Mechanisms of vascular injury in neurotrauma: A critical review of the literature

Abstract

One in every two individuals will experience a traumatic brain injury in their lifetime with significant impacts on the global economy and healthcare system each year. Neurovascular injury is a key aspect of neurotrauma to both the brain and the spinal cord and an important avenue of current and future research seeking innovative therapies. In this paper, we discuss primary and secondary neurotrauma, mechanisms of injury, the glymphatic system, repair and recovery. Each of these topics are directly connected to the vasculature of the central nervous system, affecting severity of injury and recovery. Consequently, neurovascular injury in trauma represents a promising target for future therapeutics and innovation.

Key Words: Neurotrauma; Neurovascular injury; Primary neurotrauma; Secondary neurotrauma; Traumatic brain injury; Traumatic spinal cord injury; Glymphatic system; Vascular Injury

Core Tip: Primary neurotrauma is an initial mechanical insult to the central nervous system. Secondary neurotrauma involves metabolic and cellular derangements that occur days to months after the initial insult. Together, this neurotrauma disrupts cerebral autoregulation and neurovascular coupling, leading to derangements in neurovascular flow and blood-brain barrier dysfunction. Similarly, the glymphatic system, responsible for clearing waste products through the perivascular space, becomes impaired following neurotrauma, leading to increased protein deposition and cognitive decline. Emerging therapeutics focus on reducing neuroedema, decreasing blood-brain barrier dysfunction, and promoting neuroregeneration.

INTRODUCTION

Statistics suggest that one in every two individuals will experience a traumatic brain injury (TBI) in their lifetimes and the ensuing cost to the global economy has grown upwards of 400 billion United States dollars per year[1]. As a result, TBI remains a grave social, economic, and clinical concern.

Disruption and damage to the vascular unit and perivascular glymphatic system may play integral roles in the mechanisms underlying neurotrauma in the immediate and long-term setting[2]. It follows that the vascular disturbances associated with neurotrauma represent a significant avenue of prognostication and treatment for the future of neurotrauma therapy in both TBI and traumatic spinal cord injuries (TSCI).

TBIs may occur in any demographic and range in intensity from severe to moderate to mild. However, the majority of TBI cases are mild and, amongst adult patients, most are male[3]. This sex difference is commonly attributed to an association between male sex and increased ‘risk-taking behavior’[4]. Similarly, TSCI most often occur in males and the elderly with less than one-third of cases resulting from motor vehicle collisions, less than one-third from occupation accidents, and the remainder from other causes[5-7]. The majority of TSCIs are cervical injuries which have the highest mortality rates when compared with thoracic or lumbar lesions[6]. In addition, TSCIs are associated with significant morbidity and medical costs, even years after the primary hospital stay with pressure ulcers and urological concerns being some of the most common causes of readmission[8]. Likewise, even mild TBI patients may report long-lasting symptoms. A subgroup of mild TBI patients report persistent symptoms of reduced cognitive ability and depressed mood months to years after the initial TBI[9-11]. The elderly and those with reduced cognitive reserve appear to be at highest risk for persistent symptoms[10,12]. Common chronic ailments associated with TBI include but are not limited to sleep disturbances, cognitive deficits, depression, post-traumatic stress disorder (PTSD), chronic pain, and increased risk of neurodegenerative diseases[13]. Studies of blast-related TBIs in soldiers appear to exhibit even higher rates of comorbidities such as headache, PTSD, and anxiety[14]. While recent advances in helmet design have reduced the number and severity of TBIs, there has been little reduction in the occurrence of SCIs[15]. Consequently, although admittedly less common, SCIs in the primary occurrence setting remain a largely unaddressed cause of morbidity and mortality. With the growing elderly population worldwide and corresponding higher rates, SCI burden is predicted to increase globally in the coming years[16].

