**2.2 Metabolic cascade**

*Sports, Health and Exercise Medicine*

which is defined as:

ing studies.

changes [10].

of concussion most recently published by an international consensus group [9],

be utilized in defining the nature of a concussive head injury include:

Concussion is a brain injury and is defined as a complex pathophysiological process affecting the brain, induced by biomechanical forces. Several common features that incorporate clinical, pathologic and biomechanical injury constructs that may

1.Concussion may be caused either by a direct blow to the head, face, neck or elsewhere on the body with an "impulsive' force transmitted to the head.

2.Concussion typically results in the rapid onset of short-lived impairment of neurological function that resolves spontaneously. However, in some cases,

3.Concussion may result in neuropathological changes, but the acute clinical symptoms largely reflect a functional disturbance rather than a structural injury and, as such, no abnormality is seen on standard structural neuroimag-

4.Concussion results in a graded set of clinical symptoms that may or may not involve loss of consciousness. Resolution of the clinical and cognitive symptoms typically follows a sequential course. However, it is important to note that

Concussions result in a myriad of symptomatology which are generally categorized into four main domains: (1) physical (i.e. headache, dizziness, visual dysfunction), (2) cognitive (i.e. difficult with concentration and memory), (3) emotional (i.e. depression, anxiety and mood lability), (4) sleep disturbance (hypersomnia and insomnia). The most commonly reported symptoms include headache, dizziness and difficulties with concentration and memory. Symptoms are likely caused by functional, metabolic and microstructural abnormalities as routine neuroimaging is typically unhelpful at demonstrating anatomical evidence of neuropathic

Exposure to repetitive concussion or sub-concussive impacts, in which a significant traumatic brain injury may have occurred even in the absence of visible signs or symptoms, is now recognized as having possible long-term neurological consequences, including neurodegenerative disease [11–15]. Given the growing incidence and concern around sports concussion as well as the potential long-term sequelae associated with the injury, awareness of the current understanding of the pathophysiology is vital within the general field of sports medicine. Additionally, as targeted screening and management options are becoming increasingly available, knowledge of the current evidence-based tools for effective screening and subse-

Biomechanical forces from sports impact that result in traumatic brain injury or concussion leads to functional impairment at the level of individual cells or neurons. This abnormal cellular function results in overall neurological function

in some cases symptoms may be prolonged [9].

quent management of the injury are important.

**2. Concussion pathophysiology**

**2.1 Biomechanics of the injury**

symptoms and signs may evolve over a number of minutes to hours.

**4**

Changes in intracellular ion concentrations occur due to disruption of cell membranes causing an abnormal outflux of potassium causes irregular neuronal depolarization which in turn leads to increased extracellular potassium and neurotransmitter release. Glutamate, an excitatory neurotransmitter, further promotes potassium efflux and binds to N-methyl-D-aspartate receptors which additionally allows for hyperexcitability and continued unhindered depolarization of the neuron. Simultaneously, accumulation of excitatory neurotransmitters also leads to influx of calcium which promotes proteases, reactive oxygen species and mitochondrial impairment all of which contribute to cellular dysfunction, damage and death when the neuron is unable to recover cellular stability [17, 18].

Dysfunction in the regulation of neurotransmitters as well as the inciting excitotoxicity of the neuron causes significant stress on the cellular mitochondria to maintain to energy demands through ATP production. The sodium/potassium (Na+ /K+ ) pumps which require ATP struggle to maintain the cellular ion homeostasis. The glycolysis process is activated in an attempt to provide this increased energy demand which leads to accumulation of lactic acid. This lactic acid breaks down the blood-brain barrier and leads to cerebral edema [17].

### **2.3 Neuroinflammatory response and cerebral blood flow alterations**

There is also a neuroinflammatory response that occurs after brain trauma which increases microglial cells, cytokine mediators, proteases and reactive oxygen species which promotes widespread inflammation and breakdown of the blood-brain barrier. This leads to cerebral blood flow changes [17, 18]. Other cerebral blood flow changes also occur as a result of carbon dioxide that accumulates from the metabolic changes occurring. Carbon dioxide causes decreases in vasoreactivity acutely and chronically. These changes can lead to many of the acute and chronic symptoms experienced by individuals suffering from sportsrelated concussion and also puts them at increased risk for subsequent head injury during this recovery period [17, 18].

#### **2.4 Chronic pathophysiology**

Repetitive traumatic brain injury exposure and sub-concussive injuries, in which a substantial injury is sustain however no outward signs or symptoms are apparent, can lead to persistent neurodegenerative changes. The acute neuroinflammatory response discussed above as well as the sustained neuroinflammation that may occur can result in the development of more permanent neurocognitive deficit symptoms and neurodegenerative changes. Additionally, diffuse axonal injury that occurs from concussive impacts can result in further neurodegenerative processes and permanent changes [17, 19].

Concussion has been linked to sequelae such as post-concussion syndrome and long-term neurodegenerative disease [14]. Studies have shown a 1.5 fold increased risk of depression and a 4.5 fold increased risk of Alzheimer's-like symptoms in patients with concussion history [11]. Pathological neurodegeneration markers typically found in Alzheimer's disease has also been seen in individuals with a history of repetitive traumatic brain injury. Although no causal relationship has yet been established, recent research also suggests that repeated head trauma may be associated with the development of chronic traumatic encephalopathy (CTE), a neuropathological neurodegenerative disease defined by abnormal phosphorylated tau accumulation in a pattern distinct from other tauopathies and believed to be caused by the series of metabolic, ionic, membrane, and cytoskeletal disturbances [12, 15, 20]. Tau, a normal structural axonal protein, can become disrupted during brain trauma and accumulate in a phosphorylated form. This further destabilizes microtubules and results in impaired axonal function [12, 15, 20].
