S172. GLUTAMATE RELATED CONNECTIVITY DISTURBANCES OF THE SALIENCE AND DEFAULT MODE NETWORKS IN PSYCHOSIS

Abstract Background Cortical dysconnectivity and dysfunctional glutamatergic signalling are both implicated in the pathophysiology of psychotic illness. The relationship between these two systems, and the relevance to psychotic disorders remains unknown. Methods 50 individuals with a psychotic disorder and 54 healthy controls received baseline imaging using 1H-MRS to measure anterior cingulate glutamate concentrations, and resting state MRI to characterise functional brain networks. These measures were subsequently repeated following 3 days treatment with either the glutamatergic regulator riluzole (N=36), or a dopamine antagonist (N=14). The network-based statistic was used to examine relationships between glutamate concentrations and connectivity of the salience and default mode networks in patients and controls, and to investigate how this changed following pharmacological manipulation. Results In healthy controls higher baseline anterior cingulate glutamate concentrations were associated with reduced salience network connectivity, particularly for interhemispheric connections. This pattern was not seen in patients, and the greater the divergence from the relationship observed in controls, the greater the severity of negative symptoms. Default mode-salience internetwork connectivity was greater in patients compared to controls, and inversely correlated with baseline glutamate concentrations. Furthermore, riluzole associated changes in glutamate concentrations were associated with an inverse change in internetwork connectivity suggesting a causal relationship. Discussion Individuals with a psychotic disorder showed marked alterations in the relationship between anterior cingulate cortex glutamate concentration and connectivity of the salience and default mode networks. A pharmacological challenge with a glutamate regulating agent modulated this association, highlighting that the relationship is potentially malleable.

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Glutamate connectivity associations converge upon the salience network in schizophrenia and healthy controls

Translational Psychiatry ◽

10.1038/s41398-021-01455-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Robert A. McCutcheon ◽

Toby Pillinger ◽

Maria Rogdaki ◽

Juan Bustillo ◽

Oliver D. Howes

Keyword(s):

Functional Connectivity ◽

Frontal Cortex ◽

Network Connectivity ◽

Resonance Spectroscopy ◽

Salience Network ◽

Healthy Controls ◽

1H Mrs ◽

Before And After ◽

Functional Brain Networks ◽

The Relationship

AbstractAlterations in cortical inter-areal functional connectivity, and aberrant glutamatergic signalling are implicated in the pathophysiology of schizophrenia but the relationship between the two is unclear. We used multimodal imaging to identify areas of convergence between the two systems. Two separate cohorts were examined, comprising 195 participants in total. All participants received resting state functional MRI to characterise functional brain networks and proton magnetic resonance spectroscopy (1H-MRS) to measure glutamate concentrations in the frontal cortex. Study A investigated the relationship between frontal cortex glutamate concentrations and network connectivity in individuals with schizophrenia and healthy controls. Study B also used 1H-MRS, and scanned individuals with schizophrenia and healthy controls before and after a challenge with the glutamatergic modulator riluzole, to investigate the relationship between changes in glutamate concentrations and changes in network connectivity. In both studies the network based statistic was used to probe associations between glutamate and connectivity, and glutamate associated networks were then characterised in terms of their overlap with canonical functional networks. Study A involved 76 individuals with schizophrenia and 82 controls, and identified a functional network negatively associated with glutamate concentrations that was concentrated within the salience network (p < 0.05) and did not differ significantly between patients and controls (p > 0.85). Study B involved 19 individuals with schizophrenia and 17 controls and found that increases in glutamate concentrations induced by riluzole were linked to increases in connectivity localised to the salience network (p < 0.05), and the relationship did not differ between patients and controls (p > 0.4). Frontal cortex glutamate concentrations are associated with inter-areal functional connectivity of a network that localises to the salience network. Changes in network connectivity in response to glutamate modulation show an opposite effect compared to the relationship observed at baseline, which may complicate pharmacological attempts to simultaneously correct glutamatergic and connectivity aberrations.

