Limbic Hyperactivity in Response to Emotionally Neutral Stimuli in Schizophrenia: A Neuroimaging Meta-Analysis of the Hypervigilant Mind

Abstract

Objective: It has long been assumed that paranoid ideation may stem from an aberrant limbic response to threatening stimuli. However, results from functional neuroimaging studies using negative emotional stimuli have failed to confirm this assumption. One of the potential reasons for the lack of effect is that study participants with psychosis may display aberrant brain responses to neutral material rather than to threatening stimuli. The authors conducted a functional neuroimaging meta-analysis to test this hypothesis.

Methods: A literature search was performed with PubMed, Google Scholar, and Embase to identify functional neuroimaging studies examining brain responses to neutral material in patients with psychosis. A total of 23 studies involving schizophrenia patients were retrieved. Using t-maps of peak coordinates to calculate effect sizes, a random-effects model meta-analysis was performed with the anisotropic effect-size version of Seed-based d Mapping software.

Results: In schizophrenia patients relative to healthy control subjects, increased activations were observed in the left and right amygdala and parahippocampus and the left putamen, hippocampus, and insula in response to neutral stimuli.

Conclusions: Given that several limbic regions were found to be more activated in schizophrenia patients than in control subjects, the results of this meta-analysis strongly suggest that these patients confer aberrant emotional significance to nonthreatening stimuli. In theory, this abnormal brain reactivity may fuel delusional thoughts. Studies are needed in individuals at risk of psychosis to determine whether aberrant limbic reactivity to neutral stimuli is an early neurofunctional marker of psychosis vulnerability.

Keywords: Amygdala; Meta-Analysis; Psychosis; Salience; Schizophrenia; fMRI.