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Neurotransmitter changes after traumatic brain injury: an update for new treatment strategies

Molecular Psychiatry volume 24, pages 995–1012 (2019)Cite this article

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Abstract

Traumatic brain injury (TBI) is a pervasive problem in the United States and worldwide, as the number of diagnosed individuals is increasing yearly and there are no efficacious therapeutic interventions. A large number of patients suffer with cognitive disabilities and psychiatric conditions after TBI, especially anxiety and depression. The constellation of post-injury cognitive and behavioral symptoms suggest permanent effects of injury on neurotransmission. Guided in part by preclinical studies, clinical trials have focused on high-yield pathophysiologic mechanisms, including protein aggregation, inflammation, metabolic disruption, cell generation, physiology, and alterations in neurotransmitter signaling. Despite successful treatment of experimental TBI in animal models, clinical studies based on these findings have failed to translate to humans. The current international effort to reshape TBI research is focusing on redefining the taxonomy and characterization of TBI. In addition, as the next round of clinical trials is pending, there is a pressing need to consider what the field has learned over the past two decades of research, and how we can best capitalize on this knowledge to inform the hypotheses for future innovations. Thus, it is critically important to extend our understanding of the pathophysiology of TBI, particularly to mechanisms that are associated with recovery versus development of chronic symptoms. In this review, we focus on the pathology of neurotransmission after TBI, reflecting on what has been learned from both the preclinical and clinical studies, and we discuss new directions and opportunities for future work.

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References

  1. Taylor CA, Bell JM, Breiding MJ, Xu L. Traumatic brain injury–related emergency department visits, hospitalizations, and deaths—United States, 2007 and 2013. Morb Mortal Wkly Rep Surveill Summ. 2017;66:1–16.

    Google Scholar 

  2. Roozenbeek B, Maas AI, Menon DK. Changing patterns in the epidemiology of traumatic brain injury. Nat Rev Neurol. 2013;9:231–6.

    PubMed  Google Scholar 

  3. Griesbach GS, Kreber LA, Harrington D, Ashley MJ. Post-acute traumatic brain injury rehabilitation: effects on outcome measures and life care costs. J Neurotrauma. 2015;32:704–11.

    PubMed  Google Scholar 

  4. Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen CH, et al. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature. 2015;523:431–6.

    PubMed  PubMed Central  Google Scholar 

  5. Hartings JA, Strong AJ, Fabricius M, Manning A, Bhatia R, Dreier JP, et al. Spreading depolarizations and late secondary insults after traumatic brain injury. J Neurotrauma. 2009;26:1857–66.

    PubMed  PubMed Central  Google Scholar 

  6. Han X, Tong J, Zhang J, Farahvar A, Wang E, Yang J, et al. Imipramine treatment improves cognitive outcome associated with enhanced hippocampal neurogenesis after traumatic brain injury in mice. J Neurotrauma. 2011;28:995–1007.

    PubMed  PubMed Central  Google Scholar 

  7. Ngwenya LB, Mazumder S, Porter ZR, Minnema A, Oswald DJ, Farhadi HF. Implantation of neuronal stem cells enhances object recognition without increasing neurogenesis after lateral fluid percussion injury in mice. Stem Cells Int. 2018;2018:4209821.

    PubMed  PubMed Central  Google Scholar 

  8. Kovesdi E, Kamnaksh A, Wingo D, Ahmed F, Grunberg NE, Long JB, et al. Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. Front Neurol. 2012;3:111.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Siopi E, Llufriu-Daben G, Fanucchi F, Plotkine M, Marchand-Leroux C, Jafarian-Tehrani M. Evaluation of late cognitive impairment and anxiety states following traumatic brain injury in mice: the effect of minocycline. Neurosci Lett. 2012;511:110–5.

    CAS  PubMed  Google Scholar 

  10. Lama S, Auer RN, Tyson R, Gallagher CN, Tomanek B, Sutherland GR. Lactate storm marks cerebral metabolism following brain trauma. J Biol Chem. 2014;289:20200–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Dorsett CR, McGuire JL, DePasquale EA, Gardner AE, Floyd CL, McCullumsmith RE. Glutamate neurotransmission in rodent models of traumatic brain injury. J Neurotrauma. 2017;34:263–72.

    PubMed  PubMed Central  Google Scholar 

  12. Giacino JT, Whyte J, Bagiella E, Kalmar K, Childs N, Khademi A, et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Eng J Med. 2012;366:819–26.

    CAS  Google Scholar 

  13. Klein P, Herr D, Pearl PL, Natale J, Levine Z, Nogay C, et al. Results of phase 2 safety and feasibility study of treatment with levetiracetam for prevention of posttraumatic epilepsy. Arch Neurol. 2012;69:1290–5.

    PubMed  PubMed Central  Google Scholar 

  14. Szaflarski JP, Sangha KS, Lindsell CJ, Shutter LA. Prospective, randomized, single-blinded comparative trial of intravenous levetiracetam versus phenytoin for seizure prophylaxis. Neurocrit Care. 2010;12:165–72.

    CAS  PubMed  Google Scholar 

  15. Menn SJ, Yang R, Lankford A. Armodafinil for the treatment of excessive sleepiness associated with mild or moderate closed traumatic brain injury: a 12-week, randomized, double-blind study followed by a 12-month open-label extension. J Clin Sleep Med. 2014;10:1181–91.

    PubMed  PubMed Central  Google Scholar 

  16. Jorge RE, Acion L, Burin DI, Robinson RG. Sertraline for preventing mood disorders following traumatic brain injury: a randomized clinical trial. JAMA Psychiatry. 2016;73:1041–7.

    PubMed  Google Scholar 

  17. Choe MC, Giza CC. Diagnosis and management of acute concussion. Semin Neurol. 2015;35:29–41.

    PubMed  Google Scholar 

  18. Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol. 2014;13:844–54.

    PubMed  Google Scholar 

  19. Saatman KE, Duhaime AC, Bullock R, Maas AI, Valadka A, Manley GT. Classification of traumatic brain injury for targeted therapies. J Neurotrauma. 2008;25:719–38.

    PubMed  PubMed Central  Google Scholar 

  20. Farkas O, Povlishock JT. Cellular and subcellular change evoked by diffuse traumatic brain injury: a complex web of change extending far beyond focal damage. Prog Brain Res. 2007;161:43–59.

    CAS  PubMed  Google Scholar 

  21. Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury—an update. Phys Med Rehabil Clin N Am. 2016;27:373–93.

