The human head is, without question, an essential body part. The skull encapsulates and protects the brain, which encompasses the central nervous system, responsible for controlling all other organs and, thus, necessary to sustain life. The intricacy and fragility of the brain require extensive research and mapping mechanisms in brain injuries.

Head injuries are one of the leading causes of death in the world. Over the years, the scientific community joined efforts to understand the biomechanics of these traumas and the best way to diagnose and prevent them. Traumatic Brain Injuries (TBIs) contribute to worldwide death and disability more than any other traumatic insult [1]. TBI is a broad concept that describes a vast dispersion of injuries that happen to the brain structures. The inflicted damage can either be focal (confined to one area of the brain) or diffuse (occurs in several brain areas). The severity of a TBI can range from a mild concussion to a severe injury that may result in death [2].

Despite the urgent research on this topic, literature studies of numerically-modelled TBI and concussion usually relate to male or unspecified-sex subjects. There are currently a growing number of studies evaluating factors associated with TBI; however, there remains relatively little research on women or sex differences [3].

When referring to Head and Neck (HN) injuries, one must consider the occurrence rate of each specific trauma in males and females. Concerning head injuries, male subjects are more likely to have extreme sport-related TBI ^[4][5][4,5], TBI resulting from road accidents [6] or, for example, in 2013, TBI-related Emergency Department visits, Hospitalizations, and Deaths (TBI-EDHDs) due to the following: being struck against or by an object; motor vehicle crashes; intentional self-harm; and assault [7]. However, women scored a higher number of TBI-EDHD as a result of falls, usually sustained by older adults.

Another head injury issue affecting mainly women is Intimate Partner Violence-related TBI (IPV-TBI), it being estimated that around one-third of women have experienced IPV at least once in their lifetime and that 23.2% of women have experienced severe physical violence by a partner, following a 2017 Centers for Disease Control and Prevention (CDC) survey [8]. The CDC defines IPV as physical violence, sexual violence, stalking or psychological aggression by a current or former intimate partner to both current and former spouses and dating partners [9]. IPV often includes physical assault (including injuries to the head and strangulation injuries). St. Ivany et al. [10] found a prevalence of 60% to 92% of abused women suffering a TBI correlated with IPV. A significant issue concerning IPV, sports-related impacts, or even falls are isolated or repetitive mild Traumatic Brain Injuries (mTBI) which, until recently, were often overlooked by health specialists and were rarely associated with hospitalization of the patient [11]. More recently, mTBI effects and long-term sequelae are being extensively studied, such as noise sensitivity [12], insomnia [13], cognitive impairment [14], visual field defects [15], changes in White Matter (WM) Fractional Anisotropy (FA) [16], among many others. However, most of these studies regarding mTBI lack sex-specific data, even though distinct effects on women and men are often reported in the literature ^[17][18][17,18].

Gupte et al. [19] performed an extensive literature review on sex differences in TBI, concluding that human studies are usually associated with worse outcomes in women than men, also showing that multiple factors including severity, sample size and experimental injury modelling may deferentially interact with sex to affect TBI outcomes.

Regarding neck injuries, these can be related to different types of whiplash (usually associated with rear-end vehicle collisions), neck fractures and cervical spinal cord injuries. Regarding Whiplash-associated Disorders (WAD), it is well established that its prevalence is higher in females when compared to males, usually more than double ^[20][21][22][20,21,22].

2. A Brief Recap on Brain and Neck Injuries

The brain is the most complex organ in the human body and is surrounded by a bone structure. One of the primary purposes of the skull bones is to protect and encapsulate the brain. The brain and the spinal cord make up the central nervous system. To control the body’s activities, it processes, integrates and coordinates the information received from the sensory organs. The human brain can be divided into three distinguishable entities: the cerebrum, the brainstem and the cerebellum ^[23][24][23,24]. The cerebrum consists of the left and right cerebral hemispheres. While the left and right hemispheres are similar in structure and function, some differences exist. Each of the hemispheres comprise inner white matter and outer grey matter tissue. White matter compartments consist mainly of myelinated axons, although it also contains unmyelinated axons. Grey matter, on the other hand, consists of a few cell bodies and mostly unmyelinated axons, dendrites, and glia cell processes, forming a synaptically dense region. The corpus callosum (CC) is a broad band of white matter carrying axons which connect the cerebral hemispheres ^[23][24][25][23,24,25]. The cerebrum is connected to the spinal cord by the brainstem. The brainstem consists of the pons, the midbrain, and the medulla oblongata. It has the critical role of regulating visceral organs ^[23][24][23,24]. The cerebellum plays a vital role in motor control. It is part of the metencephalon and serves as a control body for coordinating and fine-tuning movement sequences [26].