PRIMARY NEUROTRAUMA

Neurotrauma is divided into two stages: Primary trauma and secondary trauma. Primary trauma is defined by the initial neurological and vascular insult caused by direct mechanical forces acting on the central nervous system (CNS)[17]. The mechanism of trauma may vary from blunt to penetrating and may include projectile, nonprojectile, or blast-associated[17,18]. Neurotrauma may result in a number of immediate gross vascular consequences including epidural hematoma, subdural hematoma, subarachnoid hemorrhage, and intraparenchymal bleeds, in addition to neuronal lesions such as diffuse axonal injury (DAI)[17]. However, not all primary vascular injury is macroscopic. There is growing evidence that primary neurotrauma may cause significant microvascular injury which may lead directly to substantial secondary trauma[18]. A recent study by Reiter et al[19] examined how mechanical impacts displaced human and porcine neurons and vessels in brain tissue. They found that neurons surrounding blood vessels displaced further creating a heterogeneous interface between two entities, potentially generating an environment of substantial strain on the vessels[19]. Blast injuries, in particular, stress the microvessels and damage the endothelium and surrounding micro environment[2].

Cortical spreading depolarization (CSD) is a term that refers to electrical derangement, depolarization, neuronal swelling, and vascular constriction following a CNS insult such as neurotrauma[20]. This vasoconstriction in the setting of TBI may significantly exacerbate ischemia and contribute to morbidity[21]. As it has been estimated that over one-half of patients with TBI experience this sequence of events, CSD represents another significant avenue of future research in the field of neurotrauma vascular pathogenesis[20].

Primary neurotrauma may be further subdivided into primary TBI and primary SCI.

Primary neurotrauma-mechanisms of traumatic brain injury

Based on the pattern of injury TBI may be further subdivided into focal and diffuse injuries[22]. Focal injuries are predominantly due to the linear acceleration of an impact[23]. The skull may warp or fracture on the “coup” side (the same side as the impact) causing vascular trauma with associated contusions or meningeal arterial trauma with an associated epidural hematoma[22-25]. On the opposite side of the brain from the linear impact, a “contrecoup” injury may occur due to the rebound of the brain within the skull[24]. These injuries may cause damage to the bridging cortical veins with a resultant subdural hematoma[24].

Diffuse injuries, on the other hand, are more strongly associated with rotational or angular acceleration[23]. This type of acceleration is often caused by oblique impacts and may cause significant white matter and microvascular deformation[26]. The growing body of evidence suggests that, while previously overlooked, rotational acceleration may cause as much or more trauma as linear acceleration[26,27]. Specifically, rotational acceleration may cause both diffuse vascular injury and DAI through sheering forces[25,28-31]. This DAI is characterized by extensive microtubule and axonal trauma with resultant synapse failure and apoptosis[32-34]. This DAI results in extensive real-world consequences both economically and in patient outcomes with chronic neurological deficits[34]. One study by Lota et al[35] examined impacts in combat sports and found high rates of rotational acceleration in mixed martial arts, boxing, and taekwondo, yet headgear use alone, much less headgear designed to mitigate rotational acceleration, remains contentious.

The field of TBI therapy research is quickly changing. For example, Mesenchymal stem cell-derived extracellular vesicles is one promising treatment that, in the lab setting, appears to stabilize vascular trauma, reduce inflammation, and promote neuroprotection[36,37]. However, further research is needed to clarify real-world benefits and ideal routes of delivery. Virtual reality-based therapy represents another novel treatment that may represent a useful tool for alleviating cognitive and mood dysfunctions post-TBI[38,39]. In short, there are numerous studies examining disparate routes of treatment for TBI.

Primary neurotrauma-mechanisms of traumatic spinal cord injury

TSCI may cause autonomic dysfunction, motor inhibition with damage to the corticospinal tract, and loss of sensation with damage to the spinothalamic tract or gracillis-cuneatus fasciculi of the dorsal columns[40-42]. In addition, TSCI may include damage or pressure on structures surrounding the cord, including ligaments, vertebrae, and vessels[40]. Particularly vulnerable vessels include the single anterior spinal artery and the duo of posterior spinal arteries[40]. Radicular arteries also play a vital role with the artery of Adamkiewicz contributing to the vascular supply of the lower segments of the spinal cord[40,41].

