Intimate Partner Violence-Related Brain Injury: Unmasking and Addressing the Gaps

Abstract

Intimate partner violence (IPV) is a significant, global public health concern. Women, individuals with historically underrepresented identities, and disabilities are at high risk for IPV and tend to experience severe injuries. There has been growing concern about the risk of exposure to IPV-related head trauma, resulting in IPV-related brain injury (IPV-BI), and its health consequences. Past work suggests that a significant proportion of women exposed to IPV experience IPV-BI, likely representing a distinct phenotype compared with BI of other etiologies. An IPV-BI often co-occurs with psychological trauma and mental health complaints, leading to unique issues related to identifying, prognosticating, and managing IPV-BI outcomes. The goal of this review is to identify important gaps in research and clinical practice in IPV-BI and suggest potential solutions to address them. We summarize IPV research in five key priority areas: (1) unique considerations for IPV-BI study design; (2) understanding non-fatal strangulation as a form of BI; (3) identifying objective biomarkers of IPV-BI; (4) consideration of the chronicity, cumulative and late effects of IPV-BI; and (5) BI as a risk factor for IPV engagement. Our review concludes with a call to action to help investigators develop ecologically valid research studies addressing the identified clinical-research knowledge gaps and strategies to improve care in individuals exposed to IPV-BI. By reducing the current gaps and answering these calls to action, we will approach IPV-BI in a trauma-informed manner, ultimately improving outcomes and quality of life for those impacted by IPV-BI.

Introduction

Intimate partner violence (IPV), which includes physical and sexual violence, psychological or emotional aggression, and/or stalking by a former or current intimate partner,¹ represents a significant public health concern that impacts all communities globally, but not equally. An IPV is a gender-based issue with a greater proportion of women (∼27%^2–4) compared with men (range: ∼3–20%⁵) experiencing IPV annually.

Women also experience more severe forms of physical IPV with worse physical health sequelae, compared with men.^1,6 Women with a disability are more likely to report all forms of IPV (e.g., sexual and physical violence, control of reproductive health) compared with women without disability,⁷ and sexual and gender minorities (SGM) face even higher rates of IPV than their cisgender, heterosexual peers.⁸

In addition, although IPV is prevalent worldwide, it varies substantially based on geographical region.² Further, Indigenous communities are at the greatest risk of IPV exposure, with approximately 80% of Indigenous women and men in the United States (US) reporting exposure to IPV.⁹

Exposure to IPV can result in a constellation of psychological, cognitive, physical, and neurological consequences^10–17 that can significantly impact a survivor's quality of life. There is also a substantial and growing global concern surrounding the risk of exposure to IPV-related head trauma with probable brain injury (IPV-BI) and its myriad of devastating health consequences. Data from IPV-BI studies, completed mainly in cisgender women and representing a range of settings and the use of different assessment methodologies, show estimates of between 27 and 100% of women exposed to IPV have experienced IPV-BI.^18–22 However, these estimates are sometimes from shelters or do not include women who have sustained only psychological IPV, so we know these are not valid estimates of the general population of all abuse survivors.

Indeed, these samples are biased by study recruitment and inclusion criteria (i.e., specifically recruiting women who have experienced IPV-related head, neck, and facial trauma). Even at the lowest estimates (∼27%), however, IPV-BI represents a significant health concern. Further adding to this problem, many women report experiencing repetitive head trauma events and brain injury (BI) exposures,²³ with some women even reporting that they have experienced “too many head impacts to count.”^19,24

Importantly for identifying, prognosticating, and managing injury outcomes, IPV-BI likely represents a distinct phenotype of BI because of unique mechanisms of injury. For example, traumatic brain injury (TBI) can occur because of acceleration and deceleration forces in the brain as a result of being violently shoved, pushed, or hit, which may result in focal or diffuse axonal injury.^21–23,25 Non-fatal strangulation (NFS), or other forms of impeded breathing, are an understudied mechanism of IPV-BI and can result in anoxic or hypoxic, ischemic, hypoxic-ischemic, or intracranial pressure-related BIs from oxygen deprivation to the brain^{23,24,26–29} (see the following reviews for full descriptions of injury mechanisms and outcomes^21,22,25).

For more than 20 years, we have known that IPV-BI is associated with cognitive, psychological, and neurological consequences^23,30,31; however, screening and diagnosis of IPV-BI by clinical providers is limited. Thus, many individuals exposed to IPV-related head trauma and BI may be living with the undetected effects of IPV-BI.

The aims of this article are to identify important gaps in research and clinical practice in IPV-BI and suggest potential solutions to address them. This review summarizes IPV research in five key clinical-research priority areas: (1) unique considerations for IPV-BI study design; (2) understanding NFS as a form of BI (NFS-BI); (3) identification of objective biomarkers of IPV-BI; (4) consideration of the chronicity, cumulative and late effects of IPV-BI; and (5) BI as a risk factor for IPV engagement.

By addressing these gaps, we hope to advance both knowledge and clinical practice in IPV-BI. We conclude this review with a call to action to help investigators develop ecologically valid research studies addressing the identified knowledge gaps and strategies for service providers (e.g., physicians, neurologists, neuropsychologists, allied healthcare workers, and law enforcement) to improve care in individuals exposed to IPV-BI (Fig. 1).

FIG. 1.

Key priority areas and knowledge gaps in the study of intimate partner violence-related brain injury (IPV-BI). NFS, non-fatal strangulation. Color image is available online.

Key Clinical-Research Priority Areas and Knowledge Gaps in the Study of IPV-BI

BI has a long and extensive history of study in the general population, as well as other specific groups including sports-related concussion in athletes and blast- and impact-related injuries in military personnel.^32–34 This has led to a wealth of information on the chronic and long-term effects of BI in general; however, the effects of IPV-BI have long been underrepresented. The nature, etiology, and exposure pattern of IPV-BI likely results in a unique constellation of functional outcomes, contributing to a distinct BI phenotype. Thus, research focused on IPV-BI is necessary to characterize the specific outcomes.

In the following section, we outline key priority areas our group of experts has identified for both assessing research outcomes and clinical considerations for IPV-BI. For each priority area, we describe what is known to date, followed by knowledge gaps and how best to address these gaps in future studies.

Study design considerations unique to IPV-BI

An IPV-BI can be caused by a unique constellation of injury mechanisms resulting in TBI and anoxic or hypoxic, ischemic, hypoxic-ischemic, or pressure-related BIs. Because of the often repetitive and violent nature of the injuries during abusive episodes, the effects of IPV-BI can be compounded over time.^23,35 Further, this complex neurotrauma, coupled with other co-existing and co-occurring polytrauma (e.g., verbal and emotional abuse) and resulting mental health effects, such as post-traumatic stress disorder (PTSD), complicates the understanding of IPV-BI.

