Neuroscience in pictures: 2. Sleep, wakefulness, and mental state biology.

Sleep is a vital restorative process that has occupied our curiosity for millennia. Despite our longstanding research efforts, the biology of sleep and its connection to mental states remains enigmatic. Unsurprisingly, sleep and wakefulness, the fundamental processes between which our mental states oscillate, are inseparable from our physical and mental health. Thus, clinical consideration of sleep impairments warrants a transdiagnostic approach whilst appropriately acknowledging that certain individual disorders (e.g. depression, schizophrenia) may have somewhat distinct sleep disturbances. Moreover, our knowledge of the anatomy and physiology of sleep regulation-albeit limited-forms the foundation for current treatments for sleep difficulties. This pictorial article overviews the core concepts and future of sleep neuroscience and mental state biology for trainees and practitioners in psychiatry and related professions.

Interleukin-1ß moderates the relationships between middle frontal-mACC/insular connectivity and depressive symptoms in bipolar II depression.

The functional alterations of the brain in bipolar II depression (BDII-D) and their clinical and inflammatory associations are understudied. We aim to investigate the functional brain alterations in BDII-D and their relationships with inflammation, childhood adversity, and psychiatric symptoms, and to examine the moderating effects among these factors. Using z-normalized amplitude of low-frequency fluctuation (zALFF), we assessed the whole-brain resting-state functional activity between 147 BDII-D individuals and 150 healthy controls (HCs). Differential ALFF regions were selected as seeds for functional connectivity analysis to observe brain connectivity alterations resulting from abnormal regional activity. Four inflammatory cytokines including interleukin (IL)-6, IL-1ß, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) and five clinical scales including Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), Positive and Negative Syndrome Scale (PANSS), Columbia-Suicide Severity Rating Scale (C-SSRS), and Childhood Trauma Questionnaire (CTQ) were tested and assessed in BDII-D. Partial correlations with multiple comparison corrections identified relationships between brain function and inflammation, childhood adversity, and psychiatric symptoms. Moderation analysis was conducted based on correlation results and previous findings. Compared to HCs, BDII-D individuals displayed significantly lower zALFF in the superior and middle frontal gyri (SFG and MFG) and insula, but higher zALFF in the occipital-temporal area. Only the MFG and insula-related connectivity exhibited significant differences between groups. Within BDII-D, lower right insula zALFF value correlated with higher IL-6, CRP, and emotional adversity scores, while lower right MFG zALFF was related to higher CRP and physical abuse scores. Higher right MFG-mid-anterior cingulate cortex (mACC) connectivity was associated with higher IL-1ß. Moreover, IL-1ß moderated associations between higher right MFG-mACC/insula connectivity and greater depressive symptoms. This study reveals that abnormal functional alterations in the right MFG and right insula were associated with elevated inflammation, childhood adversity, and depressive symptoms in BDII-D. IL-1ß may moderate the relationship between MFG-related connectivity and depressive symptoms.

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.

Lesion network guided delta frequency neuromodulation improves cognition in patients with psychosis spectrum disorders: A pilot study.

BACKGROUND: Transcranial electric stimulation (tES) may improve cognition in psychosis spectrum disorders. However, few studies have used novel tES approaches, such as high definition tES (HD-tES) to target specific brain circuits. Recently, the extrastriate visual cortex (V5/MT) has been causally linked to visual hallucinations through lesion network mapping and this may be a promising approach for improving cognition. OBJECTIVE: We aim to determine if causal lesion network guided HD-tES to V5/MT improves cognitive performance as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). METHODS: A single-blind pilot study with a within-subjects crossover design was performed to characterize the effect of cathodal HD-transcranial direct current stimulation (tDCS) and 2 Hz HD-transcranial alternating current stimulation (tACS) on cognition. Enrolled patients received 20 mins of HD-tES twice daily for 5 consecutive days applied bilaterally to V5/MT with a washout between conditions. BACS assessments were performed at baseline, day-5, and 1-month. RESULTS: 6 participants with psychosis spectrum disorder were enrolled. 6 individuals received cathodal HD-tDCS. 4 individuals received 2 Hz HD-tACS. HD-tACS resulted in significant (p < 0.1 baseline to 1-month improvements for Digit Sequencing, Verbal Fluency, and Tower of London. HD-tDCS did not result in significant improvement on any task. CONCLUSIONS: HD-tACS targeting V5/MT may be a promising treatment to improve cognitive abilities in individuals with psychosis. By promoting delta oscillations, tACS may enhance cortico-cortico communications across brain networks to improve verbal working memory, processing speed, and executive function. Large-scale investigations are needed to replicate these results.

