Linking enlarged choroid plexus with plasma analyte and structural phenotypes in clinical high risk for psychosis: A multisite neuroimaging study.

BACKGROUND: Choroid plexus (ChP) enlargement exists in first-episode and chronic psychosis, but whether enlargement occurs before psychosis onset is unknown. This study investigated whether ChP volume is enlarged in individuals with clinical high-risk (CHR) for psychosis and whether these changes are related to clinical, neuroanatomical, and plasma analytes. METHODS: Clinical and neuroimaging data from the North American Prodrome Longitudinal Study 2 (NAPLS2) was used for analysis. 509 participants (169 controls, 340 CHR) were recruited. Conversion status was determined after 2-years of follow-up, with 36 psychosis converters. The lateral ventricle ChP was manually segmented from baseline scans. A subsample of 31 controls and 53 CHR had plasma analyte and neuroimaging data. RESULTS: Compared to controls, CHR (d = 0.23, p = 0.017) and non-converters (d = 0.22, p = 0.03) demonstrated higher ChP volumes, but not in converters. In CHR, greater ChP volume correlated with lower cortical (r = -0.22, p < 0.001), subcortical gray matter (r = -0.21, p < 0.001), and total white matter volume (r = -0.28,p < 0.001), as well as larger lateral ventricle volume (r = 0.63,p < 0.001). Greater ChP volume correlated with makers functionally associated with the lateral ventricle ChP in CHR [CCL1 (r = -0.30, p = 0.035), ICAM1 (r = 0.33, p = 0.02)], converters [IL1ß (r = 0.66, p = 0.004)], and non-converters [BMP6 (r = -0.96, p < 0.001), CALB1 (r = -0.98, p < 0.001), ICAM1 (r = 0.80, p = 0.003), SELE (r = 0.59, p = 0.026), SHBG (r = 0.99, p < 0.001), TNFRSF10C (r = 0.78, p = 0.001)]. CONCLUSIONS: CHR and non-converters demonstrated significantly larger ChP volumes compared to controls. Enlarged ChP was associated with neuroanatomical alterations and analyte markers functionally associated with the ChP. These findings suggest that the ChP may be a key an important biomarker in CHR.

A pilot study to investigate the efficacy and tolerability of lesion network guided transcranial electrical stimulation in outpatients with psychosis spectrum illness.

BACKGROUND: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. OBJECTIVE: To determine if lesion network guided High Definition-tES (HD-tES) to the eVC is safe and efficacious in reducing symptoms related to psychosis. METHODS: We conducted a single-blind crossover pilot study (NCT04870710) in patients with psychosis spectrum disorders. Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 2 Hz HD-tACS (alternating current). Participants received 5 days of daily (2×20 min) stimulation bilaterally to the eVC. Primary outcomes included the Positive and Negative Syndrome Scale (PANSS), biological motion task, and Event Related Potentials (ERP) from a steady state visual evoked potential (SSVEP) paradigm. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale, Global Assessment of Functioning (GAF), velocity discrimination and visual working memory task, and emotional ERP. RESULTS: HD-tDCS improved PANSS general psychopathology in the short-term (d=0.47; pfdr=0.03), with long-term improvements in general psychopathology (d=0.62; pfdr=0.05) and GAF (d=-0.56; pfdr=0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; pfdr=0.005), which correlated with general psychopathology (ß = 0.274, t = 3.59, p = 0.04). No significant differences in safety or tolerability measures were identified. CONCLUSION: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis.

Synergistic effects of high early-life stress exposure and HIV infection on reaction time variability.

Addressing comorbidities contributing to cognitive impairment in people living with HIV (PLWH) remains imperative. Prior studies utilizing reaction time intra-individual variability (RT-IIV), a robust behavioral marker of cognitive dysfunction, demonstrate increased cognitive impairment in adults living with HIV who have high early life stress (ELS) exposure relative to those with low-ELS exposure. Yet, it is unknown whether RT-IIV elevations are due to high-ELS alone or both HIV-status and high-ELS. In the current study, we explore the potential additive effects of HIV and high-ELS exposure on RT-IIV to better characterize the independent and combined effects of these factors on RT-IIV among PLWH. We assessed 59 PLWH and 69 HIV-negative healthy control (HC) participants with either low or high ELS on RT-IIV during a working memory task (1-back). We observed a significant interaction between HIV status and ELS exposure on RT-IIV, PLWH who had experienced high ELS demonstrating RT-IIV elevations relative to all other groups. In addition, RT-IIV was significantly associated with ELS exposure in PLWH, but not in the HC group. We also observed associations between RT-IIV and measures of HIV-disease severity (plasma HIV viral load, nadir CD4) among PLWH. Taken as a whole, these findings provide novel evidence of the combined effects of HIV and high-ELS exposure on RT-IIV, and thus suggest HIV-related and ELS-related neural abnormalities may act in an additive or synergistic manner to affect cognition. Such data warrant further investigation into the neurobiological mechanisms associated with HIV and high-ELS exposure that contribute to increased neurocognitive dysfunction among PLWH.

