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.

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.

Inflammatory Subtypes in Antipsychotic-Naïve First-Episode Schizophrenia are Associated with Altered Brain Morphology and Topological Organization.

BACKGROUND: Peripheral inflammation is implicated in schizophrenia, however, not all individuals demonstrate inflammatory alterations. Recent studies identified inflammatory subtypes in chronic psychosis with high inflammation having worse cognitive performance and displaying neuroanatomical enlargement compared to low inflammation subtypes. It is unclear if inflammatory subtypes exist earlier in the disease course, thus, we aim to identify inflammatory subtypes in antipsychotic naïve First-Episode Schizophrenia (FES). METHODS: 12 peripheral inflammatory markers, clinical, cognitive, and neuroanatomical measures were collected from a naturalistic study of antipsychotic-naïve FES patients. A combination of unsupervised principal component analysis and hierarchical clustering was used to categorize inflammatory subtypes from their cytokine data (17 FES High, 30 FES Low, and 33 healthy controls (HCs)). Linear regression analysis was used to assess subtype differences. Neuroanatomical correlations with clinical and cognitive measures were performed using partial Spearman correlations. Graph theoretical analyses were performed to assess global and local network properties across inflammatory subtypes. RESULTS: The FES High group made up 36% of the FES group and demonstrated significantly greater levels of IL1ß, IL6, IL8, and TNFα compared to FES Low, and higher levels of IL1ß and IL8 compared to HCs. FES High had greater right parahippocampal, caudal anterior cingulate, and bank superior sulcus thicknesses compared to FES Low. Compared to HCs, FES Low showed smaller bilateral amygdala volumes and widespread cortical thickness. FES High and FES Low groups demonstrated less efficient topological organization compared to HCs. Individual cytokines and/or inflammatory signatures were positively associated with cognition and symptom measures. CONCLUSIONS: Inflammatory subtypes are present in antipsychotic-naïve FES and are associated with inflammation-mediated cortical expansion. These findings support our previous findings in chronic psychosis and point towards a connection between inflammation and blood-brain barrier disruption. Thus, identifying inflammatory subtypes may provide a novel therapeutic avenue for biomarker-guided treatment involving anti-inflammatory medications.

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.

Neuroretinal Alterations in Schizophrenia and Bipolar Disorder: An Updated Meta-analysis.

Schizophrenia (SZ) and bipolar disorder (BD) are characterized by major symptomatic, cognitive, and neuroanatomical changes. Recent studies have used optical coherence tomography (OCT) to investigate retinal changes in SZ and BD, but their unique and shared changes require further evaluation. Articles were identified using PubMed and Google Scholar. 39 studies met the inclusion criteria. Diagnostic groups were proband (SZ/BD combined), SZ, BD, and healthy control (HC) eyes. Meta-analyses utilized fixed and random effects models when appropriate, and publication bias was corrected using trim-and-fill analysis ("meta" package in R). Results are reported as standardized mean differences with 95% CIs. Data from 3145 patient eyes (1956 SZ, 1189 BD) and 3135 HC eyes were included. Studies identified thinning of the peripapillary retinal nerve fiber layer (pRNFL, overall and in 2 subregions), m-Retina (overall and all subregions), mGCL-IPL, mIPL, and mRPE in SZ patients. BD showed thinning of the pRNFL (overall and in each subregion), pGCC, and macular Retina (in 5 subregions), but no changes in thickness or volume for the total retina. Neither SZ nor BD patients demonstrated significant changes in the fovea, mRNFL, mGCL, mGCC, mINL, mOPL, mONL, or choroid thicknesses. Moderating effects of age, illness duration, and smoking on retinal structures were identified. This meta-analysis builds upon previous literature in this field by incorporating recent OCT studies and examining both peripapillary and macular retinal regions with respect to psychotic disorders. Overall, this meta-analysis demonstrated both peripapillary and macular structural retinal abnormalities in people with SZ or BD compared with HCs.

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.

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.

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.

Quantifying Retinal Microvascular Morphology in Schizophrenia Using Swept-Source Optical Coherence Tomography Angiography.

BACKGROUND: Retinovascular changes are reported on fundus imaging in schizophrenia (SZ). This is the first study to use swept-source optical coherence tomography angiography (OCT-A) to comprehensively examine retinal microvascular changes in SZ. METHODS: This study included 30 patients with SZ/schizoaffective disorder (8 early and 15 chronic) and 22 healthy controls (HCs). All assessments were performed at Beth Israel Deaconess Medical Center and Massachusetts Eye and Ear. All participants underwent swept-source OCT-A of right (oculus dextrus [OD]) and left (oculus sinister [OS]) eye, clinical, and cognitive assessments. Macular OCT-A images (6 × 6 mm) were collected with the DRI Topcon Triton for superficial, deep, and choriocapillaris vascular regions. Microvasculature was quantified using vessel density (VD), skeletonized vessel density (SVD), fractal dimension (FD), and vessel diameter index (VDI). RESULTS: Twenty-one HCs and 26 SZ subjects were included. Compared to HCs, SZ patients demonstrated higher overall OD superficial SVD, OD choriocapillaris VD, and OD choriocapillaris SVD, which were primarily observed in the central, central and outer superior, and central and outer inferior/superior, respectively. Early-course SZ subjects had significantly higher OD superficial VD, OD choriocapillaris SVD, and OD choriocapillaris FD compared to matched HCs. Higher bilateral (OU) superficial VD correlated with lower Positive and Negative Syndrome Scale (PANSS) positive scores, and higher OU deep VDI was associated with higher PANSS negative scores. CONCLUSIONS AND RELEVANCE: These results suggest the presence of microvascular dysfunction associated with early-stage SZ. Clinical associations with microvascular alterations further implicate this hypothesis, with higher measures being associated with worse symptom severity and functioning in early stages and with lower symptom severity and better functioning in later stages.