Overlap between ophthalmology and psychiatry - A narrative review focused on congenital and inherited conditions.

A number of congenital and inherited diseases present with both ocular and psychiatric features. The genetic inheritance and phenotypic variants play a key role in disease severity. Early recognition of the signs and symptoms of those disorders is critical to earlier intervention and improved prognosis. Typically, the associations between these two medical subspecialties of ophthalmology and psychiatry are poorly understood by most practitioners so we hope to provide a narrative review to improve the identification and management of these disorders. We conducted a comprehensive review of the literature detailing the diseases with ophthalmic and psychiatric overlap that were more widely represented in the literature. Herein, we describe the clinical features, pathophysiology, molecular biology, diagnostic tests, and the most recent approaches for the treatment of these diseases. Recent studies have combined technologies for ocular and brain imaging such as optical coherence tomography (OCT) and functional imaging with genetic testing to identify the genetic basis for eye-brain connections. Additional work is needed to further explore these potential biomarkers. Overall, accurate, efficient, widely distributed and non-invasive tests that can help with early recognition of these diseases will improve the management of these patients using a multidisciplinary approach.

Effects of inflammation, childhood adversity, and psychiatric symptoms on brain morphometrical phenotypes in bipolar II depression.

BACKGROUND: The neuroanatomical alteration in bipolar II depression (BDII-D) and its associations with inflammation, childhood adversity, and psychiatric symptoms are currently unclear. We hypothesize that neuroanatomical deficits will be related to higher inflammation, greater childhood adversity, and worse psychiatric symptoms in BDII-D. METHODS: Voxel- and surface-based morphometry was performed using the CAT toolbox in 150 BDII-D patients and 155 healthy controls (HCs). Partial Pearson correlations followed by multiple comparison correction was used to indicate significant relationships between neuroanatomy and inflammation, childhood adversity, and psychiatric symptoms. RESULTS: Compared with HCs, the BDII-D group demonstrated significantly smaller gray matter volumes (GMVs) in frontostriatal and fronto-cerebellar area, insula, rectus, and temporal gyrus, while significantly thinner cortices were found in frontal and temporal areas. In BDII-D, smaller GMV in the right middle frontal gyrus (MFG) was correlated with greater sexual abuse (r = -0.348, q < 0.001) while larger GMV in the right orbital MFG was correlated with greater physical neglect (r = 0.254, q = 0.03). Higher WBC count (r = -0.227, q = 0.015) and IL-6 levels (r = -0.266, q = 0.015) was associated with smaller GMVs in fronto-cerebellar area in BDII-D. Greater positive symptoms was correlated with larger GMVs of the left middle temporal pole (r = 0.245, q = 0.03). CONCLUSIONS: Neuroanatomical alterations in frontostriatal and fronto-cerebellar area, insula, rectus, temporal gyrus volumes, and frontal-temporal thickness may reflect a core pathophysiological mechanism of BDII-D, which are related to inflammation, trauma, and psychiatric symptoms in BDII-D.

Neuroscience in pictures:1. History of psychiatric neuroscience.