Individuals exposed to IPV-BI likely also experience stigma associated with abuse,³⁶ limited partner or social support,³⁷ and fear that reporting injuries can trigger another violent episode,³⁸ all of which can further impact mental and physical health outcomes. Arguably, IPV-BI represents a distinct BI phenotype, because these unique characteristics typically do not occur in TBI in the general population. Therefore, it is likely inappropriate to apply general BI screening, interventions, and outcomes from a more general population to those living with IPV-BI.

As outlined in a recent review by Esopenko and associates,²⁵ future research studies need to identify measures that can (1) accurately screen for the presence of IPV-BI and (2) assess the additive effects of IPV-BI and other forms of IPV (e.g., psychological aggression/abuse) on cognitive, emotional, and neural outcomes. Importantly, studies should consider the feasibility of adopting common data elements (CDEs) developed for TBI studies and determining psychometrics for these CDEs in IPV-BI populations specifically.

Researchers must be prepared to modify study designs for this vulnerable population, because stigma and fear of revictimization contribute to both initial study recruitment and loss to follow-up in longitudinal studies. Another important consideration in IPV-BI research studies is ensuring the recruitment of appropriate comparison groups. Future IPV-BI studies could include individuals who have experienced IPV, but not IPV-BI or head trauma, as a comparison group to account for the effects of IPV more broadly on health and functioning.

Gap to Address: identification and screening of IPV-BI

An IPV-BI is not commonly screened for by healthcare professionals, resulting in many injuries going undetected and untreated. Survivors of IPV are unlikely to report their experiences of violence, partly because of the lack of awareness of IPV-BI among healthcare workers, sociocultural factors, and challenges in accessing care.^21,39

IPV survivors may be reluctant to report the injury to healthcare providers or law enforcement because of assumptions that the injury does not require treatment, and/or fear of retribution from or negative consequences for the partner (e.g., incarceration). Also problematic is that IPV-BIs are often only witnessed by the perpetrator, reducing the likelihood that observations of altered brain functioning would be reported.³⁶ When IPV survivors present to healthcare providers with an injury, the assessment and treatment of other readily visible injuries (e.g., broken limbs, bruises, lacerations) may take precedence over examination of potential BI.

In rural areas, where rates of IPV are higher and injuries are more severe, proper screening may be less likely to occur because of limited access to healthcare providers, and particularly those adept at identifying IPV.^40,41 Many individuals may continue living with undiagnosed IPV-BI because of gaps in awareness of BI screening and the importance of early diagnosis.^21,42

Some IPV-BI specific tools such as the Brain Injury Severity Assessment (BISA²³), the Brain Injury Screening Questionnaire with IPV Module (BISQ-IPV⁴³), the Boston Assessment of Traumatic Brain Injury-Lifetime for female survivors of IPV (BATL/IPV⁴⁴), and the Ohio State University TBI Identification Method (OSU-TBI-ID⁴⁵) were developed for use in research contexts.⁴³

Some of these measures are not clinically validated, however, and others tend to be lengthy, limiting their feasibility in clinical practice. Therefore, identification of a gold standard screening tool for early detection of IPV-BI by healthcare professionals is needed to improve identification of IPV-BI. The gold standard screening tool will likely consist of a combination of self-reported information and objective assessments, when warranted.⁴²

Knowledge translation of IPV-BI is a necessary and vital component to ensure survivors are adequately screened for BI.⁴⁶ Programs designed to increase IPV-BI knowledge among service providers are essential and can be achieved by conducting educational workshops for healthcare providers and other professionals working with women, and spreading awareness of tools such as the Concussion Awareness Training Tool for Women's Support Workers.⁴⁷

In addition, the clinical validation of IPV-BI screening tools described above is needed. Moreover, collaborative networks among researchers, clinicians, community advocates, and frontline service providers are needed to develop and expand training on how to use validated screening tools and to provide appropriate care and/or referrals to other medical and social support service.⁴²

Gap to Address: Accounting for cumulative lifetime trauma in IPV-BI outcomes

Exposure to potentially traumatic events (PTEs), including IPV, is widespread. Responses to the World Health Organization World Mental Health Surveys found that 70% of adults (mean age 43.7 years) reported at least one PTE in their lifetime, with an average of 4.5 distinct PTEs.⁴⁸ Importantly, repeated exposure to the same type of PTE increases odds of mental health sequelae, with repeated exposure to physical assault increasing the likelihood of PTSD by more than three times (odds ratio [OR] = 3.2).

An IPV-BI may be complicated further by the cumulative, or added affects, of adverse childhood experiences.^49,50 Consequently, treatment and prognosis could be informed by clinically assessing the unique contributions of these cumulative effects, yet parsing out the unique contributions of each risk factor is often difficult.^51,52 Thus, measures to identify and assess cumulative, lifetime trauma are needed to differentiate the effects of IPV-BI from other trauma exposures.

Gap to Address: Ability to access services

Very limited research has focused on the specific needs of IPV-BI survivors in accessing services. Overall, IPV survivors require a safe environment to access health and social services and share their experiences. Help-seeking behavior and experiences within the healthcare system are affected by societal perceptions and stigma of IPV, normalization of violence, and individual characteristics such as race, socioeconomic status, education, insurance status, and disability status.^53–59

These factors interact with racism, sexism, and classism within the healthcare, legal, and societal systems,⁶⁰ influencing access to resources through formal channels (e.g., domestic violence shelters, police officers, etc.).⁶¹ This underscores the need for intersectional approaches in the design and implementation of resources for women who experience IPV. More broadly, widespread change within the legal, educational, and medical systems is paramount to better support survivors of IPV-BI.⁶⁰

Gap to Address: Intersection of SGM and IPV prevalence and outcomes

Most of our understanding of IPV-BI is rooted in studies of cisgender women. While this work is extremely important, there are no IPV-BI studies that specifically include SGM individuals. This is a significant issue, as emerging evidence shows that SGM individuals may experience higher rates of IPV compared with heterosexual, cisgender men and women.^8,62–64

According to the Centers for Disease Control and Prevention, bisexual women experience higher rates of sexual and physical IPV, as well as non-partnered assault, relative to lesbian and heterosexual women, while gay men and lesbian women experience higher or equal rates of IPV or sexual violence compared with heterosexual individuals.^64,65 Data from the 2015 US Transgender Survey demonstrates that nearly one-quarter (24%) of transgender or gender diverse individuals report having experienced severe physical violence by an intimate partner.⁶⁶ The high rates of exposure to physical IPV, which has been found to be associated with high risk for IPV-BI among cisgender women,^21,22,25 likely place SGM individuals at a similar, if not higher, risk of IPV-BI, yet no research has screened for IPV-BI specifically in SGM individuals.

