Retinal vascular abnormalities in schizophrenia and bipolar disorder: A window to the brain.

OBJECTIVES: The examination of retinal microvascular abnormalities through fundus photography is currently the best available non-invasive technique for assessment of cerebral vascular status. Several studies in the last decade have reported higher incidences of adverse cerebrovascular events in Schizophrenia (SCZ) and bipolar disorder (BD). However, retinal microvasculature abnormalities in SCZ and BD have remained under-explored, and no study has compared this aspect of SCZ and BD till date. METHODS: Retinal Images of 100 SCZ patients, BD patients, and healthy volunteers each were acquired by trained individuals using a non-mydriatic camera with a 40-degree field of view. The retinal images were quantified using a valid semi-automated method. The average of left and right eye diameters of the venules and arterioles passing through the extended zone between 0.5 and 2 disc diameters from the optic disc were calculated. RESULTS: The groups differed significantly with respect to average diameters of both retinal venules (P < 0.001) and retinal arterioles (P < 0.001), after controlling for age and sex. Both SCZ and BD patients had significantly narrower arterioles and wider venules compared to HV. There were also significant differences between SCZ and BD patients; patients with BD had narrower arterioles and wider venules. CONCLUSION: Considering the affordability and easy accessibility of the investigative procedure, retinal microvascular examination could serve as a potential screening tool to identify individuals at risk for adverse cerebrovascular events. The findings of the current study also provide a strong rationale for further systematic examination of retinal vascular abnormalities in SCZ and BD.

Examination of retinal vascular trajectory in schizophrenia and bipolar disorder.

AIM: Evidence suggests microvascular dysfunction (wider retinal venules and narrower arterioles) in schizophrenia (SCZ) and bipolar disorder (BD). The vascular development is synchronous with neuronal development in the retina and brain. The retinal vessel trajectory is related to retinal nerve fiber layer thinning and cerebrovascular abnormalities in SCZ and BD and has not yet been examined. Hence, in this study we examined the retinal vascular trajectory in SCZ and BD in comparison with healthy volunteers (HV). METHODS: Retinal images were acquired from 100 HV, SCZ patients, and BD patients, respectively, with a non-mydriatic fundus camera. Images were quantified to obtain the retinal arterial and venous trajectories using a validated, semiautomated algorithm. Analysis of covariance and regression analyses were conducted to examine group differences. A supervised machine-learning ensemble of bagged-trees method was used for automated classification of trajectory values. RESULTS: There was a significant difference among groups in both the retinal venous trajectory (HV: 0.17 ± 0.08; SCZ: 0.25 ± 0.17; BD: 0.27 ± 0.20; P < 0.001) and the arterial trajectory (HV: 0.34 ± 0.15; SCZ: 0.29 ± 0.10; BD: 0.29 ± 0.11; P = 0.003) even after adjusting for age and sex (P < 0.001). On post-hoc analysis, the SCZ and BD groups differed from the HV on retinal venous and arterial trajectories, but there was no difference between SCZ and BD patients. The machine learning showed an accuracy of 86% and 73% for classifying HV versus SCZ and BD, respectively. CONCLUSION: Smaller trajectories of retinal arteries indicate wider and flatter curves in SCZ and BD. Considering the relation between retinal/cerebral vasculatures and retinal nerve fiber layer thinness, the retinal vascular trajectory is a potential marker for SCZ and BD. As a relatively affordable investigation, retinal fundus photography should be further explored in SCZ and BD as a potential screening measure.

Acmella oleracea induced nanostructured Ca2Fe2O5 for evaluation of photo catalytic degradation of cardiovascular drugs and bio toxicity.

