Neuroanatomical changes in people with high schizotypy: relationship to glutamate levels

Modinos, Gemma; Egerton, Alice; McLaughlin, Anna; McMullen, Katrina; Kumari, Veena; Lythgoe, David J.; Barker, Gareth J.; Alemán, André; Williams, Steve

doi:10.1017/s0033291717003403

Cited by 24 publications

(33 citation statements)

References 62 publications

(90 reference statements)

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“…Thus, the observed group differences in hippocampal CBF in the present study are unlikely to be confounded by underlying GMV effects from this region. Noteworthy, our recent multimodal structural imaging study in this same sample did not find hippocampal volume differences between the groups (Modinos et al, 2017a), consistent with all other neuroanatomical investigations in schizotypy (DeRosse et al, 2015;Ettinger et al, 2012;Kuhn, Schubert, & Gallinat, 2012;Modinos et al, 2010;Nenadic et al, 2015;Wang et al, 2015;Wiebels, Waldie, Roberts, & Park, 2016).…”

Section: Discussionsupporting

confidence: 89%

“…There are some limitations to this study. First, subjects were recruited from a university sample, had relatively high IQs and groups showed no differences in self-reported substance use; therefore, our Third, our sample was relatively small, and recruitment through selfreport has previously been related to higher rates in schizotypy scores (Linscott & van Os, 2010 (Modinos et al, 2017a), following the proposal that GMV could represent a potential confounder in ASL studies (Asllani, Borogovac, & Brown, 2008;Chappell et al, 2011). This analysis yielded no significant effects within or between groups either at p < .05 FWE or at a more lenient threshold of p < .001 uncorrected.…”

Section: Discussionmentioning

confidence: 99%

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Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study

Modinos

Egerton

McMullen

et al. 2018

Human Brain Mapping

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Arterial spin labeling (ASL) provides absolute quantification of resting tissue cerebral blood flow (CBF) as an entirely noninvasive approach with good reproducibility. As a result of neurovascular coupling, ASL provides a useful marker of resting neuronal activity. Recent ASL studies in individuals at clinical high risk of psychosis (CHR) have reported increased resting hippocampal perfusion compared with healthy controls. Schizotypy refers to the presence of subclinical psychotic‐like experiences in healthy individuals and represents a robust framework to study neurobiological mechanisms involved in the extended psychosis phenotype while avoiding potentially confounding effects of antipsychotic medications or disease comorbidity. Here we applied pseudo‐continuous ASL to examine differences in resting CBF in 21 subjects with high positive schizotypy (HS) relative to 22 subjects with low positive schizotypy (LS), as determined by the Oxford and Liverpool Inventory of Feelings and Experiences. Based on preclinical evidence that hippocampal hyperactivity leads to increased activity in mesostriatal dopamine projections, CBF in hippocampus, midbrain, and striatum was assessed. Participants with HS showed higher CBF of the right hippocampus compared to those with LS (p = .031, family‐wise error corrected). No differences were detected in the striatum or midbrain. The association between increased hippocampal CBF and HS supports the notion that hippocampal hyperactivity might be a central characteristic of the extended psychosis phenotype, while hyperactivity in subcortical dopamine pathways may only emerge at a higher intensity of psychotic experiences.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study

Modinos

Egerton

McMullen

et al. 2018

Human Brain Mapping

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“…In several previous studies, primarily variations in precuneus structure and function have, repeatedly, been associated with schizotypal traits and subclinical PLEs (Modinos et al ., 2010, 2018; van Lutterveld et al ., 2014; Falkenberg et al ., 2015; Nenadic et al ., 2015b). It is, therefore, unexpected that we did not find any association with any of the SPQ dimensions in this region in our data.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, there is growing evidence for fronto-striatal circuits to be involved in the generation of PLEs. Recent studies have suggested positive schizotypal traits to be associated with variations in frontal volume, but the direction is unclear, with increases (Kühn et al ., 2012; Nenadic et al ., 2015b; Modinos et al ., 2018) as well as decreases (Ettinger et al ., 2012; DeRosse et al ., 2015) being reported. As most studies have focused on variations in volumetric parameters, apart from one study finding increased right prefrontal lobe gyrification in participants scoring above v. below a clinical cut-off (Stanfield et al ., 2008), there is no study using a dimensional approach to schizotypy and folding analysis.…”

Section: Introductionmentioning

confidence: 99%

“…Nonetheless, psychometrically-assessed estimates of schizotypy (like schizotypal traits, measured through scales based on DSM-criteria for Schizotypal Personality Disorder) have, repeatedly, been associated with variations in brain structures also implicated in schizophrenia. One finding replicated in several studies is that of structural and functional variation within the precuneus: Evidence for an association of schizotypy and schizotypal traits with increased grey matter volume (GMV) in the precuneus has been reported in several structural imaging studies (Modinos et al ., 2010, 2018; Nenadic et al ., 2015b), although not in all (Ettinger et al ., 2012; Kühn et al ., 2012). Furthermore, PLEs have been shown to be associated with increased precuneus activation (van Lutterveld et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

