Lena Palaniyappan

Clinical utility of a short resting-state MRI scan in differentiating bipolar from unipolar depression

Depression in bipolar disorder (BipD) requires a therapeutic approach that is from treating unipolar major depressive disorder (UniD), but to date, no reliable methods could separate these two disorders. The aim of this study was to establish the clinical validity and utility of a non‐invasive functional MRI‐based method to classify BipD from UniD.

Abnormally increased and incoherent resting-state activity is shared between patients with schizophrenia and their unaffected siblings

BACKGROUND Several resting-state neuroimaging studies in schizophrenia indicate an excessive brain activity while others report an incoherent brain activity at rest. No direct evidence for the simultaneous presence of both excessive and incoherent brain activity has been established to date. Moreover, it is unclear whether unaffected siblings of schizophrenia patients who share half of the affected patients genotype also exhibit the excessive and incoherent brain activity that may render them vulnerable to the development of schizophrenia. METHODS 27 pairs of schizophrenia patients and their unaffected siblings, as well as 27 healthy controls, were scanned using gradient-echo echo-planar imaging at rest. By using amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (Reho), we investigated the intensity and synchronization of local spontaneous neuronal activity in three groups. RESULTS We observed that increased amplitude and reduced synchronization (coherence) of spontaneous neuronal activity were shared by patients and their unaffected siblings. The key brain regions with this abnormal neural pattern in both patients and siblings included the middle temporal, orbito-frontal, inferior occipital and fronto-insular gyrus. CONCLUSIONS This abnormal neural pattern of excessive and incoherent neuronal activity shared by schizophrenia patients and their healthy siblings may improve our understanding of neuropathology and genetic predisposition in schizophrenia.

Progressive cortical reorganisation: A framework for investigating structural changes in schizophrenia

Graphical abstract The process of cortical reorganization in schizophrenia: deficiency in NMDA receptor function produces excitation‐inhibition (EI) imbalance that affects the normal transmission of information across synapses, contributing to a ‘bottleneck effect’ at brain regions that have rich long‐distance multisynaptic cortical connections (i.e. cortical hubs). Functional defects in synaptic communication convert hubs to cliques of resistance, whereby diffusion of neuronal information becomes protracted and inefficient when routed through them. The cortical reorganization seen in schizophrenia is a response to this defect. The reorganization process intends to de‐escalate cortical hubs by reducing the clustering of connections around hubs ‐ either through excitatory synaptic elimination or accelerated intracortical myelination or both. But reorganization does not restore the synaptic efficiency per se; instead, it only serves to have a ‘re‐routing’ effect, so alternate ‘longer’ paths of communication can now be preferentially utilised for recruiting extant regions in the service of a brain function. Symbol. No caption available. HighlightsProgressive Grey Matter Changes (PGMC) are spatially concentrated in the topological hubs of the brain.PGMC are temporally concentrated in the immediate post‐onset phase of schizophrenia.Subtle increases in GM tissue accompany PGMC in schizophrenia.PGMC in schizophrenia represent a remodeling response. Abstract One of the few well‐replicated features of schizophrenia is the demonstration of neuroanatomical abnormalities affecting cortical and subcortical grey matter (GM). Evidence to date suggests that the greatest reduction in GM occurs in the immediate post‐onset phase. The predominant view to date is that the accelerated grey matter (GM) loss represents an adverse process (degenerative or developmental deficit) contributing to the unfavourable course of schizophrenia. This prevailing emphasis on decompensation often overlooks the fact that human brain has an inherent capacity to remodel itself in response to insults that affect its function. In the wake of emerging insights into both micro‐ and macro‐scale brain connectivity, a substantial amount of the longitudinal structural changes seen in patients with schizophrenia could result from a distributed, nevertheless inefficient, cortical reorganization response. Quantifying cortical reorganization in the early stages of illness can enable prospective grading of the underlying pathophysiological process in schizophrenia.

Effective connectivity within a triple network brain system discriminates schizophrenia spectrum disorders from psychotic bipolar disorder at the single-subject level

OBJECTIVE Schizophrenia spectrum disorders (SSD) and psychotic bipolar disorder share a number of genetic and neurobiological features, despite a divergence in clinical course and outcome trajectories. We studied the diagnostic classification potential that can be achieved on the basis of the structure and connectivity within a triple network system (the default mode, salience and central executive network) in patients with SSD and psychotic bipolar disorder. METHODS Directed static connectivity and its dynamic variance was estimated among 8 nodes of the three large-scale networks. Multivariate autoregressive models of deconvolved resting state functional magnetic resonance imaging time series were obtained from 57 patients (38 with SSD and 19 with bipolar disorder and psychosis). We used 2/3 of the patients for training and validation of the classifier and the remaining 1/3 as an independent hold-out test data for performance estimation. RESULTS A high level of discrimination between bipolar disorder with psychosis and SSD (combined balanced accuracy = 96.2%; class accuracies 100% for bipolar and 92.3% for SSD) was achieved when effective connectivity and morphometry of the triple network nodes was combined with symptom scores. Patients with SSD were discriminated from patients with bipolar disorder and psychosis as showing higher clinical severity of disorganization and higher variability in the effective connectivity between salience and executive networks. CONCLUSIONS Our results support the view that the study of network-level connectivity patterns can not only clarify the pathophysiology of SSD but also provide a measure of excellent clinical utility to identify discrete diagnostic/prognostic groups among individuals with psychosis.