It is vital that future research focus on the experiences of IPV in SGM individuals, with an emphasis on the prevalence of IPV-BI and the multi-faceted deleterious effects of IPV-BI. This is particularly important when considering the stigma surrounding SGM and systemic barriers to healthcare access, all of which may negatively affect reporting behavior and medical care.

Importance of recognizing NFS as a form of brain injury

Non-fatal strangulation is one mechanism of IPV-BI⁶⁷ that is often overlooked as a potential cause of BI. NFS has been defined as compression of airways and/or compression of the blood vessels in the neck, leading to restricted blood flow into or out of the brain.^68,69 Women are not only at risk for experiencing intimate partner perpetrated NFS, as shown in a study of women survivors of abuse seeking services where 68% experienced NFS,^70,71 but exposure to NFS also increases the risk for more severe violence (e.g., homicide).⁷²

Pathophysiology of NFS

The pathophysiology of NFS on the brain likely differs from other common BI mechanisms, such as impact-related TBI,^68,73 and requires different identification and management strategies. NFS potentially leads to BI by one or more of the following mechanisms: (1) anoxic or hypoxic brain injury from compression of the trachea; (2) ischemic BI from occlusion of arterial blood flow; (3) hypoxic-ischemic BI (HIBI) from the combined compression of the trachea and the carotid arteries, and/or by triggering carotid sinus reflex leading to dysrhythmia or cardiac arrest, which subsequently could cause BI; and (4) pressure-related BI from the occlusion of the jugular veins, leading to venous congestion and increased intracranial pressure, blocking the removal of metabolic byproducts and leading to pinpoint hemorrhage.^29,68,69

Importantly, a lack of oxygen to the brain for 1–6 min can lead to cerebral infarction, disseminated cell death, and potentially, permanent brain damage, suggesting the brain can be quickly damaged by any, or all, of the mechanisms described above.^67,68,74

NFS may cause loss of consciousness (LOC) or alteration of consciousness (AOC).²⁹ One study reported that 38% of survivors of NFS experienced LOC.⁶⁷ Reporting of AOC-related presentation was relatively lower when assessed at a later date post-NFS, however, possibly because of the survivors' impaired memory or a lack of understanding of the significance of AOC-related symptoms^67,68 or inability to self-assess AOC.

The AOC-related indications include memory loss, confusion, disorientation, dizziness, seeing stars, or blurred vision, “blacking out,” “greying out,” or “passing out.”^23,29,68 Only ∼50% of NFS survivors, however, show visible signs of the injury,^75,76 creating challenges for identifying NFS. Misdiagnosis, or failure to assess the consequences of NFS-BI may increase the risk for further abuse, resulting in cumulative injury effects and missed opportunities for intervention with mental health and supportive services.⁷⁷

Here, we provide a brief overview of potential neurological, cognitive, and psychological consequences of NFS-BI that should be examined in follow-up studies.

Evidence shows that the constellation of symptoms occurring after hypoxic or ischemic BI differ from those that occur from blunt force TBI.^23,78 Dizziness, limb weakness, eyelid droop, facial or limb paralysis, imbalance, incontinence of bowel or bladder, and seizures are some of the neurological and physical consequences of NFS.^30,68,79

In addition, survivors of NFS may report typical BI symptoms including lightheadedness, muscle spasm, tinnitus, pain, headache, and general weakness or fatigue.^68,80 NFS survivors may also show contusions or abrasions to the neck or throat, petechiae, sore throat, hoarse voice, trouble swallowing, and other internal injuries such as fracture of the hyoid bone.^79,81

Cognitive consequences of NFS include decreases in processing speed, executive function, learning and memory, attention, reasoning, object and spatial perception, and language and comprehension.^30,79,82,83 For example, one study found that women who had sustained strangulation-related AOCs performed worse on tests of long-term episodic and working memory than women who did not sustain strangulation-related AOCs, independent of IPV-BIs.²⁹

Depression, anxiety, suicidal thoughts, and PTSD symptoms are common mood disturbances secondary to NFS.^{29,68,83–85} One study demonstrated that the risk of depression is twice as high for women who experienced IPV-related NFS compared with women who had not, and the severity of NFS was associated with more severe psychological symptoms.⁸⁵ Likewise, PTSD symptoms can be activated or exacerbated with continued or repeated use of coercive control or threats among those with a history of NFS.⁸⁶ Thus, NFS is a risk factor for depression and PTSD in survivors of IPV.²⁹ Taken together, the resulting effects these experiences can have on a survivor's behavior may impact their treatment by first responders⁸⁷ and in subsequent legal proceedings.^60,88

Gap to Address: Immediate and delayed consequences after NFS

Assessment of NFS-BI, especially many years after the injury, can be challenging because of the complex sequelae of BI, high prevalence of psychological and trauma symptoms, and history of repeated incidents and exposure to multiple forms of abuse across the lifespan.

Signs and symptoms after NFS-BI depend on various factors including strength and frequency of strangulation and the brain areas affected. For example, structures such as the caudate nucleus (involved in voluntary movement, motivation, and emotion), putamen (involved in cognition, learning, and motor control), frontal lobe (involved in voluntary control and higher level executive functions), and hippocampus (involved in the formation and retrieval of memories) are vulnerable to reduced or lack of blood flow.^89,90 The hippocampus is also very susceptible to hypoxic injury.⁹¹ Therefore, NFS-BI would lead to regional ischemia of the brain, and the functions related to these structures may become impaired.

A handful of case reports demonstrate a correlation between NFS and subsequent stroke,^92–94 despite the fact that only 39% of survivors of these strokes reported symptoms on the day of NFS.⁷⁵ There is evidence that delayed stroke can occur two weeks to several months after NFS, possibly because injured brain cells may survive for days before permanent death.^68,89 Other work suggests the magnitude (strength and duration), number (single vs. repeated), and methods (hands, ligature) of NFS may contribute to the likelihood of stroke developing subsequently.^92,94 As such, studies are urgently needed to determine the immediate and delayed consequences of NFS to better predict acute and chronic outcomes.

Gap to Address: Repeated NFS and cumulative effects of IPV-BI

Albeit limited, there is evidence that repeated exposure to NFS events can have a cumulative impact on cognitive, neurological, sensory-motor, and psychological functioning.^79,95 It has been reported that participants who experienced multiple NFS events had approximately three times greater odds of reporting LOC compared with those who did not.⁹⁶ Moreover, the proportions of IPV-exposed women seeking healthcare is higher for those with exposure to multiple NFS events (29.92%) relative to those with exposure to one (21.38%) or no (8.78%) NFS events.⁹⁶ This suggests a dose-response relationship between repeated exposure to NFS and greater brain damage or symptom severity.

