Pathological resting-state executive and language system perfusion in first-episode psychosis

Abstract

Background and hypothesis: Cortical (e.g., Broca's area and Wernicke's area) and subcortical (e.g., putamen) language-related areas and executive control areas (e.g., inferior frontal gyrus (IFG), dorsolateral prefrontal cortex (DLPFC)) show functional and structural dysconnectivity in long-term psychosis. We examined whether resting-state basal perfusion levels revealed selective pathophysiology (likely hypo- and hyper-activation) of language-related and executive areas in first-episode psychosis (FEP).

Study design: Basal resting-state perfusion was measured using pseudo-continuous Arterial Spin Labeling (pcASL). Relative cerebral blood flow (rCBF) was compared between 32 FEP and 34 matched healthy comparison (HC) individuals. Structural and functional MRI scans were acquired using a 3T Prisma scanner during the same session.

Study results: Whole-brain comparison of resting rCBF identified 8 clusters with significant between-group differences. Reduced rCBF was found in executive control areas in left and right IFG, right DLPFC, and right parietal cortex. Increased rCBF was found in left and right temporal cortex (including Wernicke's area), and left and right putamen. A positive correlation was observed between auditory hallucination severity and rCBF in the left putamen.

Conclusions: To the degree that perfusion implies activation, language and auditory processing areas in bilateral temporal lobe and putamen showed pathological hyper-activity, and cognitive control areas (IFG, DLPFC, right parietal) showed pathological hypo-activity in FEP at rest. Pathological basal activity was present across the range of symptom severity, suggesting it may be a common underlying pathology for psychosis that may be targeted with non-invasive brain stimulation to normalize resting activity levels.

Keywords: Arterial spin labeling; Auditory hallucinations; Basal perfusion; First episode psychosis.

Fig. 1

Systems-level model of auditory hallucinations incorporation bottom-up sensory deficits, top-down auditory executive control deficits, and semantic memory intrusion deficits. (After circuit model in (Salisbury et al., 2021).

Fig. 2

Whole brain analysis of pcASL revealed: A. Increased basal activity in left and right temporal-parietal areas and in right anterior STS auditory cortex; B. Reduced basal activity in right and left IFG, and right parietal executive control areas; and C. Increased basal activity in left and right putamen, with a role in semantic access.

Fig. 3

Distribution of rCBF between HC and FEP. A. Areas where FEP shoed hypo-perfusion. B. Areas where FEP showed hyper-perfusion. FEP are further separated into hallucinators (AH+, red) and non-hallucinators (AH−,blue). Pathophysiology was generally similar between FEP AH subgruops. AH+ showed a bimodal distribution in right DLPFC, while AH+ were uniformly increased in left putamen comapered with AH−. Note: Black p values indicate HC vs FEP comparisons and red p values indicate AH+ vs AH− FEP comparisons, and red p valued indicate AH+ vs AH− FEP subgroup comparisions. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

Significant and trend-level correlations between altered rCBF and: A. Social functioning; B. Cognition; and C. Auditory hallucinations.

Fig. 5

Revised model of systems-level pathophysiology in FEP. In addition to the bottom up and executive semantic/auditory deficits decribed Fig. 1, general purpose executive control areas (right DLPFC and parietal cortex) show reduced activity. Each node within this circuitry presents a potential target for non-invasive brain stimulation.