Exercise to Enhance Neurocognitive Function After Traumatic Brain Injury

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<ul><li><p>Theme Issue: Exercise and Sports</p><p>ti</p><p>mamanh hain hole wcise</p><p>r brase aftcts on</p><p>08-913</p><p>d longact on</p><p>basicrotro-</p><p>eiotro-</p><p>umaticies arere, we</p><p>ize thes mostic andtential</p><p>rved inrentialentate</p><p>xerciseain of</p><p>e beenopula-e will</p><p>perfor-</p><p>D.F. Department of Physical Medicine andRehabilitation, Spaulding Rehabilitation Hos-pital, Harvard Medical SchoolDisclosure: nothing to disclose</p><p>R.Z. Department of Physical Medicine andRehabilitation, Spaulding Rehabilitation Hos-pital, Massachusetts General Hospital, Har-vard Medical School. Address correspondenceto: D.F., 125 Nashua St, Boston, MA 02114;e-mail: rzafonte@partners.org.Disclosures related to this publication: grant(paid to institution), Department of Defense.</p><p>utside this publication: boardtipend), PM&amp;R; board member-ment) ACRM, Journal of Neu-roeng and Rehabil; expert testi-artment of Justice; grants/grantsto institution) NIH, DOD, NIDRR;s Brain Injury Medicine</p><p>dicine and Rehabilitationol. 4, 908-913, November 2012</p><p>org/10.1016/j.pmrj.2012.09.028MECHANISTIC EFFECTS OF EXERCISE ON THE BRAIN ANDNEUROCOGNITIVE FUNCTION</p><p>The relationship between exercise and brain neurophysiology has been studied in animalmodels, and a number of mechanisms have been proposed. Churchill et al [4] presentedevidence that persons with better cardiovascular fitness have increased cerebral blood flow,</p><p>Disclosures omembership (sship (no payrotrauma, Neumony, US Deppending (paidroyalties, demo</p><p>PM&amp;R 2012 by the American Academy of Physical Me1934-1482/12/$36.00 V</p><p>Printed in U.S.A. http://dx.doi.908Exercise to Enhance Neurocognitive FuncTraumatic Brain InjuryDavid Fogelman, MD, Ross Zafonte, DO</p><p>Abstract: Vigorous exercise has long been associated with improved health indomains. Results of clinical observation have suggested that neurocognitive perforalso is improved by vigorous exercise. Data derived from animal modelbased researcbeen emerging that show molecular and neuroanatomic mechanisms that may explaexercise improves cognition, particularly after traumatic brain injury. This articsummarize the current state of the basic science and clinical literature regarding exeran intervention, both independently and in conjunction with other modalities, foinjury rehabilitation. A key principle is the factor of timing of the initiation of exercimild traumatic brain injury, balancing potentially favorable and detrimental efferecovery.</p><p>PM R 2012;4:9</p><p>INTRODUCTION</p><p>The benefits of exercise are thought to be ubiquitous in the short, intermediate, anterm [1]. A growing body of literature suggests that exercise has a positive impneurocognitive function. This potential positive impact of exercise is derived fromscience and from the animal translational literature that suggest upregulation of neuphins and neurogenesis within the hippocampus. Exercise also may function in a plpic manner and affect a broad array of cellular signaling systems.</p><p>The role of exercise as a clinical intervention for severe, moderate, and mild trabrain injury (mTBI) has been enticing but not conclusively proven. Many of the studsmall, and the populations are ill defined. However, it appears likely that, in the futuwill be able to define subpopulations that may benefit most from exercise, optimtiming of an exercise intervention, and understand the dosing of exercise that ibeneficial. In addition, exercise as an adjuvant therapy to various pharmacolognonpharmacologic treatments of TBI will be explored as a means to enhance the poefficacy of such therapies.