15 “if in doubt, sit them out” Pathophysiology The pathophysiology of concussion is not yet completely understood. Theoretical models are based on animal research and functional neuroimaging studies. Evidence points toward a series of interrelated changes that result in impaired neuronal function6,7 . It is thought that biomechanical forces cause neuronal cell membrane disruption and axonal stretching. The ion channels on the cell membranes become dysregulated and allow an indiscriminate flux of ions. Potassium efflux and calcium influx will result in depolarisation leading to the indiscriminate release of the excitatory neurotransmitter glutamate. In an attempt to restore the resting membrane potential, ATP-dependent membrane ion pumps become overactive. This increases glucose demands resulting in a temporary depletion of intracellular energy reserves. There may also be a reduction in cerebral blood flow during this time that can worsen the energy shortage. The intracellular accumulation of calcium due to uncontrolled influx may result in sequestration of calcium within the mitochondria. Mitochondrial calcium overload causes mitochondrial dysfunction, which would further aggravate energy supply issues. These changes are also thought to result in increased free radical production and inflammatory processes, which may be implicated in some of the longer term symptoms associated with concussion. Functional imaging studies have been used to assess physiological alterations underlying concussion and their time course post-injury. Most of these imaging modalities suggest long-term alterations beyond the return to normality in clinical and neuropsychological measures. As such, they may be useful in a research setting to detect changes consistent with concussion and monitor progress beyond recovery of symptoms, however the current level of evidence in favour of their clinical application is low. They include magnetic resonance spectroscopy (MRS), functional MRI (fMRI), diffusion tensor imaging, cerebral blood flow measurements, electrophysiology36 and positron emission tomography (PET) scanning37 . MRS can detect metabolic changes associated with concussion up to day 30 post-concussion. fMRI has found differences in functional brain activation patterns from 3 days up to 23 months post-concussion in concussed athletes compared to controls. Different diffusion tensor imaging methods have revealed changes in white matter orientation up to 6 months after concussion. Alterations in cerebral blood flow resolved 30 – 40 days post-concussion and electrophysiology did not return to normal levels until 45 days after the injury. PET scans have revealed changes in cerebral glucose metabolism in some brain regions when comparing military veterans with post- concussive symptoms to controls. This suggests metabolic abnormalities may be implicated in post-concussive symptoms38 . These neuroimaging modalities suggest presence of physiological alterations beyond clinical recovery from concussion. However, they are currently limited to characterising the pathophysiology of concussion, not to be used as tools for clinical assessment. Increased availability and further research and reliability assessment are required before implementation in a clinical setting36 . An improved understanding of the pathophysiology of concussion will allow more accurate diagnosis and evidence-based management of the condition. It may provide enhanced appreciation of the long term consequences of concussion and particularly recurrent concussion, to inform risk profiling and mitigation. Assessment of suspected sport-related concussion The diagnosis of concussion can be difficult13 . There is no specific diagnostic test which confirms the presence or otherwise of concussion. Diagnosis of concussion relies on clinical assessment of symptoms and signs including cognitive and behavioural disturbance. In some instances, it will be obvious that there has been a significant injury where the athlete loses consciousness, has a seizure or has significant balance difficulties. Symptoms of concussion however can be very subtle and may present as nothing more than the athlete reporting that they do not ‘feel right’. Symptoms commonly reported by concussed athletes include visual disturbance, feeling ‘foggy’, lethargic or slow, having sensitivity to light or noise, feeling dizzy or nauseous, or headache. Signs of concussion are also variable and may be difficult to detect. The athlete may appear normal apart from appearing vacant, dazed or stunned. The athlete may be disoriented and unable to recall team plays, scores, who the opponent is or be disoriented in terms of place and time. Parents, coaches and attending medical personnel need to be alert for evidence that an athlete is behaving unusually or out of character, exhibits signs of disorientation, clumsiness or loss of balance. Amnesia is common in the setting of concussion. The athlete