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The association of striatal volume and positive schizotypy in healthy subjects: intelligence as a moderating factor

2019

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BackgroundSchizotypy, a putative schizophrenia endophenotype, has been associated with brain-structural variations partly overlapping with those in psychotic disorders. Variations in precuneus structure have been repeatedly reported, whereas the involvement of fronto-striatal networks – as in schizophrenia – is less clear. While shared genetic architecture is thought to increase vulnerability to environmental insults, beneficial factors like general intelligence might buffer their effect.MethodsTo further investigate the role of fronto-striatal networks in schizotypy, we examined the relationship of voxel- and surface-based brain morphometry and a measure of schizotypal traits (Schizotypal Personality Questionnaire, with subscores Cognitive-Perceptual, Interpersonal, Disorganised) in 115 healthy participants [54 female, mean age (s.d.) = 27.57(8.02)]. We tested intelligence (MWT-B) as a potential moderator.ResultsWe found a positive association of SPQ Cognitive-Perceptual with putamen volume (p = 0.040, FWE peak level-corrected), moderated by intelligence: with increasing IQ, the correlation of SPQ Cognitive-Perceptual and striatal volume decreased (p = 0.022). SPQ Disorganised was positively correlated with precentral volume (p = 0.013, FWE peak level-corrected). In an exploratory analysis (p < 0.001, uncorrected), SPQ total score was positively associated with gyrification in the precuneus and postcentral gyrus, and SPQ Disorganised was negatively associated with gyrification in the inferior frontal gyrus.ConclusionsOur findings support the role of fronto-striatal networks for schizotypal features in healthy individuals, and suggest that these are influenced by buffering factors like intelligence. We conclude that protective factors, like general cognitive capacity, might attenuate the psychosis risk associated with schizotypy. These results endorse the idea of a continuous nature of schizotypy, mirroring similar findings in schizophrenia.

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Dopamine and glutamate in individuals at high risk for psychosis: a meta‐analysis of in vivo imaging findings and their variability compared to controls

2021

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Dopaminergic and glutamatergic dysfunction is believed to play a central role in the pathophysiology of schizophrenia. However, it is unclear if abnormalities predate the onset of schizophrenia in individuals at high clinical or genetic risk for the disorder. We systematically reviewed and meta-analyzed studies that have used neuroimaging to investigate dopamine and glutamate function in individuals at increased clinical or genetic risk for psychosis. EMBASE, PsycINFO and Medline were searched form January 1, 1960 to November 26, 2020. Inclusion criteria were molecular imaging measures of striatal presynaptic dopaminergic function, striatal dopamine receptor availability, or glutamate function. Separate meta-analyses were conducted for genetic high-risk and clinical high-risk individuals. We calculated standardized mean differences between high-risk individuals and controls, and investigated whether the variability of these measures differed between the two groups. Fortyeight eligible studies were identified, including 1,288 high-risk individuals and 1,187 controls. Genetic high-risk individuals showed evidence of increased thalamic glutamate + glutamine (Glx) concentrations (Hedges' g=0.36, 95% CI: 0.12-0.61, p=0.003). There were no significant differences between high-risk individuals and controls in striatal presynaptic dopaminergic function, striatal D2/D3 receptor availability, prefrontal cortex glutamate or Glx, hippocampal glutamate or Glx, or basal ganglia Glx. In the meta-analysis of variability, genetic high-risk individuals showed reduced variability of striatal D2/D3 receptor availability compared to controls (log coefficient of variation ratio, CVR=-0.24, 95% CI: -0.46 to -0.02, p=0.03). Meta-regressions of publication year against effect size demonstrated that the magnitude of differences between clinical high-risk individuals and controls in presynaptic dopaminergic function has decreased over time p=0.025). Thus, other than thalamic glutamate concentrations, no neurochemical measures were significantly different between individuals at risk for psychosis and controls. There was also no evidence of increased variability of dopamine or glutamate measures in high-risk individuals compared to controls. Significant heterogeneity, however, exists between studies, which does not allow to rule out the existence of clinically meaningful differences.

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Neuroanatomical changes in people with high schizotypy: relationship to glutamate levels

Abstract: Our study shows that GMV findings in schizotypy are related to glutamate levels, supporting the hypothesis that glutamatergic function may lead to structural changes associated with the expression of psychotic-like experiences.

Cited by 24 publications

References 62 publications

Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study

Increased resting perfusion of the hippocampus in high positive schizotypy: A pseudocontinuous arterial spin labeling study

The association of striatal volume and positive schizotypy in healthy subjects: intelligence as a moderating factor

Dopamine and glutamate in individuals at high risk for psychosis: a meta‐analysis of in vivo imaging findings and their variability compared to controls

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