</p><p>The specificity of the link between exercise and executive function has been obseanimal models. Rodent and nonhuman primate models have demonstrated prefeimprovements in neural plasticity and cellular regeneration in the hippocampal dgyrus via various molecular and neurochemical mechanisms as a result of vigorous eafter brain injury, which may lead to improved cognition, particularly in the domtemporospatial memory and performance. The cognitive benefits of exercise havdemonstrated clinically among elderly persons and within the neurodegenerative ption, and clinical trials among persons with TBI are under way [2,3]. In this review, wsummarize current knowledge regarding the impact of exercise on neurocognitivemance after TBI and will include both animal and human data.on After</p><p>nycevewillasiner</p></li><li><p>articuto immany. Evites anesis in]. Theodelsate [6</p><p>ithoutementnitive,is the</p><p>ng. AsatomicI andiologyemon-strain,</p><p>neu-enon</p><p>in ex-lishing5,16].flow,</p><p>ial pe-bene-ic andd be ainjuryt-termeks of</p><p>Vascgg</p><p>EX</p><p>MP resMP resbind</p><p>olic fa</p><p>909PM&amp;R Vol. 4, Iss. 11, 2012oxygen extraction, and glucose utilization. Exercise, plarly cardiovascular conditioning, has been positedprove cognitive measures indirectly as a result of thephysiologic responses to increased physical activitydence has emerged in animal models that demonstraincrease in both neural plasticity and focal neurogenthe hippocampus as a response to voluntary exercise [5vast majority of this research has involved rodent mwith several findings corroborated in nonhuman primand human research [7]. This work has led to an undering of the direct mechanisms by which exercise may imaspects of cognitive performance after acquired brainboth traumatic and ischemic, as well as protect againstinsults.</p><p>Cellular regeneration in the dentate gyrus of thpocampus is correlated with improved performance iporospatial memory tasks [8,9]. This regeneration appbe due to local upregulation of numerous neurotrosuch as brain-derived neurotrophic factor, synapsin-insulin-like growth factor I in the hippocampus, specthe dentate gyrus (see Figure 1). Voluntary exercise hademonstrated to upregulate proteins involved in signaduction, synaptic trafficking, and transcriptional reguExercise also has a role in upregulating receptors foratory neurotransmitters and downregulating receptinhibitory neurotransmitters. It also has been showproteins associated with glycolysis, adenosine triphosynthesis and transduction, and glutamate turnovercreased after a period of brief voluntary exercise[10-12]. A detailed discussion of the aforementioned</p><p>Brain-derived neurotrophic factor</p><p>Insulin-like growth factor-1</p><p>Fibroblast growth factor-2</p><p>cA</p><p>Ca2+ dependent protein kinase</p><p>cA</p><p>Figure 1. Metabular mechanisms is available in a prior review by Devine andZafonte [13].--</p><p>-</p><p>,]-</p><p>,</p><p>--</p><p>,</p><p>-.-rt</p><p>-s-</p><p>EXERCISE AFTER mTBI</p><p>mTBI commonly is defined as a head injury, with or wloss of consciousness, that results in a temporary decrin brain function in the domains of physical, cogand/or emotional symptoms. One hallmark of mTBIabsence of objective findings on standard neuroimagisuch, it is regarded as a metabolic rather than an aninjury [14]. In this section, we chose to use mTBconcussion as similar terms. Although the pathophysof mTBI is not fully understood, animal models have dstrated that biomechanical trauma results in neuralwhich leads to ionic fluxes and release of excitatoryrotransmitters into the extracellular space. This phenomresults in increased metabolism of glucose as the brapends increased energy in neural healing and reestabnormal intra- and extracellular ionic concentrations [1Coupled with a concomitant decrease in cerebral bloodthe result is an energy mismatch.