Biosynthesis of nanoparticles is increasingly becoming popular due to the demand for sustainable technologies worldwide. In the present investigation, Acmella oleracea plant extract fuelled combustion technique followed by calcination at 600 °C was adopted to prepare nanocrystalline Ca2Fe2O5. The prepared nano compound was characterised using X-ray powder diffraction (XRD), scanning electron microscopy (SEM), Ultra Violet (UV) spectroscopy, Infrared (IR) spectroscopy and its role was assessed for photocatalytic pollutant degradation along with bactericidal action in the concentration range of 1 µg/mL to 320 µg/mL. The photocatalytic degradation efficiency of pollutant drugs Clopidogrel Bisulphate and Asprin used for cardiovascular disorders is around 80% with 10 mg/L photocatalyst. The results showed that the photocatalytic activity increased with rising pH from 4, to 10, along with a significant antibacterial action against Enterococcus faecalis bacteria and a slight cytotoxic effect at high concentrations. The antibacterial property was reinforced by Minimum inhibitory concentrations (MIC) and Minimum bactericidal concentrations (MBC) studies with an average value of 0.103 at 600 nm which was further proved by significant anti-biofilm activeness. Adhesion tests in conjunction with cryogenic-scanning electron microscopy displayed a morphological change through agglomeration that caused an expansion in nano particles from 181 nm to 223.6 nm due to internalization followed by inactivation of bacteria. In addition, the non-toxicity of nano Ca2Fe2O5 was confirmed by subtle cytological changes in microscopic images of Allium Cepa root cells in the concentration range 0.01-100 µg/mL and a slight inhibition in HeLa cell proliferation indicated by IC50 value of 170.94 µg/mL. In total, the current investigation for the first time reveals the application of bio based synthesis of Nano Ca2Fe2O5 to new possibilities in bioremediation namely degrading cardiovascular pharmaceutical pollutants, endodontic antibacterial action and cytological activity.

NeuroBridge ontology: computable provenance metadata to give the long tail of neuroimaging data a FAIR chance for secondary use.

Background: Despite the efforts of the neuroscience community, there are many published neuroimaging studies with data that are still not findable or accessible. Users face significant challenges in reusing neuroimaging data due to the lack of provenance metadata, such as experimental protocols, study instruments, and details about the study participants, which is also required for interoperability. To implement the FAIR guidelines for neuroimaging data, we have developed an iterative ontology engineering process and used it to create the NeuroBridge ontology. The NeuroBridge ontology is a computable model of provenance terms to implement FAIR principles and together with an international effort to annotate full text articles with ontology terms, the ontology enables users to locate relevant neuroimaging datasets. Methods: Building on our previous work in metadata modeling, and in concert with an initial annotation of a representative corpus, we modeled diagnosis terms (e.g., schizophrenia, alcohol usage disorder), magnetic resonance imaging (MRI) scan types (T1-weighted, task-based, etc.), clinical symptom assessments (PANSS, AUDIT), and a variety of other assessments. We used the feedback of the annotation team to identify missing metadata terms, which were added to the NeuroBridge ontology, and we restructured the ontology to support both the final annotation of the corpus of neuroimaging articles by a second, independent set of annotators, as well as the functionalities of the NeuroBridge search portal for neuroimaging datasets. Results: The NeuroBridge ontology consists of 660 classes with 49 properties with 3,200 axioms. The ontology includes mappings to existing ontologies, enabling the NeuroBridge ontology to be interoperable with other domain specific terminological systems. Using the ontology, we annotated 186 neuroimaging full-text articles describing the participant types, scanning, clinical and cognitive assessments. Conclusion: The NeuroBridge ontology is the first computable metadata model that represents the types of data available in recent neuroimaging studies in schizophrenia and substance use disorders research; it can be extended to include more granular terms as needed. This metadata ontology is expected to form the computational foundation to help both investigators to make their data FAIR compliant and support users to conduct reproducible neuroimaging research.

A systematic review and meta-analysis of optical coherence tomography studies in schizophrenia, bipolar disorder and major depressive disorder.