Future research is needed to determine whether repetitive exposure to NFS results in worse outcomes than single events, as well as whether there are differences in symptom presentation and cognitive outcomes compared with other forms of IPV-BI.

Emerging objective biomarkers of diagnosis and prognostication of IPV-BI

There is a profound lack of objective tools to accurately diagnose IPV-BI in both the acute and chronic/remote settings.^35,77 For BI in general, there have been several National Institutes of Neurological Disorders and Stroke (NINDS) and Department of Defense (DoD) consensus conferences over the past decade suggesting that validated biomarkers for multiple contexts of use will prove instrumental to BI research and care.^97-99 As described above, there are physiological markers that point to the presence of BI and specifically IPV-BI acutely (e.g., LOC, AOC); however, reliance on these markers to determine BI can be problematic in the context of IPV, given underreporting of the injuries and co-occurring injuries (e.g., broken bones) taking precedence on the acute stage.

As such, there has been a focus on identifying other biomarkers sensitive to detecting IPV-BI and related alterations both acutely and chronically. Regardless of mechanism (e.g., blast-related, violence-related) or population (e.g., military personnel, sports-related concussion), there have been on-going efforts to advance methods for identifying and prognosticating outcome after BI.

Based on past TBI research and limited work in IPV-BI, there is some evidence of neuroimaging methods and fluid biomarkers that may identify and prognosticate IPV-BI. There will be IPV-BI specific challenges, however, in advancing these methods, such as being able to detect NFS-BI and differentiate it from occult or traumatic BI, both at acute and chronic post-injury intervals.

Current support for using neuroimaging to detect NFS-BI

Although neuroimaging methods for identifying TBI and TBI-related outcomes have been a significant clinical and research focus for decades (for reviews, see: ^25,100–03), the use of neuroimaging for IPV-BI, and particularly NFS, has been rare or limited (see ¹⁰⁴ for a recent review of neuroimaging studies in IPV-BI). Although clinical guidelines for using neuroimaging to characterize NFS have been developed,^105,106 given the underreporting of IPV-BI and NFS specifically, neuroimaging may not be routinely acquired clinically.

There is some evidence, however, that different neuroimaging modalities, and specific magnetic resonance imaging (MRI) sequences may help us better understand the neural effects of different mechanisms of IPV-BI. There is evidence that computed tomography (CT) angiography may be useful in detecting vascular compromise, which is a significant consequence in NFS-BI. While one investigation of CT angiography in the neck detected vascular injury in only 2% of 142 patients presenting with strangulation,¹⁰⁷ others suggest that CT angiography may aid in the identification of the vascular effects of NFS.^73,108-110

One significant concern of NFS-BI is HIBI, with the earliest signs of HIBI being cytotoxic edema. Cytotoxic edema occurs in the first hours post-injury when the sustained lack of oxygen to the brain causes neurons to lose their ability to regulate the influx of sodium ions and water.^111,112 This results in an increase in intracellular water content, or cellular swelling, leading to a decrease in the free diffusion of water molecules within the affected tissue.¹¹³ Use of diffusion-weighted imaging (DWI) is particularly sensitive to detecting cytotoxic edema because of its ability to detect changes to the diffusion of water molecules within tissues on a microscopic scale. As a result, DWI may be a valuable tool in the early detection and assessment of HIBI secondary to NFS-BI.¹¹⁴

In addition, there is some evidence that gray matter (particularly the sensorimotor and visual cortices) and structures with high metabolic activity, including the basal ganglia, thalami, hippocampi, and cerebellum, arepreferentially affected by HIBI.^113,115,116 Past work has shown the appearance of lesions in these areas changes over time with different MRI sequences.^117–119 For instance, between a few hours and a few days of the insult, high DWI signal is coupled with low signal on apparent diffusion coefficient (ADC) maps in the affected area, resultant from true restricted diffusion.^119–121 Within the first few hours, conventional T2-weighted imaging, on the other hand, may appear normal or demonstrate only subtle abnormalities,¹¹⁷ such as a loss of distinction between the gray and white matter in the cortex^122,123 or signal hyperintensity in the basal ganglia.¹²⁴

In the subacute phase post-injury, DWI hyperintensity persists, although low signal on ADC maps pseudonormalizes by the end of the first week.^125–127 In this phase, hyperintense signals may still appear using other MRI sequences, such as T2-weighted images and fluid attenuated inversion recovery (FLAIR).¹¹⁶ The T2-weighted images, however, may also show areas of hypointensity because of deoxyhemoglobin and hemosiderin accumulation from ischemia and hemorrhage, with the size and intensity gradually increasing over the first two weeks post-injury.¹²⁸

Hippocampal damage may also occur during this time.¹²⁹ In the chronic phase, the area of restricted diffusion on DWI may evolve into an area of encephalomalacia, the softening or loss of brain tissue after injury, and gliosis, a reactive change of glial cells in response to injury, in the affected regions, and during this process cortical necrosis takes place, identified by high signal intensity on T1-weighted images.^119,121 The severity and duration of insult can further affect the appearance of HIBI-related lesions over time.¹¹⁷

Gaps to Address: Implementation of neuroimaging in individuals reporting IPV-BI

Further research using advanced neuroimaging techniques is needed to characterize how the different mechanisms of injury in IPV-BI affect the brain. Based on work done to date, thoughtful use of different neuroimaging modalities (CT angiography and MRI) and specific MRI sequences (e.g., DWI and FLAIR) sensitive to potential abnormalities at different injury time points may provide a more comprehensive understanding of pathological changes associated with IPV-BI over time. Thus, prospective studies that acquire multi-sequence MRI longitudinally after IPV-BI would help to better characterize the progression of neuropathology and aid in developing time-sensitive markers of IPV-BI.

When interpreting neuroimaging measures over time, however, it is important to consider that atrophy, typically only observed in the chronic post-injury phase, could be attributed to the effects of other traumatic or acquired BIs the individual has experienced. In addition, the repetitive nature of injuries needs to be considered when interpreting neuroimaging outcomes. In particular, alterations in brain structure may not represent acute injury, but rather the accumulation of repetitive injuries to the brain. Therefore, imaging findings may not be specific to IPV-BI, and a thorough life history is required when interpreting neuroimaging outcomes.