Our understanding of the brain basis of mental illness has evolved over three and half millennia. Early insights into the role of the brain in relation to the mind faded during the middle ages as mental illness became the province of religion, spirituality, and philosophy. Psychiatry became a medical discipline again as medical and scientific thinking evolved during the 17th century. However, progress in neuroscience and astute clinical observations were punctuated by setbacks due to lingering dualism, reductionistic thinking, and dogma. Accelerating neuroscience discoveries and methodological innovations are beginning to bring neuroscience and psychiatry closer than ever as we begin the 21st century, This pictorial article seeks to briefly highlight this journey for an early trainee in psychiatry and related professions in mind.

Implementing Technologies to Enhance Coordinated Specialty Care Framework: Implementation Outcomes From a Development and Usability Study.

BACKGROUND: Coordinated specialty care (CSC) has demonstrated efficacy in improving outcomes in individuals at clinical high risk for psychosis and individuals with first-episode psychosis. Given the limitations of scalability and staffing needs, the augmentation of services using digital mental health interventions (DMHIs) may be explored to help support CSC service delivery. OBJECTIVE: In this study, we aimed to understand the methods to implement and support technology in routine CSC and offered insights from a quality improvement study assessing the implementation outcomes of DMHIs in CSC. METHODS: Patients and clinicians including psychiatrists, therapists, and supported education and employment specialists from a clinical-high-risk-for-psychosis clinic (Center for Early Detection Assessment and Response to Risk [CEDAR]) and a first-episode-psychosis clinic (Advancing Services for Psychosis Integration and Recovery [ASPIRE]) participated in a quality improvement project exploring the feasibility of DMHIs following the Access, Alignment, Connection, Care, and Scalability framework to implement mindLAMP, a flexible and evidenced-based DMHI. Digital navigators were used at each site to assist clinicians and patients in implementing mindLAMP. To explore the differences in implementation outcomes associated with the app format, a menu-style format was delivered at CEDAR, and a modular approach was used at ASPIRE. Qualitative baseline and follow-up data were collected to assess the specific implementation outcomes. RESULTS: In total, 5 patients (ASPIRE: n=3, 60%; CEDAR: n=2, 40%) were included: 3 (60%) White individuals, 2 (40%) male and 2 (40%) female patients, and 1 (20%) transgender man, with a mean age of 19.6 (SD 2.05) years. Implementation outcome data revealed that patients and clinicians demonstrated high accessibility, acceptability, interest, and belief in the sustainability of DMHIs. Clinicians and patients presented a wide range of interest in unique use cases of DMHI in CSC and expressed variable feasibility and appropriateness associated with nuanced barriers and needs. In addition, the results suggest that adoption, penetration, feasibility, and appropriateness outcomes were moderate and might continue to be explored and targeted. CONCLUSIONS: Implementation outcomes from this project suggest the need for a patient- and clinician-centered approach that is guided by digital navigators and provides versatility, autonomy, and structure. Leveraging these insights has the potential to build on growing research regarding the need for versatility, autonomy, digital navigator support, and structured applications. We anticipate that by continuing to research and improve implementation barriers impeding the adoption and penetration of DMHIs in CSC, accessibility and uptake of DMHIs will improve, therefore connecting patients to the demonstrated benefits of technology-augmented care.

Brain microvascular endothelial cells and blood-brain barrier dysfunction in psychotic disorders.

