Study Confirms Sex-Differences in Neuroscience and Long-Term Outcomes Following Concussion

A new study conducted by researchers at the University of Arizona College of Medicine – Phoenix and Barrow Neurological Institute at Phoenix Children’s Hospital has provided evidence that female brains communicate and respond differently to mild traumatic brain injuries (TBIs) than males. However, historically, a majority of TBI research has been male-dominated.

The study was led by Gokul Krishna, PhD, a postdoctoral research associate in the laboratory of Theresa Currier Thomas, PhD. Their findings were published in the journal Frontiers in Neurology special issue “On the Basis of Sex: Impact on Traumatic Brain Injury” in August 2020.

In this research, the group fixed small electrodes of micrometer diameter to specific areas of the brain, including those involved in the glutamatergic pathway and somatosensory function. Using an experimental model, the research evaluated females at various points in their estrous phase (reproductive cycle) and studied males. These translational experiments indicated that female brains communicated differently than males on the level of neurotransmitters, independent of a TBI; that a mild traumatic brain injury can have a long-term influence on estrous/menstrual cycles; and that the long-term differences exist in how the female brain responds to head injury.

“TBI affects several million individuals each year,” Dr. Krishna said. “Women may be living with crippling emotional and cognitive symptoms associated with TBI that can be improved with more research, more informed clinicians that can provide an accurate diagnosis and better access to medical care.”

Prior to this study, neurotrauma researchers have started to uncover that women compared to men are more vulnerable to long-term TBI effects. However, this is the first study to demonstrate that the near real-time communication in the brain is different, using online high-resolution microelectrode array technology.

“Identifying the changes in chemical neurotransmission underlying hypersensitive behavior is an essential component to understand and treat TBI pathology,” said Dr. Currier Thomas, a U of A College of Medicine – Phoenix associate professor of Child Health, and senior investigator of the study. “This study changes the way we think about TBI research to emphasize the need to further understand female patients.”

Around 2.87 million mild TBIs are reported in the U.S. every year, with about 40 percent occurring in reproductively mature women. The National Women’s Health Network estimates that overall, 20 million women have sustained at least one TBI from domestic violence in the U.S., exceeding the numbers of athletes and military combined.

It is known that women with a mild brain injury have increased emotional symptoms — including post-traumatic stress disorder, anxiety, depression and other stress-related problems. Although women account for a significant portion of the TBI cases annually &mdash' and there is evidence that their brains react differently — most neuroscience studies do not examine how females are affected and little is known about how sex affects chronic recovery from mild brain injury.

“Most translational neuroscience research is carried out on males,” said Dr. Currier Thomas, who is also a scientist track associate professor of Barrow Neurological Institute at Phoenix Children’s Hospital and a research investigator at Phoenix VA Health Care System. “Therefore, therapies are geared toward males and not females, increasing the likelihood that females are not being treated with the best possible therapeutic strategies. This leads to suboptimal clinical care for females.”

Dr. Krishna added, “Increasing public awareness of this is essential for supporting translational neuroscience research in both sexes. Our research underscores the unique insight into brain function after head injury from studying both sexes. This approach enables the TBI field/community to develop optimized/evidence-based treatments for women as well as men.”

Researchers say the next steps are to study the direct effect of hormones on how the brain communicates and to understand when and why some of these effects take a long time to manifest as symptoms.

Significant contributors to this study also include Caitlin E. Bromberg, graduate student, Emily C. Connell, a former international intern, Erum Mian, MBBS, a clinical trainee in Currier Thomas’s lab, and colleagues from University of Arizona College of Medicine – Phoenix and Barrow Neurological Institute at Phoenix Children’s Hospital.

Dr. Currier Thomas’s research is funded by the National Institutes of Health (grant R01NS100793). Equipment was provided through a grant by the Phoenix Children’s Hospital Leadership Circle.