There are four primary mechanisms of force delivery to the spine[43]. These include axial compression, flexion compression, distraction, and rotational force[43]. Axial or vertical compression is commonly associated with burst fractures, especially of the thoracolumbar region[43-45]. Similarly, flexion compression is often associated with compression fractures of the anterior spinal column and a distinct “wedge fracture” [43,46,47]. Distraction force, which is essentially stretching force acting on the spine, has been associated with significant rates of blunt vascular trauma especially in the cervical region[48,49]. This force must often be significant to overpower spinal ligaments[50]. Rotational force especially when combined with other forces may result in significant damage to the cord and may cause vascular dissection, especially in the cervical region[43,51].

Furthermore, there are four main categories of TSCI[52]. These include TSCI with transient compression of the cord in which the initial cause of the compression is acutely self-corrected, TSCI with persistent compression of the cord in which the lesion remains uncorrected, distraction injury in which the spine remains extended due to a persistent lesion, and lastly direct laceration or transection in which the neural and vascular pathways are transected[52]. Compression, distraction, and laceration may all cause axonal and vascular disruption with ischemia and significant sequela[53].

In the setting of acute TSCI and traumatic stenosis, urgent surgery must often be performed with the goal decompressing vascular and neuronal lesions and stabilizing the spine[54] (Figure 1).

Figure 1 In the setting of traumatic spinal cord injuries, forces can act on the spine in a number of fashions with unique consequences. Some of those force directionalities include vertical compression, distraction, rotation, and flexion. Parts of the figure were drawn by using modified pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

SECONDARY NEUROTRAUMA

The immediate effects of primary neurotrauma are followed by secondary neurotrauma which is a collection of metabolic and cellular derangements that occur for days to months after the initial force event[17]. This cascade includes ischemia, excitotoxicity, oxidative stress, mitochondrial and endoplasmic reticulum dysfunction, vasogenic and cytotoxic edema, immune cell derangement, and neuronal cell death[17,55-58]. Excitotoxicity refers to the early release and failure of clearance of high concentrations of excitatory neurotransmitters such as glutamate and the consequent spreading depolarization or activation that occurs as a result[56]. Excitotoxicity is a neuronal derangement that has been identified in many CNS ailments from ischemic strokes to Alzheimer's disease[59].

The cell lysis from primary neurotrauma causes an increase in extracellular glutamate which binds N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors receptors which causes an influx of both calcium and sodium ions[60,61]. This influx of ions leads to deleterious effects on both the endoplasmic reticulum and the mitochondria[60]. Under normal conditions, mitochondria contain a complex and delicate network of membranes and channels that allow for oxidation and reduction through the electron transport chain[62,63]. The increased levels of intracellular calcium activate enzymes that damage the mitochondrial membrane, which in turn increases intra-organelle calcium levels, uncouples the mitochondrial electron transport chain, releases free radicals including reactive oxygen species, and triggers the activation of pro-apoptotic factors, and ultimately cell death[56,64,65]. As free radical formation and ischemia increase due to neurotrauma, there is a resultant increase in misfolded proteins within the endoplasmic reticulum (ER), a major site of protein production[57,66,67]. This causes an activation of the unfolded protein response (UPR)[68]. Persistent ER stress, free radical formation, and failed resolution of elevated protein misfolding cause the three sensor elements of the UPR, inositol-requiring protein 1 (IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor-6 (ATF6) to dissociate from the stabilizing protein GRP78[68]. IRE1 ultimately activates apoptotic protease-activating factor 1 (Apaf1)-dependent caspase, while PERK and ATF6 induce the pro-apoptotic factor C/EBP homologous protein[68]. Together, these proteins induce cell death[68].

Immune cell derangement is common post-neurotrauma. Levels of neutrophils in particular are elevated within CNS tissue immediately post neurotrauma, possibly as a result of elevated catecholamine concentrations[69]. These neutrophils play a significant role in ROS and inflammatory generation in the first days of recovery[69]. There is even some evidence that immune cells may contribute to blood-brain barrier (BBB) breakdown within minutes of an impact[55,69].