OBJECTIVES: Due to the common neurodevelopmental origin and easy accessibility, the retina serves as a surrogate marker for changes in the brain. Hence, Optical Coherence Tomography (OCT), a tool to examine the neuronal layers of retina has gained importance in investigating psychiatric disorders. Several studies in the last decade have reported retinal structural alterations in schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). However, the findings are inconsistent. Hence, we conducted a meta-analysis to investigate alterations in OCT parameters in patients with SCZ, BD and MDD. METHODS: We searched electronic databases for studies that examined OCT parameters in patients with SCZ, BD and MDD published up to January 2023. The primary outcome measures were thickness and volumes of the retinal Nerve Fibre Layer (RNFL). We conducted meta-analysis using a random effects model. RESULTS: The searches yielded 2638 publications of which 43 studies were included in the final analysis across all disorders. Compared to controls, the RNFL was thinner in SCZ patients (SMD = -0.37, p = <0.001) and BD patients (SMD = -0.67, p = < 0.001), but not in MDD patients (SMD = -0.08, p = 0.54). On quadrant wise analysis, temporal quadrant RNFL was thinner in SCZ but not in BD, while all other quadrants were thinner in both SCZ and BD. CONCLUSION: We found significant reductions in RNFL thickness in SCZ and BD, but not in MDD. The differential involvement in various quadrants and parameters across the disorders has potential implications for using retinal parameters as a diagnostic biomarker.

NeuroBridge: a prototype platform for discovery of the long-tail neuroimaging data.

Introduction: Open science initiatives have enabled sharing of large amounts of already collected data. However, significant gaps remain regarding how to find appropriate data, including underutilized data that exist in the long tail of science. We demonstrate the NeuroBridge prototype and its ability to search PubMed Central full-text papers for information relevant to neuroimaging data collected from schizophrenia and addiction studies. Methods: The NeuroBridge architecture contained the following components: (1) Extensible ontology for modeling study metadata: subject population, imaging techniques, and relevant behavioral, cognitive, or clinical data. Details are described in the companion paper in this special issue; (2) A natural-language based document processor that leveraged pre-trained deep-learning models on a small-sample document corpus to establish efficient representations for each article as a collection of machine-recognized ontological terms; (3) Integrated search using ontology-driven similarity to query PubMed Central and NeuroQuery, which provides fMRI activation maps along with PubMed source articles. Results: The NeuroBridge prototype contains a corpus of 356 papers from 2018 to 2021 describing schizophrenia and addiction neuroimaging studies, of which 186 were annotated with the NeuroBridge ontology. The search portal on the NeuroBridge website https://neurobridges.org/ provides an interactive Query Builder, where the user builds queries by selecting NeuroBridge ontology terms to preserve the ontology tree structure. For each return entry, links to the PubMed abstract as well as to the PMC full-text article, if available, are presented. For each of the returned articles, we provide a list of clinical assessments described in the Section "Methods" of the article. Articles returned from NeuroQuery based on the same search are also presented. Conclusion: The NeuroBridge prototype combines ontology-based search with natural-language text-mining approaches to demonstrate that papers relevant to a user's research question can be identified. The NeuroBridge prototype takes a first step toward identifying potential neuroimaging data described in full-text papers. Toward the overall goal of discovering "enough data of the right kind," ongoing work includes validating the document processor with a larger corpus, extending the ontology to include detailed imaging data, and extracting information regarding data availability from the returned publications and incorporating XNAT-based neuroimaging databases to enhance data accessibility.

Evaluation of macular perfusion in eyes with proliferative diabetic retinopathy using optical coherence tomography - Angiography following panretinal photocoagulation.

AIM: The aim of this study is to evaluate the effect of panretinal photocoagulation (PRP) on macular perfusion using optical coherence tomography-angiography (OCT-A) in eyes with proliferative diabetic retinopathy (PDR) by assessing the vessel density (VD) and the size of the foveal avascular zone (FAZ) of the superficial capillary plexus (SCP) and the deep capillary plexus (DCP), before and after PRP. SETTINGS AND DESIGN: Prospective interventional study. SUBJECTS AND METHODS: Twenty-nine eyes of 17 patients with PDR underwent a measurement of best-corrected visual acuity (BCVA) and were imaged using OCT and OCT-A at baseline and 6-months of follow-up. Patients received three sittings of PRP using frequency-doubled neodymium-doped yttrium aluminum garnet laser. STATISTICAL ANALYSIS USED: The OCT-A variables were analyzed using generalized estimating equations. RESULTS: BCVA was unchanged at 6-months follow-up (P = 0.09). FAZ of SCP and DCP (P = 0.28 and 0.89, respectively), VD at foveal SCP (P = 0.08), foveal DCP (P = 0.05), parafoveal SCP (P = 0.13), and parafoveal DCP (P = 0.07) showed no statistically significant difference at 6 months post PRP. CONCLUSIONS: OCT-A parameters were not significantly affected by PRP at 6-months follow-up indicating no alteration in macular perfusion. Further analyses with larger samples and longer duration are warranted to confirm our results.

