • The microRNA-195 - BDNF pathway and cognitive deficits in schizophrenia patients with minimal antipsychotic medication exposure.

      Pan, Shujuan; Feng, Wei; Li, Yanli; Huang, Junchao; Chen, Song; Cui, Yimin; Tian, Baopeng; Tan, Shuping; Wang, Zhiren; Yao, Shangwu; et al. (Springer Nature, 2021-02-08)
      Cognitive impairment is a core characteristic of schizophrenia, but its underlying neural mechanisms remain poorly understood. Reduced brain-derived neurotrophic factor (BDNF), a protein critical for neural plasticity and synaptic signaling, is one of the few molecules consistently associated with cognitive deficits in schizophrenia although the etiological pathway leading to BDNF reduction in schizophrenia is unclear. We examined microRNA-195 (miR-195), a known modulator of BDNF protein expression, as a potential mechanistic component. One-hundred and eighteen first-episode patients with schizophrenia either antipsychotic medication-naïve or within two weeks of antipsychotic medication exposure and forty-seven age- and sex-matched healthy controls were enrolled. MiR-195 and BDNF mRNA and BDNF protein levels in peripheral blood were tested. Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). MiR-195 was significantly higher (p = 0.01) whereas BDNF mRNA (p < 0.001) and protein (p = 0.016) levels were significantly lower in patients compared with controls. Higher miR-195 expression was significantly correlated to lower BDNF protein levels in patients (partial r = −0.28, p = 0.003) and lower BDNF protein levels were significantly associated with poorer overall cognitive performance by MCCB and also in speed of processing, working memory, and attention/vigilance domains composite score (p = 0.002–0.004). The subgroup of patients with high miR-195 and low BDNF protein showed the lowest level of cognitive functions, and miR-195 showed significant mediation effects on cognitive functions through BDNF protein. Elevated miR-195 may play a role in regulating BDNF protein expression thereby influencing cognitive impairments in schizophrenia, suggesting that development of cognition enhancing treatment for schizophrenia may consider a micro-RNA based strategy. © 2021, The Author(s).
    • Multiple dimensions of stress vs. genetic effects on depression

      Kvarta, Mark D; Bruce, Heather A; Chiappelli, Joshua; Hare, Stephanie M; Goldwaser, Eric L; Sewell, Jessica; Sampath, Hemalatha; Lightner, Samantha; Marshall, Wyatt; Hatch, Kathryn; et al. (Springer Nature, 2021-04-29)
      Many psychiatric disorders including depression involve complex interactions of genetics and environmental stressors. Environmental influence is challenging to measure objectively and account for in genetic studies because the necessary large population samples in these studies involve individuals with varying cultures and life experiences, clouding genetic findings. In a unique population with relative sociocultural homogeneity and a narrower range of types of stress experiences, we quantitatively assessed multiple stress dimensions and measured their potential influence in biasing the heritability estimate of depression. We quantified depressive symptoms, major lifetime stressors, current perceived stress, and a culturally specific community stress measure in individuals with depression-related diagnoses and community controls in Old Order Amish and Mennonite populations. Results showed that lifetime stressors measured by lifetime stressor inventory (R2 = 0.06, p = 2 × 10-5) and current stress measured by Perceived Stress Scale (R2 = 0.13, p < 1 × 10-6) were both associated with current depressive symptoms quantified by Beck Depression Inventory in community controls, but current stress was the only measure associated with current depressive symptoms in individuals with a depression diagnosis, and to a greater degree (R2 = 0.41, p < 1 × 10-6). A novel, culturally specific community stress measure demonstrated internal reliability and was associated with current stress but was not significantly related to depression. Heritability (h2) for depression diagnosis (0.46 ± 0.14) and quantitative depression severity as measured by Beck Depression Inventory (0.45 ± 0.12) were significant, but h2 for depression diagnosis decreased to 0.25 ± 0.14 once stressors were accounted for in the model. This quantifies and demonstrates the importance of accounting for environmental influence in reducing phenotypic heterogeneity of depression and improving the power and replicability of genetic association findings that can be better translated to patient groups.
    • Stressful life events and openness to experience: Relevance to depression