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.

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.

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.

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.

A Meta-analysis of Retinal Cytoarchitectural Abnormalities in Schizophrenia and Bipolar Disorder.

BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) are characterized by reductions in gray matter and white matter. Limitations in brain imaging have led researchers to use optical coherence tomography (OCT) to explore retinal imaging biomarkers of brain pathology. We examine the retinal layers that may be associated with SZ or BD. METHODS: Articles identified using PubMed, Web of Science, Cochrane Database. Twelve studies met inclusion for acutely/chronically ill patients. We used fixed or random effects meta-analysis for probands (SZ and BD), SZ or BD eyes vs healthy control (HC) eyes. We adjusted for sources of bias, cross-validated results, and report standardized mean differences (SMD). Statistical analysis performed using meta package in R. RESULTS: Data from 820 proband eyes (SZ = 541, BD = 279) and 904 HC eyes were suitable for meta-analysis. The peripapillary retinal nerve fiber layer (RNFL) showed significant thinning in SZ and BD eyes compared to HC eyes (n = 12, SMD = -0.74, -0.51, -1.06, respectively). RNFL thinning was greatest in the nasal, temporal, and superior regions. The combined peripapillary ganglion cell layer and inner plexiform layer (GCL-IPL) showed significant thinning in SZ and BD eyes compared to HC eyes (n = 4, SMD = -0.39, -0.44, -0.28, respectively). No statistically significant differences were identified in other retinal or choroidal regions. Clinical variables were unrelated to the RNFL or GCL-IPL thickness by meta-regression. CONCLUSION: The observed retinal layer thinning is consistent with the classic gray- and white-matter atrophy observed on neuroimaging in SZ and BD patients. OCT may be a useful biomarker tool in studying the neurobiology of psychosis.

Visual Cortical Alterations and their Association with Negative Symptoms in Antipsychotic-Naïve First Episode Psychosis.

Visual perceptual and processing deficits are common in schizophrenia and possibly point towards visual pathway alterations. However, no studies have examined visual cortical morphology in first-episode psychosis (FEP). In an antipsychotic-naïve FEP population, we investigated primary visual (V1), association area (V2), and motion perception (V5/MT) morphology compared to controls. We found reductions in the V1 and V2 areas, greater MT area and lower MT thickness in the FEP-schizophrenia group when compared to controls. Also, lower MT thickness was associated with worse negative symptoms. Our results shed light on this poorly studied area of visual cortex morphology in FEP.

Retinal layer abnormalities and their association with clinical and brain measures in psychotic disorders: A preliminary study.

Studies utilizing optical coherence tomography (OCT) in psychosis have identified abnormalities in retinal cytoarchitecture. We aim to analyze retinal layer topography in psychosis and its correlation with clinical and imaging parameters. Macular retinal images were obtained via OCT in psychosis probands (n = 25) and healthy controls (HC, n = 15). Clinical, cognitive and structural MRI data were collected from participants. No thinning was noted for the retinal nerve fiber, ganglion cell or inner plexiform layers. We found significant thinning in the right inner temporal, right central, and left inner superior quadrants of the outer nuclear layer (ONL) in probands compared to HC. Thickening of the outer plexiform layer (OPL) was observed in the right inner temporal, left inner superior, and left inner temporal quadrants. The right inner temporal and left inner superior quadrants of both the OPL and ONL showed significant inverse correlations. Retinal pigment epithelium thinning correlated with worse mania symptoms, and thinning in the ONL was associated with worse cognitive function. ONL thinning was also associated with smaller total brain and white matter volume. Our findings suggest that outer retinal layers may provide additional insights into the pathophysiology of psychosis, possibly reflecting synaptic or inflammatory aberrations that lead to retinal pathologies.

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.

Behavioral Deficits Following Withdrawal from Chronic Ethanol Are Influenced by SLO Channel Function in Caenorhabditis elegans.

Symptoms of withdrawal from chronic alcohol use are a driving force for relapse in alcohol dependence. Thus, uncovering molecular targets to lessen their severity is key to breaking the cycle of dependence. Using the nematode Caenorhabditis elegans, we tested whether one highly conserved ethanol target, the large-conductance, calcium-activated potassium channel (known as the BK channel or Slo1), modulates ethanol withdrawal. Consistent with a previous report, we found that C. elegans displays withdrawal-related behavioral impairments after cessation of chronic ethanol exposure. We found that the degree of impairment is exacerbated in worms lacking the worm BK channel, SLO-1, and is reduced by selective rescue of this channel in the nervous system. Enhanced SLO-1 function, via gain-of-function mutation or overexpression, also dramatically reduced behavioral impairment during withdrawal. Consistent with these results, we found that chronic ethanol exposure decreased SLO-1 expression in a subset of neurons. In addition, we found that the function of a distinct, conserved Slo family channel, SLO-2, showed an inverse relationship to withdrawal behavior, and this influence depended on SLO-1 function. Together, our findings show that modulation of either Slo family ion channel bidirectionally regulates withdrawal behaviors in worm, supporting further exploration of the Slo family as targets for normalizing behaviors during alcohol withdrawal.