Testosterone rapidly increases neural reactivity to threat in healthy men: a novel two-step pharmacological challenge paradigm

Abstract

Background: Previous research suggests that testosterone (T) plays a key role in shaping competitive and aggressive behavior in humans, possibly by modulating threat-related neural circuitry. However, this research has been limited by the use of T augmentation that fails to account for baseline differences and has been conducted exclusively in women. Thus, the extent to which normal physiologic concentrations of T affect threat-related brain function in men remains unknown.

Methods: In the current study, we use a novel two-step pharmacologic challenge protocol to overcome these limitations and to evaluate causal modulation of threat- and aggression-related neural circuits by T in healthy young men (n = 16). First, we controlled for baseline differences in T through administration of a gonadotropin releasing hormone antagonist. Once a common baseline was established across participants, we then administered T to within the normal physiologic range. During this second step of the protocol we acquired functional neuroimaging data to examine the impact of T augmentation on neural circuitry supporting threat and aggression.

Results: Gonadotropin releasing hormone antagonism successfully reduced circulating concentrations of T and brought subjects to a common baseline. Administration of T rapidly increased circulating T concentrations and was associated with heightened reactivity of the amygdala, hypothalamus, and periaqueductal grey to angry facial expressions.

Conclusions: These findings provide novel causal evidence that T rapidly potentiates the response of neural circuits mediating threat processing and aggressive behavior in men.

Keywords: Aggression; amygdala; androgens; anger; emotion; fMRI; testosterone.

Conflict of interest statement

All authors declare no biomedical financial interests or potential conflicts of interests.

Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Experimental design and serum testosterone concentrations. Androgel (Abbvie, North Chicago, Illinois) administration increased serum testosterone concentrations above the placebo condition within 30 min of drug application. Error bars depict SEM. *p < .05. GnRH, gonadotropin releasing hormone; MRI, magnetic resonance imaging; POMS, Profile of Mood States.

Figure 2.

Testosterone (T) administration increased corticomedial amygdala (CMA) reactivity to angry compared with neutral faces. (A) Statistical parametric map illustrating relatively increased left CMA reactivity to angry compared with neutral expressions (p < .05, corrected for multiple comparisons within the CMA) after T administration. (B) Parameter estimates obtained from peak voxel in CMA demonstrating effect of drug (T > placebo) for the contrast of angry versus neutral faces. Error bars depict SEM. a.u., arbitrary units.

Figure 3.

Testosterone administration increased hypothalamus reactivity to angry but not fearful or surprise compared with neutral expressions. (A) Statistical parametric map illustrating a significant drug × emotion interaction in the hypothalamus (p < .05, corrected for multiple comparisons within the hypothalamus). (B) Parameter estimates obtained from peak voxel in the hypothalamus demonstrating drug × emotion interaction. Error bars depict SEM. a.u., arbitrary units.