Manipulating the hypothalamic-pituitary-adrenal axis: effects on cognitive and emotional information processing and neural connectivity

Despite extensive evidence documenting abnormal hypothalamic-pituitary-adrenal (HPA) axis functioning as a risk factor for the development of depression and other psychiatric disorders, and experimental evidence from acute stress manipulations, the effects of sustained cortisol alterations on clinically relevant cognitive-behavioural and neural processing remain poorly understood. The aim of this thesis was to characterise how non-acute changes in cortisol levels modify behavioural and neural biases implicated in stress-related disorders by following two complementary lines of evidence: firstly, by increasing cortisol via a direct pharmacological intervention; and secondly, by testing the ability of gut microbiota manipulations to alter cortisol reactivity.
The first study found that sustained increases in cortisol following 10-day administration of hydrocortisone were associated with altered memory and emotional processing in healthy volunteers. Specifically, participants receiving hydrocortisone showed enhanced recognition of emotional words, while their neutral memory performance was unaffected despite lower parahippocampal and occipital activation during viewing and encoding of neutral pictures. Furthermore, we found that resting-state functional connectivity between limbic-temporal regions of interest (amygdala and hippocampus) and the striatum (head of the caudate), as well as frontal and prelimbic cortices was decreased. In contrast, hippocampal and visual processing during negative facial expressions, and functional connectivity between the amygdala and the brainstem at rest, were increased in the hydrocortisone versus placebo groups. Overall, these findings suggest that non-acute increases in glucocorticoids enhance processing of emotionally salient information in limbic-temporal regions, which may modulate further neural mechanisms of sensory and homeostatic relevance. Enhancements in declarative emotional memory following hydrocortisone also implicate the modulation of amygdalar-hippocampal interactions by cortisol. Conversely, neutral stimulus processing was found to be either reduced or unaffected across a number of cognitive and memory domains. A specific increase for negative processing was further supported by poorer self-reported well-being at the mid-point of the study in participants receiving hydrocortisone.
In a separate study exploring the ability of prebiotic supplements to affect cortisol reactivity and emotional processing, a Bimuno-galactooligosaccharide prebiotic was found to reduce the waking cortisol response and increase positive versus negative attentional processing in healthy volunteers. While these effects were not found to be associated, they provide initial promising evidence of the ability to target the HPA axis and emotional processing via the gut microbiota in humans.
Overall, this thesis supports the idea that stress-induced physiological changes after prolonged or repeated cortisol exposure are associated with neural and behavioural alterations, which in turn have been crucial in understanding neuropsychological mechanisms underlying psychiatric disease. A better stratification of the effects of sustained HPA axis alterations on psychiatrically relevant cognitive-emotional domains and neural mechanisms thus remains of high priority.

Keywords: Cortisol
Emotional processing
Stress
Memory
Neuroimaging
Advisor: Harmer, C
Cowen, P