Deep learning model using retinal vascular images for classifying schizophrenia.

Contemporary psychiatric diagnosis still relies on the subjective symptom report of the patient during a clinical interview by a psychiatrist. Given the significant variability in personal reporting and differences in the skill set of psychiatrists, it is desirable to have objective diagnostic markers that could help clinicians differentiate patients from healthy individuals. A few recent studies have reported retinal vascular abnormalities in patients with schizophrenia (SCZ) using retinal fundus images. The goal of this study was to use a trained convolution neural network (CNN) deep learning algorithm to detect SCZ using retinal fundus images. A total of 327 subjects [139 patients with Schizophrenia (SCZ) and 188 Healthy volunteers (HV)] were recruited, and retinal images were acquired using a fundus camera. The images were preprocessed and fed to a convolution neural network for the classification. The model performance was evaluated using the area under the receiver operating characteristic curve (AUC). The CNN achieved an accuracy of 95% for classifying SCZ and HV with an AUC of 0.98. Findings from the current study suggest the potential utility of deep learning to classify patients with SCZ and assist clinicians in clinical settings. Future studies need to examine the utility of the deep learning model with retinal vascular images as biomarkers in schizophrenia with larger sample sizes.

Association between retinal vascular measures and brain white matter lesions in schizophrenia.

OBJECTIVE: Recent studies have examined retinal vascular abnormalities in schizophrenia as retinal vascular imaging is a non-invasive proxy to cerebral microvasculature. However, relation between retinal vascular abnormalities and brain structure is not well examined in schizophrenia. Hence in this study, for the first time, we examined the relationship between retinal vascular measures and brain white matter lesions in schizophrenia. We examined brain white matter lesions as they are considered a predictive marker for future adverse cerebrovascular event. METHODS: We acquired retinal vascular images of both eyes using a non-mydriatic camera and calculated retinal vascular diameter, tortuosity, trajectory and fractal dimension using validated methods. All patients underwent Magnetic Resonance Imaging of bran and we computed white matter hypo-intensities using Freesurfer software. We performed a linear regression analysis to examine the relationship between white matter hypo-intensities and retinal vascular measures controlling for age, sex, fasting blood sugar, creatinine, whole-brain volume, and antipsychotic dose. RESULTS: The regression model was significant in Schizophrenia patients (R=0.983;R2 =0.966;-F=10.849;p = 0.008) but not in healthy volunteers (R=0.828;R2 =0.686;F=0.182; p = 0.963). Among the retinal vascular measures, arterial tortuosity (ß = 0.963;p-0.002), tortuosity (ß = -1.002;p = 0.001) and fractal dimension (ß = -0.688;p = 0.014) were significant predictors of white matter lesions. DISCUSSION: The current study's findings support the conclusion that retinal vascular fractal dimension and tortuosity are associated with changes in cerebral white matter and may be considered proxy markers for cerebral microvasculature in schizophrenia. Considering the relationship between white matter lesions and stroke, these observations could have important clinical implications to screen schizophrenia patients for risk of adverse cerebrovascular event.

Enabling Scientific Reproducibility through FAIR Data Management: An ontology-driven deep learning approach in the NeuroBridge Project.