Gap to Address: Identification of multi-modal fluid biomarkers

Fluid (e.g., blood, saliva) biomarkers have considerable potential in providing relatively non-invasive, objective, and sensitive indicators of the pathobiology induced by various forms of IPV-BI, including mild TBI, NFS (e.g., ischemia, hypoxia, reperfusion), and stress. Blood biomarkers have advanced tremendously in TBI research with proteins related to neuroaxonal (e.g., ubiquitin C-terminal hydrolase L1, UCH-L1; neurofilament light, NfL; tau) and glial injury (e.g., glial fibrillary acidic protein, GFAP; S100 calcium binding protein B, S100B), among the best established in this context.^130,131

In the hours immediately after injury, UCH-L1 and S100B have shown a moderate ability to distinguish between patients with and without mild TBI, and some studies found a similar ability of GFAP in the days after injury.^132–134 GFAP and UCH-L1 measured in tandem using the Banyan Brain Trauma Indicator and Abbott i-STAT Point-of Care tests are approved by the US Food and Drug Administration to aid in the clinical decisions surrounding mild TBI, and S100B is included in clinical mild TBI guidelines in Scandinavia.^135,136 Last, recent studies have demonstrated that NfL, as a biomarker of damage to large myelinated axons, appears particularly sensitive to mild TBI in the days to weeks post-injury.^137–139

Given the prominent role of neuroinflammation in the aftermath of TBI, inflammation-associated proteins have been studied as potential fluid biomarkers. Evidence shows that multiple cytokines appear altered in the acute or chronic period of mild TBI.^140,141 Blood biomarkers related to cerebral microvascular injury are also relevant and currently studied in the context of mild TBI.^142,143 Phosphorylated tau markers are highly relevant to TBI, as chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with exposure to head trauma, is defined by deposition of tau in neurons.¹⁴⁴ Circulating microRNA (miRNA) in addition to proteins have emerged as other promising biomarkers for TBI, with multiple studies finding evidence of miRNA changes in blood and saliva at various stages post-injury.^145–147

Most TBI blood biomarker studies to date are in the context of head impacts (e.g., sport-related concussion, motor vehicle accident, falls) or blast injuries that involve biomechanical deformation of brain tissue resulting from mechanical or pressure wave forces applied to the head. There are two critical questions that need to be addressed moving forward, however. First, whether these findings are generalizable to the multiple mechanisms of injury common in IPV-BI, and second, how these biomarkers are affected by stress, PTSD, and other mental health comorbidities.

In the military context, circulating cytokines and tau were each significantly elevated in those with combined TBI and PTSD compared with TBI only,^148,149 and C-reactive protein could differentiate PTSD from TBI and healthy controls in military veterans.¹⁵⁰ Importantly, there is a profound gap in knowledge about biomarker responses in NFS-induced hypoxic injuries, although studies on blood biomarkers after HIBI following cardiac arrest may provide some insight.

Hoiland and colleagues¹⁵¹ published a systematic review and meta-analysis of 86 HIBI studies where NfL measured within 48h after return of spontaneous circulation demonstrated the highest predicted value for unfavorable neurological outcome with an area under the curve (AUC) of 0.92, relative to total tau (AUC = 0.89), and GFAP (AUC = 0.77).¹⁵¹ Further, the new release of NfL, GFAP, UCH-L1 and total tau are higher in jugular venous blood samples of HIBI patients who fail to regain brain tissue normoxia compared with those who become normoxic after restoration of spontaneous circulation. To our knowledge, p-tau has not yet been examined in HIBI.

Findings from the stroke literature may also hold relevance, because circulating NfL distinguishes patients after stroke from controls and correlates with functional outcome, and tau, UCHL1, and GFAP are acutely elevated post-stroke.^152–154 With respect to stress and PTSD, existing IPV studies focused on inflammatory markers such as C-reactive protein (CRP) and cytokines, brain derived neurotrophic factor (BDNF), markers of stress such as cortisol, markers that report on disruption of the hypothalamic pituitary axis, and changes in the microbiome-inflammatory axis.^155–159 Future research is needed to determine how these blood biomarkers translate to NFS-BI and other forms of IPV-BI and whether these markers can aid in earlier identification of injury and prognosticating of injury outcomes.

Accounting for cumulative neurotrauma and their late effects

An IPV-BI often occurs repetitively over the course of months or years and can lead to chronic cognitive, neurological, and/or psychological symptoms that can often become debilitating.⁷⁹ This is an important consideration because evidence from studies of other TBI mechanisms, such as sports-related concussion, demonstrates that exposure to repetitive neurotrauma can have devastating long-term effects.^160–162 Although extremely limited, evidence shows that IPV is associated with an increased risk of dementia developing.¹⁶³

There is also sparse literature demonstrating evidence of CTE in women with exposure to repetitive head trauma, with the first case of “dementia pugilistica” described in a 76-year old woman with a known history of IPV exposure.¹⁶⁴ More than 30 years later, the post-mortem immunohistochemical staining in a 29-year-old woman who died as a result of IPV showed clear evidence of CTE.¹⁶⁵ In addition, a recent study has demonstrated CTE pathology in a female, professional, Australian footballer also with exposure to repetitive head trauma, but not from IPV.¹⁶⁶ Thus, the available evidence suggests that women are not immune to CTE, and survivors of IPV-BI are at risk for experiencing neurodegeneration later in life. Many studies to date on neurodegenerative disease risk, however, do not account for possible IPV, let alone IPV-BI.

Gap to Address: Characterization and assessment of remote IPV-BI

In general, there are limits to the screening and assessment of BI, and there are specific challenges in the IPV population, as described above. Another challenge, however, is that recognition of IPV-related sequelae, including IPV-BI, is often delayed and may not be appreciated until years later.

As such, understanding the long-term effects of IPV-BI often includes use of remote assessments (i.e., the assessment may take place long after the injury occurs).^21,38

One challenge of remote assessment is the necessary reliance on self-report via interview or questionnaire for evidence of acute alterations in brain function associated with the injury (e.g., LOC, AOC, post-traumatic amnesia, focal neurological deficits). While self-report often is the best available method of obtaining information about changes in brain function post-injury, it may be unreliable because of impaired recall of events before, during, and after head trauma, particularly within the context of post-traumatic amnesia, psychological trauma, or substance use at the time of injury.

Many studies, however, have used retrospective self-report of injury history to inform the effects of remote BI on neurological^167–169 and behavioral^170–172 outcomes successfully. Future studies exploring the long-term consequences of IPV-BI should employ improved screening methods for remote IPV-BI and identify the risk of neurodegenerative disorders developing within these individuals.

