Sex Differences in Traumatic Brain Injury: What We Know and What We Should Know

Abstract

There is growing recognition of the problem of male bias in neuroscience research, including in the field of traumatic brain injury (TBI) where fewer women than men are recruited to clinical trials and male rodents have predominantly been used as an experimental injury model. Despite TBI being a leading cause of mortality and disability worldwide, sex differences in pathophysiology and recovery are poorly understood, limiting clinical care and successful drug development. Given growing interest in sex as a biological variable affecting injury outcomes and treatment efficacy, there is a clear need to summarize sex differences in TBI. This scoping review presents an overview of current knowledge of sex differences in TBI and a comparison of human and animal studies. We found that overall, human studies report worse outcomes in women than men, whereas animal studies report better outcomes in females than males. However, closer examination shows that multiple factors including injury severity, sample size, and experimental injury model may differentially interact with sex to affect TBI outcomes. Additionally, we explore how sex differences in mitochondrial structure and function might contribute to possible sex differences in TBI outcomes. We propose recommendations for future investigations of sex differences in TBI, which we hope will lead to improved patient management, prognosis, and translation of therapies from bench to bedside.

Keywords: TBI; biological sex; chromosomal factors; mitochondria; sex hormones.

FIG. 1.

Flowchart for search strategy and study inclusion criteria.

FIG. 2.

Sex effects on TBI in human studies: distribution by severity. All human studies identified by our search criteria were classified based on post-TBI outcomes (upper panel). The total studies were then analyzed based on injury severity. Studies that included patients of all injury severities (GCS 15–3) or where data on injury severity were not available, were grouped under “Non-stratified” (lower left). Studies that recruited patients with GCS 9–15 were classified into the “Mild–moderate” category (lower middle). Studies with GCS <12 were grouped into the “Moderate–severe” category (lower right). In each category, we quantified percentage of studies showing worse outcomes in women than men, studies showing better outcomes in women than men, those showing no significant difference between men and women, and studies reporting mixed results where women do better on some outcome measures and men on others. GCS, Glasgow Coma Scale; TBI, traumatic brain injury.

FIG. 3.

Sex effects on TBI in human studies: distribution by sample size. We categorized the human studies identified by our search criteria based on the number of patients recruited. Small studies enrolled no more than 1000 patients (left), medium-sized studies enrolled 1000–10,000 patients (middle), and large studies enrolled more than 10,000 patients (right). In each category, we quantified percentage of studies showing worse outcomes in women than men, studies showing better outcomes in women than men, those showing no significant difference between men and women, and studies reporting mixed results where women do better on some outcome measures and men on others. TBI, traumatic brain injury.

FIG. 4.

Sex effects on TBI in animal studies: distribution by severity. All animal studies identified by our search criteria were classified based on post-TBI outcomes (upper panel). Animal studies were then categorized into those investigating mild (lower left) or moderate–severe (lower right) injury severity. In each category, we quantified percentage of studies showing worse outcomes in females than males, better outcomes in females than males, no sex differences, or mixed results where females do better on some outcome measures and males on others. TBI, traumatic brain injury.

FIG. 5.

Sex effects on TBI in animal studies: distribution by injury model. Animal studies were classified based on injury model used: CCI, CHI, LFPI, and other injury models. In each category, we quantified percentage of studies showing worse outcomes in females than males, better outcomes in females than males, no sex differences, or mixed results where females do better on some outcome measures and males on others. CCI, controlled cortical impact; CHI, closed head injury; LFPI, lateral fluid percussion injury; TBI, traumatic brain injury.

FIG. 6.

Comparison of TBI outcomes in human versus animal studies. All human studies (white bars) and animal studies (black bars) were divided into four categories based on study findings: 1) those showing women/females do better than men/males, 2) studies showing women/females do worse than men/males, 3) no sex differences, and 4) those reporting mixed results by sex. TBI, traumatic brain injury.