Efficacy and Tolerability of Lesion Network Guided Transcranial Electrical Stimulation in Outpatients with Psychosis Spectrum Illness: A Nonrandomized Controlled Trial.

Importance: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. Objective: To determine if lesion network guided HD-tES to the eVC is safe and efficacious in reducing symptoms related to psychosis. Design Setting and Participants: Single-center, nonrandomized, single-blind trial using a crossover design conducted in two 4-week phases beginning November 2020, and ending January 2022. Participants were adults 18-55 years of age with a diagnosis of schizophrenia, schizoaffective or psychotic bipolar disorder as confirmed by the Structured Clinical Interview for DSM-V, without an antipsychotic medication change for at least 4 weeks. A total of 8 participants consented and 6 participants enrolled. Significance threshold set to <0.1 due to small sample size. Interventions: 6 Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 4 received 2Hz HD-tACS (alternating current). Participants received 5 consecutive days of daily (2 × 20min) stimulation applied bilaterally to the eVC. Main Outcomes and Measures: Primary outcomes included the Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, biological motion task, and Event Related Potential (ERP) measures obtained from a steady state visual evoked potential (SSVEP) task across each 4-week phase. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF), velocity discrimination task, visual working memory task, and emotional ERP across each 4-week phase. Results: HD-tDCS improved general psychopathology in the short-term (d=0.47; p fdr =0.03), with long-term improvements in general psychopathology (d=0.62; p fdr =0.05) and GAF (d=-0.56; p fdr =0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; p fdr =0.005), which correlated with general psychopathology (ß=0.274, t=3.59, p=0.04). No significant differences in safety or tolerability measures were identified. Conclusions and Relevance: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04870710. Key Points: Question: Is lesion network guided neurostimulation an efficacious, safe, and targeted approach for treating psychosis?Findings: In this single-center, nonrandomized, crossover, single-blind trial of 6 outpatients with psychosis, improvement in general psychopathology was seen in the short-term with HD-tDCS (high-definition transcranial direct current stimulation) and long-term with HD-tACS (alternating current) targeting the extrastriate visual cortex (eVC). HD-tDCS reduced early visual evoked responses which linked to general psychopathology improvements. Overall, both stimulations were well tolerated.Meaning: Study findings suggest that lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via neuroplastic changes.

Effects of Early-Life Adversities on Neuropsychiatric and Executive Functions in HIV-Positive Adults.

OBJECTIVE: Adverse childhood experiences (ACEs) contribute to elevations in neuropsychiatric and neurocognitive symptoms in HIV+ adults. Emerging data suggest that exposures to threat-related and deprivation-related ACEs may have differential impacts on function, with threat exposure contributing to neuropsychiatric symptoms, and deprivation contributing to executive dysfunction. Yet, it remains unclear how specific types of ACEs impact neuropsychiatric and neurocognitive symptoms in HIV+ adults. Hence, the current study examined whether these two dimensions of adversity contribute differentially to neuropsychiatric symptoms and executive dysfunction in HIV+ adults. METHODS: We included a sample of demographically matched HIV+ (N = 72) and HIV-negative (N = 85) adults. Standardized self-report measures assessed threat-related (interpersonal violence) and deprivation-related (poverty/neglect) ACEs, as well as neuropsychiatric symptoms (depression, anxiety, apathy). A brief battery of neuropsychological tests assessed executive functions. RESULTS: Compared to HIV-negative participants, HIV+ participants reported significantly higher rates of threat exposure (51% vs. 67%, p = .04), while rates of deprivation did not differ significantly (8% vs. 13%, p = .38). In the HIV+ sample, threat exposure was associated with neuropsychiatric symptoms (p < .01) but not executive dysfunction (p = .75). By contrast, deprivation was associated with executive dysfunction, at a trend level (p = .09), but not with neuropsychiatric symptoms (p = .70). CONCLUSIONS: Our data suggest that, relative to HIV-negative samples, HIV+ samples experience higher rates of threat-related ACEs, which contribute to neuropsychiatric symptom elevations. Moreover, our preliminary findings suggest that different types of ACEs could be associated with different profiles of neuropsychiatric and neurocognitive difficulty in HIV+ adults, highlighting the importance of considering dimensions of adversity in future studies.