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S131. NEIGHBOURHOOD-LEVEL SOCIAL CAPITAL, MARGINALIZATION, AND THE INCIDENCE OF PSYCHOTIC DISORDERS IN TORONTO, CANADA: A RETROSPECTIVE POPULATION-BASED COHORT STUDY

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa031.197 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S85-S85

Author(s):

Martin Rotenberg ◽

Andrew Tuck ◽

Kelly Anderson ◽

Kwame McKenzie

Keyword(s):

Social Capital ◽

Psychotic Disorder ◽

Psychotic Disorders ◽

Population Based ◽

Ethnic Concentration ◽

Schizophrenia Spectrum ◽

Neighbourhood Level ◽

Incident Cases ◽

The Impact ◽

The Relationship

Abstract Background Previous studies have shown mixed results regarding the relationship between social capital and the risk of developing a psychotic disorder, and this has yet to be studied in North America. This study aims to examine the relationship between neighbourhood-level social capital, marginalization, and the incidence of psychotic disorders in Toronto, Canada. Methods A retrospective cohort of people aged 14 to 40 years residing in Toronto, Canada in 1999 (followed to 2008) was constructed from population-based health administrative data. Incident cases of schizophrenia spectrum psychotic disorders were identified using a validated algorithm. Voter participation rates in a municipal election were used as a proxy neighbourhood-level indicator of social capital. Exposure to neighbourhood-level marginalization was obtained from the Ontario Marginalization Index. Poisson regression models adjusting for age and sex were used to calculate incidence rate ratios (IRR) for each social capital quintiles and marginalization quintile. Results In the study cohort (n = 640,000) over the 10-year follow-up period, we identified 4,841 incident cases of schizophrenia spectrum psychotic disorders. We observed elevated rates of psychotic disorders in areas with the highest levels (IRR = 1.13, 95% CI 1.00–1.27) and moderate levels (IRR = 1.23, 95% CI 1.12–1.36) of social capital, when compared to areas with the lowest levels of social capital, after adjusting for neighbourhood-level indicators of marginalization. The risk associated with social capital was not present when analyzed in only the females in the cohort. All neighbourhood marginalization indicators, other than ethnic concentration, were significantly associated with risk. Discussion The risk of developing a psychotic disorder in Toronto, Canada is associated with socioenvironmental exposures. Social capital is associated with risk, however, the impact of social capital on risk differs by sex and social capital quintile. Across the entire cohort, exposure to all neighbourhood-level marginalization indicators, except ethnic concentration, impacts risk. Future research should examine how known individual-level risk factors, including immigration, ethnicity, and family history of a mental disorder may interact with these findings.

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Theory of mind in the early course of schizophrenia: stability, symptom and neurocognitive correlates, and relationship with functioning

Psychological Medicine ◽

10.1017/s0033291714003171 ◽

2015 ◽

Vol 45 (10) ◽

pp. 2031-2043 ◽

Cited By ~ 38

Author(s):

J. Ventura ◽

A. Ered ◽

D. Gretchen-Doorly ◽

K. L. Subotnik ◽

W. P. Horan ◽

...

Keyword(s):

Theory Of Mind ◽

Negative Symptoms ◽

Chronic Schizophrenia ◽

First Episode ◽

Positive Symptoms ◽

Healthy Controls ◽

Role Functioning ◽

Recent Onset ◽

Early Course ◽

The Relationship

BackgroundNumerous studies have reported links between theory of mind (ToM) deficits, neurocognition and negative symptoms with functional outcome in chronic schizophrenia patients. Although the ToM deficit has been observed in first-episode patients, fewer studies have addressed ToM as a possible trait marker, neurocognitive and symptom correlations longitudinally, and associations with later functioning.MethodRecent-onset schizophrenia patients (n = 77) were assessed at baseline after reaching medication stabilization, and again at 6 months (n = 48). Healthy controls (n = 21) were screened, and demographically comparable with the patients. ToM was assessed with a Social Animations Task (SAT), in which the participants’ descriptions of scenes depicting abstract visual stimuli ‘interacting’ in three conditions (ToM, goal directed and random) were rated for degree of intentionality attributed to the figures and for appropriateness. Neurocognition, symptoms and role functioning were also assessed.ResultsOn the SAT, patients had lower scores than controls for both intentionality (p < 0.01) and appropriateness (p < 0.01) during the ToM condition, at baseline and 6 months. The ToM deficit was stable and present even in remitted patients. Analyses at baseline and 6 months indicated that for patients, ToM intentionality and appropriateness were significantly correlated with neurocognition, negative symptoms and role functioning. The relationship between ToM and role functioning was mediated by negative symptoms.ConclusionsThe ToM deficit was found in recent-onset schizophrenia patients and appears to be moderately trait-like. ToM is also moderately correlated with neurocognition, negative and positive symptoms, and role functioning. ToM appears to influence negative symptoms which in turn makes an impact on role functioning.