Gap to Address: Studies Focusing on the late effects of IPV-BI

Studies focused on the long-term and later life sequelae of IPV-BI are lacking, particularly when compared with the breadth of research focused on the chronic effects of contact sport and military brain trauma exposure^173–176 primarily in men. One historical barrier has been the lack of awareness of the prevalence and consequences of IPV-BI. Thanks to strong advocacy from those working on the late effects of TBI, all major federal funding agencies in the US are aware of this issue,¹⁷⁷ and a lack of awareness no longer accounts for the jarring knowledge gaps.

Practical considerations for implementing research on chronic IPV-BI, such as recruitment and retention strategies, CDEs, and safety considerations for research participants, are increasingly appreciated, and global partnerships have been established to promote and share best practices for research [e.g., Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) IPV working group, Global Knowledge Exchange Network, and International Initiative on Traumatic Brain Injury Research Special Populations Working Group].

Accelerating scientific discovery will require major infrastructure, capacity building, and operational investments into prospective longitudinal studies of IPV survivors with multi-modal clinical characterization to understand the phenotype(s) of IPV-BI. Best practices for comprehensive characterization of lifetime IPV-BI exposure require additional validation alongside biological indices of head trauma and BI; this work is foundational to identifying exposure patterns associated with diverse clinical and neuropathological phenotypes.

Further, widespread community implementation of remote IPV-BI screening is necessary to inform the true population prevalence of IPV-BI, both from a public health perspective and for the personal benefit of individuals living with occult, undiagnosed, untreated IPV-BI. These efforts will further support the development of diagnostics that will permit clinical trial selection and risk stratification for chronic BI care management.^161,178 Inclusion of autopsy end points in prospective clinical-pathological studies of the late effects of IPV-BI is crucial to advance our understanding of the underlying pathophysiology of neurodegeneration and clinical decline secondary to IPV-BI.

Association between BI exposure and engagement in IPV

To prevent revictimization, one must consider how BI is associated with engagement in IPV. A history of BI is significantly more common among those who engage in IPV compared with estimates in the general population.¹⁷⁹ Evidence of this also derives from populations that tend to have higher rates of BI, including military veterans, with some studies suggesting higher rates of engagement in IPV.^180,181

Interestingly, a recent study of veterans showed that particularly persistent post-concussive symptoms were predictive of engagement in IPV.¹⁸² Indeed, it has been suggested that sustaining a BI is associated with neurophysiological and neurochemical alterations that may initiate and exacerbate neuropsychological symptoms, including anger, aggressiveness, and emotional dysregulation.¹⁸³ Aggression after BI is associated with mental health problems such as PTSD, depressive symptoms, and substance misuse.^{182,184–186}

Symptoms following BI may significantly interfere with relationship functioning by compromising emotional regulation and information processing. This, in turn, could leave an abuser to misinterpret a partner's social cues for malicious intent and struggle with self-regulation when experiencing episodes of rage, thus increasing the probability of engaging in IPV.^{182,187–190}

Given the bidirectional nature of couple conflict and IPV, this increased risk of engaging in IPV after sustaining IPV-BI puts an individual at risk for an additional IPV-BI from their partner.^183,191 In fact, laboratory observations of violent couples identified interaction patterns of “negative reciprocity” in which hostility and aggression reciprocally escalate over time, presumably resulting in physical violence in other contexts.^192,193

Gap to Address: BI and associated neurological changes that may increase the risk for engagement in IPV

Unfortunately, brain research in the domain of engagement in IPV is still scarce, despite the necessity to identify underlying pathomechanisms that may serve as treatment targets. There are initial indications that IPV engagement is associated with altered prefrontal and limbic structure and function, including smaller amygdala volume,¹⁹⁴ reduced orbitofrontal, cingulate, insula, and parahippocampal thickness,¹⁹⁵ and overall limbic hyperresponsivity.¹⁹⁶

Interestingly, individuals who have engaged in IPV appear to have decreased connectivity between subcortical and cortical structures,^197,198 a finding that has similarly been demonstrated in individuals with stress-related conditions, such as PTSD.¹⁹⁹ Moreover, persistent post-concussive symptoms are closely linked to psychiatric symptoms²⁰⁰ and have been linked to functional and structural alterations of the amygdala and further associated with emotion dysregulation.^201,202

To date, however, no neuroimaging studies have examined the relationship between history of BI, alterations in brain structure and function, and engagement in IPV.

To help reduce the risk of future IPV victimization, more research is needed to determine whether altered brain structure and function after BI are associated with engagement in IPV. If such is the case, targeting alterations in brain structure and function with novel therapeutic options, such as neuromodulation, may help with adaptive neuroplastic remodeling after BI²⁰³ and, thus, regulate the overreactive emotional states, psychopathology, and information processing deficits that appear to lead to maladaptive relational interaction patterns and engagement in IPV.^182-193 Indeed, development and empirical examination of treatment programs that include knowledge of, and interventions for, post-concussive symptoms alongside interventions to alleviate anger, aggression, and IPV are urgently required.

Call to action

We have identified key clinical-research priority areas for the study of IPV-related head trauma and BI, as well as gaps that urgently need to be addressed. Knowledge gaps include, but are not limited to, representation of SGM in IPV-BI studies, the importance of early identification and screening for IPV-BI, accounting for cumulative and remote IPV-BI, studies specific to the late effects of IPV-BI, the development of objective biomarkers to improve diagnosis and prognosis, and the association between BI exposure and engagement in IPV. We now highlight specific calls to action with recommendations for further stakeholder education, systems of care for managing IPV-BI, and collaborative opportunities to approach IPV-BI in a trauma-informed manner that is sensitive to the needs of survivors.

Together, we expect that closing the abovementioned gaps combined with the calls to action below will aid those working with survivors of IPV-BI clinically to improve systems of care and support and increase our ability to develop more effective studies to disentangle the complexities of IPV-BI.

Educating non-medical first points of contact

Many individuals who experience IPV-BI do not seek medical attention for acute symptoms or the often-debilitating chronic challenges of IPV-BI.³⁸ Thus, first responders and critical health workers, such as law enforcement and women's shelter and transition house staff, are often first points of contact when individuals leave an abusive situation. Improved training in recognizing and responding to IPV-BI for non-allied health workers will more effectively support survivors and identify those in need of follow-up services.

Recent work from Supporting Survivors of Abuse and Brain Injury through Research (SOAR) highlights this need. In surveying 150 women's shelter workers from across Canada, SOAR found that staff reported little knowledge of IPV-BI, and very few screened their clients for these injuries.⁴⁶ This led to provider-informed recommendations that include the need for further staff training, a desire to assess for BI in a conversational style rather than at intake, and educating clients about BI.