Scientific reproducibility that effectively leverages existing study data is critical to the advancement of research in many disciplines including neuroscience, which uses imaging and electrophysiology modalities as primary endpoints or key dependency in studies. We are developing an integrated search platform called NeuroBridge to enable researchers to search for relevant study datasets that can be used to test a hypothesis or replicate a published finding without having to perform a difficult search from scratch, including contacting individual study authors and locating the site to download the data. In this paper, we describe the development of a metadata ontology based on the World Wide Web Consortium (W3C) PROV specifications to create a corpus of semantically annotated published papers. This annotated corpus was used in a deep learning model to support automated identification of candidate datasets related to neurocognitive assessment of subjects with drug abuse or schizophrenia using neuroimaging. We built on our previous work in the Provenance for Clinical and Health Research (ProvCaRe) project to model metadata information in the NeuroBridge ontology and used this ontology to annotate 51 articles using a Web-based tool called Inception. The Bidirectional Encoder Representations from Transformers (BERT) neural network model, which was trained using the annotated corpus, is used to classify and rank papers relevant to five research hypotheses and the results were evaluated independently by three users for accuracy and recall. Our combined use of the NeuroBridge ontology together with the deep learning model outperforms the existing PubMed Central (PMC) search engine and manifests considerable trainability and transparency compared with typical free-text search. An initial version of the NeuroBridge portal is available at: https://neurobridges.org/.

Association between retinal vascular caliber and brain structure in schizophrenia.

OBJECTIVE: Several lines of research in the last decade have indicated the potential utility of retina as a window to the brain. Emerging evidence suggests abnormalities in retinal vascular caliber in schizophrenia. However, the relationship between retinal vascular measures and brain structure has not been examined in schizophrenia to date. Hence, we examined the relationship between retinal vasculature measured using fundus photography and brain structure measured using magnetic resonance imaging. METHOD: We recruited 17 healthy volunteers and 20 patients with schizophrenia. Using a non-mydriatic camera, we captured the images for left and right eyes separately and retinal vascular calibers were calculated using a semi-automated software package. Whole-brain anatomical T1 MPRAGE images were acquired using a 3-Tesla MRI scanner. Whole-brain and regional volume and cortical thickness were calculated using the Freesurfer software package. We used FreeSurfer's QDEC interface to compute vertex-by-vertex for analysis of the volume and cortical thickness. The relation between brain volume, cortical thickness, and retinal vascular caliber was examined using partial correlation and regression analysis. RESULTS: There was a significant negative correlation between average CRVE and global cortical mean thickness in schizophrenia but not in healthy. In schizophrenia patients, there was a significant negative correlation between average CRVE and cortical thickness in frontal regions - left rostral middle frontal, left superior frontal, and right caudal middle frontal gyri and posterior brain regions - left lateral occipital gyrus and left posterior cingulate cortex. DISCUSSION: The findings of the study suggest potential utility of retinal venular diameter as a proxy marker to abnormal neurodevelopment in schizophrenia.

Relation between retinal vascular abnormalities and working memory impairment in patients with schizophrenia and bipolar disorder.

Emerging evidence indicates abnormal retinal micro-vasculature in schizophrenia (SCZ) and bipolar disorder (BD) and its relation to cognitive functions. However, the association of these abnormalities with the cognitive deficits in these disorders has not been examined till date. Hence, we explored this aspect in patients with SCZ, BD, and healthy volunteers (HV). We examined 34 with SCZ, 39 with BD, and 45 HV. Retinal images were acquired using nonmydriatic fundus camera. The retinal images were analyzed, and average diameters of retinal arterioles and venules were calculated. Working memory was assessed using computerized one-back test from Cogstate® battery. There was significant difference between groups in retinal venules and arterioles caliber (p < 0.001). Both SCZ and BD patients had wider venules and narrower arterioles. They had significantly lower working memory accuracy (p = 0.008) and higher log mean speed (p < 0.001). There was significant positive correlation between one-back test accuracy and retinal arteriolar caliber (r = 0.22; p = 0.01) and between log mean speed score and retinal venular caliber (r = 0.20; p = 0.02). Findings suggest association between working memory and retinal vascular caliber, a potential pointer towards understanding the vascular pathology in cognitive deficits in SCZ and BD. Future studies need to examine whether retinal vascular could be a biomarker for SCZ and BD.

Retinal vascular tortuosity in schizophrenia and bipolar disorder.

