Abstract
The diagnosis of schizophrenia is thought to embrace several distinct subgroups. The manifold entities in a single clinical patient group increase the variance of biological measures, ...deflate the group-level estimates of causal factors, and mask the presence of treatment effects. However, reliable neurobiological boundaries to differentiate these subgroups remain elusive. Since cortical thinning is a well-established feature in schizophrenia, we investigated if individuals (patients and healthy controls) with similar patterns of regional cortical thickness form naturally occurring morphological subtypes. K-means algorithm clustering was applied to regional cortical thickness values obtained from 256 structural MRI scans (179 patients with schizophrenia and 77 healthy controls HCs). GAP statistics revealed three clusters with distinct regional thickness patterns. The specific patterns of cortical thinning, clinical characteristics, and cognitive function of each clustered subgroup were assessed. The three clusters based on thickness patterns comprised of a morphologically impoverished subgroup (25% patients, 1% HCs), an intermediate subgroup (47% patients, 46% HCs), and an intact subgroup (28% patients, 53% HCs). The differences of clinical features among three clusters pertained to age-of-onset, N-back performance, duration exposure to treatment, total burden of positive symptoms, and severity of delusions. Particularly, the morphologically impoverished group had deficits in N-back performance and less severe positive symptom burden. The data-driven neuroimaging approach illustrates the occurrence of morphologically separable subgroups in schizophrenia, with distinct clinical characteristics. We infer that the anatomical heterogeneity of schizophrenia arises from both pathological deviance and physiological variance. We advocate using MRI-guided stratification for clinical trials as well as case–control investigations in schizophrenia.
Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. ...In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high-frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)—increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal–striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling of resting state fMRI in a sample of 19 first episode psychosis subjects. We found that the total score of positive symptoms of schizophrenia is strongly associated with the frontostriatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as decreased bidirectional excitatory influence between the LDLPFC and the LSTR is related to the severity of positive symptoms, especially delusions. We interpret that an increase in striatal dopaminergic tone that underlies positive symptoms is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal ‘brake’. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low-frequency (1 Hz) rTMS of the prefrontal area.
Schizophrenia and related psychoses are complex neuropsychiatric diseases representing dysconnectivity across multiple scales, through the micro (cellular), meso (brain network), manifest ...(behavioral), and social (interpersonal) levels.
human neuroimaging, particularly at ultra-high field (UHF), offers unprecedented opportunity to examine multiscale dysconnectivity in psychosis. In this review, we provide an overview of the literature to date on UHF in psychosis, focusing on microscale findings from magnetic resonance spectroscopy (MRS), mesoscale studies on structural and functional magnetic resonance imaging (fMRI), and multiscale studies assessing multiple neuroimaging modalities and relating UHF findings to behavior. We highlight key insights and considerations from multiscale and longitudinal studies and provide recommendations for future research on UHF neuroimaging in psychosis.
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.
A striking feature of psychosis is its heterogeneity. Presentations of psychosis vary from transient symptoms with no functional consequence in the general population to a tenacious illness at the ...other extreme, with a wide range of variable trajectories in between. Even among patients with schizophrenia, who are diagnosed on the basis of persistent deterioration, marked variation is seen in response to treatment, frequency of relapses and degree of eventual recovery. Existing theoretical accounts of psychosis focus almost exclusively on how symptoms are initially formed, with much less emphasis on explaining their variable course. In this review, I present an account that links several existing notions of the biology of psychosis with the variant clinical trajectories. My aim is to incorporate perspectives of systems neuroscience in a staging framework to explain the individual variations in illness course that follow the onset of psychosis.
Recent genetic evidence implicates glutamatergic-receptor variations in schizophrenia. Glutamatergic excess during early life in people with schizophrenia may cause excitotoxicity and produce ...structural deficits in the brain. Cortical thickness and gyrification are reduced in schizophrenia, but only a subgroup of patients exhibits such structural deficits. We delineate the structural variations among unaffected siblings and patients with schizophrenia and study the role of key glutamate-receptor polymorphisms on these variations.