There are two forms of edema that occur as a consequence of neurotrauma: vasogenic and cytotoxic edema. Vasogenic edema is the expansion of extracellular fluid as a result of CNS vascular injury[58]. Conversely, cytotoxic edema is intracellular edema caused by the pathologic accumulation of ions such as sodium within cells, post neurotrauma[58].

GLYMPHATIC SYSTEM

While it had long been believed that cerebral spinal fluid (CSF) ultimately drained into the lymphatic system, it was not until 2012 with the publication of a seminal paper by Iliff, Nedergaard, and colleagues that the CNS connection to the lymphatic system was discovered[70-72]. In their paper, Iliff et al[72] coined the term “glymphatic” by combining glial and lymphatic. This discovery has had substantial effects on the field since.

The glymphatic system is a perivascular network of astrocyte foot processes that create a space beneath the BBB where CSF and interstitial fluid between neuronal cells may cycle[70,73]. This is chiefly accomplished through aquaporin 4 (AQP4) water channels and allows for the clearance of waste products from neuronal tissue[73]. Ultimately, the CSF is absorbed by the arachnoid granulations or cervical lymphatics and is thus cleared from the CNS[70]. Following neurotrauma, the AQP4 channels become depolarized, and glymphatic system clearance becomes greatly impaired[74,75]. This appears to cause an increase in detrimental protein deposition including tau and amyloid beta and may account for some of the cognitive depression following TBI[74]. In addition, as the glymphatic system is naturally most active during sleep, there is some evidence that sleep disturbances caused by neurotrauma may contribute to a negative cycle of reduced sleep quality and worsening glymphatic function[70,76].

Consequently, the theoretical benefits of future therapeutics that might target glymphatic system malfunction in neurotrauma could include enhanced clearance of toxic excitatory or inflammatory byproducts and improved recovery (Figure 2).

Figure 2 The perivascular space created by the interplay between the central nervous system blood vessels and the foot processes of the astrocytes allows for the cycling of waste through the cerebral spinal fluid and interstitial fluids. Parts of the figure were drawn by using modified pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

EFFECTS OF NEUROTRAUMA ON THE NEUROVASCULATURE

Cerebrovascular disruption in CNS injuries can have significant effects due to impairment of cerebral autoregulation, a key factor influencing cerebral perfusion pressure, even when vascular injury is not apparent.

The CNS relies heavily on a consistent blood supply that dynamically adjusts to its metabolic demands through neurovascular units (NVUs)[77]. NVUs consist of endothelial cells, smooth muscle cells, pericytes, neurons, and perivascular astrocytes, working together to regulate cerebral blood flow, vascular permeability, and nutrient supply[77]. The endothelial cells form part of the BBB, which tightly controls the exchange of substances between the systemic circulation and CNS tissue[77]. NVUs communicate in a process known as neurovascular coupling to ensure consistent blood flow in response to neuronal activity[77]. However, following brain injury, communication within the NVU can be disrupted, leading to inappropriate changes in cerebral blood flow and BBB dysfunction[77]. This disruption can result in protein and electrolyte leakage into the brain parenchyma, triggering downstream processes such as microglia activation, that persist long after the primary injury, potentially contributing to ongoing neuropathology[77].

The brain relies heavily on consistent cerebral blood flow (CBF) to function optimally, unlike other organs, as it cannot withstand prolonged blood supply shortages. CBF is intricately linked to neuronal activity and is regulated by cerebral autoregulation, which maintains cerebral perfusion pressure (CPP) within a specific range to safeguard neural tissues from ischemia and subsequent neurodegeneration[78]. CPP is primarily determined by the difference between mean arterial pressure and intracranial pressure and it is maintained between 70–90 mmHg in healthy patients[79]. Cerebral autoregulation involves several interconnected processes, including neurogenic, myogenic, vasogenic, and metabolic mechanisms, mediated by various cellular components such as endothelial cells, smooth muscle cells, neurons, and glial cells[57]. These mechanisms adjust CBF in response to changes in systemic blood pressure, with different brain regions exhibiting distinct regulatory patterns[57].

