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Chloe Y Li,1,* Itika Garg,1,2,* Deepthi Bannai,3 Megan Kasetty,1 Raviv Katz,1,2 Iniya Adhan,3 Konstantinos AA Douglas,1 Jay C Wang,1 Leo A Kim,2 Matcheri Keshavan,3 Paulo Lizano,3,* John B Miller1,2,* 1Harvard Retinal Imaging Laboratory, Massachusetts Eye and Ear, Boston, MA, USA; 2Retina Service, Massachusetts Eye and Ear, Boston, MA, USA; 3Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA, USA*These authors contributed equally to this workCorrespondence: John B Miller, Harvard Medical School, Department of Ophthalmology, Massachusetts Eye and Ear, 243 Charles St, Boston, MA, 02114, USA, Tel +1 617-573-3529, Email john_miller@meei.harvard.edu Paulo Lizano, Harvard Medical School, Department of Psychiatry, Beth Israel Deaconess Medical Center, 75 Fenwood Road, Room 612, Boston, MA, 02115, USA, Tel +1 617-754-1227, Email plizano@bidmc.harvard.eduPurpose: 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.Keywords: choroid vascular density, swept source optical coherence tomography angiography, psychosis, schizophrenia, bipolar disorder

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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.

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., (Copyright © 2017 by the Genetics Society of America.)