    PubMed  Google Scholar 

  22. Gaetz M. The neurophysiology of brain injury. Clin Neurophysiol. 2004;115:4–18.

    CAS  PubMed  Google Scholar 

  23. Bramlett HM, Deitrich WD. Long-term consequences of traumatic brain injury: current status of 10.1038/s41380-018-0239-6 potential mechanisms of injury and neurological outcomes. J Neurotrauma. 2015;32:1834–48.

  24. Ruff RM, Crouch JA, Troster AI, Marshall LF, Buchsbaum MS, Lottenberg S, et al. Selected cases of poor outcome following a minor brain trauma: comparing neuropsychological and positron emission tomography assessment. Brain Inj. 1994;8:297–308.

    CAS  PubMed  Google Scholar 

  25. Tortella FC. Challenging the paradigms of experimental TBI models: from preclinical to clinical practice. In: Kobeissy FH, Dixon CE, Hayes RL, Mondello S, editors. Injury models of the central nervous system: methods and protocols. New York, NY: Springer New York; 2016. p. 735−40.

    Google Scholar 

  26. Bolouri H, Zetterberg H. Frontiers in neuroengineering animal models for concussion: molecular and cognitive assessments—relevance to sport and military concussions. In: Kobeissy FH, editor. Brain neurotrauma: molecular, neuropsychological, and rehabilitation aspects. Boca Raton, FL: CRC Press/Taylor & Francis; 2015.

  27. Wong VS, Langley B. Epigenetic changes following traumatic brain injury and their implications for outcome, recovery and therapy. Neurosci Lett. 2016;625:26–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Corrigan JD, Harrison-Felix C, Bogner J, Dijkers M, Terrill MS, Whiteneck G. Systematic bias in traumatic brain injury outcome studies because of loss to follow-up. Arch Phys Med Rehabil. 2003;84:153–60.

    PubMed  Google Scholar 

  29. Xiong Y, Mahmood A, Chopp M. Animal models of traumatic brain injury. Nat Rev Neurosci. 2013;14:128–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Dewitt DS, Perez-Polo R, Hulsebosch CE, Dash PK, Robertson CS. Challenges in the development of rodent models of mild traumatic brain injury. J Neurotrauma. 2013;30:688–701.

    PubMed  Google Scholar 

  31. Blanchard RJ, Blanchard DC. Attack and defense in rodents as ethoexperimental models for the study of emotion. Prog Neuropsychopharmacol Biol Psychiatry. 1989;13(Suppl):S3–14.

    PubMed  Google Scholar 

  32. Belanger HG, Proctor-Weber Z, Kretzmer T, Kim M, French LM, Vanderploeg RD. Symptom complaints following reports of blast versus non-blast mild TBI: does mechanism of injury matter? Clin Neuropsychol. 2011;25:702–15.

    PubMed  Google Scholar 

  33. Morrison B 3rd, Elkin BS, Dolle JP, Yarmush ML. In vitro models of traumatic brain injury. Annu Rev Biomed Eng. 2011;13:91–126.

    CAS  PubMed  Google Scholar 

  34. Isaacson JS, Scanziani M. How inhibition shapes cortical activity. Neuron. 2011;72:231–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Alwis DS, Rajan R. Environmental enrichment and the sensory brain: the role of enrichment in remediating brain injury. Front Syst Neurosci. 2014;8:156.

    PubMed  PubMed Central  Google Scholar 

  36. Bach-y-Rita P. Theoretical basis for brain plasticity after a TBI. Brain Inj. 2003;17:643–51.

    PubMed  Google Scholar 

  37. Dymowski AR, Owens JA, Ponsford JL, Willmott C. Speed of processing and strategic control of attention after traumatic brain injury. J Clin Exp Neuropsychol. 2015;37:1024–35.

    PubMed  Google Scholar 

  38. Nelson LD, Ranson J, Ferguson AR, Giacino J, Okonkwo DO, Valadka A, et al. Validating multidimensional outcome assessment using the TBI common data elements: an analysis of the TRACK-TBI pilot sample. J Neurotrauma. 2017;34:3158–72.

  39. McDonald BC, Flashman LA, Saykin AJ. Executive dysfunction following traumatic brain injury: neural substrates and treatment strategies. NeuroRehabilitation. 2002;17:333–44.

    PubMed  Google Scholar 

  40. Draper K, Ponsford J. Cognitive functioning ten years following traumatic brain injury and rehabilitation. Neuropsychology. 2008;22:618–25.

    PubMed  Google Scholar 

  41. Whelan-Goodinson R, Ponsford J, Johnston L, Grant F. Psychiatric disorders following traumatic brain injury: their nature and frequency. J Head Trauma Rehabil. 2009;24:324–32.

    PubMed  Google Scholar 

  42. Guillamondegui OD, Montgomery SA, Phibbs FT, McPheeters ML, Alexander PT, Jerome RN, et al. AHRQ comparative effectiveness reviews. Traumatic brain injury and depression. Rockville, MD: Agency for Healthcare Research and Quality (US); 2011.

  43. Perry DC, Sturm VE, Peterson MJ, Pieper CF, Bullock T, Boeve BF, et al. Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis. J Neurosurg. 2016;124:511–26.

    PubMed  Google Scholar 

  44. Vaishnavi S, Rao V, Fann JR. Neuropsychiatric problems after traumatic brain injury: unraveling the silent epidemic. Psychosomatics. 2009;50:198–205.

    PubMed  Google Scholar 

  45. Gould KR, Ponsford JL, Spitz G. Association between cognitive impairments and anxiety disorders following traumatic brain injury. J Clin Exp Neuropsychol. 2014;36:1–14.

    PubMed  Google Scholar 

  46. Osborn AJ, Mathias JL, Fairweather-Schmidt AK. Depression following adult, non-penetrating traumatic brain injury: a meta-analysis examining methodological variables and sample characteristics. Neurosci Biobehav Rev. 2014;47:1–15.

    CAS  PubMed  Google Scholar 

  47. Jesulola E, Micalos P, Baguley IJ. Understanding the pathophysiology of depression: from monoamines to the neurogenesis hypothesis model—are we there yet? Behav Brain Res. 2017;341:79–90.

    PubMed  Google Scholar 

  48. Bhattacharya A, Drevets WC. Role of neuro-immunological factors in the pathophysiology of mood disorders: implications for novel therapeutics for treatment resistant depression. Curr Top Behav Neurosci. 2017;31:339–56.

    CAS  PubMed  Google Scholar 

  49. Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. Neuropharmacology. 2012;62:63–77.

    CAS  PubMed  Google Scholar 

  50. Danbolt NC, Chaudhry FA, Dehenes Y, Lehre KP, Ullensvang K, Storm-Mathisen J. Properties and localization of glutamate transporters. Prog Brain Res. 1998;116:23–43.