2.1. Microtubules Role in Axons

Brain cells include supportive glial cells and neurons. Brain functions are possible due to interconnections of neurons and the release of neurotransmitters in response to nerve impulses. Neurons consist of a cell body, axon, and dendrites. The transmission of information starts when a dendrite receives data in the form of signals from the axon terminals of another neuron. This transmission of information can cause the neuron to initiate an action potential. The action potential is transmitted along the neuron’s axon to the axon terminal to communicate with the cell body or dendrites of another neuron [27]. When an action potential reaches the presynaptic terminal, it triggers the release of a neurotransmitter into the synaptic gap that propagates a signal that acts on the postsynaptic cell [28]. Microtubules, neurofilaments and microfilaments form the axonal cytoskeleton [29]. Microtubules are the most robust cytoskeletal filaments in eukaryotic cells. Therefore, they play a significant role in various cellular processes. In neurons, they maintain structural stability and provide highways for axonal transport. Microtubules are stabilized and cross-linked to form the axonal cytoskeleton via microtubule-associated proteins [30]. Tau is an abbreviated term for the Microtubule-Associated Protein Tau (MAPT). There are six major tau isoforms due to alternative mRNA splicing. By binding to microtubules, tau loses its natively disordered state and contributes to essential structural and regulatory cellular functions. Moreover, within individual microtubules, tau controls microtubule polymerization, regulates axonal transport and controls microtubule structure ^[31][32][31,32]. Within the axon, tau promotes the packing of microtubules into well-organized, evenly spaced bundles [33]. To this day, two hypotheses have emerged to explain the packing of microtubules within the axon: the cross-bridging and the polymer brush hypothesis [34]. Despite its importance for axonal structure and function, the precise mechanism by which tau regulates microtubules packing remains poorly understood [30]. The addition of a site-specific phosphate group, also known as phosphorylation, is the primary mechanism for regulating tau activity [35]. Under physiological conditions, tau phosphorylation promotes the association with tubulin and stabilizes microtubule structure [30].

2.2. Chronic Traumatic Encephalopathy, CTE

Damage to the brain caused by external mechanical forces to the head is defined as a TBI. Damage to the brain structure occurs when a load exceeds the tolerance level of a brain tissue [36]. According to Graham et al. [37] TBI can be classified as focal and diffuse. Focal injuries include contusions, intracerebral hematomas, lacerations of the brain and burst lobe lesions. Typical diffuse brain injuries include Diffuse Axonal Injury (DAI), hypoxic brain injury, brain swelling, and diffuse vascular injury [37]. Bigler et al. classified post-traumatic neuropathological changes into primary and secondary changes. Primary changes consist of immediate alterations after a TBI, whereas secondary post-traumatic changes can include complex vascular and neuroinflammatory mechanisms. Even though TBI is a leading cause of worldwide death and disability, sex differences in the pathophysiology and recovery are poorly understood, limiting clinical care and successful drug development [19]. Recent studies have convincingly documented a close correlation between TBI and pituitary dysfunction [38] and CTE [36]. Currently, the only method to reliably diagnose CTE is post-mortem histopathology with a complete autopsy and immunohistochemical analysis [39]. Although the exact cause of mechanically induced tauopathy is unknown, CTE is usually associated with repeated mTBI, not a single trauma [40], although there are also reports that suggest a single moderate-severe TBI can induce CTE-like pathologies ^[41][42][41,42]. At this time, it remains controversial whether misfolding of tau into Neurofibrillary Tangles (NFTs) is a consequence or a cause of neurodegeneration [43]. An accumulation of hyperphosphorylated tau (p-tau) protein, progressive axonal failure, and gradual structural degradation are the hallmarks of the disease [44]. To understand sex differences in the pathologies following HN injuries, it is vital to establish where the conditions occur and define the respective neuroanatomical and hormonal differences according to sex [45]. The further discovery of the sexual dimorphism of the brain will lead to important insights regarding the neurodegenerative disorders and their different ages of onset, prevalence, and symptomatology between males and females.

2.3. Axonal Injury

According to Braun et al. [40], mechanical stretching of axons impairs axonal transport by disrupting the organization of microtubules. Under physiological strain and strain rates, tau-microtubule interactions deform axons reversibly and make them an almost entirely elastic material [46]. Under abnormal conditions, tau-microtubule dynamics result in brittle axons at pathological strain and strain rates, and their cytoskeleton becomes more easily damaged [47]. Cytoskeletal destruction disrupts axonal transport; the transport products build up at the site of damage, the axon starts to swell, and will eventually break [48]. Upon retraction of the transected axon, a bulb forms close to the cell body, which is a classical hallmark of DAI [49]. Recent findings suggest that axonal failure is a gradual interplay of biomechanical and biochemical events, including the initial biomechanical injury followed by secondary biochemical events within hours or days, a phenomenon known as the secondary axotomy [50]. The disruption of microtubules is believed to precede the detachment of tau proteins from microtubules and subsequent tau hyperphosphorylation. Therefore, it is likely that microtubule disruption caused by axonal injury may impair presynaptic function through tau-independent mechanisms. In contrast, tau hyperphosphorylation is essential for aberrant accumulation of tau proteins in postsynaptic structures and subsequent postsynaptic dysfunction [40].

