Oxytocin modulates hippocampal perfusion in people at clinical high risk for psychosis

Abstract

Preclinical and human studies suggest that hippocampal dysfunction is a key factor in the onset of psychosis. People at Clinical High Risk for psychosis (CHR-P) present with a clinical syndrome that can include social withdrawal and have a 20-35% risk of developing psychosis in the next 2 years. Recent research shows that resting hippocampal blood flow is altered in CHR-P individuals and predicts adverse clinical outcomes, such as non-remission/transition to frank psychosis. Previous work in healthy males indicates that a single dose of intranasal oxytocin has positive effects on social function and marked effects on resting hippocampal blood flow. The present study examined the effects of intranasal oxytocin on hippocampal blood flow in CHR-P individuals. In a double-blind, placebo-controlled, crossover design, 30 CHR-P males were studied using pseudo-continuous Arterial Spin Labelling on 2 occasions, once after 40IU intranasal oxytocin and once after placebo. The effects of oxytocin on left hippocampal blood flow were examined in a region-of-interest analysis of data acquired at 22-28 and at 30-36 minutes post-intranasal administration. Relative to placebo, administration of oxytocin was associated with increased hippocampal blood flow at both time points (p = .0056; p = .034), although the effect at the second did not survive adjustment for the effect of global blood flow. These data indicate that oxytocin can modulate hippocampal function in CHR-P individuals and therefore merits further investigation as a candidate novel treatment for this group.

Fig. 1

Simplified schematic of proposed neural circuit mechanisms of hippocampal pathophysiology in those at CHR-P. In (1), low glutamate signal/input from hypofunctioning NMDARs (akin to ‘faulty homeostatic sensors’) leads GABAergic interneurons to seek to homeostatically increase excitation by reducing inhibition (disinhibition) of glutamatergic pyramidal cells. However, by disinhibiting pyramidal cells (and thus increasing glutamate signalling) in this dysfunctional neural environment, the potential homeostatic adaptation becomes allostatic (2). In (3), enhanced excitation leads to an overdrive in the responsivity of midbrain dopamine neurons which project to the associative striatum (note that the connection between hippocampal pyramidal cells and midbrain dopamine neurons is presented as monosynaptic but is actually polysynaptic via the ventral striatum and ventral pallidum). Completing the (simplified) circuit, local glutamatergic tone is increased in (4) but is not detected as such by hypofunctioning NMDARs on GABAergic interneurons. For detailed original diagrams and discussion of evidence for this proposed circuit or its component processes, see [7, 11, 12, 14, 74]. Glu glutamate, NMDAR N-methyl-D-aspartate receptor, E/I excitation/inhibition

Fig. 2

rCBF Effects in Left Hippocampus. a ROI mask for the left hippocampus (yellow) overlaid on a standard brain template, and (b) overlaid on a representative subject-level cerebral blood flow map in normalised space, and (c) bar charts showing mean hippocampal rCBF in the oxytocin and placebo conditions in run 1 and run 2 after adjustment for global effects

Fig. 3

rCBF in Left Hippocampal Subregions. a ROI masks for left hippocampal subregions: dentate gyrus (pink), subiculum (yellow), CA1 (cyan), CA2 (blue), and CA3 (green) displayed on a standard brain template, and (b) bar charts showing mean hippocampal subregion rCBF in the oxytocin and placebo conditions in run 1 after adjustment for global effects