    CAS  PubMed  Google Scholar 

  51. O’Donovan SM, Sullivan CR, McCullumsmith RE. The role of glutamate transporters in the pathophysiology of neuropsychiatric disorders. NPJ Schizophr. 2017;3:32.

    PubMed  PubMed Central  Google Scholar 

  52. Levenson J, Weeber E, Selcher JC, Kategaya LS, Sweatt JD, Eskin A. Long-term potentiation and contextual fear conditioning increase neuronal glutamate uptake. Nat Neurosci. 2002;5:155–61.

    CAS  PubMed  Google Scholar 

  53. 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. 1990;73:889–900.

    CAS  PubMed  Google Scholar 

  54. Zhang H, Zhang X, Zhang T, Chen L. Excitatory amino acids in cerebrospinal fluid of patients with acute head injuries. Clin Chem. 2001;47:1458–62.

    CAS  PubMed  Google Scholar 

  55. Yamamoto T, Rossi S, Stiefel M, Doppenberg E, Zauner A, Bullock R, et al. CSF and ECF glutamate concentrations in head injured patients. Acta Neurochir Suppl. 1999;75:17–9.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  57. Rimmele TS, Rocher AB, Wellbourne-Wood J, Chatton JY. Control of glutamate transport by extracellular potassium: basis for a negative feedback on synaptic transmission. Cereb Cortex. 2017;27:3272–83.

    PubMed  Google Scholar 

  58. Dorsett CR, McGuire JL, Niedzielko TL, DePasquale EA, Meller J, Floyd CL, et al. Traumatic brain injury induces alterations in cortical glutamate uptake without a reduction in glutamate dransporter-1 protein expression. J Neurotrauma. 2017;34:220–34.

    PubMed  PubMed Central  Google Scholar 

  59. Hinzman JM, Wilson JA, Mazzeo AT, Bullock MR, Hartings JA. Excitotoxicity and metabolic crisis are associated with spreading depolarizations in severe traumatic brain injury patients. J Neurotrauma. 2016;33:1775–83.

    PubMed  PubMed Central  Google Scholar 

  60. Torrente D, Cabezas R, Avila MF, Garcia-Segura LM, Barreto GE, Guedes RC. Cortical spreading depression in traumatic brain injuries: is there a role for astrocytes? Neurosci Lett. 2014;565:2–6.

    CAS  PubMed  Google Scholar 

  61. Hartings JA. Spreading depolarization monitoring in neurocritical care of acute brain injury. Curr Opin Crit Care. 2017;23:94–102.

    PubMed  Google Scholar 

  62. Shohami E, Biegon A. Novel approach to the role of NMDA receptors in traumatic brain injury. CNS Neurol Disord Drug Targets. 2014;13:567–73.

    CAS  PubMed  Google Scholar 

  63. Henry LC, Tremblay S, Boulanger Y, Ellemberg D, Lassonde M. Neurometabolic changes in the acute phase after sports concussions correlate with symptom severity. J Neurotrauma. 2010;27:65–76.

    PubMed  Google Scholar 

  64. Biegon A, Fry PA, Paden CM, Alexandrovich A, Tsenter J, Shohami E. Dynamic changes in N-methyl-d-aspartate receptors after closed head injury in mice: Implications for treatment of neurological and cognitive deficits. Proc Natl Acad Sci USA. 2004;101:5117–22.

    CAS  PubMed  Google Scholar 

  65. Miller LP, Lyeth BG, Jenkins LW, Oleniak L, Panchision D, Hamm RJ, et al. Excitatory amino acid receptor subtype binding following traumatic brain injury. Brain Res. 1990;526:103–7.

    CAS  PubMed  Google Scholar 

  66. Lopez-Picon F, Snellman A, Shatillo O, Lehtiniemi P, Gronroos TJ, Marjamaki P, et al. Ex vivo tracing of NMDA and GABA-A receptors in rat brain after traumatic brain injury using 18F-GE-179 and 18F-GE-194 autoradiography. J Nucl Med. 2016;57:1442–7.

    CAS  PubMed  Google Scholar 

  67. Kharlamov EA, Lepsveridze E, Meparishvili M, Solomonia RO, Lu B, Miller ER, et al. Alterations of GABA(A) and glutamate receptor subunits and heat shock protein in rat hippocampus following traumatic brain injury and in posttraumatic epilepsy. Epilepsy Res. 2011;95:20–34.

    CAS  PubMed  Google Scholar 

  68. Spaethling JM, Klein DM, Singh P, Meaney DF. Calcium-permeable AMPA receptors appear in cortical neurons after traumatic mechanical injury and contribute to neuronal fate. J Neurotrauma. 2008;25:1207–16.

    PubMed  PubMed Central  Google Scholar 

  69. Rao VL, Baskaya MK, Dogan A, Rothstein JD, Dempsey RJ. Traumatic brain injury down-regulates glial glutamate transporter (GLT-1 and GLAST) proteins in rat brain. J Neurochem. 1998;70:2020–7.

    CAS  PubMed  Google Scholar 

  70. Yi JH, Pow DV, Hazell AS. Early loss of the glutamate transporter splice-variant GLT-1v in rat cerebral cortex following lateral fluid-percussion injury. Glia. 2005;49:121–33.

    PubMed  Google Scholar 

  71. Yi JH, Herrero R, Chen G, Hazell AS. Glutamate transporter EAAT4 is increased in hippocampal astrocytes following lateral fluid-percussion injury in the rat. Brain Res. 2007;1154:200–5.

    CAS  PubMed  Google Scholar 

  72. van Landeghem FK, Stover JF, Bechmann I, Bruck W, Unterberg A, Buhrer C, et al. Early expression of glutamate transporter proteins in ramified microglia after controlled cortical impact injury in the rat. Glia. 2001;35:167–79.

    PubMed  Google Scholar 

  73. Beschorner R, Dietz K, Schauer N, Mittelbronn M, Schluesener HJ, Trautmann K, et al. Expression of EAAT1 reflects a possible neuroprotective function of reactive astrocytes and activated microglia following human traumatic brain injury. Histol Histopathol. 2007;22:515–26.

    CAS  PubMed  Google Scholar 

  74. van Landeghem FK, Weiss T, Oehmichen M, von Deimling A. Decreased expression of glutamate transporters in astrocytes after human traumatic brain injury. J Neurotrauma. 2006;23:1518–28.

    PubMed  Google Scholar 

  75. Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: past experience and current developments. Neurotherapeutics. 2010;7:115–26.

