Effect of Intranasal Oxytocin on Resting-state Effective Connectivity in Schizophrenia.

OBJECTIVES: Evidence from several lines of research suggests the critical role of neuropeptide oxytocin in social cognition and social behavior. Though a few studies have examined the effect of oxytocin on clinical symptoms of schizophrenia, the underlying neurobiological changes are underexamined. Hence, in this study, we examined the effect of oxytocin on the brain's effective connectivity in schizophrenia. METHODS: 31 male patients with schizophrenia (SCZ) and 21 healthy male volunteers (HV) underwent resting functional magnetic resonance imaging scans with intra-nasal oxytocin (24 IU) and placebo administered in counterbalanced order. We conducted a whole-brain effective connectivity analysis using a multivariate vector autoregressive granger causality model. We performed a conjunction analysis to control for spurious changes and canonical correlation analysis between changes in connectivity and clinical and demographic variables. RESULTS: Three connections, sourced from the left caudate survived the FDR correction threshold with the conjunction analysis; connections to the left supplementary motor area, left precentral gyrus, and left frontal inferior triangular gyrus. At baseline, SCZ patients had significantly weaker connectivity from caudate to these three regions. Oxytocin, but not placebo, significantly increased the strength of connectivity in these connections. Better cognitive insight and lower negative symptoms were associated with a greater increase in connectivity with oxytocin. CONCLUSIONS: These findings provide a preliminary mechanistic understanding of the effect of oxytocin on brain connectivity in schizophrenia. The study findings provide the rationale to examine the potential utility of oxytocin for social cognitive deficits in schizophrenia.

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.

Stimulus-induced gamma rhythms are weaker in human elderly with mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) in elderly adds substantially to socioeconomic burden necessitating early diagnosis. While recent studies in rodent models of AD have suggested diagnostic and therapeutic value for gamma rhythms in brain, the same has not been rigorously tested in humans. In this case-control study, we recruited a large population (N = 244; 106 females) of elderly (>49 years) subjects from the community, who viewed large gratings that induced strong gamma oscillations in their electroencephalogram (EEG). These subjects were classified as healthy (N = 227), mild cognitively impaired (MCI; N = 12), or AD (N = 5) based on clinical history and Clinical Dementia Rating scores. Surprisingly, stimulus-induced gamma rhythms, but not alpha or steady-state visually evoked responses, were significantly lower in MCI/AD subjects compared to their age- and gender-matched controls. This reduction was not due to differences in eye movements or baseline power. Our results suggest that gamma could be used as a potential screening tool for MCI/AD in humans.

Alzheimer's disease is one of the most common forms of dementia, characterised by declining memory and thinking skills, and behavioural changes that worsen over time. It affects millions of people worldwide, mostly in older age, and yet early indicators of the disease are lacking. Most cases are only diagnosed once a person's brain function becomes noticeably impaired, even though known biological changes underpin the disease. Detecting Alzheimer's disease early could aid diagnosis and enable early intervention, while also improving the chances of finding treatments to halt or reverse the disease. Currently, brain function is measured by performing cognitive tests, such as remembering a set of words, imaging the brain with MRIs or CT scans, and blood or spinal fluid tests. Many of these tests can be invasive and expensive, so researchers are exploring whether measuring oscillations in the brain's electrical activity can be a non-invasive and chepaer way of testing brain function. Gamma oscillations are rhythmic signals, thought to be involved in attention and working memory. Animals used to study Alzheimer's disease have shown some abnormalities in gamma oscillations, and studies of healthy humans have also observed a decline in the strength and frequency of these oscillations with age. These findings have spurred an interest in understanding the link between gamma oscillations and AD in humans. To investigate this link, Murty et al. measured patterns of brain activity in elderly people chosen from the community using electrodes placed on their scalps (a technique called electroencephalography). These participants watched certain images previously shown to elicit gamma oscillations. Participants who were later diagnosed with early Alzheimer's disease had weaker gamma oscillations than their cognitively healthy peers in the part of the brain that processes visual images. These results build upon previous findings from animal research suggesting that gamma oscillations may be disrupted in early Alzheimer's disease. The work by Murty et al. could lead the way to new ways of diagnosing Alzheimer's disease, where early indicators are urgently needed.

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.

Add on yoga treatment for negative symptoms of schizophrenia: A multi-centric, randomized controlled trial.