Disparities in Access to Early Psychosis Intervention Services: Comparison of Service Users and Nonusers in Health Administrative Data

Objective: There is a dearth of information on people with first-episode psychosis who do not access specialized early psychosis intervention (EPI) services. We sought to estimate the proportion of incident cases of nonaffective psychosis that do not access these services and to examine factors associated with EPI admission. Methods: Using health administrative data, we constructed a retrospective cohort of incident cases of nonaffective psychosis in the catchment area of the Prevention and Early Intervention Program for Psychoses (PEPP) in London, Ontario, between 1997 and 2013. This cohort was linked to primary data from PEPP to identify EPI users. We used multivariate logistic regression to model sociodemographic and service factors associated with EPI admission. Results: Over 50% of suspected cases of nonaffective psychosis did not have contact with EPI services for screening or admission. EPI users were significantly younger, more likely to be male (odds ratio [OR] 1.58; 95% confidence interval [CI] 1.24 to 2.01), and less likely to live in areas of socioeconomic deprivation (OR 0.51; 95% CI 0.36 to 0.73). EPI users also had higher odds of psychiatrist involvement at the index diagnosis (OR 7.35; 95% CI 5.43 to 10.00), had lower odds of receiving the index diagnosis in an outpatient setting (OR 0.50; 95% CI 0.38 to 0.65), and had lower odds of prior alcohol-related (OR 0.42; 95% CI 0.28 to 0.63) and substance-related (OR 0.68; 95% CI 0.50 to 0.93) disorders. Conclusions: We need a greater consideration of patients with first-episode psychosis who are not accessing EPI services. Our findings suggest that this group is sizable, and there may be sociodemographic and clinical disparities in access. Nonpsychiatric health professionals could be targeted with interventions aimed at increasing detection and referral rates.

Glutathione and glutamate in schizophrenia: a 7T MRS study

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with “residual schizophrenia”, in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione–glutamate component; an insula-visual glutathione–glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione–glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Topographic diversity of structural connectivity in schizophrenia

The neurobiological heterogeneity of schizophrenia is widely accepted, but it is unclear how mechanistic differences converge to produce the observed phenotype. Establishing a pathophysiological model that accounts for both heterogeneity and phenotypic similarity is essential to inform stratified treatment approaches. In this cross-sectional diffusion tensor imaging (DTI) study, we recruited 77 healthy controls (HC), and 71 patients with DSM-IV diagnosis of schizophrenia (SCZ), and reconstructed the structural connectivity of 90 brain regions covering entire cerebral cortex. We first confirmed the heterogeneity in structural connectivity by showing a reduced inter-individual similarity in SCZ compared with HC. Moreover, we found it was not possible to cluster patients into subgroups with shared patterns of dysconnectivity, indicating a high degree of mechanistic divergence in schizophrenia. Instead of the strength of connectivity between any particular brain regions, we investigated the diversity (or statistically, the variance) of the topographic distribution of the strength was reduced. HC had higher topographic diversity in whole brain structural connectivity compared to the patient group (P = 2 × 10−6, T = 4.96, Cohen′S d = 0.87). In 62 of the 90 brain regions, the topographic diversity was significantly reduced in patients compared to controls after FDR correction (<0.05). When topographic diversity was used as a discriminant feature for classification between patients and controls, we significantly (P = 4.29 × 10−24) improved the classification accuracy to 79.6% (sensitivity 78.3%, specificity 81.3%). This finding suggests highly individualized pattern of structural dysconnectivity underlying the heterogeneity of schizophrenia converges to a convergent common pathway as reduced topographic diversity for the clinical construct of the disease.