    PubMed  PubMed Central  Google Scholar 

  76. Ikonomidou C, Turski L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol. 2002;1:383–6.

    CAS  PubMed  Google Scholar 

  77. Muir KW. Glutamate-based therapeutic approaches: clinical trials with NMDA antagonists. Curr Opin Pharmacol. 2006;6:53–60.

    CAS  PubMed  Google Scholar 

  78. Temkin NR, Anderson GD, Winn HR, Ellenbogen RG, Britz GW, Schuster J, et al. Magnesium sulfate for neuroprotection after traumatic brain injury: a randomised controlled trial. Lancet Neurol. 2007;6:29–38.

    CAS  PubMed  Google Scholar 

  79. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002;5:405–14.

    CAS  PubMed  Google Scholar 

  80. Ikonomidou C, Stefovska V, Turski L. Neuronal death enhanced by N-methyl-d-aspartate antagonists. Proc Natl Acad Sci USA. 2000;97:12885–90.

    CAS  PubMed  Google Scholar 

  81. Meunier CN, Chameau P, Fossier PM. Modulation of synaptic plasticity in the cortex needs to understand all the players. Front Synaptic Neurosci. 2017;9:2.

    PubMed  PubMed Central  Google Scholar 

  82. Nutt D. GABAA receptors: subtypes, regional distribution, and function. J Clin Sleep Med. 2006;2:S7–11.

    PubMed  Google Scholar 

  83. Wu X, Huang L, Wu Z, Zhang C, Jiang D, Bai Y, et al. Homeostatic competition between phasic and tonic inhibition. J Biol Chem. 2013;288:25053–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Wu X, Wu Z, Ning G, Guo Y, Ali R, Macdonald RL, et al. gamma-Aminobutyric acid type A (GABAA) receptor alpha subunits play a direct role in synaptic versus extrasynaptic targeting. J Biol Chem. 2012;287:27417–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Guerriero RM, Giza CC, Rotenberg A. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015;15:545.

    Google Scholar 

  86. Raible DJ, Frey LC, Cruz Del Angel Y, Russek SJ, Brooks-Kayal AR. GABA(A) receptor regulation after experimental traumatic brain injury. J Neurotrauma. 2012;29:2548–54.

    PubMed  PubMed Central  Google Scholar 

  87. Sihver S, Marklund N, Hillered L, Langstrom B, Watanabe Y, Bergstrom M. Changes in mACh, NMDA and GABA(A) receptor binding after lateral fluid-percussion injury: in vitro autoradiography of rat brain frozen sections. J Neurochem. 2001;78:417–23.

    CAS  PubMed  Google Scholar 

  88. Wong VS, Langley B. Epigenetic changes following traumatic brain injury and their implications for outcome, recovery and therapy. Neurosci Lett. 2016;625:26–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Tomaszczyk JC, Green NL, Frasca D, Colella B, Turner GR, Christensen BK, et al. Negative neuroplasticity in chronic traumatic brain injury and implications for neurorehabilitation. Neuropsychol Rev. 2014;24:409–27.

    PubMed  PubMed Central  Google Scholar 

  90. Miyazaki S, Katayama Y, Lyeth BG, Jenkins LW, DeWitt DS, Goldberg SJ, et al. Enduring suppression of hippocampal long-term potentiation following traumatic brain injury in rat. Brain Res. 1992;585:335–9.

    CAS  PubMed  Google Scholar 

  91. Sick TJ, Perez-Pinzon MA, Feng ZZ. Impaired expression of long-term potentiation in hippocampal slices 4 and 48 h following mild fluid-percussion brain injury in vivo. Brain Res. 1998;785:287–92.

    CAS  PubMed  Google Scholar 

  92. Reeves TM, Lyeth BG, Povlishock JT. Long-term potentiation deficits and excitability changes following traumatic brain injury. Exp Brain Res. 1995;106:248–56.

    CAS  PubMed  Google Scholar 

  93. Reeves TM, Kao CQ, Phillips LL, Bullock MR, Povlishock JT. Presynaptic excitability changes following traumatic brain injury in the rat. J Neurosci Res. 2000;60:370–9.

    CAS  PubMed  Google Scholar 

  94. Sanders MJ, Dietrich WD, Green EJ. Behavioral, electrophysiological, and histopathological consequences of mild fluid-percussion injury in the rat. Brain Res. 2001;904:141–4.

    CAS  PubMed  Google Scholar 

  95. Smith CJ, Xiong G, Elkind JA, Putnam B, Cohen AS. Brain injury impairs working memory and prefrontal circuit function. Front Neurol. 2015;6:240.

    PubMed  PubMed Central  Google Scholar 

  96. Ping X, Jin X. Transition from initial hypoactivity to hyperactivity in cortical layer V pyramidal neurons after traumatic brain injury in vivo. J Neurotrauma. 2016;33:354–61.

    PubMed  PubMed Central  Google Scholar 

  97. Witgen BM, Lifshitz J, Smith ML, Schwarzbach E, Liang SL, Grady MS, et al. Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation. Neuroscience. 2005;133:1–15.

    CAS  PubMed  Google Scholar 

  98. Schwarzbach E, Bonislawski DP, Xiong G, Cohen AS. Mechanisms underlying the inability to induce area CA1 LTP in the mouse after traumatic brain injury. Hippocampus. 2006;16:541–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Almeida-Suhett CP, Prager EM, Pidoplichko V, Figueiredo TH, Marini AM, Li Z, et al. Reduced GABAergic inhibition in the basolateral amygdala and the development of anxiety-like behaviors after mild traumatic brain injury. PLoS ONE. 2014;9:e102627.

    PubMed  PubMed Central  Google Scholar 

  100. Hoskison MM, Moore AN, Hu B, Orsi S, Kobori N, Dash PK. Persistent working memory dysfunction following traumatic brain injury: evidence for a time-dependent mechanism. Neuroscience. 2009;159:483–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Allitt BJ, Iva P, Yan EB, Rajan R. Hypo-excitation across all cortical laminae defines intermediate stages of cortical neuronal dysfunction in diffuse traumatic brain injury. Neuroscience. 2016;334:290–308.

    CAS  PubMed  Google Scholar 

  102. Pavlov I, Huusko N, Drexel M, Kirchmair E, Sperk G, Pitkanen A, et al. Progressive loss of phasic, but not tonic, GABAA receptor-mediated inhibition in dentate granule cells in a model of post-traumatic epilepsy in rats. Neuroscience. 2011;194:208–19.