TBI can impair cerebral autoregulation, which is vital during low systemic blood pressure scenarios, leading to diminished CBF[80]. Even mild TBIs (mTBI) can lead to cerebrovascular injury[81]. While cerebral autoregulation can maintain CPP between a wide range of pressures, neurotrauma can hinder this ability. This can manifest as symptoms ranging from a headache to chronic seizures or neuroendocrine abnormalities[82]. TBI can induce functional disruptions and neurodegenerative changes that impact CBF, potentially leading to lasting alterations in CBF regulation and post-traumatic complications.

Cerebral vascular dysfunction can arise from direct injury to vascular components or from secondary cascades initiated post-injury; as a result, cerebral vascular dysfunction can manifest either before or after neuronal damage in TBIs[83]. Reductions in CBF and microvascular circulation can lead to the formation of microthrombi, causing tissue hypoxia[77]. Microthrombi aggregation can then lead to secondary injuries such as hematoma formation and edema[77]. Vasogenic edema can cause hemispheric expansion and midline shift[77]. These effects of microvasculature disturbances, endothelial irregularities, dysmorphic capillaries, and disruption of pericytes and perivascular astrocytes, are seen even when models are used to simulate mTBIs[77].

Additionally, cerebrovascular reactivity (CVR) is a dynamic assessment of microvascular function that can serve as a sensitive biomarker of traumatic cerebrovascular injury (TCVI) in individuals with chronic moderate to severe TBIs[84]. CVR can be assessed with either functional near-infrared spectroscopy (fNIRS) or functional magnetic resonance imaging (fMRI), each offering its own set of advantages and drawbacks[84]. While fMRI stands as the benchmark due to its high resolution and compatibility with structural imaging, fNIRS presents superior temporal resolution, lower cost, and greater ease of use in outpatient settings[84]. Employing either imaging modality for CVR assessment not only holds potential as an additional diagnostic tool for evaluating TBI, but also emerges as a promising predictive and pharmacodynamic biomarker for interventions aimed at addressing TCVI[84].

Additionally, vascular risk factors such as hypertension, diabetes, hyperlipidemia, and especially smoking, lead to worse outcomes after TBI[85]. This necessitates aggressive treatment to improve patient outcomes for those with these risk factors[85] (Figure 3).

Figure 3 The neurovascular unit is a network created by the communication between pericytes, neurons, smooth muscle, and endothelial cells. Parts of the figure were drawn by using modified pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/).

REPAIR AND RECOVERY AFTER TRAUMATIC BRAIN INJURY AND SPINAL CORD INJURY

As shown through microdialysis, positron emission tomography, and magnetic resonance spectroscopy studies, TBIs can trigger a state of hypermetabolism characterized by increased glucose demand following biochemical brain injury, leading to neurotransmitter release and subsequent cellular responses[86]. This hyperactivity, aimed at restoring cellular and ionic homeostasis against progressing neuronal injury, can induce apoptotic events and mitochondrial impairment[86]. This causes a decrease in available energy for the body, which combined with the pre-existing microvascular ischemia, can lead to poor patient recovery[86]. Therefore, recovery after TBI is a complex process influenced by numerous factors, including the severity and type of injury or stress, vascular anatomy, comorbidities, access to medical care and rehabilitation, as well as social support networks[87].

In TBI, the inherent mechanisms responsible for cerebrovascular repair remain incompletely understood. However, studies have shown that hypoxia-inducible factor 1α (HIF-1) plays a pivotal role in both natural recuperation and safeguarding against neurological damage following TBI[88]. HIF-1 is a vital regulator of homeostasis that can induce angiogenesis, erythropoiesis, as well as anti-apoptotic cascades[88,89].

Additionally, vascular endothelial growth factor-A (VEGF-A) is also released, increasing angiogenesis, vascular permeability, and vasogenic edema[90]. Moreover, it has been shown that veterans with blast-related mTBIs show persistently elevated levels of plasma VEGF-A, indicating continued cerebrovascular dysfunction following injury[91]. Animal studies have shown that levels of VEGF-A reach their highest levels at 24 hours after a TBI. The same study showed that bevacizumab, a common antitumor drug, can be given immediately after TBI to suppress VEGF-A expression and decrease cerebral edema[90].

