| Summary: | There is increasing evidence that the renin-angiotensin-system, which is usually involved in blood pressure regulation, is relevant in posttraumatic stress disorder (PTSD) development and treatment. For example, population-based studies have shown that angiotensin-II receptor blockers (ARBs) were associated with reduced PTSD symptom development. However, the underlying mechanisms are currently not understood. In this DPhil thesis, I aim to advance the comprehension of core neurocognitive mechanisms of ARB action related to PTSD, using the most widely studied ARB ‘losartan’ in a series of double-blind placebo-controlled experiments. Most neurocognitive research on ARBs has focused on emotional processing and the amygdala as the brain’s centre of fear. However, animal models showed that ARBs modulate hippocampal functioning, memory formation and the endocrine stress response – domains which are crucial in PTSD development. Yet, their human translation alongside supporting neuroimaging work is lacking. In the first two data chapters, I investigate memory formation and demonstrate that ARBs facilitated parahippocampal processing – a core brain region at the intersection of higher-order visual processing and memory formation. Subsequently, I investigate the brain’s intrinsic organisation at rest. I demonstrate that ARBs decouple functional connectivity of regions within the memory system from regions in the frontal cortex involved in emotional processing and executive control. In my final data chapter, I focus on subjective and biological stress markers. I demonstrate that the proposed stress reducing effects of ARBs do not translate to a performance stress paradigm. Yet, exploratory analyses indicate interactions between ARB administration and hormonal contraceptive use on the cortisol stress response. Results are discussed in light of PTSD psychopathology with a particular focus on implications for re-experiencing symptoms like memory intrusions. In addition, I outline future directions for ARB research including hippocampus functioning beyond memory formation, modulatory effects of oestrogens and practical considerations for future study design.
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