The Science of Brain Injury Concussion and SubConcussion

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The Science of Brain Injury Concussion and SubConcussion by Mind Map: The Science of Brain Injury Concussion and SubConcussion

1. Specifically, liberation of potassium, certain neurotransmitters and excitatory amino acids occurs, particularly glutamate

1.1. Katayama Y, Becker DP, Tamura T, Hovda DA: Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889–900, 1990

1.1.1. ATP-overdrive Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DP: Administration of excitatory amino acid antagonists via microdialysis attenuates the increase in glucose utilization seen following concussive brain injury. J Cereb Blood Flow Metab 12:12–24, 1992 Yoshino A, Hovda DA, Kawamata T, Katayama Y, Becker DP: Dynamic changes in local cerebral glucose utilization following cerebral conclusion in rats: evidence of a hyper- and subsequent hypometabolic state. Brain Res 561:106–119, 1991

1.1.2. Switch from a hypermetabolic state to a hypometabolic state 5–6 hours later, which can last up to 5 days or longer. Bergsneider M, Hovda DA, Shalmon E, Kelly DF, Vespa PM, Martin NA, et al.: Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg 86:241–251, 1997 Kalimo H, Rehncrona S, Söderfeldt B: The role of lactic acidosis in the ischemic nerve cell injury. Acta Neuropathol Suppl 7:20–22, 1981

2. Glutamate-mediated accumulation of intracellular calcium ions also results in mitochondrial oxidative dysfunction

2.1. Lifshitz J, Sullivan PG, Hovda DA, Wieloch T, McIntosh TK: Mitochondrial damage and dysfunction in traumatic brain injury. Mitochondrion 4:705–713, 2004

2.2. Robertson CL, Saraswati M, Fiskum G: Mitochondrial dysfunction early after traumatic brain injury in immature rats. J Neurochem 101:1248–1257, 2007

2.3. Verweij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP: Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N-type calcium channel antagonist (SNX-111). Neurol Res 19:334–339, 1997

2.4. Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP: Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:23–34, 1997

3. Faden AI, Demediuk P, Panter SS, Vink R: The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800, 1989



5. Pathophysiological processes of the "Secondary Injury" Sequelae involve both immediate and delayed cellular events

5.1. Ultrastructural damage

5.1.1. Neurofilament Compaction Nakamura Y, Takeda M, Angelides KJ, Tanaka T, Tada K, Nishimura T: Effect of phosphorylation on 68 KDa neurofilament subunit protein assembly by the cyclic AMP dependent protein kinase in vitro. Biochem Biophys Res Commun 169:744–750, 1990 Nixon RA: The regulation of neurofilament protein dynamics by phosphorylation: clues to neurofibrillary pathobiology. Brain Pathol 3:29–38, 1993 Sternberger LA, Sternberger NH: Monoclonal antibodies distinguish phosphorylated and nonphosphorylated forms of neurofilaments in situ. Proc Natl Acad Sci U S A 80:6126–6130, 1983 Maxwell WL, Graham DI: Loss of axonal microtubules and neurofilaments after stretch-injury to guinea pig optic nerve fibers. J Neurotrauma 14:603–614, 1997 Saatman KE, Abai B, Grosvenor A, Vorwerk CK, Smith DH, Meaney DF: Traumatic axonal injury results in biphasic calpain activation and retrograde transport impairment in mice. J Cereb Blood Flow Metab 23:34–42, 2003 Axonal detachment lasts between 4hrs and 2-weeks in humans

5.2. Ionic shifts

5.2.1. Disregualtion of Protein Oxidative Deregualtion Hovda DA, Yoshino A, Kawamata T, Katayama Y, Becker DP: Diffuse prolonged depression of cerebral oxidative metabolism following concussive brain injury in the rat: a cytochrome oxidase histochemistry study. Brain Res 567:1–10, 1991

5.3. Neurotransmission effects

5.4. Effects on cerebral blood flow dynamics and the BBB

5.4.1. Cerebral Blood Flow (CBF) is highly regulated in the uninjured brain CBF has been shown to be decreased immediately after injury. Ginsberg MD, Zhao W, Alonso OF, Loor-Estades JY, Dietrich WD, Busto R: Uncoupling of local cerebral glucose metabolism and blood flow after acute fluid-percussion injury in rats. Am J Physiol 272:H2859–H2868, 1997 Muir JK, Boerschel M, Ellis EF: Continuous monitoring of posttraumatic cerebral blood flow using laser-Doppler flowmetry. J Neurotrauma 9:355–362, 1992 Yamakami I, McIntosh TK: Effects of traumatic brain injury on regional cerebral blood flow in rats as measured with radiolabeled microspheres. J Cereb Blood Flow Metab 9:117–124, 1989 A study of human CBF in 125 patients with severe TBI by Martin et al Martin NA, Patwardhan RV, Alexander MJ, Africk CZ, Lee JH, Shalmon E, et al.: Characterization of cerebral hemodynamic phases following severe head trauma: hypoperfusion, hyperemia, and vasospasm. J Neurosurg 87:9–19, 1997 Suwanwela C, Suwanwela N: Intracranial arterial narrowing and spasm in acute head injury. J Neurosurg 36:314–323, 1972 Maugans TA, Farley C, Altaye M, Leach J, Cecil KM: Pediatric sports-related concussion produces cerebral blood flow alterations. Pediatrics 129:28–37, 2012