2.4. Molecular Mechanism of CTE and Tau Pathology

The tau-microtubule compound plays a significant role in regulating axonal cytoskeletal structure, mechanics, and function [51]. Recent studies ^[40][47][40,47] have shown direct evidence that cell-scale mechanical deformation can lead to tauopathy and, therefore, to synaptic deficits in neurons. It was shown that the mechanical energy of TBI alone could induce tau hyperphosphorylation and mislocalization. Yet, the precise mechanisms of tau-mediated neurotoxicity are still not completely understood. Several pathological mechanisms are currently being studied. According to recent studies ^[36][40][47][36,40,47] p-tau translocates to the cell body and aggregates to form NFTs, leading to impaired axonal function. Under physiological conditions, tau is an intrinsically disordered protein before an array of posttranslational modifications [52]. Furthermore, pathological hyperphosphorylation reduces tau to microtubules binding affinity, promotes tau fibrillization, and disrupts intracellular function [53]. In addition, there is growing evidence that tau aggregates can recruit other tau aggregates and then spread to surrounding regions. Eventually, intracellular transport is disrupted, which induces synapse loss, cell death, and loss of neural circuits. Ultimately, neurodegeneration leads to cognitive decline and impaired motor function. Pathologies that share these common neurodegenerative pathways are defined as “tauopathies” [30].

2.5. Location of Tauopathies

Although NFTs are a common pathophysiological hallmark of tauopathies, their distribution and spreading throughout the brain differ between diseases. Studies have shown that white matter tissue exhibits a gradual stiffness gradient [54] and a discrete stiffness jump across the grey-and-white-matter interface [55]. In addition, simulations revealed stress discontinuities at the tissue-vasculature interface [56]. DAI occur primarily at the grey-and-white-matter and tissue-vasculature interface, where mechanical stress fields undergo a discrete jump, supporting the concept that biomechanical factors initiate CTE [50]. In CTE, p-tau NFTs primarily aggregate focally and perivascularly in the cerebral cortex, with a predilection for deep sulci in the superficial neocortical layers [36]. These areas of NFT aggregations correlate with the brain regions that experience the most considerable strains during impact [56]. During an impact, a finite element model by Braun et al. [40] predicted that the first principal strains were most significant in the sulcal depths and that the most considerable strains were stretch strains. In addition, a depression model demonstrated that the most considerable strains occur immediately around the vessel. Recent studies have shown that CTE-associated p-tau NFTs accumulate in regions of the brain that undergo the most significant mechanical deformation during TBI [40]. Eventually, NFTs spread prion-like to the neocortex, medial temporal lobe, diencephalon, basal ganglia, and brainstem [36]. The gradual loss of neurons across the brain leads to pronounced grey and white matter atrophy, enlarged lateral and third ventricles, cavum septum pellucidum, septal fenestrations, locus ceruleus and substantia nigra depigmentation, thalamic and hypothalamic atrophy (including the mamillary bodies), as well as an overall reduction in brain mass ^[57][58][57,58]. In contrast to CTE, in Alzheimer’s Disease (AD), the NFT localization is more uniformly distributed in the deeper-lying cortical layers and not concentrated in sulcal depths, or perivasculature [59]. These results support the hypothesis of a causal relationship between mechanical deformation and tau pathology in CTE patients.

2.6. Pituitary Dysfunction

TBI can lead to varying degrees of Post-Traumatic Hypopituitarism (PTHP). The most common hormonal deficits after TBI include decreased Growth Hormone (GH) secretion and hypogonadism, followed by hypothyroidism, hypocortisolism, and diabetes insipidus ^[60][61][60,61]. In a study by Schneider et al. [62], the incidence of PTHP after TBI was evaluated. Three months after experiencing head trauma, it was shown that in 22 patients with mild, moderate, or severe TBI, 36.4% of patients showed subnormal responses in at least one hormonal axis. The pituitary gland is uniquely situated within a protective bone structure called sella turcica and is attached to the brain by blood vessels and neurites. There are several cell types within the pituitary glands that produce various hormones; they regulate the endocrine activities of the adrenal cortex, thyroid, and gonads. It can be divided into the larger anterior pituitary (adenohypophysis) and the smaller posterior pituitary (neurohypophysis). The vasculature of the gland is a complex system of blood vessels which connects the adenohypophysis to the hypothalamus. The blood vessels carry the hypothalamic releasing and inhibiting hormones that control the pituitary hormone-producing cells. About 70–90% of the blood is supplied by the long portal vessels [63]. Although the exact underlying pathogenesis of PTHP has not yet been elucidated, various theories have been studied. A widely-accepted hypothesis suggests that as a consequence of a TBI, there is an ischemic insult to the pituitary gland [64]. The long hypophysial vessels are in particular vulnerable to vascular injury. The lateral somatotroph and gonadotroph axes directly depend on the long portal vessels. The hormone deficiencies pattern of hormonal loss and cellular distribution, which frequently involve the lateral somatotroph and gonadotroph axes, supports the vascular hypothesis [65]. In addition to ischemic injury, various other possible underlying pathophysiological pathways exist. Two other underlying mechanisms of impairment in the anterior pituitary have been extensively studied, neuroendocrine insults to the pituitary gland [66] and hypothalamic-pituitary autoimmunity mechanism [67].