The spectrum of traumatic brain injury (TBI) ranges in severity from sub-concussion (no loss of consciousness), to concussion (loss of consciousness), to mTBI (diffuse axonal injury and microhenorrhage) to more severe injury with contusions and hematoma formation. The temporal spectrum of the injury must also be considered as acute and chronic forms exist even for mild injury. For example, chronicity can manifest even in simple concussion where a significant number of patients fail to recover an outcome tied to the number of post-concussion symptoms (figure 1 and reference 1). Not only do complex structural and physiological deficits occur following brain injury, but the response to the injury is at least as complex and is also incompletely understood. An additional challenge is the difficulty in detecting injury following concussion. For example, there are no diagnostic biomarkers that can establish the presence of a concussion in a single subject. Conventional MRI is normal. How is it then that such a “minor” injury with no visible abnormalities on MRI can have such profound and long lasting effects? In order to answer these questions an understanding of the pathophysiology of concussion and the physiological responses to the injury is required (2). Following a blow to the head, there is stretching and shearing of the fragile vessels of the microcirculation and shearing of axons with injury to cell membranes that together initiate four “cascades” leading to sudden loss of consciousness and concussion. These include disruption of blood flow regulation, abnormal cellular ion fluxes, release of excitatory neurotransmitters, and disruption intra-cellular neurofilaments and microtubules. The sum-total of these effects is rapid failure of neuronal function and sudden loss of consciousness. Traumatic injury to injure vessels, neurons, and glia will interrupt neurovascular and gliovascular coupling leading to potential mismatches between available blood flow and metabolic demand. Since metabolic demand is acutely increased secondary to release of excitatory neurotransmitters, an increase in blood flow to match the demand is required. If unmet by injured vessels, ischemia ensues. Structural and ischemic injury can then initiate an inflammatory response promoting secondary injury mechanisms with the microglia playing a central role. Currently there is debate as to whether intervention targeting this inflammatory response is able to improve neuronal survivability and patient outcome. Regulation of blood flow is clearly essential for maintaining neuronal health and repair from injury. Dysregulation of flow has been demonstrated in all forms of brain injury interrupting this homeostasis. Normally, blood flow is regulated by the tone of smooth muscles in the wall of arteries. Increased tone leads to vasoconstriction and decreased flow. Decreased tone leads to vasodilation and increased flow. The tone of the smooth muscle is influenced by a number of different inputs including blood pressure, neuronal activity, tissue pH, ions (K+), nitric oxide, prostaglandins, etc, as well as dissolved arterial gasses predominantly CO2. Dysregulation following trauma can result in excessive vasodilatation leading to edema, hemorrhage, and over-oxygenation of the tissue with free radical formation. Excessive vasoconstriction can lead to ischemia. There are numerous clinical studies showing the presence of blood flow dysregulation in mild and severe forms of TBI in all age groups (3). For example, in patients with moderate to severe brain injury, it has been found that the ability to maintain constant flow at blood pressures at the higher end of the normal blood pressure range is lost (figure 2 from reference 4). Numerous studies have shown Impaired autoregulation in adults and this has recently been reported in 17% of pediatric patients with mild TBI injuries (5). In concussed pediatric patients with persistence of symptoms, both CBF and CBV are reduced showing both a global trend, as well as a statistically significant finding in the thalami compared to controls (6) also supporting similar observations made in adults. Alteration in white matter diffusion metrics are well known to occur in concussion and mTBI, so it is interesting to speculate on a possible association between de-afferentation secondary to axonal dysfunction as a cause of reduced CBF to axonal targets. Correlative studies between CBF and axonal injury are needed. It has been proposed that reduced thalamic blood flow could also result in alterations of resting state networks secondary to existing extensive thalamo-cortical connections (7). This has implications for adaptive or maladaptive responses in network re-organization and possibly persistence of symptoms post-concussion. Mechanical injury may also lead to changes in vascular permeability with compartmental fluid shifts that impair autoregulation (2). Impaired autoregulation may in and of itself induce an increase in permeability via mechanical stretching of the endothelium due to ncontrolled higher perfusion pressures. A vicious cycle can ensue. Therefore permeability assessment may also provide insight into the magnitude of the vascular injury present. In spite of considerable information available on the microanatomy of neurovascular/gliovascular structures, flow signaling biochemical pathways (nitric oxide, reactive oxygen species such as peroxynitrite, prostaglandins, neurotransmitters, ionic species, etc.), and trauma induced spreading depression, there is much to learn about the relative contribution of structural and biochemical alterations to overall vascular dysfunction following acute traumatic injury and subsequent evolution of this injury. In terms of the investigation of neurovascular dysfunction, it makes sense that the blood flow metric with the potential to provide the most meaningful information is vascular reactivity, i.e. the ability of the circulation to respond to changes in blood pressure as well as tissue metabolic demand. This is especially true since resting blood flow measurement can be normal under circumstances where there is very limited ability of the vasculature respond to flow modulation. Despite the fundamental difference between pressure autoregulation and vasoreactity in response to metabolic demand, it has been shown that the vasomotor response can be effectively interrogated using exogenous vasomotor stimuli such as CO2. This has been shown in studies of TBI that demonstrate good correlation between vascular reactivity using CO2 stimuli and clinical outcome (8-10). The combination of BOLD MRI during application of vasomotor stimuli such as CO2 has been well established for the assessment of cerebral vasoreactivity and is poised to become an important tool in the assessment of patients with TBI. Correlation with functional metrics such as resting state networks and structural metrics such a white mater tract analysis should provide important new information that could lead to a potential diagnosis of concussion in single subjects as well as informing new therapeutic strategies such as those related to timing and degree of exercise therapy.

Acknowledgements

No acknowledgement found.