5.4.2. The BBB is the highly regulated separation between the intravascular and extravascular content of the CNS. Blood-brain barrier breakdown is well documented in animal models of severe TBI Shapira Y, Setton D, Artru AA, Shohami E: Blood-brain barrier permeability, cerebral edema, and neurologic function after closed head injury in rats. Anesth Analg 77:141–148, 1993 A study of patients with post-concussion syndrome demonstrated that BBB disruption can be observed weeks to months after the original insult Korn A, Golan H, Melamed I, Pascual-Marqui R, Friedman A: Focal cortical dysfunction and blood-brain barrier disruption in patients with postconcussion syndrome. J Clin Neurophysiol 22:1–9, 2005 Shearing forces of primary injury are believed to damage the BBB endothelium, resulting in increased small vessel permeability and dysregulation Shlosberg D, Benifla M, Kaufer D, Friedman A: Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Nephrol 6:393–403, 2010 Breakdown of the BBB has several untoward consequences First and foremost, fluid exudation from BBB breakdown results in brain edema. This edema may result in increased intracranial pressure, and lower cerebral perfusion pressure can ensue with sufficient fluid accumulation Excitotoxicity from neuronal membrane damage may be further exacerbated by the loss of ionic flux control from BBB breakdown, resulting in extravasation of excitatory amino acids As other ions and molecules equilibrate in the serum and CSF, a neuronal microenvironment develops that creates a predisposition for focal seizure activity

5.5. Shear stress to neurons

5.5.1. mTBI Axonal Shear Injuries

5.6. The role of immunoexcitotoxicity is significant in TBI. In the brain, microglia play a key role in the initiation of inflammatory events following injury

5.6.1. Engel S, Wehner HD, Meyermann R: Expression of microglial markers in the human CNS after closed head injury. Acta Neurochir Suppl 66:89–95, 1996

5.6.2. Ghirnikar RS, Lee YL, Eng LF: Inflammation in traumatic brain injury: role of cytokines and chemokines. Neurochem Res 23:329–340, 1998

5.6.3. Homsi S, Piaggio T, Croci N, Noble F, Plotkine M, Marchand-Leroux C, et al.: Blockade of acute microglial activation by minocycline promotes neuroprotection and reduces locomotor hyperactivity after closed head injury in mice: a twelve-week follow-up study. J Neurotrauma 27:911–921, 2010

5.6.4. In normal reactions to a single mild TBI, over time microglia eventually enter a reparative phase composed of phagocytic activity to repair any debris and damaged cells, and ultimately return to their resting state Blaylock RL, Maroon J: Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy—a unifying hypothesis. Surg Neurol Int 2:107:2011

5.6.5. With repeated brain injury, microglia may enter a constitutively activated state and become neurodestructive, which may translate into risk for chronic traumatic encephalopath

6. Rotational Forces or Torque

6.1. torque = moment of inertia x angular acceleration

7. Linear Forces: Newton's Second Law of Motion enables the visualization of how forces in head impacts result in head, and consequently brain, acceleration

7.1. Force = Mass x Acceleration (Newton's 2nd Law)

8. Laws of Conservation of Energy

8.1. kinetic energy = 1/2 mass x (velocity) squared

9. Early Working Non-Human (Primate) Model

9.1. Yarnell P, Ommaya AK: Experimental cerebral concussion in the rhesus monkey. Bull N Y Acad Med 45:39–45, 1969

9.2. Ommaya AK, Hirsch AE: Tolerances for cerebral concussion from head impact and whiplash in primates. J Biomech 4:13–21, 1971

9.2.1. Analyses of the data at that time led investigators to believe that approximately half of the potential for concussion during impact to the unprotected movable head was related to head rotation, with the remaining brain injury potential of the blow being related to the contact phenomena of the impact

9.3. Sass DJ, Corrao P, Ommaya AK: Brain motion during vibration of water immersed rhesus monkeys. J Biomech 4:331–334, 1971

9.4. Ommaya AK, Corrao P, Letcher FS: Head injury in the chimpanzee. 1. Biodynamics of traumatic unconsciousness. J Neurosurg 39:152–166, 1973

9.5. Masuzawa H, Nadamura N, Hirakawa K, Sano K, Matsuno M: Experimental head injury & concussion in monkey using pure linear acceleration impact. Neurol Med Chir (Tokyo) 16:77–90, 1976

9.6. Sekino H, Nakamura N, Kanda R, Yasue M, Masuzawa H, Aoyagi N, et al.: [Experimental head injury in monkeys using rotational acceleration impact (author's transl).]. Neurol Med Chir (Tokyo) 20:127–136, 1980. (Jpn)

10. Use of in-helmet telemetry devices to gather Real-Time data related to Acceleration, Velocity and Forces involved in TBI

10.1. Hootman JM, Dick R, Agel J: Epidemiology of collegiate injuries for 15 sports: summary and recommendations for injury prevention initiatives. J Athl Train 42:311–319, 2007

11. NFL-Led Investigation 1996-2001

11.1. Pellman EJ, Viano DC, Tucker AM, Casson IR, Waeckerle JF: Concussion in professional football: reconstruction of game impacts and injuries. Neurosurgery 53:799–814, 2003


12. SECONDARY INJURY is classically described as the indirect result of the trauma and its subsequent pathophysiological processes