Although there is convergent evidence for blood-brain barrier (BBB) dysfunction and peripheral inflammation in schizophrenia (SZ) and bipolar disorder (BD), it is unknown whether BBB deficits are intrinsic to brain microvascular endothelial cells (BMECs) or arise via effects of peripheral inflammatory cytokines. We examined BMEC function using stem cell-based models to identify cellular and molecular deficits associated with BBB dysfunction in SZ and BD. Induced pluripotent stem cells (iPSCs) from 4 SZ, 4 psychotic BD and 4 healthy control (HC) subjects were differentiated into BMEC-"like" cells. Gene expression and protein levels of tight junction proteins were assessed. Transendothelial electrical resistance (TEER) and permeability were assayed to evaluate BBB function. Cytokine levels were measured from conditioned media. BMECs derived from human iPSCs in SZ and BD did not show differences in BBB integrity or permeability compared to HC BMECs. Outlier analysis using TEER revealed a BBB-deficit (n = 3) and non-deficit (n = 5) group in SZ and BD lines. Stratification based on BBB function in SZ and BD patients identified a BBB-deficit subtype with reduced barrier function, tendency for increased permeability to smaller molecules, and decreased claudin-5 (CLDN5) levels. BMECs from the BBB-deficit group show increased matrix metallopeptidase 1 (MMP1) activity, which correlated with reduced CLDN5 and worse BBB function, and was improved by tumor necrosis factor α (TNFα) and MMP1 inhibition. These results show potential deficits in BMEC-like cells in psychotic disorders that result in BBB disruption and further identify TNFα and MMP1 as promising targets for ameliorating BBB deficits.

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.

Brain-derived subgroups of bipolar II depression associate with inflammation and choroid plexus morphology.

AIM: Elevated inflammation and larger choroid plexus (ChP) volume has been previously identified in mood disorders. Connections between inflammation, ChP, and clinical symptoms in bipolar II depression (BDII-D) are unclear. Data-driven clustering based on neuroanatomical phenotypes may help to elucidate neurobiological associations in BDII-D. METHODS: Inflammatory cytokines, clinical symptoms, and neuroanatomical features were assessed in 150 BDII-D patients. Sixty-eight cortical surface area (SA) and 19 subcortical volumes were extracted using FreeSurfer. The ChP volume was segmented manually using 3D Slicer. Regularized canonical correlation analysis was used to identify significantly correlated components between cortical SA and subcortical volumes (excluding the ChP), followed by k-means clustering to define brain-derived subgroups of BDII-D. Low-grade inflammation was derived by averaging the standardized z scores of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α), which were computed to create a composite z-value score. Partial Pearson correlations followed by multiple comparison correction were conducted to explore associations between inflammation, clinical symptoms, and ChP volume. RESULTS: Subgroup I demonstrated smaller subcortical volume and cortical SA, higher inflammation, and larger ChP volume compared with subgroup II. Greater ChP volume was associated with a higher low-grade inflammation (mean r = 0.289, q = 0.003), CRP (mean r = 0.249, q = 0.007), IL-6 (left r = 0.200, q = 0.03), and TNF-α (right r = 0.226, q = 0.01), while greater IL-1ß was significantly associated with severe depressive symptoms in BDII-D (r = 0.218, q = 0.045). CONCLUSIONS: Neuroanatomically-derived subgroups of BDII-D differed in their inflammation levels and ChP volume. These findings suggest an important role of elevated peripheral inflammation and larger ChP in BDII-D.

Peripheral inflammatory subgroup differences in anterior Default Mode network and multiplex functional network topology are associated with cognition in psychosis.