The micro-vasculature of retina and brain share common morphological, physiological, and pathological properties. Retina being easily accessible, retinal vascular examination provides an indirect assessment of cerebral vasculature. Considering the high prevalence of vascular morbidity in SCZ and BD a few studies have examined retinal vascular caliber and have reported increased retinal venular caliber in schizophrenia (SCZ). Retinal vascular tortuosity could serve as a better structural measure than caliber as it is static and less susceptible to pulse period variations. However, to date, no study has examined retinal vascular tortuosity in SCZ and bipolar disorder (BD). Hence, we examined retinal vascular tortuosity in comparison with healthy volunteers (HV). We included 255 subjects (78 HV, 79 SCZ, and 86 BD) in the age range of 18 to 50 years. Trained personnel acquired images using a non-mydriatic fundus camera. To measure the average retinal arteriolar tortuosity index (RATI) and retinal venular tortuosity index (RVTI), we used a previously validated, semi-automatic algorithm. The results showed significant differences across the three groups in RATI but not in RVTI; both BD and SCZ had significantly increased RATI compared to HV. There was also a significant difference between SCZ and BD, with BD having higher RATI. If shown to be of predictive utility in future longitudinal studies, it has the potential to identify patients at risk of development of adverse vascular events. As retinal vascular imaging is non-invasive and inexpensive, it could serve as a proxy marker and window to cerebral vasculature.

Retinal vascular fractal dimension in bipolar disorder and schizophrenia.

BACKGROUND: Bipolar disorder (BD) and schizophrenia (SCZ), are associated with greater vascular co-morbidities and adverse vascular events. Owing to shared developmental origins and morphology, retinal vasculature is a proxy assessment measure of the cerebral vasculature. Although retinal vascular fractal dimension (Df), a measure of vascular geometry and complexity of branching, has been shown to be directly associated with cerebrovascular pathology, it has not been examined in SCZ and BD. METHODS: We studied 277 participants (92 healthy volunteers, 98 SCZ, and 87 BD) from 18 to 50 years of age. Images were acquired by trained personnel using a non-mydriatic fundus camera and the retinal vascular Df was calculated by the box-counting method using an automated algorithm. The average Df across the left and right eyes were calculated. RESULTS: Both SCZ and BD had significantly increased Df compared to HV despite controlling for possible confounding factors. However, there was no significant difference between SCZ and BD. These findings suggest abnormal retinal vascular Df in psychoses. LIMITATIONS: The study design was cross-sectional, and patients were on medications. Confound of lifestyle factors such as diet and exercise, if any, was not controlled. Sub-group analysis between BD-I and BD-II was not performed in view of the small sample. CONCLUSIONS: Considering the easy accessibility, affordability, and non-invasive nature of the examination, retinal vascular Df could serve as a surrogate marker for cerebral vascular abnormality and could potentially identify BD and SCZ patients at risk of developing adverse vascular events.

Characteristics and quantification of vascular changes in macular telangiectasia type 2 on optical coherence tomography angiography.

BACKGROUND: Macular telangiectasia type 2 (MacTel 2) is a bilateral idiopathic, rare neurodegenerative disease with alterations in the macular capillary network leading to vision loss and is the most common of three subtypes. Optical coherence tomography angiography (OCTA) is a non-invasive imaging modality which helps understand the complex pathological changes, and images the blood vessels across different layers based on their flow characteristics. METHODS: A cross-sectional study was conducted on 56 eyes of Asian Indian eyes of 28 consecutive patients with MacTel 2 studied during a 3-month period in a tertiary eye care hospital of South India. Clinically diagnosed cases of MacTel 2 underwent fundus photography, spectral domain OCT and OCTA. Fluorescein angiography was performed only when clinically indicated. Mean capillary density was calculated using a MATLAB-based automated software. The images were thresholded and binarised to derive the mean value. RESULTS: The mean age at presentation was 60±5.2, with a female preponderance of 71.42%. Vascular network on OCTA shows an increase in the intervascular spaces with progressive capillary rarefaction and abnormal capillary anastomosis. The outer retina and choroid were involved during the later stages and showed a prominent vascular network. The mean capillary density of the superficial and deep layers was 39.99% and 39.03% as against 45.18% and 44.21% in the controls, respectively. There was a statistically significant difference between the two groups (p<0.01). There is a positive and statistically significant correlation between the superficial and deep layers. CONCLUSION: OCTA helps understand the pathology and disease progression better in MacTel 2.