</p><p>DETRIMENTAL EFFECT OF EXERCISE ONRECOVERY FROM mTBI</p><p>Conventional wisdom has long suggested that an initriod of rest after mTBI in a broad population range isficial. The duration of this rest period and its metabolsocial consequences are as yet unclear. Exercise coulpotent therapy when timed correctly after the acuteperiod. Pereira et al [17] demonstrated improved shormemory in uninjured young adults undergoing 12 we</p><p>ular endothelial rowth factor</p><p>Synapsin-1</p><p>Hippocampal Neurogenesis</p><p>Collagen IVERCISE</p><p>ponse element</p><p>Inhibition of TNF-alpha</p><p>ponse element ing protein</p><p>ctors associated with exercise.standprove</p><p>injuryfuture</p><p>e hipn temears tophins1, andificallys beenl translationexcit</p><p>ors fon thasphateare inin ratmolecaerobic exercise and showed a relationship with cerebralblood flow change in the hippocampus. The role of exercise</p></li><li><p>pic oeline</p><p>n [18]t queslianceas welon byelativee dataivity ignitiveility aavoidvoguehe resed by</p><p>al care</p><p>sympionerssymp</p><p>st earlyctivityin the</p><p>ometaer, noctivityter theg-termcerbaenergyise hams in</p><p>severa</p><p>ts, andto berthermany</p><p>d usedand/opileddetri</p><p>as deks thaequirein perighes</p><p>ailabilration</p><p>ter theh et albrain-in thereasedhis in-</p><p>TBI</p><p>as wellented</p><p>umingced incur inerfor-ay be</p><p>s beenaps inever, ay as a</p><p>ontacthoughtrendat thet wellobser-vity inl out-ropsy-study</p><p>neuro-s pre-</p><p>d at ataineded ac-rdinal</p><p>ol andg per-s aftermod-</p><p>sicallying theall theignifi-e wasearly,</p><p>school</p><p>ts after</p><p>910 Fogelman and Zafonte EXERCISE, NEUROCOGNITIVE FUNCTION, AND TBIafter brain injury in humans continues to be a towidespread investigation. In particular, exercise guidafter mTBI recently have been a major topic of discussioSimilar to other medical interventions, the paramountions to be answered involve safety, efficacy, and comp</p><p>The functional definition of what constitutes rest,as its prescribed duration, is by no means agreed upconsensus. Some practitioners prescribe a period of rrest, whereas others recommend bed rest; however, thto support bed rest are, at best, minimal. Physical inactrecommended, at least initially, by most providers. Corest, including accommodations for reduced responsibschool or work, minimal or no computer usage, andance of exposure to loud noise, also is very much inyet few data support these recommendations [19]. Tperiod also is vaguely defined and frequently is guidduration of symptoms. As a result, this area of clinicdeserves further investigation.</p><p>Clinically, exercise may reproduce or exacerbatetoms and thus is treated with caution by many practitThe potential of exercise to reproduce or exacerbatetoms may be the rationale for recommendations againexercise after mTBI [20]. This period of rest and/or aavoidance is based on theoretical risks that underppathophysiology of acute mTBI and concern that neurbolically taxing activity may hinder healing. Howevclear linkage has been made between mild cognitive a(such as reading or watching a television program) afacute injury period and enhanced metabolic or lonbrain dysfunction. It is unlikely that this symptom exation is exclusively due to incomplete recovery andmismatch in the central nervous system because exercbeen shown to bring about postconcussion symptopatients who are removed from their injury formonths and even years [21].</p><p>A very wide variability in symptom duration exismany postconcussive symptoms have been shownpresent in persons with no history of mTBI [22]. Fumore, symptom burden appears to be influenced byfactors outside of the injury itself, including the methoto ascertain symptoms, motivation, and personalitypsychiatric factors. As more and more evidence is comit may be determined that prolonged rest is far moremental than once believed after mTBI.</p><p>Functional magnetic resonance imaging studies,scribed by Jantzen [23], have demonstrated that tasinvolve working memory tasks of moderate difficulty rrecruitment of additional neural resources to maintaformance during recovery from mTBI. For tasks of hdifficulty, there may be a lack of metabolic resource avity to maintain performance [23]. Yet the timing and du</p><p>of this metabolic mismatch are not clear, especially as theyrelate to the chronic setting.fs.