Testosterone Is Inversely Related to Brain Activity during Emotional Inhibition in Schizophrenia

Thomas W Weickert,Ashley J Skilleter,Stanley V Catts,Cynthia Shannon Weickert,Rhoshel Lenroot,Ans Vercammen,Ryota Hashimoto

doi:10.1371/journal.pone.0077496

Abstract

Sex steroids affect cognitive function as well as emotion processing and regulation. They may also play a role in the pathophysiology of schizophrenia. However, the effects of sex steroids on cognition and emotion-related brain activation in schizophrenia are poorly understood. Our aim was to determine the extent to which circulating testosterone relates to brain activation in men with schizophrenia compared to healthy men during cognitive-emotional processing. We assessed brain activation in 18 men with schizophrenia and 22 age-matched healthy men during an emotional go/no-go task using fMRI and measured total serum testosterone levels on the same morning. We performed an ROI analysis to assess the relationship between serum testosterone and brain activation, focusing on cortical regions involved the emotional go/no-go task. Slower RT and reduced accuracy was observed when participants responded to neutral stimuli, while inhibiting responses to negative stimuli. Healthy men showed a robust increase in activation of the middle frontal gyrus when inhibiting responses to negative stimuli, but there was no significant association between activation and serum testosterone level in healthy men. Men with schizophrenia showed a less pronounced increase in activation when inhibiting responses to negative stimuli; however, they did show a strong inverse association between serum testosterone level and activation of the bilateral middle frontal gyrus and left insula. Additionally, increased accuracy during inhibition of response to negative words was associated with both higher serum testosterone levels and decreased activation of the middle frontal gyrus in men with schizophrenia only. We conclude that endogenous hormone levels, even within the normal range, may play an enhanced modulatory role in determining the neural and behavioural response during cognitive-emotional processing in schizophrenia.

Highlights

Many observations support the relationship between sex steroid hormones and the development and course of schizophrenia
The evidence for a relationship with testosterone is strengthened by reports of increased negative symptoms and worse cognitive function in association with low endogenous testosterone levels in men with schizophrenia [7,8,9,10,11]
Positive and Negative Syndrome Scale (PANSS) scores for the men with schizophrenia were within the mild to moderately severe range

Summary

Introduction

Many observations support the relationship between sex steroid hormones and the development and course of schizophrenia. Sex differences have been demonstrated in the onset and severity of schizophrenia with men being more severely affected [1]. The peak in age-of-onset during adolescence suggests a link between exposure to increased androgens and development of schizophrenia in at-risk men. A number of studies, including first episode and ultra-high risk, have reported either low or normal circulating testosterone levels in men with schizophrenia [3,4,5,6]. The evidence for a relationship with testosterone is strengthened by reports of increased negative symptoms and worse cognitive function in association with low endogenous testosterone levels in men with schizophrenia [7,8,9,10,11]

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