Abstract
Evidence suggests that people at Clinical High Risk for Psychosis (CHR) have a blunted cortisol response to stress and altered mediotemporal activation during fear processing, which may be neuroendocrine–neuronal signatures of maladaptive threat responses. However, whether these facets are associated with each other and how this relationship is affected by cannabidiol treatment is unknown. We examined the relationship between cortisol response to social stress and mediotemporal function during fear processing in healthy people and in CHR patients. In exploratory analyses, we investigated whether treatment with cannabidiol in CHR individuals could normalise any putative alterations in cortisol-mediotemporal coupling. 33 CHR patients were randomised to 600 mg cannabidiol or placebo treatment. Healthy controls (n = 19) did not receive any drug. Mediotemporal function was assessed using a fearful face-processing functional magnetic resonance imaging paradigm. Serum cortisol and anxiety were measured immediately following the Trier Social Stress Test. The relationship between cortisol and mediotemporal blood-oxygen-level-dependent haemodynamic response was investigated using linear regression. In healthy controls, there was a significant negative relationship between cortisol and parahippocampal activation (p = 0.023), such that the higher the cortisol levels induced by social stress, the lower the parahippocampal activation (greater deactivation) during fear processing. This relationship differed significantly between the control and placebo groups (p = 0.033), but not between the placebo and cannabidiol groups (p = 0.67). Our preliminary findings suggest that the parahippocampal response to fear processing may be associated with the neuroendocrine (cortisol) response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis.
Highlights
Interactions between environmental stress and brain pathophysiology are thought to drive the onset of psychosis in people at Clinical High Risk (CHR), with hypothalamic–pituitary–adrenal (HPA) axis dysfunction as a putative mediator [1, 2]
Our preliminary findings suggest that the parahippocampal response to fear processing may be associated with the neuroendocrine response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis
Our key—albeit preliminary—findings are that in healthy individuals, there exists a coupling between the mediotemporal response during fear processing and the neuroendocrine response to experimentally induced social stress, and that this relationship may be altered in patients at clinical high risk for psychosis (CHR)
Summary
Interactions between environmental stress and brain pathophysiology are thought to drive the onset of psychosis in people at Clinical High Risk (CHR), with hypothalamic–pituitary–adrenal (HPA) axis dysfunction as a putative mediator [1, 2]. Evidence suggests a blunting of the normative cortisol response to acute stress induction (phasic HPA blunting [4]) in CHR individuals [6], which is thought to underlie their enhanced vulnerability to the deleterious effects of stress [7, 8]. Stress (especially repeated or prolonged stress) increases the responsivity of midbrain dopamine neurons leading to striatal dopamine release [10], an effect that is normalised by inhibiting the hippocampus [11] (for reviews see [9, 12]) and which is translationally relevant given that mesolimbic hyperdopaminergia is thought to be the final common pathway to psychosis in humans [13]. While CHR individuals appear to have normal stress-induced prefrontal dopamine release, combined with a normative correlation with stress-induced salivary cortisol [25], those CHR patients with greater stress (chronic or life events) or anxiety had both lower prefrontal dopamine release as well as blunted cortisol responses following stress [25]
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