Corticolimbic hyper-response to emotion and glutamatergic function in people with high schizotypy: a multimodal fMRI-MRS study

Abstract

Animal models and human neuroimaging studies suggest that altered levels of glutamatergic metabolites within a corticolimbic circuit have a major role in the pathophysiology of schizophrenia. Rodent models propose that prefrontal glutamate dysfunction could lead to amygdala hyper-response to environmental stress and underlie hippocampal overdrive in schizophrenia. Here we determine whether changes in brain glutamate are present in individuals with high schizotypy (HS), which refers to the presence of schizophrenia-like characteristics in healthy individuals, and whether glutamate levels are related to altered corticolimbic response to emotion. Twenty-one healthy HS subjects and 22 healthy subjects with low schizotypy (LS) were selected based on their Oxford and Liverpool Inventory of Feelings and Experiences rating. Glutamate levels were measured in the anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, followed by a functional magnetic resonance imaging (fMRI) scan to measure corticolimbic response during emotional processing. fMRI results and fMRI × glutamate interactions were considered significant after voxel-wise P<0.05 family-wise error correction. While viewing emotional pictures, HS individuals showed greater activation than did subjects with LS in the caudate, and marginally in the ACC, hippocampus, medial prefrontal cortex (MPFC) and putamen. Although no between-group differences were found in glutamate concentrations, within the HS group ACC glutamate was negatively correlated with striatal activation (left: z=4.30, P=0.004 and right: z=4.12 P=0.008 caudate; left putamen: z=3.89, P=0.018) and marginally with MPFC (z=3.55, P=0.052) and amygdala (left: z=2.88, P=0.062; right: z=2.79, P=0.079), correlations that were not present in LS subjects. These findings provide, to our knowledge, the first evidence that brain glutamate levels are associated with hyper-responsivity in brain regions thought to be critical in the pathophysiology of psychosis.

Emerging Temporal Lobe Dysfunction in People at Clinical High Risk for Psychosis

“…Taken together, studies in SPD cohorts seem to provide more evidence for lateral temporal and frontal lobe dysfunction than they do for dysfunction in a hippocampal–striatal–midbrain circuit, although this may be because far less research has been conducted that explicitly examines the hippocampal–striatal–midbrain circuit in psychometric schizotypy/SPD populations (110–113).…”

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

“…The recruitment procedure has been described in detail in our recent publications in a largely overlapping sample (Modinos et al, 2017a, 2017b). Briefly, 250 healthy individuals who responded to online advertisement were prescreened with the short version of the O‐LIFE questionnaire (Mason et al, 2005).…”

“…With a large body of evidence supporting shared genetic, environmental, neurobiological, and cognitive‐emotional factors between HS and psychotic disorders (Barrantes‐Vidal, Grant, & Kwapil, 2015; Ettinger, Meyhofer, Steffens, Wagner, & Koutsouleris, 2014; Kwapil & Barrantes‐Vidal, 2015; Nelson et al, 2013), the continuum model would predict that resting hippocampal perfusion is also elevated in individuals with subclinical psychotic‐like experiences. Although neuroimaging studies are yet to test this hypothesis, HS individuals show elevated hippocampal responses to a range of cognitive and emotional tasks (Bourque et al, 2017; Modinos et al, 2017b; Mohanty et al, 2005). Thus, our study sought to investigate whether hippocampal hyperperfusion is present in this group, compared to a matched group of people with low schizotypy.…”

Identifying disease foci from static and dynamic effective connectivity networks: Illustration in soldiers with trauma

“…Similarly, we associated the connectivity paths exhibiting higher SEC with overdrive, or pathologically enhanced engagement, given that hyper‐connectivity is considered as a response to neurological disruption [Hillary et al, ], and has been observed in individuals with PTSD [Cisler et al, ; Hayes et al, ; Simmons and Matthews, ]. The use of the word “overdrive” in such a context is not new, and has been prevalent in the literature [Modinos et al, ; Reiss et al, ]. The foci were identified using whole‐brain connectivity data without imposing any priors, while the affected connectivity paths conforming to our hypothesis were restricted to those connections that were associated with the foci.…”