Diazepam modulates hippocampal CA1 functional connectivity in people at clinical high-risk for psychosis

Abstract

Background: Preclinical evidence suggests that diazepam enhances hippocampal γ-aminobutyric acid (GABA) signalling and normalises a psychosis-relevant cortico-limbic-striatal circuit. Hippocampal network dysconnectivity, particularly from the CA1 subfield, is evident in people at clinical high-risk for psychosis (CHR-P), representing a potential treatment target. This study aimed to forward-translate this preclinical evidence.

Methods: In this randomised, double-blind, placebo-controlled study, 18 CHR-P individuals underwent resting-state functional magnetic resonance imaging twice, once following a 5 mg dose of diazepam and once following a placebo. They were compared to 20 healthy controls (HC) who did not receive diazepam/placebo. Functional connectivity (FC) between the hippocampal CA1 subfield and the nucleus accumbens (NAc), amygdala, and ventromedial prefrontal cortex (vmPFC) was calculated. Mixed-effects models investigated the effect of group (CHR-P placebo/diazepam vs. HC) and condition (CHR-P diazepam vs. placebo) on CA1-to-region FC.

Results: In the placebo condition, CHR-P individuals showed significantly lower CA1-vmPFC (Z = 3.17, P_FWE = 0.002) and CA1-NAc (Z = 2.94, P_FWE = 0.005) FC compared to HC. In the diazepam condition, CA1-vmPFC FC was significantly increased (Z = 4.13, P_FWE = 0.008) compared to placebo in CHR-P individuals, and both CA1-vmPFC and CA1-NAc FC were normalised to HC levels. In contrast, compared to HC, CA1-amygdala FC was significantly lower contralaterally and higher ipsilaterally in CHR-P individuals in both the placebo and diazepam conditions (lower: placebo Z = 3.46, P_FWE = 0.002, diazepam Z = 3.33, P_FWE = 0.003; higher: placebo Z = 4.48, P_FWE < 0.001, diazepam Z = 4.22, P_FWE < 0.001).

Conclusions: This study demonstrates that diazepam can partially restore hippocampal CA1 dysconnectivity in CHR-P individuals, suggesting that modulation of GABAergic function might be useful in the treatment of this clinical group.

Keywords: benzodiazepine; early intervention; neuroimaging; pharmacological MRI; resting-state; schizophrenia.

Figure 1.

Within-group CA1-to-voxel functional connectivity. CA1-to-voxel functional connectivity networks averaged across each group independently (healthy controls, CHR-P placebo, and CHR-P diazepam) for the left and right CA1 subfield using study-specific masks (Z > 2.3, P _FWE < 0.05). CHR-P, ‘clinical high-risk for psychosis’.

Figure 2.

Region-of-interest functional connectivity results for the CA1. Parameter estimates of functional connectivity strength between left (a) and right (b) CA1 and output regions (nucleus accumbens, amygdala, and ventromedial prefrontal cortex) displayed for healthy controls and individuals at clinical high-risk for psychosis (in the placebo and diazepam conditions) at peak coordinate of significant effect of group/condition (Z > 2.3, P _FWE < 0.05). CA1 (green), amygdala (red), nucleus accumbens (yellow), and vmPFC (purple) are visualised on the brain using masks. CHR-P, ‘clinical high-risk for psychosis’; Amy, ‘amygdala’; NAc, ‘nucleus accumbens’; vmPFC, ‘ventromedial prefrontal cortex’; *** < 0.001; * < 0.05, ns, ‘not significant’.

Figure 3.

Voxel-wise whole-brain functional connectivity results for the CA1. Significant clusters showing differences (Z > 2.3, P _FWE < 0.05) in functional connectivity between HC and CHR-P placebo (a) and CHR-P diazepam (b) for the CA1. Areas showing functional hyperconnectivity (CHR-P placebo/diazepam > HC) are displayed in red colourbar, whilst areas displaying functional hypoconnectivity are displayed in blue. N.B., no significant differences were found for the anterior hippocampus, nor for any of the regions (CA1 or anterior hippocampus) when contrasting CHR-P diazepam versus placebo. CHR-P, ‘clinical high-risk for psychosis’; HC, ‘healthy controls’.