Investigating sleep spindle density and schizophrenia: A meta-analysis.

Sleep abnormalities are an early feature of schizophrenia (SZ) characterized by reductions in sleep spindles that are associated with deficits in brain connectivity and cognitive function. This study investigated sleep spindle density (SSD) differences between SZ, first episode psychosis (FEP), and family high-risk (FHR) populations and matched healthy controls (HC) by investigating recent studies via a meta-analysis. We collected experimental, demographic, and methodological metrics from eligible studies across multiple online databases. 14 total studies survived the inclusion and exclusion criteria for a total of 337 patients and relatives and 339 HC. R-Studio was used to run the meta-analysis via the meta and metaphor packages. A heterogeneity score of I2 = 80% was calculated and thus a random effects model was chosen. We report a large effect size for SSD in patients compared to controls. Furthermore, illness duration was significantly associated with SSD. Our next step to understanding sleep spindles would be to investigate SSD's use as a predictor for SZ or attempt to normalize SSD deficits as a therapeutic option.

Theory of Mind impairments in early course schizophrenia: An fMRI study.

Theory of Mind (ToM) refers to the ability to perceive others' mental states. Lower ToM has often been associated with poorer functional outcomes in schizophrenia, making it an important treatment target. However, little is known about the underlying neural mechanisms associated with ToM impairments in early course schizophrenia. This study aimed to validate the False Belief task to measure ToM in schizophrenia and to identify aberrant brain activity associated with impairments. 36 individuals with early course schizophrenia and 17 controls were administered the Hinting Task and performed a functional magnetic resonance imaging (fMRI) False Belief task. Between-group differences were examined in a priori regions of interest (ROIs) known to be associated with ToM tasks: medial prefrontal cortex, ventral medial prefrontal cortex, and both the left and right temporal parietal junction (TPJ). We observed a significant positive association between Hinting Task performance and False Belief accuracy, validating the False Belief task as a measure of ToM. Compared to controls, individuals with schizophrenia exhibited reduced brain activation in all four ROIs during the fMRI False Belief task. Furthermore, task-related activations in bilateral TPJs were shown to be positively associated with ToM abilities regardless of diagnosis. Individuals with schizophrenia with lower performance on the False Belief task showed significant reductions in task-related activation in the bilateral TPJ compared to controls, while reductions were not significant for those with higher performance. Our findings suggest that lower neural activity in the bilateral TPJ are associated with ToM impairments observed in individuals with early course schizophrenia.

Association of white matter microstructure and extracellular free-water with cognitive performance in the early course of schizophrenia.

Schizophrenia (SZ) is proposed as a disorder of dysconnectivity underlying cognitive impairments and clinical manifestations. Although previous studies have shown extracellular changes in white matter of first-episode SZ, little is known about the transition period towards chronicity and its association with cognition. Free-water (FW) imaging was applied to 79 early course SZ participants and 29 controls to detect white matter axonal and extracellular differences during this phase of illness. Diffusion-weighted images were collected from two sites, harmonized, and processed using a pipeline separately modeling water diffusion in tissue (FAt) and extracellular space (FW). Tract-Based Spatial Statistics was performed using the ENIGMA-DTI protocols. SZ showed FAt reductions in the posterior thalamic radiation (PTR) and FW elevations in the cingulum compared to controls, suggesting FAt and FW changes in the early course of SZ. In SZ, greater FAt of the fornix & stria terminalis (FXST) was positively associated with Theory of Mind performance; average whole-brain FAt, FAt of the FXST and the PTR were positively associated with greater working memory performance; average whole-brain FAt was positively associated with visual learning. Further studies are necessary to better understand the neurobiological mechanisms of SZ for developing intervention strategies to preserve brain structure and function.