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Effective Connectivity of the Hippocampus Can Differentiate Patients with Schizophrenia from Healthy Controls: A Spectral DCM Approach

Brain Topography ◽

10.1007/s10548-021-00868-8 ◽

2021 ◽

Author(s):

Lavinia Carmen Uscătescu ◽

Lisa Kronbichler ◽

Renate Stelzig-Schöler ◽

Brandy-Gale Pearce ◽

Sarah Said-Yürekli ◽

...

Keyword(s):

Negative Symptoms ◽

Effective Connectivity ◽

Anterior Insula ◽

Anterior Cingulate ◽

Frontal Eye Fields ◽

Healthy Controls ◽

Dorsal Anterior Cingulate Cortex ◽

Left Hippocampus ◽

Male Patients ◽

The Right

AbstractWe applied spectral dynamic causal modelling (Friston et al. in Neuroimage 94:396–407. 10.1016/j.neuroimage.2013.12.009, 2014) to analyze the effective connectivity differences between the nodes of three resting state networks (i.e. default mode network, salience network and dorsal attention network) in a dataset of 31 male healthy controls (HC) and 25 male patients with a diagnosis of schizophrenia (SZ). Patients showed increased directed connectivity from the left hippocampus (LHC) to the: dorsal anterior cingulate cortex (DACC), right anterior insula (RAI), left frontal eye fields and the bilateral inferior parietal sulcus (LIPS & RIPS), as well as increased connectivity from the right hippocampus (RHC) to the: bilateral anterior insula (LAI & RAI), right frontal eye fields and RIPS. In SZ, negative symptoms predicted the connectivity strengths from the LHC to: the DACC, the left inferior parietal sulcus (LIPAR) and the RHC, while positive symptoms predicted the connectivity strengths from the LHC to the LIPAR and from the RHC to the LHC. These results reinforce the crucial role of hippocampus dysconnectivity in SZ pathology and its potential as a biomarker of disease severity.

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Cognitive impairment as a risk factor for psychosis

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2005.7.1/areichenberg ◽

2005 ◽

Vol 7 (1) ◽

pp. 31-38 ◽

Cited By ~ 1

Keyword(s):

Risk Factor ◽

Cognitive Impairment ◽

Cognitive Functioning ◽

Brain Function ◽

Negative Symptoms ◽

Psychotic Disorders ◽

Epidemiological Studies ◽

Psychotic Symptoms ◽

Future Research ◽

The Relationship

Since the time of Kraepelin and Bleuler, it has been recognized that schizophrenia is associated with a profound and persistent cognitive impairment. This paper reviews the major clinical and epidemiological studies of cognitive functioning in schizophrenia and other psychotic disorders, and presents several possible models to explain the association between cognitive impairment and psychosis. Cognitive impairment is present in the majority of patients with schizophrenia, and, in some, it is already evident in the premorbid stages of the disorder. This cognitive impairment is not secondary to psychotic symptoms, negative symptoms, or socioeconomic status. Cognitive impairment can also be observed in nonpsychotic family members of psychotic patients. On the basis of this evidence, it has been proposed that abnormal cognitive functioning can be considered as a possible causal risk factor for psychosis. Recent studies assessing the relationship between genetic background, cognition, brain function, and schizophrenia are presented here as an outline for future research.

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Resting-state functional connectivity of the striatum predicts improvement in negative symptoms and general functioning in patients with first-episode psychosis: A 1-year naturalistic follow-up study

Australian & New Zealand Journal of Psychiatry ◽

10.1177/0004867419885452 ◽

2019 ◽

Vol 54 (5) ◽

pp. 509-518 ◽

Cited By ~ 1

Author(s):

Sanghoon Oh ◽

Minah Kim ◽

Taekwan Kim ◽

Tae Young Lee ◽

Jun Soo Kwon

Keyword(s):