Education offered to survivors of IPV-BI should be provided by individuals who are knowledgeable, able to assess the survivor's cognitive and emotional preparation in comprehension and practical application of the information, and who are aware of the potential ill effects of providing inappropriate or inaccurate information. The goal in these settings is to prevent further violence, inspire realistic and meaningful hope for recovery, and facilitate optimal recovery in less-than-ideal circumstances.

There are resources available to help train non-allied healthcare and frontline workers working with IPV-BI. As a result of responses from non-allied health providers, SOAR developed a new module of the Concussion Awareness Training Tool (CATT) with a specific focus on IPV-BI for Women's Support Workers (WSW). Given that the CATT-WSW focuses on IPV, it was the first CATT module to incorporate NFS and the first to include the voice of an IPV-BI survivor. In evaluating the effectiveness of the CATT-WSW, the team found increased IPV-BI knowledge in women's shelter staff and improvements in how they advocated for, and were mindful of, those who have a history of IPV-BI.⁴⁷

The Abused and Brain Injured (ABI) Toolkit is another freely available online resource for IPV-BI that was developed by the Acquired Brain Injury Research Lab (www.abitoolkit.ca). The ABI Toolkit seeks to improve life for survivors and frontline workers by offering information, resources, and recommendations for delivering trauma-informed service. The toolkit contains survivor stories, information on IPV-BI, care guidelines, links to community resources across Canada, and tips on service provision when working with survivors.

A partnership between researchers at The Ohio State University and the Ohio Domestic Violence Network led to the development of a new trauma-informed approach: Connect, Acknowledge, Respond, and Evaluate (CARE). CARE is an advocacy framework designed to address and accommodate survivors of IPV who are also experiencing challenges because of mental health and BI.²⁰⁴ It considers BI in the complex set of circumstances that need to be addressed for survivors to receive safety, health, and social services.

CARE was created in response to previous research that found eight in 10 survivors seeking help experienced head injuries and NFS at the hands of their abusers.^204,205 Further, it allowed organizations to offer better support because advocates were able to recognize BI and address symptoms and other repercussions. Each of these resources has shown feasibility in use as well as promotion of education and support of individuals with IPV-BI, and therefore could be included in training of those working with IPV-BI.

Systems of care

Optimizing IPV-BI education, recognition, management, support, and prevention will require development of context-specific, comprehensive systems of care that meet the diverse needs of this unique population. Across the world, integrated systems have been developed to coordinate the interdisciplinary care needed by those who experience trauma, cancer, and stroke.

The recognition and treatment of individuals with sport-related concussion have benefitted from the development of national and international evidence-based clinical practice guidelines and specialized protocols (e.g., Ontario Neurotrauma Foundation (ONF) Guidelines,²⁰⁶ Parachute,²⁰⁷ Concussion in Sport Group consensus statement²⁰⁸); however, a similar approach has yet to be applied to those who sustain head trauma and probable BI in the setting of IPV.

Adding to this challenge, previous work has demonstrated deficiencies in research across various components of the coordinated community response to IPV, including healthcare and criminal justice systems, counseling, advocacy, child services, and vocational programs.²⁰⁹

To develop a comprehensive system of care for IPV-BI, coordinated referral linkages between all essential service providers interacting with IPV-BI survivors must be developed. Optimizing the clinical care of those with IPV-BI will necessitate development of specialized interdisciplinary clinical programs that meet the medical, allied health, and supportive needs of survivors and their families. Given the complex intersection of factors and barriers experienced by those with IPV-BI, it is critical that this ideal system of care include appropriate navigational and advocacy services, ensuring survivors receive timely and equitable access to comprehensive patient-centered care.

Figure 2 illustrates a proposed ideal system of care that follows the course of an IPV-BI survivor from the time of initial injury recognition to emergency response, acute and follow-up medical care, and onward toward long-term patient- and family-centered support and healing. It outlines the essential service providers within different sectors and stages of care, as well as the resources needed to enable these professionals to optimally fulfill their responsibilities. This framework can be used to guide further research devoted to IPV-BI education, care, and knowledge translation. This system of care should be modified by future research and feedback by IPV-BI survivors and their families.

FIG. 2.

A proposed ideal system of care to provide multi-disciplinary, holistic support to an intimate partner violence-brain injury (IPV-BI) survivor from the initial time of injury through follow-up andlong-term care, including patient- and family-centered support and healing. Modified from authors (Ellis, Haag, and Toccalino) original work included in Allen (2022): “Beyond the Headline: Exploring collaborative responses to non-fatal strangulation and head injury experienced by domestic violence victims, USA and Canada”. NFS, non-fatal strangulation. Color image is available online.

Table 1 outlines the multi-disciplinary referral considerations after IPV-BI, including the role and responsibilities of multi-disciplinary medical and allied health professionals who provide specialized care to IPV-BI survivors. It is important that these multi-disciplinary medical and allied health professionals be available for consultation to comprehensively address the diverse medical and supportive needs of IPV-BI patients. In addition, it would be beneficial if these were incorporated into training for medical and allied health personnel.

Table 1.

Multi-Disciplinary Referral Considerations After Intimate Partner Violence-Brain Injury^*

sub-specialists
Clinician	Indication for Referral
Emergency medicine physician	Cranial or extracranial injuries requiring urgent assessment in the emergency department
Radiologist	Need to arrange and review diagnostic imaging (e.g., computerized tomography, magnetic resonance imaging)
Neurosurgeon	Structural brain or spine injury
Maxillofacial/plastic surgeon	Facial fractures and injuries (e.g., fractures of orbit, mandible, or other facial bones)
Ophthalmologist	Suspected or diagnosed structural eye injury
Orthopedic surgeon	Traumatic orthopedic injuries (e.g., fractures involving extremities, hands, etc.)
ENT surgeon	Suspected or diagnosed injuries to ears, nose, or throat including hearing deficits and temporal bone pathology
Oral surgeon/dentist	Oral or dental injuries
Psychiatrist	Suspected or diagnosed mental health conditions (anxiety, depression, post-traumatic stress disorder), addictions, sleep disorders, or suicidal ideation
Neuro-ophthalmologist	Suspected or diagnosed cranial neuropathy or visual field defect
Primary care physician	General medical care and follow-up
Neurologist	Persistent post-traumatic headaches, migraines, facial pain, cerebrovascular injury, seizures, or stroke
Obstetrician/gynecologist	Pregnancy or gynecological concerns