    CAS  PubMed  Google Scholar 

  103. Boychuk JA, Butler CR, Halmos KC, Smith BN. Enduring changes in tonic GABAA receptor signaling in dentate granule cells after controlled cortical impact brain injury in mice. Exp Neurol. 2016;277:178–89.

    CAS  PubMed  Google Scholar 

  104. Mtchedlishvili Z, Lepsveridze E, Xu H, Kharlamov EA, Lu B, Kelly KM. Increase of GABAA receptor-mediated tonic inhibition in dentate granule cells after traumatic brain injury. Neurobiol Dis. 2010;38:464–75.

    CAS  PubMed  Google Scholar 

  105. Hunt RF, Scheff SW, Smith BN. Synaptic reorganization of inhibitory hilar interneuron circuitry after traumatic brain injury in mice. J Neurosci. 2011;31:6880–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Cantu D, Walker K, Andresen L, Taylor-Weiner A, Hampton D, Tesco G, et al. Traumatic brain injury increases cortical glutamate network activity by compromising GABAergic control. Cereb Cortex. 2015;25:2306–20.

    PubMed  Google Scholar 

  107. Sanders MJ, Sick TJ, Perez-Pinzon MA, Dietrich WD, Green EJ. Chronic failure in the maintenance of long-term potentiation following fluid percussion injury in the rat. Brain Res. 2000;861:69–76.

    CAS  PubMed  Google Scholar 

  108. Ritter AC, Kammerer CM, Brooks MM, Conley YP, Wagner AK. Genetic variation in neuronal glutamate transport genes and associations with posttraumatic seizure. Epilepsia. 2016;57:984–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Temkin NR, Dikmen SS, Wilensky AJ, Keihm J, Chabal S, Winn HR. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Eng J Med. 1990;323:497–502.

    CAS  Google Scholar 

  110. Hammond FM, Bickett AK, Norton JH, Pershad R. Effectiveness of amantadine hydrochloride in the reduction of chronic traumatic brain injury irritability and aggression. J Head Trauma Rehabil. 2014;29:391–9.

    PubMed  Google Scholar 

  111. Hammond FM, Sherer M, Malec JF, Zafonte RD, Whitney M, Bell K, et al. Amantadine effect on perceptions of irritability after traumatic brain injury: results of the Amantadine Irritability Multisite Study. J Neurotrauma. 2015;32:1230–8.

    PubMed  PubMed Central  Google Scholar 

  112. Dougall D, Poole N, Agrawal N. Pharmacotherapy for chronic cognitive impairment in traumatic brain injury. Cochrane Database Syst Rev. 2015:Cd009221.

  113. Spritzer SD, Kinney CL, Condie J, Wellik KE, Hoffman-Snyder CR, Wingerchuk DM, et al. Amantadine for patients with severe traumatic brain injury: a critically appraised topic. Neurologist. 2015;19:61–4.

    PubMed  Google Scholar 

  114. Xia P, Chen HS, Zhang D, Lipton SA. Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci. 2010;30:11246–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov. 2006;5:160–70.

    CAS  PubMed  Google Scholar 

  116. Ma S, Hangya B, Leonard CS, Wisden W, Gundlach AL. Dual-transmitter systems regulating arousal, attention, learning and memory. Neurosci Biobehav Rev. 2018;85:21–33.

    CAS  PubMed  Google Scholar 

  117. Gu Q. Neuromodulatory transmitter systems in the cortex and their role in cortical plasticity. Neuroscience. 2002;111:815–35.

    CAS  PubMed  Google Scholar 

  118. Parikh V, Kozak R, Martinez V, Sarter M. Prefrontal acetylcholine release controls cue detection on multiple timescales. Neuron. 2007;56:141–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Shin SS, Dixon CE. Alterations in cholinergic pathways and therapeutic strategies targeting cholinergic system after traumatic brain Injury. J Neurotrauma. 2015;32:1429–40.

    PubMed  PubMed Central  Google Scholar 

  120. Ostberg A, Virta J, Rinne JO, Oikonen V, Luoto P, Nagren K, et al. Cholinergic dysfunction after traumatic brain injury: preliminary findings from a PET study. Neurology. 2011;76:1046–50.

    CAS  PubMed  Google Scholar 

  121. Donat CK, Schuhmann MU, Voigt C, Nieber K, Deuther-Conrad W, Brust P. Time-dependent alterations of cholinergic markers after experimental traumatic brain injury. Brain Res. 2008;1246:167–77.

    CAS  PubMed  Google Scholar 

  122. Dixon CE, Bao J, Long DA, Hayes RL. Reduced evoked release of acetylcholine in the rodent hippocampus following traumatic brain injury. Pharmacol Biochem Behav. 1996;53:679–86.

    CAS  PubMed  Google Scholar 

  123. Mufson EJ, Perez SE, Nadeem M, Mahady L, Kanaan NM, Abrahamson EE, et al. Progression of tau pathology within cholinergic nucleus basalis neurons in chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study. Brain. 2016;30:1399–413.

    Google Scholar 

  124. Pike BR, Hamm RJ. Post-injury administration of BIBN 99, a selective muscarinic M2 receptor antagonist, improves cognitive performance following traumatic brain injury in rats. Brain Res. 1995;686:37–43.

    CAS  PubMed  Google Scholar 

  125. Pike BR, Hamm RJ. Activating the posttraumatic cholinergic system for the treatment of cognitive impairment following traumatic brain injury. Pharmacol Biochem Behav. 1997;57:785–91.

    CAS  PubMed  Google Scholar 

  126. Dixon CE, Ma X, Marion DW. Effects of CDP-choline treatment on neurobehavioral deficits after TBI and on hippocampal and neocortical acetylcholine release. J Neurotrauma. 1997;14:161–9.

    CAS  PubMed  Google Scholar 

  127. Zhang L, Plotkin RC, Wang G, Sandel ME, Lee S. Cholinergic augmentation with donepezil enhances recovery in short-term memory and sustained attention after traumatic brain injury. Arch Phys Med Rehabil. 2004;85:1050–5.

    PubMed  Google Scholar 

  128. Tenovuo O. Central acetylcholinesterase inhibitors in the treatment of chronic traumatic brain injury-clinical experience in 111 patients. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:61–7.

    CAS  PubMed  Google Scholar 

  129. Silver JM, Koumaras B, Chen M, Mirski D, Potkin SG, Reyes P, et al. Effects of rivastigmine on cognitive function in patients with traumatic brain injury. Neurology. 2006;67:748–55.