Functional Connectivity ◽

Anterior Cingulate Cortex ◽

Negative Symptoms ◽

Primary Motor Cortex ◽

Cingulate Cortex ◽

First Episode Psychosis ◽

Anterior Cingulate ◽

First Episode ◽

Healthy Controls ◽

Episode Psychosis

Objective: The persistent disease burden of psychotic disorders often comes from negative symptoms; however, prognostic biomarkers for negative symptoms have not been fully understood. This study investigated whether the altered functional connectivity of the striatum predicts improvement in negative symptoms and functioning after 1 year of usual treatment in patients with first-episode psychosis. Methods: Resting-state functional magnetic imaging was obtained from 40 first-episode psychosis patients and 40 age- and sex-matched healthy control subjects. Whole-brain functional connectivity maps were generated with subdivisions of the striatum as seed regions and compared between first-episode psychosis patients and healthy controls. In 22 patients with first-episode psychosis, follow-up assessments of negative symptom severity and general functional status were conducted after 1 year of usual treatment. Multiple regression analyses were performed to examine factors predictive of symptomatic or functional improvements over the 1-year period. Results: First-episode psychosis patients showed greater functional connectivity between the left dorsal caudate and left primary motor cortex, as well as between the left ventral rostral putamen and right temporal occipital fusiform cortex, than healthy controls. Lower functional connectivity between the right dorsal rostral putamen and anterior cingulate cortex was observed in the first-episode psychosis patients than in healthy controls. In multiple regression analyses, lower functional connectivity of the left dorsal caudate–left primary motor cortex/right dorsal rostral putamen–anterior cingulate cortex predicted improvement in negative symptoms. In addition, lower right dorsal rostral putamen–anterior cingulate cortex functional connectivity predicted improvement in general functioning. Conclusion: These results suggest that altered striatal functional connectivity can be a potent neurobiological marker in the prognosis prediction of first-episode psychosis. Furthermore, altered striatal functional connectivity may provide a potential target in developing treatments for negative symptoms.

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Stronger default mode network connectivity is associated with poorer clinical insight in youth at ultra high-risk for psychotic disorders

Schizophrenia Research ◽

10.1016/j.schres.2017.06.043 ◽

2018 ◽

Vol 193 ◽

pp. 244-250 ◽

Cited By ~ 18

Author(s):

Sarah V. Clark ◽

Vijay A. Mittal ◽

Jessica A. Bernard ◽

Aral Ahmadi ◽

Tricia Z. King ◽

...

Keyword(s):

High Risk ◽

Default Mode Network ◽

Psychotic Disorders ◽

Network Connectivity ◽

Default Mode ◽

Ultra High Risk

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Childhood Trauma and Neurocognition in Adults With Psychotic Disorders: A Systematic Review and Meta-analysis

Schizophrenia Bulletin ◽

10.1093/schbul/sby150 ◽

2018 ◽

Vol 45 (6) ◽

pp. 1195-1208 ◽

Cited By ~ 6

Author(s):

Teresa Vargas ◽

Phoebe H Lam ◽

Matilda Azis ◽

K Juston Osborne ◽

Amy Lieberman ◽

...

Keyword(s):

Working Memory ◽

Childhood Trauma ◽

Psychotic Disorder ◽

Visual Memory ◽

Psychotic Disorders ◽

Meta Analysis ◽

Negative Relationship ◽

Neurocognitive Function ◽

Healthy Controls ◽

Memory And Attention

Abstract Background Characterizing the link between childhood trauma and adult neurocognitive function in psychosis is crucial for improving the fields understanding of how early environmental risk factors impact the presentation of the disorder. To date, the literature has been inconsistent: meta-analytic synthesis is lacking, and it is unclear whether specific cognitive functions are affected. Methods A meta-analysis was performed on a total of 3315 subjects with a psychotic disorder. The links between childhood trauma, overall neurocognitive function, and four cognitive subdomains (working memory, executive function, verbal/visual memory, and attention/processing speed) were examined. Relevant sample characteristics and methodological moderators were tested. The strength of the association between trauma and overall neurocognition in individuals with psychotic disorders was also compared to that of healthy controls. Results Among individuals with psychotic disorders, there was a significant association between overall cognition and childhood trauma, r = −.055; 95% CI = −0.09, −0.02, P = .002. There was also a modest, negative relationship between childhood trauma and working memory, r = −.091; 95% CI = −0.15, −0.03, P = .002. Moderators did not have a significant effect on these analyses. Further, the association between childhood trauma and neurocognition was significantly stronger in healthy controls compared to patients with a psychotic disorder. Conclusion A small negative association was found between overall cognition and childhood trauma in individuals with psychotic disorders. Results suggest the association is less strong for individuals with a psychotic disorder compared to healthy populations. Findings are informative for prominent etiological models of psychosis.