The efficacy of antipsychotic medications in the treatment of negative symptoms of schizophrenia is modest at best. Preliminary studies suggest the beneficial effects of add on Yoga, a traditional Indian practice, in the treatment of schizophrenia. Hence, in this study, we examined the efficacy of yoga as an add-on treatment for negative symptoms of schizophrenia in a randomized, wait-list controlled design from two clinical institutes in south India. 89 patients (age - 34.20 ± 8.06 years; education - 14.22 ± 2.69 years; 28 females) were randomized into the add-on yoga or treatment as usual (TAU - wait-list control) group. Patients had a mean illness duration of 10.97 ± 7.24 years with an age at onset of 23.34 ± 5.81 years. Central block randomization was followed to ensure concealed allocation. Participants randomized to the yoga treatment group attended 12 supervised yoga training sessions over two weeks and practiced yoga sessions at home for the subsequent 10 weeks. 64 patients completed the trial. An intent to treat analysis was conducted with 89 participants using a linear mixed model. Improvement in negative symptoms was our primary outcome measure. The two groups were matched on demographic variables and baseline psychopathology severity. Participants in the add-on yoga group had significantly greater improvement in negative symptoms (SANS baseline: 49.13 ± 2.30; 12-weeks follow up: 31.55 ± 2.53) compared to the TAU group (SANS baseline: 51.22 ± 2.40; 12-weeks follow up: 45.30 ± 2.93; t = 3.36; p = 0.006; Cohen's d-0.65). The current study findings suggest the efficacy of yoga as an add-on treatment for negative symptoms of schizophrenia. The effectiveness of yoga practice as a regular clinical intervention for patients needs to be explored in future studies by integrating yoga services along with other clinical services.

Comparison of first-episode and multiple-episode bipolar disorder: A surface-based morphometry study.

It is still unclear whether the structural abnormalities in Bipolar disorder (BD) are static or progressive. We aimed to compare differences in cortical thickness, surface area, and volume between patients with BD and healthy volunteers (HV) and to examine whether there are differences between patients who have had a single manic episode and those with multiple episodes. We recruited 30 patients with Type I BD and 30 age and sex matched HV. All participants underwent structural magnetic resonance imaging. Cortical volume, thickness, and surface area were measured using the QDEC tool from the Freesurfer software with age and intracranial volume as covariates. Study groups were comparable across age, sex distribution, and intracranial volume. Patients had significantly lower surface area in bilateral cuneus, right postcentral gyrus, and rostral middle frontal gyri; and lower cortical volume in the left middle temporal gyrus, right postcentral gyrus, and right cuneus. BD patients with multiple episodes had lower cortical measures while those with single episode had cortical measures comparable to HV. Findings indicate that the pathophysiological processes in BD are possibly progressive in nature. Our findings underscore the potential importance of early diagnosis and intervention in preventing deterioration and improving functional recovery.

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.

Effect of psychotic symptoms on cognitive impairment in patients with bipolar disorder.

BACKGROUND: A considerable proportion of patients with bipolar disorder (BD) have psychotic symptoms during the illness. This subset of BD due to its genetic susceptibility and family segregation has considerable overlap with schizophrenia. However, the extent to which BD patients with psychotic symptoms and without psychotic symptoms differ on neurocognitive functions is still not completely clear. AIM: The aim of this study was to examine the neurocognitive functions in BD patients with psychotic symptoms and BD without psychotic symptoms in comparison with healthy volunteers (HVs). MATERIALS AND METHODS: Thirty patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition BD (16 with psychotic symptoms) and thirty age- and sex-matched HVs were recruited in the study. Clinical severity was assessed using structured rating scales. The presence of psychotic symptoms was assessed using the Lifetime Dimensions of Psychosis Scale (LDPS). All patients underwent tests, namely continuous performance test, Stroop Word-Color interference test, and Wisconsin Card Sorting Test, to measure executive functions. Differences between groups were examined using analysis of covariance with age and sex as covariates. RESULTS: There was a significant difference between groups on the performance of all the three tests, with patients performing poorer than HVs. While the HVs differed from both BD with psychotic symptoms and without psychotic symptoms, there was no difference between BD patients with and without psychotic symptoms. There was no significant correlation between LDPS score and scores on neurocognitive tests. CONCLUSION: The study findings, at least with respect to cognitive function, suggest that BD with psychotic symptoms may not be a categorically distinct subtype of BD. Cognitive functions need to be assessed in all patients with BD, regardless of psychotic symptoms, and remediation interventions need to be provided.

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.

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.

Cultural differences and neural correlates of cognitive insight in schizophrenia.

Cognitive insight refers to a person's ability to examine their psychotic experiences and the inferences they draw from these experiences. Several studies suggest that cultural factors influence cognitive insight and the processes involved therein; a few studies have suggested differences between Western and Asian societies. However, there are no studies on cognitive insight and its neural correlates in non-Western populations. Hence, we examined factor structure of Beck's cognitive insight scale (BCIS) in a large sample of patients with schizophrenia (SCZ) and healthy volunteers (HV) from India and assessed the relationship between cortical thickness and cognitive insight. We recruited 240 participants (SCZ-140; HV-100). Of these, 58 participants (SCZ-33; HV-25) underwent magnetic resonance imaging. We found a three-factor structure for BCIS which is different from the original two factor structure; self-reflection (SR) of original two-factor structure was sub-divided into- SR1, introspection and SR2, openness to feedback. There was a significant difference between HV and SCZ in the new factors, SR1 and SR2 but not in the original SR factor. Difference was also seen on MRI analysis; while there was a significant positive correlation between original SR factor and thickness of right posterior cingulate cortex, SR2 was positively correlated with thickness of left ventrolateral prefrontal cortex. The difference in factor structure in Indian participants and their distinct neural correlates point to cultural differences in cognitive insight. While in western societies the constructs of introspection and openness to feedback might integrate, they might be separate entities in Asian population.

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.