INTRODUCTION: High-inflammation subgroups of patients with psychosis demonstrate cognitive deficits and neuroanatomical alterations. Systemic inflammation assessed using IL-6 and C-reactive protein may alter functional connectivity within and between resting-state networks, but the cognitive and clinical implications of these alterations remain unknown. We aim to determine the relationships of elevated peripheral inflammation subgroups with resting-state functional networks and cognition in psychosis spectrum disorders. METHODS: Serum and resting-state fMRI were collected from psychosis probands (schizophrenia, schizoaffective, psychotic bipolar disorder) and healthy controls (HC) from the B-SNIP1 (Chicago site) study who were stratified into inflammatory subgroups based on factor and cluster analyses of 13 cytokines (HC Low n = 32, Proband Low n = 65, Proband High n = 29). Nine resting-state networks derived from independent component analysis were used to assess functional and multilayer connectivity. Inter-network connectivity was measured using Fisher z-transformation of correlation coefficients. Network organization was assessed by investigating networks of positive and negative connections separately, as well as investigating multilayer networks using both positive and negative connections. Cognition was assessed using the Brief Assessment of Cognition in Schizophrenia. Linear regressions, Spearman correlations, permutations tests and multiple comparison corrections were used for analyses in R. RESULTS: Anterior default mode network (DMNa) connectivity was significantly reduced in the Proband High compared to Proband Low (Cohen's d = -0.74, p = 0.002) and HC Low (d = -0.85, p = 0.0008) groups. Inter-network connectivity between the DMNa and the right-frontoparietal networks was lower in Proband High compared to Proband Low (d = -0.66, p = 0.004) group. Compared to Proband Low, the Proband High group had lower negative (d = 0.54, p = 0.021) and positive network (d = 0.49, p = 0.042) clustering coefficient, and lower multiplex network participation coefficient (d = -0.57, p = 0.014). Network findings in high inflammation subgroups correlate with worse verbal fluency, verbal memory, symbol coding, and overall cognition. CONCLUSION: These results expand on our understanding of the potential effects of peripheral inflammatory signatures and/or subgroups on network dysfunction in psychosis and how they relate to worse cognitive performance. Additionally, the novel multiplex approach taken in this study demonstrated how inflammation may disrupt the brain's ability to maintain healthy co-activation patterns between the resting-state networks while inhibiting certain connections between them.

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.

Characterization of childhood trauma, hippocampal mediation and Cannabis use in a large dataset of psychosis and non-psychosis individuals.

BACKGROUND: Cannabis use (CA) and childhood trauma (CT) independently increase the risk of earlier psychosis onset; but their interaction in relation to psychosis risk and association with endocannabinoid-receptor rich brain regions, i.e. the hippocampus (HP), remains unclear. The objective was to determine whether lower age of psychosis onset (AgePsyOnset) is associated with CA and CT through mediation by the HP volumes, and genetic risk, as measured by schizophrenia polygene scores (SZ-PGRS). METHODS: Cross-sectional, case-control, multicenter sample from 5 metropolitan US regions. Participants (n = 1185) included 397 controls not affected by psychosis (HC); 209 participants with bipolar disorder type-1; 279 with schizoaffective disorder; and 300 with schizophrenia (DSM IV-TR). CT was assessed using the Childhood Trauma Questionnaire (CTQ); CA was assessed by self-reports and trained clinical interviewers. Assessment included neuroimaging, symptomatology, cognition and calculation of the SZ polygenic risk score (SZ-PGRS). RESULTS: In survival analysis, CT and CA exposure interact to be associated with lower AgePsyOnset. At high CT or CA, CT or CA are individually sufficient to affect AgePsyOnset. CT relation with AgePsyOnset is mediated in part by the HP in CA users before AgePsyOnset. CA before AgePsyOnset is associated with higher SZ-PGRS and correlated with younger age at CA usage. DISCUSSION: CA and CT interact to increase risk when moderate; while severe CT and/or CA abuse/dependence are each sufficient to affect AgePsyOnset, indicating a ceiling effect. Probands with/out CA before AgePsyOnset differ on biological variables, suggesting divergent pathways to psychosis. FUNDING: MH077945; MH096942; MH096913; MH077862; MH103368; MH096900; MH122759.

Peripheral inflammation is associated with impairments of inhibitory behavioral control and visual sensorimotor function in psychotic disorders.

Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R2 = 0.100, p-value = 2.69e-4, q-value = 0.004) and suggestive associations with Visual Sensorimotor function (R2 = 0.039, p-value = 0.024, q-value = 0.180), but not with General Cognitive Ability (R2 = 0.015, p-value = 0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2 % of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control.

A preliminary choroid plexus volumetric study in individuals with psychosis.