    CAS  PubMed  Google Scholar 

  130. Ostberg A, Virta J, Rinne JO, Oikonen V, Luoto P, Nagren K, et al. Brain cholinergic function and response to rivastigmine in patients with chronic sequels of traumatic brain injury: a PET study. J Head Trauma Rehabil. 2018;33:25–32.

    PubMed  Google Scholar 

  131. Jenkins PO, Mehta MA, Sharp DJ. Catecholamines and cognition after traumatic brain injury. Brain. 2016;139(Pt 9):2345–71.

    PubMed  PubMed Central  Google Scholar 

  132. Aston-Jones G, Rajkowski J, Cohen J. Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry. 1999;46:1309–20.

    CAS  PubMed  Google Scholar 

  133. Dunn-Meynell A, Pan S, Levin BE. Focal traumatic brain injury causes widespread reductions in rat brain norepinephrine turnover from 6 to 24 h. Brain Res. 1994;660:88–95.

    CAS  PubMed  Google Scholar 

  134. Fujinaka T, Kohmura E, Yuguchi T, Yoshimine T. The morphological and neurochemical effects of diffuse brain injury on rat central noradrenergic system. Neurol Res. 2003;25:35–41.

    PubMed  Google Scholar 

  135. Levin BE, Brown KL, Pawar G, Dunn-Meynell A. Widespread and lateralization effects of acute traumatic brain injury on norepinephrine turnover in the rat brain. Brain Res. 1995;674:307–13.

    CAS  PubMed  Google Scholar 

  136. Levin BE, Pan S, Dunn-Meynell A. Chronic alterations in rat brain alpha-adrenoceptors following traumatic brain injury. Restor Neurol Neurosci. 1994;7:5–12.

    CAS  PubMed  Google Scholar 

  137. Prasad MR, Tzigaret CM, Smith D, Soares H, McIntosh TK. Decreased alpha 1-adrenergic receptors after experimental brain injury. J Neurotrauma. 1992;9:269–79.

    CAS  PubMed  Google Scholar 

  138. Ripley DL, Morey CE, Gerber D, Harrison-Felix C, Brenner LA, Pretz CR, et al. Atomoxetine for attention deficits following traumatic brain injury: results from a randomized controlled trial. Brain. 2014;28:1514–22.

    Google Scholar 

  139. Meiser J, Weindl D, Hiller K. Complexity of dopamine metabolism. Cell Commun Signal. 2013;11:34.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Hutson CB, Lazo CR, Mortazavi F, Giza CC, Hovda D, Chesselet MF. Traumatic brain injury in adult rats causes progressive nigrostriatal dopaminergic cell loss and enhanced vulnerability to the pesticide paraquat. J Neurotrauma. 2011;28:1783–801.

    PubMed  PubMed Central  Google Scholar 

  141. van Bregt DR, Thomas TC, Hinzman JM, Cao T, Liu M, Bing G, et al. Substantia nigra vulnerability after a single moderate diffuse brain injury in the rat. Exp Neurol. 2012;234:8–19.

    PubMed  Google Scholar 

  142. Massucci JL, Kline AE, Ma X, Zafonte RD, Dixon CE. Time dependent alterations in dopamine tissue levels and metabolism after experimental traumatic brain injury in rats. Neurosci Lett. 2004;372:127–31.

    CAS  PubMed  Google Scholar 

  143. Kobori N, Clifton GL, Dash PK. Enhanced catecholamine synthesis in the prefrontal cortex after traumatic brain injury: implications for prefrontal dysfunction. J Neurotrauma. 2006;23:1094–102.

    PubMed  Google Scholar 

  144. Huang EY, Tsui PF, Kuo TT, Tsai JJ, Chou YC, Ma HI, et al. Amantadine ameliorates dopamine-releasing deficits and behavioral deficits in rats after fluid percussion injury. PLoS ONE. 2014;9:e86354.

    PubMed  PubMed Central  Google Scholar 

  145. Wagner AK, Sokoloski JE, Ren D, Chen X, Khan AS, Zafonte RD, et al. Controlled cortical impact injury affects dopaminergic transmission in the rat striatum. J Neurochem. 2005;95:457–65.

    CAS  PubMed  Google Scholar 

  146. Wagner AK, Scanlon JM, Becker CR, Ritter AC, Niyonkuru C, Dixon CE, et al. The influence of genetic variants on striatal dopamine transporter and D2 receptor binding after TBI. J Cereb Blood Flow Metab. 2014;34:1328–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Whyte J, Vaccaro M, Grieb-Neff P, Hart T, Polansky M, Coslett HB. The effects of bromocriptine on attention deficits after traumatic brain injury: a placebo-controlled pilot study. Am J Phys Med Rehabil/Assoc Acad Physiatr. 2008;87:85–99.

    Google Scholar 

  148. Siddall OM. Use of methylphenidate in traumatic brain injury. Ann Pharmacother. 2005;39:1309–13.

    CAS  PubMed  Google Scholar 

  149. Jin C, Schachar R. Methylphenidate treatment of attention-deficit/hyperactivity disorder secondary to traumatic brain injury: a critical appraisal of treatment studies. CNS Spectr. 2004;9:217–26.

    PubMed  Google Scholar 

  150. De Felice LJ. A current review of serotonin transporters. F1000Res 2016, 5(F1000 Faculty Rev):1884. the article is 7 pages long so presumably it is 1884–90.

  151. Abe K, Shimada R, Okada Y, Kibayashi K. Traumatic brain injury decreases serotonin transporter expression in the rat cerebrum. Neurol Res. 2016;38:358–63.

    CAS  PubMed  Google Scholar 

  152. Wang Y, Neumann M, Hansen K, Hong SM, Kim S, Noble-Haeusslein LJ, et al. Fluoxetine increases hippocampal neurogenesis and induces epigenetic factors but does not improve functional recovery after traumatic brain injury. J Neurotrauma. 2011;28:259–68.

    PubMed  PubMed Central  Google Scholar 

  153. Yue JK, Burke JF, Upadhyayula PS, Winkler EA, Deng H, Robinson CK, et al. Selective serotonin reuptake inhibitors for treating neurocognitive and neuropsychiatric disorders following traumatic brain injury: an evaluation of current evidence. Brain Sci. 2017;7:93–120.

    PubMed Central  Google Scholar 

  154. Novack TA, Banos JH, Brunner R, Renfroe S, Meythaler JM. Impact of early administration of sertraline on depressive symptoms in the first year after traumatic brain injury. J Neurotrauma. 2009;26:1921–8.

    PubMed  Google Scholar 

  155. Ashman TA, Cantor JB, Gordon WA, Spielman L, Flanagan S, Ginsberg A, et al. A randomized controlled trial of sertraline for the treatment of depression in persons with traumatic brain injury. Arch Phys Med Rehabil. 2009;90:733–40.