Allied health professionals
Clinician	Indication for Referral
Social worker	Assistance with social needs, housing, victim, and legal services
Patient advocate/navigator	Assistance with accessing and coordinating patient care and support
Forensic nurse examiner	Acute sexual and domestic assault
Clinical psychologist or other therapy provider	Suspected or diagnosed mental health conditions, addictions, sleep disorders, suicidal ideation, or other relationship issues
Neuropsychologist	Persistent mood or cognitive symptoms
Vestibular physiotherapist/ physical therapist	Suspected or diagnosed vestibular disorders (e.g., benign paroxysmal positional vertigo)
Neuro-physiotherapist/ physical therapist	Neurological deficits requiring rehabilitation
Musculoskeletal physiotherapist/ physical therapist	Diagnosed whiplash and other musculoskeletal injuries requiring rehabilitation
Occupational therapist	Neurological and cognitive challenges or mental health needs requiring rehabilitation, or environmental modifications and support
Speech language pathologist	Deficits in speech, language, or swallowing
Chiropractor	Diagnosed whiplash-type injury
Traditional healer	Patients who wish to receive culturally based traditional healing, access to spiritual leader, and support
Clinical child protection service	Children impacted by family violence

^* List of multi-disciplinary medical and allied health professionals that must be available for consultation to comprehensively address the diverse medical and supportive needs of patents with intimate partner violence-brain injury.

Abused & Brain Injured Toolkit: Supporting Survivors of Abuse and Brain Injury Through Research; Concussion Awareness Training Tool: Intimate Partner Violence Traumatic Brain Injury Medical Provider Resource (Version 1.0), February 2023.

Promoting multidisciplinary collaboration

As we have described, relative to other fields of TBI (e.g., sports-related concussion and military-related TBI), there is an extreme knowledge gap in IPV-BI outcomes and how the mechanisms of injury specific to this population (e.g., NFS) impact cognitive, psychological, and neural outcomes. In addition, examinations of the influence of cumulative and polytrauma exposure on chronic outcomes, as well as targeted identification and intervention methods for this population, remain extremely limited.

Given the myriad of potential outcomes associated with IPV-BI, it will require substantial multi-disciplinary effort to expedite our understanding of IPV-BI. The sharing of knowledge and expertise across disciplines that include social workers, trauma-informed psychologists, neuropsychologists, medical care providers, first responders, and researchers across BI domains is urgently needed.

We advocate for less siloed work in this field and urge care providers, stakeholders, and researchers to work together to answer these important questions plaguing the field, affecting the identification and management of IPV-BI, and ultimately impacting the quality of life of those coping with the devastating effects of IPV globally.

Conclusion

An IPV-BI represents a significant public health concern affecting millions of individuals worldwide. For close to 25 years, concerns have been raised about the underrepresentation of IPV-BI research, which ultimately impacts clinical care and management of these injuries. Unfortunately, many individuals who have experienced physical IPV may live with the undetected consequences of IPV-BI, impacting overall quality of life and increasing the risk for exposure to future violence and abuse.

In this review, we provide key priority areas and knowledge gaps that need to be addressed to advance the care of those living with IPV-BI. Of particular emphasis moving forward is recognition that NFS can result in BI, those who report NFS need to be urgently screened for IPV-BI, and there is a need for the development of objective biomarkers that can differentiate the effects of different mechanisms of injury on the brain. We also urge researchers to include IPV-BI as a focus in their models of understanding the late effects of injury on aging.

We suggest IPV-BI represents a distinct BI phenotype with a unique constellation of mechanisms and symptoms that require a collaborative, multi-disciplinary effort to truly understand their immediate and long-term consequences. Together, closing these gaps and answering these calls to action will enable us to approach IPV-BI in a trauma-informed manner that is sensitive to the needs of survivors, ultimately improving overall outcomes and quality of life.

Authors' Contributions

Carrie Esopenko: Conceptualization, Writing – Original Draft, Writing – Review & Editing, Visualization, Supervision, Divya Jain: Writing – Original Draft, Writing – Review & Editing, Visualization, Shambhu Prasad Adhikari: Writing – Original Draft, Writing – Review & Editing, Kristen Dams-O'Connor: Writing – Original Draft, Writing – Review & Editing, Michael Ellis: Conceptualization, Writing – Original Draft, Writing – Review & Editing, Visualization, Halina (Lin) Haag: Writing – Original Draft, Writing – Review & Editing, Elizabeth S. Hovenden: Writing – Original Draft, Writing – Review & Editing, Finian Keleher: Writing – Original Draft, Writing – Review & Editing, Inga K. Koerte: Conceptualization, Writing – Original Draft, Writing – Review & Editing, Hannah M. Lindsey: Conceptualization, Writing – Original Draft, Writing – Review & Editing, Visualization, Amy D. Marshall:Conceptualization, Writing – Original Draft, Writing – Review & Editing, Karen Mason: Conceptualization, Writing – Original Draft, Writing – Review & Editing, J. Scott McNally: Writing – Original Draft, Writing – Review & Editing, Deleene S. Menefee: Writing – Original Draft, Writing – Review & Editing, Tricia L. Merkley: Conceptualization, Writing – Original Draft, Writing – Review & Editing, Emma N. Read: Writing – Original Draft, Writing – Review & Editing, Philine Rojcyk: Writing – Original Draft, Writing – Review & Editing, Sandy Schultz: Writing – Original Draft, Writing – Review & Editing, Mujun Sun: Writing – Original Draft, Writing – Review & Editing, Danielle Toccalino: Writing – Original Draft, Writing – Review & Editing, Eve M. Valera: Writing – Original Draft, Writing – Review & Editing, Paul van Donkelaar: Conceptualization, Writing – Original Draft, Writing – Review & Editing, Cheryl Wellington: Conceptualization, Writing – Original Draft, Writing – Review & Editing, Elisabeth A. Wilde: Conceptualization, Writing – Original Draft, Writing – Review & Editing

Funding Information

This work was supported in part by National Institute of Neurological Disorders and Stroke RF1NS128961 (Dams-O'Connor); National Institute of Neurological Disorders and Stroke RF1NS115268 (Dams-O'Connor); Michael Smith Health Research BC (Shultz); Australian National Health and Medical Research Council (Shultz); Canadian Department of Women and Gender Equality (van Donkelaar, Mason, Adhikari); Canadian Institutes of Health Research (van Donkelaar, Mason, Adhikari); Max Bell Foundation (van Donkelaar, Mason, Adhikari); National Institute of Neurological Disorders and Stroke R01NS112694 (Valera); National Institute of Neurological Disorders and Stroke R01NS100952 (Koerte); ERC-Starting Grant NEUROPRECISE (Koerte); ERA-NET Neuron NEUVASC (Koerte); National Institute of Neurological Disorders and Stroke R01NS115957 (Esopenko, Koerte, Marshall, Wilde).

Author Disclosure Statement

No competing financial interests exist.