The choroid plexus (ChP) is part of the blood-cerebrospinal fluid barrier, regulating brain homeostasis and the brain's response to peripheral events. Its upregulation and enlargement are considered essential in psychosis. However, the timing of the ChP enlargement has not been established. This study introduces a novel magnetic resonance imaging-based segmentation method to examine ChP volumes in two cohorts of individuals with psychosis. The first sample consists of 41 individuals with early course psychosis (mean duration of illness = 1.78 years) and 30 healthy individuals. The second sample consists of 30 individuals with chronic psychosis (mean duration of illness = 7.96 years) and 34 healthy individuals. We utilized manual segmentation to measure ChP volumes. We applied ANCOVAs to compare normalized ChP volumes between groups and partial correlations to investigate the relationship between ChP, LV volumes, and clinical characteristics. Our segmentation demonstrated good reliability (.87). We further showed a significant ChP volume increase in early psychosis (left: p < .00010, right: p < .00010) and a significant positive correlation between higher ChP and higher LV volumes in chronic psychosis (left: r = .54, p = .0030, right: r = .68; p < .0010). Our study suggests that ChP enlargement may be a marker of acute response around disease onset. It might also play a modulatory role in the chronic enlargement of lateral ventricles, often reported in psychosis. Future longitudinal studies should investigate the dynamics of ChP enlargement as a promising marker for novel therapeutic strategies.

Manual Segmentation of the Human Choroid Plexus Using Brain MRI.

The choroid plexus has been implicated in neurodevelopment and a range of brain disorders. Evidence demonstrates that the choroid plexus is critical for brain maturation, immune/ inflammatory regulation, and behavioral/cognitive functioning. However, current automated neuroimaging segmentation tools are poor at accurately and reliably segmenting the lateral ventricle choroid plexus. Furthermore, there is no existing tool that segments the choroid plexus located in the third and fourth ventricles of the brain. Thus, a protocol delineating how to segment the choroid plexus in the lateral, third, and fourth ventricle is needed to increase the reliability and replicability of studies examining the choroid plexus in neurodevelopmental and brain disorders. This protocol provides detailed steps to create separately labeled files in 3D Slicer for the choroid plexus based on DICOM or NIFTI images. The choroid plexus will be manually segmented using the axial, sagittal, and coronal planes of T1w images making sure to exclude voxels from gray or white matter structures bordering the ventricles. Windowing will be adjusted to assist in the localization of the choroid plexus and its anatomical boundaries. Methods for assessing accuracy and reliability will be demonstrated as part of this protocol. Gold standard segmentation of the choroid plexus using manual delineations can be used to develop better and more reliable automated segmentation tools that can be openly shared to elucidate changes in the choroid plexus across the lifespan and within various brain disorders.

Sex-Specific Changes in Choroid Vasculature Among Patients with Schizophrenia and Bipolar Disorder.

Purpose: While structural changes within the retina of psychosis patients have been established, no detailed studies of choroidal microvasculature in these patients have been performed. Given evidence of microvascular disruption in psychosis patients, this study sought to determine whether there exists evidence of microvascular disruption in the choroids in these patients. Methods: Fifty-six subjects (20 controls and 36 psychosis patients) were recruited from April 2018 to February 2020. Five were excluded due to imaging artifact or missing demographic information. Swept-source optical coherence tomography angiography (SS-OCTA) images were obtained. Choroid vascular enface images (12 mm × 9mm) were exported every 2.6 µm from Bruch's membrane to the choroid-scleral interface from Topcon to ImageJ. The images were binarized using Otsu's method, signal from the optic disk and retinal vasculature was removed, and average choroid vascular density (CVD) was calculated as the average of percent area occupied by choroidal vasculature across images in the stack. Choroid vascular volume (CVV) was calculated as the CVD multiplied by maximum CT and image area. During image analysis, study staff were blinded to the phenotype of the study subjects. Results: Compared with same-sex controls, male psychiatric patients had significantly lower CVD. Compared with same-sex controls, female psychiatric patients had significantly lower maximum CT with correspondingly decreased CVV, after adjusting for age. When all psychiatric patients were compared with all healthy controls, no significant differences in CT, CVD, or CVV were noted. Conclusion: These results suggest that the pathogenesis of psychotic illness affects choroidal microvasculature in a sex-specific manner.