Do neurobiological differences exist between paranoid and non-paranoid schizophrenia? Findings from the bipolar schizophrenia network on intermediate phenotypes study.

Subtypes of schizophrenia, constructed using clinical phenomenology to resolve illness heterogeneity, have faced criticism due to overlapping symptomatology and longitudinal instability; they were therefore dropped from the Diagnostic Statistical Manual-5. Cognitive and imaging findings comparing paranoid (P-SZ) and non-paranoid (disorganized, residual and undifferentiated; NP-SZ) schizophrenia have been limited due to small sample sizes. We assessed P-SZ and NP-SZ using symptomatology, cognition and brain structure and predicted that there would be few neurobiological differences. P-SZ (n = 237), NP-SZ (n = 127) and controls (n = 430) were included from a multi-site study. In a subset of this sample, structural imaging measures (P-SZ, n = 133; NP-SZ, n = 67; controls, n = 310) were calculated using Freesurfer 6.0. Group contrasts were run using analysis of covariance, controlling for age, sex, race and site, p-values were corrected using False Discovery Rate (FDR) and were repeated excluding the residual subtype. Compared to NP-SZ (with and without the residual subtype), P-SZ displayed fewer negative symptoms, faster speed of processing, larger bilateral hippocampus, right amygdala and their subfield volumes. Additionally, NP-SZ (with residual subtype) displayed fewer depressive symptoms and higher left transverse temporal cortical thickness (CT) but NP-SZ without residual subtype showed lower GAF scores and worse digit sequencing compared to P-SZ. No differences in positive symptoms and functioning (global or social) were detected. Subtle but significant differences were seen in cognition, symptoms, CT and subcortical volumes between P-SZ and NP-SZ. While the magnitude of these differences is not large enough to justify them as distinct categories, the paranoid- nonparanoid distinction in schizophrenia merits further investigation.

White matter abnormalities across the lifespan of schizophrenia: a harmonized multi-site diffusion MRI study.

Several prominent theories of schizophrenia suggest that structural white matter pathologies may follow a developmental, maturational, and/or degenerative process. However, a lack of lifespan studies has precluded verification of these theories. Here, we analyze the largest sample of carefully harmonized diffusion MRI data to comprehensively characterize age-related white matter trajectories, as measured by fractional anisotropy (FA), across the course of schizophrenia. Our analysis comprises diffusion scans of 600 schizophrenia patients and 492 healthy controls at different illness stages and ages (14-65 years), which were gathered from 13 sites. We determined the pattern of age-related FA changes by cross-sectionally assessing the timing of the structural neuropathology associated with schizophrenia. Quadratic curves were used to model between-group FA differences across whole-brain white matter and fiber tracts at each age; fiber tracts were then clustered according to both the effect-sizes and pattern of lifespan white matter FA differences. In whole-brain white matter, FA was significantly lower across the lifespan (up to 7%; p < 0.0033) and reached peak maturation younger in patients (27 years) compared to controls (33 years). Additionally, three distinct patterns of neuropathology emerged when investigating white matter fiber tracts in patients: (1) developmental abnormalities in limbic fibers, (2) accelerated aging and abnormal maturation in long-range association fibers, (3) severe developmental abnormalities and accelerated aging in callosal fibers. Our findings strongly suggest that white matter in schizophrenia is affected across entire stages of the disease. Perhaps most strikingly, we show that white matter changes in schizophrenia involve dynamic interactions between neuropathological processes in a tract-specific manner.

NRXN1 is associated with enlargement of the temporal horns of the lateral ventricles in psychosis.

Schizophrenia, Schizoaffective, and Bipolar disorders share behavioral and phenomenological traits, intermediate phenotypes, and some associated genetic loci with pleiotropic effects. Volumetric abnormalities in brain structures are among the intermediate phenotypes consistently reported associated with these disorders. In order to examine the genetic underpinnings of these structural brain modifications, we performed genome-wide association analyses (GWAS) on 60 quantitative structural brain MRI phenotypes in a sample of 777 subjects (483 cases and 294 controls pooled together). Genotyping was performed with the Illumina PsychChip microarray, followed by imputation to the 1000 genomes multiethnic reference panel. Enlargement of the Temporal Horns of Lateral Ventricles (THLV) is associated with an intronic SNP of the gene NRXN1 (rs12467877, P = 6.76E-10), which accounts for 4.5% of the variance in size. Enlarged THLV is associated with psychosis in this sample, and with reduction of the hippocampus and enlargement of the choroid plexus and caudate. Eight other suggestively significant associations (P < 5.5E-8) were identified with THLV and 5 other brain structures. Although rare deletions of NRXN1 have been previously associated with psychosis, this is the first report of a common SNP variant of NRXN1 associated with enlargement of the THLV in psychosis.