Gaussian Mixture Model clustering was applied to the cortical thickness and gyrification data of 114 patients, 112 healthy controls, and 42 unaffected siblings to identify subgroups. The distribution of glutamate-receptor (GRM3, GRIN2A, and GRIA1) and voltage-gated calcium channel (CACNA1C) variations across the MRI-based subgroups was studied. The comparisons in clinical symptoms and cognition between patient subgroups were conducted.
We observed a "hypogyric," "impoverished-thickness," and "supra-normal" subgroups of patients, with higher negative symptom burden and poorer verbal fluency in the hypogyric subgroup and notable functional deterioration in the impoverished-thickness subgroup. Compared to healthy subjects, the hypogyric subgroup had significant GRIN2A and GRM3 variations, the impoverished-thickness subgroup had CACNA1C variations while the supra-normal group had no differences.
Disrupted gyrification and thickness can be traced to the glutamatergic receptor and voltage-gated calcium channel dysfunction respectively in schizophrenia. This raises the question of whether MRI-based multimetric subtyping may be relevant for clinical trials of agents affecting the glutamatergic system.
Converging evidence links schizophrenia risk to synaptic dysfunction due to genetic variants. Synaptic dysplasticity in at-risk individuals lead to excessive synapse elimination, impacting brain ...connectivity. MRI studies highlight initial hyperconnectivity followed by later hypoconnectivity, impacting information transmission. Imbalance between Hebbian and homeostatic plasticity likely causes this shift. Highly connected hub regions of the brain experience synapse reduction, causing what we call as ‘global retuning’. Such post-psychotic changes aid resolution of active symptoms but lead to cognitive and motivational deficits. Antipsychotics may restore connectivity but worsen cognitive symptoms. In this framework, we present schizophrenia as an illness with disrupted ‘topological homeostasis’ due to synaptic dysplasticity. Our framework leaves room for an intrinsic, albeit inefficient, antipsychotic defense process that aids in adaptation. Studying successful adaptation in animal models and recovered individuals is crucial to design avant-garde interventions for schizophrenia.
•Genetic variants link schizophrenia risk to synaptic dysfunction, impacting brain connectivity.•MRI reveals initial hyperconnectivity followed by hypoconnectivity, affecting brain information transmission.•Highly connected brain hubs undergo synapse reduction, influencing symptom resolution and cognitive deficits.
Oxidative stress plays a key role in the pathophysiology of schizophrenia. While free radicals produced by glutamatergic excess and oxidative metabolism have damaging effects on brain tissue, ...antioxidants such as glutathione (GSH) counteract these effects. The interaction between glutamate (GLU) and GSH is centered on N-Methyl-D-aspartate (NMDA) receptors. GSH levels increase during glutamate-mediated excitatory neuronal activity, which serves as a checkpoint to protect neurons from oxidative damage and reduce excitatory overdrive. We studied the possible influence of GSH on the glutamate-mediated dysconnectivity in 19 first-episode schizophrenia (FES) patients and 20 healthy control (HC) subjects. Using ultra-high field (7 Tesla) magnetic resonance spectroscopy (MRS) and resting state functional magnetic resonance imaging (fMRI), we measured GSH and GLU levels in the dorsal anterior cingulate cortex (dACC) and blood-oxygenation level-dependent activity in both the dACC and the anterior insula (AI). Using spectral dynamic causal modeling, we found that when compared to HCs, in FES patients inhibitory activity within the dACC decreased with GLU levels whereas inhibitory activity in both the dACC and AI increased with GSH levels. Our model explains how higher levels of GSH can reverse the downstream pathophysiological effects of a hyperglutamatergic state in FES. This provides an initial insight into the possible mechanistic effect of antioxidant system on the excitatory overdrive in the salience network (dACC-AI).
PDF