-.l</p><p>s</p><p>t-,t</p><p>-.-</p><p>-</p><p>-</p><p>s</p><p>l</p><p>-</p><p>r,-</p><p>-t</p><p>-t-</p><p>Animal models suggest that exercise very early afinitial injury has a negative impact on TBI. Griesbac[24,25] found that neurotrophins in the brain (ie,derived neurotrophic factor and synapsin I) increasedhippocampus of experimental rats after TBI with incexercise beginning 1-2 weeks after injury but that tcrease was attenuated by early activation.</p><p>POSITIVE EFFECTS OF EXERCISE AFTER m</p><p>The benefits of exercise that pertain to overall health,as neurologic function, have been exhaustively documfor a broad variety of diagnoses. The importance of resexercise as soon as possible may even be more pronounthe setting of mTBI. A substantial number of mTBIs ocyounger people, many of whom are athletes whose pmance in their sport of choice, as well as their mood, mcompromised by prolonged rest [26,27]. Exercise hademonstrated to have an antidepressant effect, perhpart related to its impact on neurogenesis [28]. Howrecent randomized trial failed to demonstrate efficactreatment in depressed adults [29].</p><p>Prolonged caution in returning to strenuous noncactivity is not necessarily supported by evidence. Altseveral of the studies have methodologic issues, aregarding the results is observed. It also is of note thextent and type of vigorous activity after mTBI is nospecified or could not be controlled in several of thesevations. McCrea et al [30] demonstrated that early acticollege-aged athletes did not negatively affect clinicacomes with respect to symptomatology, formal neuchological testing, and balance. A recent retrospectiveby Moser et al [31] noted significant improvement oncognitive testing and symptom scores when rest wascribed.</p><p>A retrospective study by Majerske et al [32] lookecohort of teenaged student athletes after mTBIs susduring sports participation. The students were stratificording to their activity level after injury on a 0-4 oscale; 0 is no activity and 4 is participation in schoparticipation in a game, with neurocognitive testinformed at follow-up in a concussion clinic up to 33 dayinjury. The study found that students who returned toerate levels of exertion during the first month, both phyand cognitively (participation in school as well as mowlawn and/or light jogging) had the best outcomes ofgroups. Impaired performance that was statistically scant in the domains of visual memory and reaction timobserved among students who returned to their sportas well as among students who took time away fromand did not engage in physical exercise at all [32].</p><p>A study by de Kruijk et al [33] observed 107 patien</p><p>mTBI and found that 6 days of bed rest after injury conferredno benefit in any of the 16 symptoms that were tracked at 3-</p></li><li><p>mTBI</p><p>TBI</p><p>sculo-f mod-, maykeletalplica-</p><p>hysicallogy ofthmia,nce ofed thatercise.ardiacdverseI whot, and</p><p>nths to</p><p>oup oform oftion in</p><p>after</p><p>k; groontrol 45udiotaraining</p><p>higherres at</p><p>nofound</p><p>telyntion</p><p>k intek, execale;bove</p><p>rbal</p><p>ded rubmacreasntil as</p><p>ussivepants</p><p>admillreadmt ST, trk</p><p>ance,in all</p><p>,n did</p><p>T sym</p><p>911PM&amp;R Vol. 4, Iss. 11, 2012and 6-month follow-up. At 2 weeks after injury, onlyness was improved by bed rest, and this benefit disapby 3 months.</p><p>When mTBI symptoms are long-standing, definedsisting for more than 6 weeks, exercise can be benefireducing symptom burden. A prospective study by Leal [34] included 6 athletes and 6 nonathletes, all ofunderwent graded treadmill exercise until the point oftom exacerbation was determined individually and ecally. Each patient experienced improvement in hissymptoms, which was both statistically and clinicallyicant, and no adverse events were reported. Similarly, aby Gagnon et al [35] included 16 children an...</p></li></ul>


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