    PubMed  Google Scholar 

  156. Rapoport MJ, Mitchell RA, McCullagh S, Herrmann N, Chan F, Kiss A, et al. A randomized controlled trial of antidepressant continuation for major depression following traumatic brain injury. J Clin Psychiatry. 2010;71:1125–30.

    CAS  PubMed  Google Scholar 

  157. Banos JH, Novack TA, Brunner R, Renfroe S, Lin HY, Meythaler J. Impact of early administration of sertraline on cognitive and behavioral recovery in the first year after moderate to severe traumatic brain injury. J Head Trauma Rehabil. 2010;25:357–61.

    PubMed  Google Scholar 

  158. Fann JR, Bombardier CH, Temkin N, Esselman P, Warms C, Barber J, et al. Sertraline for major depression during the year following traumatic brain injury: a randomized controlled trial. J Head Trauma Rehabil. 2017;32:332–42.

    PubMed  PubMed Central  Google Scholar 

  159. Lusardi TA. Adenosine neuromodulation and traumatic brain injury. Curr Neuropharmacol. 2009;7:228–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Krugel U. Purinergic receptors in psychiatric disorders. Neuropharmacology. 2016;104:212–25.

    PubMed  Google Scholar 

  161. Chen JF, Lee CF, Chern Y. Adenosine receptor neurobiology: overview. Int Rev Neurobiol. 2014;119:1–49.

    PubMed  Google Scholar 

  162. Gundersen V, Storm-Mathisen J, Bergersen LH. Neuroglial transmission. Physiol Rev. 2015;95:695–726.

    CAS  PubMed  Google Scholar 

  163. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, et al. Astrocytic purinergic signaling coordinates synaptic networks. Science. 2005;310:113–6.

    CAS  PubMed  Google Scholar 

  164. Rombo DM, Ribeiro JA, Sebastiao AM. Hippocampal GABAergic transmission: a new target for adenosine control of excitability. J Neurochem. 2016;139:1056–70.

    CAS  PubMed  Google Scholar 

  165. Matos M, Augusto E, Santos-Rodrigues AD, Schwarzschild MA, Chen JF, Cunha RA, et al. Adenosine A2A receptors modulate glutamate uptake in cultured astrocytes and gliosomes. Glia. 2012;60:702–16.

    PubMed  Google Scholar 

  166. Dai SS, Zhou YG, Li W, An JH, Li P, Yang N, et al. Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J Neurosci. 2010;30:5802–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Bell MJ, Kochanek PM, Carcillo JA, Mi Z, Schiding JK, Wisniewski SR, et al. Interstitial adenosine, inosine, and hypoxanthine are increased after experimental traumatic brain injury in the rat. J Neurotrauma. 1998;15:163–70.

    CAS  PubMed  Google Scholar 

  168. Kochanek PM, Vagni VA, Janesko KL, Washington CB, Crumrine PK, Garman RH, et al. Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury. J Cereb Blood Flow Metab. 2006;26:565–75.

    CAS  PubMed  Google Scholar 

  169. Ning YL, Yang N, Chen X, Xiong RP, Zhang XZ, Li P, et al. Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction. J Cereb Blood Flow Metab. 2013;33:1789–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Zhao ZA, Zhao Y, Ning YL, Yang N, Peng Y, Li P, et al. Adenosine A2A receptor inactivation alleviates early-onset cognitive dysfunction after traumatic brain injury involving an inhibition of tau hyperphosphorylation. Transl Psychiatry. 2017;7:e1123.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Diamond ML, Ritter AC, Jackson EK, Conley YP, Kochanek PM, Boison D, et al. Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development. Epilepsia. 2015;56:1198–206.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Wagner AK, Miller MA, Scanlon J, Ren D, Kochanek PM, Conley YP. Adenosine A1 receptor gene variants associated with post-traumatic seizures after severe TBI. Epilepsy Res. 2010;90:259–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Cotter D, Kelso A, Neligan A. Genetic biomarkers of posttraumatic epilepsy: a systematic review. Seizure. 2017;46:53–8.

    PubMed  Google Scholar 

  174. Froemke RC. Plasticity of cortical excitatory−inhibitory balance. Annu Rev Neurosci. 2015;38:195–219.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Bales JW, Wagner AK, Kline AE, Dixon CE. Persistent cognitive dysfunction after traumatic brain injury: a dopamine hypothesis. Neurosci Biobehav Rev. 2009;33:981–1003.

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Froudist-Walsh S, Lopez-Barroso D, Jose Torres-Prioris M, Croxson PL, Berthier ML. Plasticity in the working memory system: life span changes and response to injury. Neuroscientist. 2018;24:261–76.

    PubMed  Google Scholar 

  177. Moreau AW, Amar M, Le Roux N, Morel N, Fossier P. Serotoninergic fine-tuning of the excitation-inhibition balance in rat visual cortical networks. Cereb cortex (New Y, NY: 1991). 2010;20:456–67.

    Google Scholar 

  178. Sommerauer C, Rebernik P, Reither H, Nanoff C, Pifl C. The noradrenaline transporter as site of action for the anti-Parkinson drug amantadine. Neuropharmacology. 2012;62:1708–16.

    CAS  PubMed  Google Scholar 

  179. Huber TJ, Dietrich DE, Emrich HM. Possible use of amantadine in depression. Pharmacopsychiatry. 1999;32:47–55.

    CAS  PubMed  Google Scholar 

  180. Cottingham C, Ferryman CJ, Wang Q. Chapter nine—α2 adrenergic receptor trafficking as a therapeutic target in antidepressant drug action. In: Wu G, editor. Progress in molecular biology and translational science, vol. 132. Academic Press: New York; 2015. p. 207−25.

  181. Bading H. Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations. J Exp Med. 2017;214:569–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Massie A, Boillee S, Hewett S, Knackstedt L, Lewerenz J. Main path and byways: non-vesicular glutamate release by system x(c)(−) as an important modifier of glutamatergic neurotransmission. J Neurochem. 2015;135:1062–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Williams LE, Featherstone DE. Regulation of hippocampal synaptic strength by glial xCT. J Neurosci. 2014;34:16093–102.

    PubMed  Google Scholar 

  184. Mosienko V, Teschemacher AG, Kasparov S. Is L-lactate a novel signaling molecule in the brain? J Cereb Blood Flow Metab. 2015;35:1069–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Bergersen LH, Gjedde A. Is lactate a volume transmitter of metabolic states of the brain? Front Neuroenergetics. 2012;4:5.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Lauritzen KH, Morland C, Puchades M, Holm-Hansen S, Hagelin EM, Lauritzen F, et al. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb Cortex. 2014;24:2784–95.