Reducing cerebral edema is a key factor in the treatment of TBI. For example, the astrocytic water channel AQP-4 system plays a critical role in brain edema and transport across the BBB[92]. Animal studies have shown that minocycline, an antibiotic, could be used in a vascular-protective fashion against TBI because it reduced AQP-4 levels, thereby decreasing cerebral edema to optimize BBB integrity and astrocyte function[92]. Minocycline was also shown to be neuroprotective by reducing apoptosis of neurons and inflammation[92]. In the same way, stromal vascular fraction was also shown to ameliorate motor skills and slow memory regression in animals after TBI[93]. Yet another study showed a promising approach for TBI treatment with a novel biological scaffold containing heparin, collagen, and VEGF that could improve motor and cognitive function by generating an optimal microenvironment for the regeneration of injured nerve tissue[94].

VEGF-C is another of the vascular endothelial growth factors, which regulates microglia polarization and reduces cell apoptosis. Administration of VEGF-C has been shown to improve motor and neurologic function after TBI in animal models[95]. Administration of VEGI recombinant protein also showed similar results[96].

Moreover, these growth factors have been used as biomarkers to monitor outcomes in patients following TBI in the Transforming Research and Clinical Knowledge in TBI Pilot Study. This study showed that higher levels of thrombomodulin, angiopoietin-2, von Willebrand factor, and P-selectin were associated with more critical injuries while higher levels of angiopoietin-1, VEGF-C, and basic fibroblast growth factor were associated with less critical injuries[97].

Lastly, exercise has been shown to improve balance and walking abilities after neurotrauma[98]. Exercise can be done with physical therapists or even with robotic devices or virtual reality to progress neurorehabilitation[98].

While many animal studies over the years have initially shown promising results, later translation in human trials has often been less impressive[99,100]. This highlights the continued importance of pursuing innovative, new models and species that better capture human biology and choosing models that are best suited for the intricacies of the individual study.

CONCLUSION

The future of treatment options and the direction of future research for neurotrauma are poised for significant advancements aimed at improving patient outcomes and quality of life. Emerging therapeutic avenues are expected to focus on reducing cerebral edema, decreasing blood-brain barrier breakdown, and decreasing neuronal cell death. Additionally, there will be a growing emphasis on multidisciplinary collaboration, bringing together experts from various fields including neuroscience, neurology, neurosurgery, rehabilitation medicine, and bioengineering.

The development of novel pharmacological agents targeting specific molecular pathways implicated in neuroinflammation, excitotoxicity, and neuroregeneration holds promise for more effective treatments. These therapies may include neuroprotective agents, anti-inflammatory drugs, stem cell therapies, and gene therapies, among others.

Moreover, the integration of neurostimulation technologies, including transcranial magnetic stimulation, deep brain stimulation, and non-invasive brain stimulation techniques, offers exciting prospects for modulating neuronal activity and promoting neural plasticity to aid in recovery and rehabilitation post-neurotrauma. Additionally, advancements in neurorehabilitation strategies, such as robot-assisted therapy, virtual reality training, and brain-computer interfaces, are expected to play a crucial role in facilitating functional recovery and enhancing patient independence.

In terms of research directions, there will be a continued focus on elucidating the underlying pathophysiology of neurotrauma, including the complex interplay between genetic, environmental, and lifestyle factors. Large-scale prospective clinical studies and translational research efforts will be essential for validating novel therapeutic approaches and establishing evidence-based guidelines for optimal patient management. Furthermore, initiatives aimed at enhancing public awareness, education, and prevention strategies for neurotrauma will remain paramount in reducing the burden of these devastating injuries on individuals and society.

Overall, the future of treatment options and research directions for neurotrauma holds great promise, driven by advancements in technology, interdisciplinary collaboration, and a deeper understanding of the underlying mechanisms of brain injury and repair. These efforts aim to improve outcomes, enhance quality of life, and ultimately transform the landscape of neurotrauma care.