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Duration of untreated psychosis: a critical examination of the concept and its importance

Psychological Medicine ◽

10.1017/s0033291701003488 ◽

2001 ◽

Vol 31 (3) ◽

pp. 381-400 ◽

Cited By ~ 282

Author(s):

ROSS M. G. NORMAN ◽

ASHOK K. MALLA

Keyword(s):

Treatment Outcome ◽

Negative Symptoms ◽

Psychotic Disorders ◽

Psychotic Symptoms ◽

First Episode ◽

Critical Examination ◽

Duration Of Untreated Psychosis ◽

Relationship Of ◽

The Relationship

Background. The concept of duration of untreated psychosis (DUP) has recently attracted much interest because of its possible relationship to treatment outcome and implications for preventive efforts with reference to psychotic disorders, especially schizophrenia. In this paper we review critically the literature concerning the concept and its importance.Methods. Articles concerned with measuring DUP and those that have been suggested to provide indirect or direct evidence of the effect of DUP on treatment outcome are reviewed.Results. Evidence thus far suggests that DUP may be related to ease of reducing psychotic symptoms once treatment begins for first episode patients, but there is no evidence of a relationship to likelihood of relapse. There has been little investigation of the relationship of DUP to other long-term outcomes such as negative symptoms and cognitive functioning neither have the possible confounds of DUP been widely investigated or controlled.Conclusions. It is important that there should be more thorough investigations of DUP, its correlates, and the extent to which it does mediate any advantages of earlier intervention.

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Insula sub-regions across the psychosis spectrum: morphology and clinical correlates

Translational Psychiatry ◽

10.1038/s41398-021-01461-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Julia M. Sheffield ◽

Anna S. Huang ◽

Baxter P. Rogers ◽

Jennifer Urbano Blackford ◽

Stephan Heckers ◽

...

Keyword(s):

Psychotic Disorder ◽

Negative Symptoms ◽

Psychotic Disorders ◽

Prenatal Development ◽

Cortical Region ◽

Somatosensory Processing ◽

Brain Images ◽

Clinical Correlates ◽

Spectrum Disorders ◽

Anterior Posterior

AbstractThe insula is a heterogeneous cortical region, comprised of three cytoarchitecturally distinct sub-regions (agranular, dysgranular, and granular), which traverse the anterior-posterior axis and are differentially involved in affective, cognitive, and somatosensory processing. Smaller insula volume is consistently reported in psychosis-spectrum disorders and is hypothesized to result, in part, from abnormal neurodevelopment. To better understand the regional and diagnostic specificity of insula abnormalities in psychosis, their developmental etiology, and clinical correlates, we characterized insula volume and morphology in a large group of adults with a psychotic disorder (schizophrenia spectrum, psychotic bipolar disorder) and a community-ascertained cohort of psychosis-spectrum youth (age 8–21). Insula volume and morphology (cortical thickness, gyrification, sulcal depth) were quantified from T1-weighted structural brain images using the Computational Anatomy Toolbox (CAT12). Healthy adults (n = 196), people with a psychotic disorder (n = 303), and 1368 individuals from the Philadelphia Neurodevelopmental Cohort (PNC) (381 typically developing (TD), 381 psychosis-spectrum (PS) youth, 606 youth with other psychopathology (OP)), were investigated. Insula volume was significantly reduced in adults with psychotic disorders and psychosis-spectrum youth, following an anterior-posterior gradient across granular sub-regions. Morphological abnormalities were limited to lower gyrification in psychotic disorders, which was specific to schizophrenia and associated with cognitive ability. Insula volume and thickness were associated with cognition, and positive and negative symptoms of psychosis. We conclude that smaller insula volume follows an anterior-posterior gradient in psychosis and confers a broad risk for psychosis-spectrum disorders. Reduced gyrification is specific to schizophrenia and may reflect altered prenatal development that contributes to cognitive impairment.

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