      Chiappelli, Joshua; Kvarta, Mark; Bruce, Heather; Chen, Shuo; Kochunov, Peter; Hong, L Elliot (Elsevier B.V., 2021-09-04)
      Background: Stressful life events are known as risk factors for depression, though there is considerable heterogeneity in how people respond to stress. Previous studies have found an association between experience of stressful life events and the personality trait of openness to experience, which itself has been associated with intelligence, creativity, risk-taking, and other clinically relevant behaviors. In this study we explore the association between stressful life events and openness to experience as a potential developmental pathway to depression in the Amish and Mennonites, rural populations with high degree of social and environmental homogeneity. Methods: Participants in the Amish Connectome Project (n=531) were assessed with the NEO personality inventory, Beck Depression Inventory, Maryland Trait and State Depression scales, a Life Stressors Inventory, and cognitive tests. Results: We found that stressful life events were significantly associated with openness to experience; that participants with a history of depression exhibited higher levels of openness; and that openness to experience was related to overall intelligence but not processing speed or working memory. We found evidence that openness to experience partially mediates the relationship between stressful life events and depression. Limitations: This was a cross-sectional study, limiting interpretation of causal pathways. High levels of inter-relatedness among participants may have led to exaggerated effects compared to the general population. Conclusions: Together these findings indicate a complex developmental influence of major stressful life events, which paradoxically by enhancing openness may be associated with both greater intellectual engagement as well as psychopathology. © 2021
    • A White Matter Connection of Schizophrenia and Alzheimer's Disease

      Kochunov, Peter; Zavaliangos-Petropulu, Artemis; Jahanshad, Neda; Thompson, Paul M; Ryan, Meghann C; Chiappelli, Joshua; Chen, Shuo; Du, Xiaoming; Hatch, Kathryn; Adhikari, Bhim; et al. (Oxford University Press, 2020-07-18)
      Schizophrenia (SZ) is a severe psychiatric illness associated with an elevated risk for developing Alzheimer's disease (AD). Both SZ and AD have white matter abnormalities and cognitive deficits as core disease features. We hypothesized that aging in SZ patients may be associated with the development of cerebral white matter deficit patterns similar to those observed in AD. We identified and replicated aging-related increases in the similarity between white matter deficit patterns in patients with SZ and AD. The white matter "regional vulnerability index" (RVI) for AD was significantly higher in SZ patients compared with healthy controls in both the independent discovery (Cohen's d = 0.44, P = 1·10-5, N = 173 patients/230 control) and replication (Cohen's d = 0.78, P = 9·10-7, N = 122 patients/64 controls) samples. The degree of overlap with the AD deficit pattern was significantly correlated with age in patients (r = .21 and .29, P < .01 in discovery and replication cohorts, respectively) but not in controls. Elevated RVI-AD was significantly associated with cognitive measures in both SZ and AD. Disease and cognitive specificities were also tested in patients with mild cognitive impairment and showed intermediate overlap. SZ and AD have diverse etiologies and clinical courses; our findings suggest that white matter deficits may represent a key intersecting point for these 2 otherwise distinct diseases. Identifying mechanisms underlying this white matter deficit pattern may yield preventative and treatment targets for cognitive deficits in both SZ and AD patients.
    • White matter in prolonged glucocorticoid response to psychological stress in schizophrenia.

      Goldwaser, Eric L; Chiappelli, Joshua; Kvarta, Mark D; Du, Xiaoming; Millman, Zachary B; Adhikari, Bhim M; O'Neill, Hugh; Sewell, Jessica; Lightner, Samantha; Vodapalli, Shreya; et al. (Springer Nature, 2021-07-01)
      Stress is implicated in psychosis etiology and exacerbation, but pathogenesis toward brain network alterations in schizophrenia remain unclear. White matter connects limbic and prefrontal regions responsible for stress response regulation, and white matter tissues are also vulnerable to glucocorticoid aberrancies. Using a novel psychological stressor task, we studied cortisol stress responses over time and white matter microstructural deficits in schizophrenia spectrum disorder (SSD). Cortisol was measured at baseline, 0-, 20-, and 40-min after distress induction by a psychological stressor task in 121 SSD patients and 117 healthy controls (HC). White matter microstructural integrity was measured by 64-direction diffusion tensor imaging. Fractional anisotropy (FA) in white matter tracts were related to cortisol responses and then compared to general patterns of white matter tract deficits in SSD identified by mega-analysis. Differences between 40-min post-stress and baseline, but not acute reactivity post-stress, was significantly elevated in SSD vs HC, time × diagnosis interaction F2.3,499.9 = 4.1, p = 0.013. All SSD white matter tracts were negatively associated with prolonged cortisol reactivity but all tracts were positively associated with prolonged cortisol reactivity in HC. Individual tracts most strongly associated with prolonged cortisol reactivity were also most impacted in schizophrenia in general as established by the largest schizophrenia white matter study (r = -0.56, p = 0.006). Challenged with psychological stress, SSD and HC mount similar cortisol responses, and impairments arise in the resolution timeframe. Prolonged cortisol elevations are associated with the white matter deficits in SSD, in a pattern previously associated with schizophrenia in general.