    PubMed  Google Scholar 

  187. Bozzo L, Puyal J, Chatton JY. Lactate modulates the activity of primary cortical neurons through a receptor-mediated pathway. PLoS ONE. 2013;8:e71721.

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Sala N, Suys T, Zerlauth JB, Bouzat P, Messerer M, Bloch J, et al. Cerebral extracellular lactate increase is predominantly nonischemic in patients with severe traumatic brain injury. J Cereb Blood Flow Metab. 2013;33:1815–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Carpenter KL, Jalloh I, Hutchinson PJ. Glycolysis and the significance of lactate in traumatic brain injury. Front Neurosci. 2015;9:112.

    PubMed  PubMed Central  Google Scholar 

  190. Ichai C, Payen JF, Orban JC, Quintard H, Roth H, Legrand R, et al. Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial. Intensive Care Med. 2013;39:1413–22.

    CAS  PubMed  Google Scholar 

  191. Lin AP, Ramadan S, Stern RA, Box HC, Nowinski CJ, Ross BD, et al. Changes in the neurochemistry of athletes with repetitive brain trauma: preliminary results using localized correlated spectroscopy. Alzheimer’s Res Ther. 2015;7:13.

    Google Scholar 

  192. Kierans AS, Kirov II, Gonen O, Haemer G, Nisenbaum E, Babb JS, et al. Myoinositol and glutamate complex neurometabolite abnormality after mild traumatic brain injury. Neurology. 2014;82:521–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Gasparovic C, Yeo R, Mannell M, Ling J, Elgie R, Phillips J, et al. Neurometabolite concentrations in gray and white matter in mild traumatic brain injury: an 1H-magnetic resonance spectroscopy study. J Neurotrauma. 2009;26:1635–43.

    PubMed  PubMed Central  Google Scholar 

  194. Yeo RA, Gasparovic C, Merideth F, Ruhl D, Doezema D, Mayer AR. A longitudinal proton magnetic resonance spectroscopy study of mild traumatic brain injury. J Neurotrauma. 2011;28:1–11.

    PubMed  PubMed Central  Google Scholar 

  195. Kawai N, Maeda Y, Kudomi N, Yamamoto Y, Nishiyama Y, Tamiya T. Focal neuronal damage in patients with neuropsychological impairment after diffuse traumatic brain injury: evaluation using (1)(1)C-flumazenil positron emission tomography with statistical image analysis. J Neurotrauma. 2010;27:2131–8.

    PubMed  Google Scholar 

  196. Kraus MF, Smith GS, Butters M, Donnell AJ, Dixon E, Yilong C, et al. Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET). Brain Inj. 2005;19:471–9.

    CAS  PubMed  Google Scholar 

  197. Green RE. Editorial: brain injury as a neurodegenerative disorder. Front Hum Neurosci. 2015;9:615.

    PubMed  Google Scholar 

  198. Hellewell S, Semple BD, Morganti-Kossmann MC. Therapies negating neuroinflammation after brain trauma. Brain Res. 2016;1640(Pt A):36–56.

    CAS  PubMed  Google Scholar 

  199. Schurman LD, Lichtman AH. Endocannabinoids: a promising impact for traumatic brain injury. Front Pharmacol. 2017;8:69.

    PubMed  PubMed Central  Google Scholar 

  200. McGinn MJ, Povlishock JT. Cellular and molecular mechanisms of injury and spontaneous recovery. Handb Clin Neurol. 2015;127:67–87.

    PubMed  Google Scholar 

  201. Lu J, Gary KW, Copolillo A, Ward J, Niemeier JP, Lapane KL. Randomized controlled trials in adult traumatic brain injury: a review of compliance to CONSORT statement. Arch Phys Med Rehabil. 2015;96:702–14.

    PubMed  Google Scholar 

  202. Maas AI, Menon DK, Lingsma HF, Pineda JA, Sandel ME, Manley GT. Re-orientation of clinical research in traumatic brain injury: report of an international workshop on comparative effectiveness research. J Neurotrauma. 2012;29:32–46.

    PubMed  PubMed Central  Google Scholar 

  203. Tosetti P, Hicks RR, Theriault E, Phillips A, Koroshetz W, Draghia-Akli R, et al. Toward an international initiative for traumatic brain injury research. J Neurotrauma. 2013;30:1211–22.

    PubMed  PubMed Central  Google Scholar 

  204. Manley GT, Maas AI. Traumatic brain injury: an international knowledge-based approach. JAMA: J Am Med Assoc. 2013;310:473–4.

    CAS  Google Scholar 

  205. Yue JK, Vassar MJ, Lingsma HF, Cooper SR, Okonkwo DO, Valadka AB, et al. Transforming research and clinical knowledge in traumatic brain injury pilot: multicenter implementation of the common data elements for traumatic brain injury. J Neurotrauma. 2013;30:1831–44.

    PubMed  PubMed Central  Google Scholar 

  206. Maas AI, Menon DK, Steyerberg EW, Citerio G, Lecky F, Manley GT, et al. Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI): a prospective longitudinal observational study. Neurosurgery. 2015;76:67–80.

    PubMed  Google Scholar 

  207. Sorani MD, Yue JK, Sharma S, Manley GT, Ferguson AR, Investigators TT, et al. Genetic data sharing and privacy. Neuroinformatics. 2015;13:1–6.

    PubMed  PubMed Central  Google Scholar 

  208. FITBIR. Federal Interagency Traumatic Brain Injury Research Informatics System. https://fitbir.nih.gov/.

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Acknowledgements

The authors would like to thank Martin Ngwenya for assistance with preparation of the figures.

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Authors and Affiliations

  1. Department of Neurosurgery, University of Cincinnati, Cincinnati, OH, USA

    Jennifer L. McGuire & Laura B. Ngwenya

  2. Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, OH, USA

    Laura B. Ngwenya

  3. Neurotrauma Center, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH, 45219, USA

    Laura B. Ngwenya

  4. Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, OH, USA

    Robert E. McCullumsmith

  5. Department of Psychiatry, Cincinnati Veterans Administration Medical Center, Cincinnati, OH, USA

    Robert E. McCullumsmith

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McGuire, J.L., Ngwenya, L.B. & McCullumsmith, R.E. Neurotransmitter changes after traumatic brain injury: an update for new treatment strategies. Mol Psychiatry 24, 995–1012 (2019). https://doi.org/10.1038/s41380-018-0239-6

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