Experiences of Discrimination Are Associated With Greater Resting Amygdala Activity and Functional Connectivity.

BACKGROUND: Social discrimination, a type of psychological stressor, is associated with poorer physical and mental health outcomes, yet we have little understanding of how discrimination affects neural functions in marginalized populations. By contrast, the effects of psychological stress on neural functions are well documented, with evidence of significant effects on the amygdala-a neural region that is central to psychosocial functions. Accordingly, we conducted an examination of the relation between self-reported discrimination exposure and amygdala activity in a diverse sample of adults. METHODS: Seventy-four adults (43% women; 72% African American; 23% Hispanic; 32% homosexual/bisexual) completed self-report ratings of discrimination exposure. Spontaneous amygdala activity and functional connectivity were assessed during resting-state functional magnetic resonance imaging. RESULTS: Greater discrimination exposure was associated with higher levels of spontaneous amygdala activity. Increases in discrimination were also associated with stronger functional connectivity between the amygdala and several neural regions (e.g., anterior insula, putamen, caudate, anterior cingulate, medial frontal gyrus), with the most robust effects observed in the thalamus. These effects were independent of several demographic (e.g., race, ethnicity, sex) and psychological (e.g., current stress, depression, anxiety) factors. CONCLUSIONS: Collectively, our findings provide the first evidence that social discrimination is independently associated with elevations in intrinsic amygdala activity and functional connectivity, thus revealing clear parallels between the neural substrates of discrimination and psychological stressors of other origins. Such results should spur future investigations of amygdala-based networks as potential etiological factors linking discrimination exposure to adverse physical and mental health outcomes.

Early Life Stress-Related Elevations in Reaction Time Variability Are Associated with Brain Volume Reductions in HIV+ Adults.

There is burgeoning evidence that, among HIV+ adults, exposure to high levels of early life stress (ELS) is associated with increased cognitive impairment as well as brain volume abnormalities and elevated neuropsychiatric symptoms. Currently, we have a limited understanding of the degree to which cognitive difficulties observed in HIV+ High-ELS samples reflect underlying neural abnormalities rather than increases in neuropsychiatric symptoms. Here, we utilized a behavioral marker of cognitive function, reaction time intra-individual variability (RT-IIV), which is sensitive to both brain volume reductions and neuropsychiatric symptoms, to elucidate the unique contributions of brain volume abnormalities and neuropsychiatric symptoms to cognitive difficulties in HIV+ High-ELS adults. We assessed the relation of RT-IIV to neuropsychiatric symptom levels and total gray and white matter volumes in 44 HIV+ adults (26 with high ELS). RT-IIV was examined during a working memory task. Self-report measures assessed current neuropsychiatric symptoms (depression, stress, post-traumatic stress disorder). Magnetic resonance imaging was used to quantify total gray and white matter volumes. Compared to Low-ELS participants, High-ELS participants exhibited elevated RT-IIV, elevated neuropsychiatric symptoms, and reduced gray and white matter volumes. Across the entire sample, RT-IIV was significantly associated with gray and white matter volumes, whereas significant associations with neuropsychiatric symptoms were not observed. In the High-ELS group, despite the presence of elevated neuropsychiatric symptom levels, brain volume reductions explained more than 13% of the variance in RT-IIV, whereas neuropsychiatric symptoms explained less than 1%. Collectively, these data provide evidence that, in HIV+ High-ELS adults, ELS-related cognitive difficulties (as indexed by RT-IIV) exhibit strong associations with global brain volumes, whereas ELS-related elevations in neuropsychiatric symptoms appear to contribute minimally to these cognitive difficulties. Such findings support a growing body of evidence indicating that high ELS exposure is a significant risk factor for neurocognitive dysfunction in HIV+ adults. Further, these data highlight the need to better understand how ELS-related pathophysiological mechanisms contribute to volumetric and other neural abnormalities in HIV+ individuals.