Traumatic Brain Injury Among Female Veterans

Maheen Mausoof Adamson, PhD • Odette A. Harris, MD, MPH

In military conflicts since 2000, more than 383,947 military personnel have sustained Traumatic Brain Injuries (TBI). 1 The majority of the non-penetrating TBI’s sustained were classified as mild (mTBI) resulting in a research focus on this sub-population. Numerous publications have detailed this cohort’s psychological and functional outcomes. 2-9 However, these data represent a cohort our PNS cohort of female veterans who have sustained an mTBI

that is almost entirely male (~95%). Despite the growing presence of females in the military, 10,11 and even though females accounted for up to 15% of the classified mTBI cases as reported by the Armed Forces Health Surveillance Center in 2010, 12 females were either included as part of the cohort and not separately analyzed or were excluded in these studies. Thus, the majority of TBI research has focused on male data13 and less is known about the natural history, pathophysiology, and outcomes for TBI among females. Although fewer in number, female veterans with TBI have been suggested to suffer from unique physical, mental, and social challenges. This potential sex bias may have broad impacts on the accurate diagnosis, treatment, and recovery of female active duty and veteran service members 13 .

More importantly, risk factors for TBI are changing. As the number of females in sports, military combat, and other high-risk activities rise, so too does the rate of females with TBI, and evidence of sex-related differences in TBI outcomes. The National Collegiate Athletic Association (NCAA) surveillance program from 2004 to 2009 demonstrated females had a 1.4 times higher concussion rate than males playing the same sport, and lost more playtime afterward; guidelines for return-to-play are already changing to consider an athlete’s sex 14 . In the military, females with TBI are 30% more likely than males to experience post-traumatic stress disorder (PTSD); 4 times as likely to develop problems with substance abuse; and 2.7 times more likely to be unemployed 13 . These difficulties interfere with reintegration into civilian society and lead to 7x higher rates of homelessness among injured female veterans 13 . Survivors of domestic violence comprise another understudied atrisk population. Thought to affect up to 20 million females, 92% of whom are thought to have been struck in the head by their abusers, domestic violence is a potential source of TBI that could dwarf cases

BRAIN INJURY professional

In addition, veteran females are at higher risk for domestic violence than civilian females; almost one-fifth of veteran females’ screen positive for intimate partner violence 13 . Given the numbers, the need to understand sex-related differences in TBI has never been greater.

Within the Veteran Administration Healthcare system, the best representation of TBI across the continuum of care in all patients is the infrastructure established by the Polytrauma Network Sites (PNS). Early reports of sex differences for the Operation Iraqi Freedom (OIF)/Operation Enduring Freedom (OEF) cohorts were often secondary findings and offer mixed results for PTSD diagnosis rates.7 More recently, there have been a few reports specifically addressing sex differences. 7,9,16 Still, limitations exist in literature representing female VA Polytrauma/TBI patients leading to major gaps in a clear understanding of the role of sex in military Polytrauma/TBI phenomenology, treatment, and outcomes. As one of the four original national centers within the Polytrauma System of Care (PSC), we sought to diminish this gap by characterizing from the military and athletics combined 15 .

and comparing them to a matched, male veteran sample 17 . We specifically matched on mechanism of injury, time from injury to assessment, and age at assessment. Sex has a moderate effect on mTBI post-concussive symptom presentation, and a significant sex difference was found in the cognitive domain of the Neurobehavioral Symptom Inventory (NSI). Additionally, we found that there were more females living alone than males, and more unemployed females not seeking employment compared to men 17 .

There has been considerable exploration of axonal integrity and functional network connectivity in TBI using diffusion tensor imaging (DTI) and resting state functional MRI (rs- fMRI), respectively. Anatomical change as measured by cortical thickness presents a relatively new modality for TBI research. Warner et al. 18 was among the first to identify specific areas of regional cortical thinning in TBI patients, including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus. Thickness in these areas predicted Glasgow Outcome Scale (GOS) scores.

Cortical thickness in specific areas also predicts a variety of functional outcomes related to TBI, such as memory and verbal learning, as measured by event- based prospective memory EBPM 19 , pain 20 , as well as PTSD, depression, and other post- concussive symptoms 21 . To our knowledge, only one other study has used cortical thickness to quantify sex differences after TBI: Shao et al. 22 found females with TBI had a significantly thicker left caudal anterior cingulate cortex (ACC) than males with TBI. Thickness also correlated with higher scores on the Posttraumatic Stress Disorder Checklist - Civilian Version (PCL-C).

To better characterize the neural mechanisms underlying these sex differences, we examined cortical thickness in males and females with and without TBI in our cohort (n=56) 23,24 . Female healthy adults had significantly greater global and local cortical thickness than male healthy subjects. In the TBI population, females showed cortical atrophy in more places than males, including in several fronto-executive regions, the insula, and critical hubs of the limbic system (p<.05). In other words, more cortical thinning was apparent in females than men years after TBI. Thickness in these areas predicted individual performance on measures of verbal memory (California Verbal Learning Test) and executive function (Trails B). Yet, this brain- behavior relationship was driven by males: for males, cortical thickness predicts California Verbal Learning Test and Trails B performance; in females, cortical thickness is uncoupled from the functions they serve in males.

To our knowledge these are the first studies to demonstrate this sex-related brain- behavior relationship in TBI population. These sex similarities and differences of anatomical properties help understand the mechanisms underlying the symptomology profiles shown in previous studies. Nonetheless, there remains a significant knowledge gap in the sex differences in TBI. Increased female representation in the military heralds an increased risk of TBI for female soldiers, and medical professionals must be prepared to address the unique health challenges in the face of changing demographics among the veteran TBI population. The Institute of Medicine has recommended that the Department of Defense and Department of Veterans Affairs take steps to reduce health and quality of life disparities between males and females and to provide health care that is sensitive to females needs and preferences 25 . This should include efforts to provide tailored treatments for this population’s unique symptom profile and brain architecture and to mitigate the impacts of symptoms on functional outcomes such as employment, marital status, and living situation.

References

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Author Bios

Maheen Mausoof Adamson, PhD, is clinical associate professor of Neurosurgery at Stanford School of Medicine and Senior Scientist at Department of Rehabilitation at VA Palo Alto. She completed her undergraduate degrees in neurobiology and women studies at the University of California, Irvine. She then completed her Ph.D. in neuroscience from the University of Southern California and a postdoctoral fellowship in Psychiatry and Behavioral Sciences at Stanford School of Medicine. Dr. Adamson’s expertise and interests span employing translational neuroscience methodologies for diagnostic and treatments for frequent health problems in patients with neurological disorders. She has been a leader in identifying gender differences in the brain injury population, particularly in Veterans. She currently serves as PI and Site-PI on numerous neuromodulation clinical trials under the Department of Veterans Affairs and Department of Defense funded grants.

Odette Harris, MD, MPH, is a Professor of Neurosurgery at Stanford University School of Medicine, Vice Chair, Diversity and Director of Brain Injury for Stanford Medical Center.  Dr Harris manages and coordinates the medical and surgical care of all patients suffering from traumatic brain injury that are admitted to the Stanford System.  Dr. Harris is also the Deputy Chief of Staff, Rehabilitation at the Veterans Affairs Palo Alto Health Care System, which includes responsibilities for the varied programs of the Polytrauma System of Care, Spinal Cord Injury, Blind Rehabilitation Services, Recreational Therapy and Physical Medicine and Rehabilitation.