The neurosteroids allopregnanolone and dehydroepiandrosterone modulate resting-state amygdala connectivity

Abstract

The neurosteroids allopregnanolone and dehydroepiandrosterone (DHEA) are integral components of the stress response and exert positive modulatory effects on emotion in both human and animal studies. Though these antidepressant and anxiolytic effects have been well established, little research to date has examined their neural correlates, and no research has been conducted into the effects of neurosteroids on large-scale networks at rest. To investigate the neurosteroid impact on intrinsic connectivity networks, participants were administered 400 mg of pregnenolone (N = 16), 400 mg of DHEA (N = 14), or placebo (N = 15) and underwent 3T fMRI. Resting-state brain connectivity was measured using amygdala as a seed region. Compared to placebo, pregnenolone administration reduced connectivity between amygdala and dmPFC, between amygdala and precuneus, and between amygdala and hippocampus. DHEA reduced connectivity between amygdala and peri-amygdala and between amygdala and insula. Reductions in amygdala to precuneus connectivity were associated with less self-reported negative affect. These results demonstrate that neurosteroids modulate amygdala functional connectivity during resting-state, and may be a target for pharmacological intervention. Additionally, allopregnanolone and DHEA may shift the balance between salience network and default network, a finding that could provide insight into the neurocircuitry of anxiety psychopathology.

An exploratory pilot investigation of neurosteroids and self-reported pain in female Iraq/Afghanistan-era Veterans

“…Identification of biomarkers associated with pain symptoms could help detect risk factors for the development of pain symptoms and guide the development of novel neurosteroid therapeutics for pain disorders. Based on these current findings and prior reports [30,38,40,48], DHEA administration could have therapeutic utility considering it markedly increases DHEAS levels [45][46]48], and quantifying these neurosteroids may have biomarker potential. For example, although the associations found in this study cannot elucidate causation, it is possible that individuals with low DHEAS levels at baseline may be more vulnerable to the development of chronic pain-and that pain symptoms could be ameliorated by restoring DHEAS and/or enhancing DHEAS levels through exogenous administration of DHEA or other neurosteroids.…”

“…In addition, an examination of DHEA and DHEAS levels in male Iraq/ Afghanistan-era Veterans and possible relationships to pain symptoms will be important; considering pronounced sex differences in DHEA and DHEAS levels, the investigation of these molecules in both males and females could contribute to the understanding of sex differences in the neurobiology of pain. Given recent promising neuroimaging findings following DHEA administration [45][46], the use of neuroimaging approaches in the future could also yield new insights into the possible mechanistic contributions of DHEA and DHEAS to the physiology and therapeutics of pain and provide potential biomarker data for the prediction of therapeutic response to neurosteroid interventions. In addition, examining the genetic underpinnings of neurosteroid synthesis and metabolism will be critical.…”

“…For example, reduced levels of DHEA are associated with depression-like symptoms in animal models [41], and reductions in DHEA [42] and DHEAS [43][44] are also associated with depression and anxiety symptoms in clinical populations. Furthermore, two recent functional magnetic resonance imaging studies in healthy adult men suggest that a single dose of DHEA modulates neurocircuitry involved in anxiety and depression [45][46]. In addition, a randomized, double-blind placebo-controlled trial of DHEA resulted in improvement for negative symptoms, depression, and anxiety symptoms in patients with schizophrenia [47]an effect that was more pronounced in females than in males.…”

Is DHEA replacement beneficial in chronic adrenal failure?

“…DHEA has demonstrated antidepressive and anxiolytic activity in different patient populations. This may, in part, be mediated by influencing the connectivity of the amygdala [43,44] In patients with AI, positive effects of DHEA replacement therapy on mood, subjective health status and sexuality have been reported in several studies [45,46]. A double-blinded, placebo-controlled study by Arlt et al [45] involving 24 women with AI showed that DHEA (25e50 mg per day over 4 months) significantly improved both, well-being and sexuality (increased frequency of sexual thoughts, sexual interest and sexual satisfaction with both mental and physical aspects of sexuality).…”

A Randomized, Double-Blind, Placebo-Controlled Trial of Pregnenolone for Bipolar Depression

“…More recent work has suggested that pregnenolone and its metabolites modulate functional connectivity in the human amygdala (Sripada et al, 2014) and enhance activation of neurocircuits pertinent to mood and emotions (Sripada et al, 2013). Clinical trials suggest that pregnenolone and its derivatives, such as allopregnanolone, have potential in treating schizophrenia (Marx et al, 2009;Ritsner et al, 2010;Zorumski et al, 2013b).…”