Retinal microvasculature and vasoreactivity changes in hypertension using optical coherence tomography-angiography.

PURPOSE: To evaluate the retinal vasculature and vasoreactivity of patients with hypertension (HTN) using spectral domain optical coherence tomography angiography (SD-OCTA). METHODS: Patients with and without a diagnosis of HTN were included in this cross-sectional observational study. All eyes were imaged with SD-OCTA using 3 mm × 3 mm and 6 mm × 6 mm centered on both the fovea and optic disk. A second 6 mm × 6 mm scan was taken after a 30 s breath-hold. Vessel density (VD), vessel skeletonized density (VSD), and fractal dimension (FD) were calculated using customized MATLAB scripts. Vessel diameter index (VDI) was obtained by taking the ratio of VD to VSD. Vasoreactivity was measured by subtracting the VD or VSD before and after breath-hold (∆VD, ∆VSD). RESULTS: Twenty-three eyes with HTN (17 patients) and 17 control eyes (15 patients) were included. In the 6 mm × 6 mm angiogram centered on fovea, the superficial capillary plexus (SCP) VD (ß = - 0.029, p = 0.012), VSD (ß = - 0.004, p = 0.043) and the choriocapillaris VD (ß = - 0.021, p = 0.030) were significantly decreased in HTN compared to control eyes. Similarly, FD was decreased in both the SCP (ß = - 0.012, p = 0.013) and choriocapillaris (ß = - 0.009, p = 0.030). In the 3 mm × 3 mm angiogram centered on optic disk, SCP VDI (ß = - 0.364, p = 0.034) was decreased. ∆VD and ∆VSD were both reduced in the DCP (ß = - 0.034, p = 0.032; ß = - 0.013, p = 0.043) and ∆VSD was elevated in the choriocapillaris of HTN eyes (ß = 0.004, p = 0.032). CONCLUSIONS: The study used SD-OCTA to show significant differences in the retinal vasculature of hypertensive patients. It was also the first to demonstrate the potential of OCT-A to investigate retinal vascular reactivity in patients with HTN.

Regional and Sex-Specific Alterations in the Visual Cortex of Individuals With Psychosis Spectrum Disorders.

BACKGROUND: Impairments of the visual system are implicated in psychotic disorders. However, studies exploring visual cortex (VC) morphology in this population are limited. Using data from the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium, we examined VC structure in psychosis probands and their first-degree relatives (RELs), sex differences in VC measures, and their relationships with cognitive and peripheral inflammatory markers. METHODS: Cortical thickness, surface area, and volume of the primary (Brodmann area 17/V1) and secondary (Brodmann area 18/V2) visual areas and the middle temporal (V5/MT) region were quantified using FreeSurfer version 6.0 in psychosis probands (n = 530), first-degree RELs (n = 544), and healthy control subjects (n = 323). Familiality estimates were determined for probands and RELs. General cognition, response inhibition, and emotion recognition functions were assessed. Systemic inflammation was measured in a subset of participants. RESULTS: Psychosis probands demonstrated significant area, thickness, and volume reductions in V1, V2, and MT, and their first-degree RELs demonstrated area and volume reductions in MT compared with control subjects. There was a higher degree of familiality for VC area than thickness. Area and volume reductions in V1 and V2 were sex dependent, affecting only female probands in a regionally specific manner. Reductions in some VC regions were correlated with poor general cognition, worse response inhibition, and increased C-reactive protein levels. CONCLUSIONS: The visual cortex is a site of significant pathology in psychotic disorders, with distinct patterns of area and thickness changes, sex-specific and regional effects, potential contributions to cognitive impairments, and association with C-reactive protein levels.