Effects of tumor necrosis factor-α polymorphism on the brain structural changes of the patients with major depressive disorder

Single Nucleotide Polymorphic (SNP) variations of proinflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α) have been reported to be closely associated with the major depressive disorder (MDD). However, it is unclear if proinflammatory genetic burden adversely affects the regional gray matter volume in patients with MDD. The aim of this study was to test whether rs1799724, an SNP of TNF-α, contributes to the neuroanatomical changes in MDD. In this cross-sectional study, a total of 144 MDD patients and 111 healthy controls (HC) well matched for age, sex and education were recruited from Shanghai Mental Health Center. Voxel-based morphometry (VBM) followed by graph theory based structural covariance analysis was applied to locate diagnosis x genotype interactions. Irrespective of diagnosis, individuals with the high-risk genotype (T-carriers) had reduced volume in left angular gyrus (main effect of genotype). Diagnosis x genotype interaction was exclusively localized to the visual cortex (right superior occipital gyrus). The same region also showed reduced volume in patients with MDD than HC (main effect of diagnosis), with this effect being most pronounced in patients carrying the high-risk genotype. However, neither global nor regional network of structural covariance was found to have group difference. In conclusion, a genetic variation which can increase TNF-α expression selectively affects the anatomy of the visual cortex among the depressed subjects, with no effect on the topographical organization of multiple cortical regions. This supports the notion that anatomical changes in depression are in part influenced by the genetic determinants of inflammatory activity.

Unmet need for mental health services among people screened but not admitted to an early psychosis intervention program

Information is lacking on people screened for early psychosis intervention (EPI) but not admitted to the program. Using health administrative data, we constructed a retrospective cohort of incident cases of psychosis in the catchment of an EPI program. Use of mental health services was compared between people screened and not admitted with an EPI-admitted group. The non-admitted group had higher rates of subsequent emergency department visits, psychiatric hospitalizations, and involuntary admissions. These patterns are indicative of unmet need, and people screened but not admitted to EPI may benefit from protocols to improve transitions of care with other service providers.

S123. TREATMENT RESISTANT SCHIZOPHRENIA AND GYRIFICATION-BASED CONNECTOME

Abstract Background Treatment-resistant schizophrenia (TRS) is a major cause of disability and functional impairment worldwide. Approximately 30% of patients with schizophrenia will develop TRS at some point during their illness course. Despite the staggering financial and emotional costs associated with TRS, this severe disorder is poorly understood. The pathophysiological basis of TRS is posited in part to have neurodevelopmental roots. If early brain development (<2 years of age) influences TRS, then cortical gyrification, which is often complete by 2 years of life, could be abnormal in TRS when compared to non-TRS subjects. Subtle but diffuse pathological changes that occur during early development are postulated to disrupt the maturational relationship (covariance) among brain regions, even if no localised morphological changes are seen in adult life. The disrupted structural covariance resulting from diffuse developmental dyscoordination in early life can be quantified using gyrification-based connectomes obtained using graph theory. We applied this method to baseline MRI data collected during first contact with mental health services for psychosis to predict the emergence of TRS in the next 5 years. Methods 70 patients with first episode schizophrenia spectrum disorder who presented to mental health services between 2005 and 2010 were followed up for 5 years using electronic case notes. Psychopathology was assessed at baseline with the Positive and Negative Syndrome Scale (PANSS) and symptom dimensions were derived using Wallwork’s model. TRS was defined according to Health and Clinical Excellence guidelines. Structural MRI images were obtained at baseline, with minimal exposure to antipsychotics (<3 months). Local gyrification indices were computed using Schaer’s method for 68 contiguous cortical regions (34 in each hemisphere) using Freesurfer’s Desikan atlas. After adjusting for age, gender and intracranial volume, group-based structural covariance was estimated (68x68 correlation indices) and each subject’s contribution to the covariance was quantified using a jack-knife procedure, providing one distance matrix for each subject. These matrices were used to construct distance-based gyrification connectomes using Graph Analysis Toolbox. We used a functional data analysis approach across a range of cost-thresholds to reduce multiple testing when comparing TRS and non-TRS groups. Results 17 (24.3%) of patients with first episode schizophrenia spectrum disorder met criteria for TRS at the end of the 5 years of follow up; 53 (75.7%) were non-TRS. TRS subjects had a significant reduction in small-worldness compared to non-TRS group (Hedges’s g=2.09, p<0.001) and reduced clustering coefficient (Hedges’s g=1.07, p<0.001) with increased path length (Hedges’s g=-2.17, p<0.001).The positive symptoms were positively correlated (after adjusting for age, gender and TRS status) with higher small-worldness (r=0.414, p=0.001) suggesting that a predominantly hyperdopaminergic status that induces positive symptoms may relate to preserved small-worldness seen in non-TRS individuals, while subtle developmental changes resulting in reduced small-worldness may underlie TRS. Discussion These changes suggest that in the presence of TRS, the cortex-wide covariance in folding patterns become less organized, with reduced regional segregation as well as reduced overall integration of the morphological connectome. Such an effect may result from weakening of the tensions that arise from inter-regional connectivity in the neonatal brain. The emergence of TRS may be characterised by a neurodevelopmentally driven abnormality in structural organisation of the human cortex in those who develop schizophrenia.