exercise to enhance neurocognitive function after traumatic brain injury

6
Theme Issue: Exercise and Sports Exercise to Enhance Neurocognitive Function After Traumatic Brain Injury David Fogelman, MD, Ross Zafonte, DO Abstract: Vigorous exercise has long been associated with improved health in many domains. Results of clinical observation have suggested that neurocognitive performance also is improved by vigorous exercise. Data derived from animal model– based research have been emerging that show molecular and neuroanatomic mechanisms that may explain how exercise improves cognition, particularly after traumatic brain injury. This article will summarize the current state of the basic science and clinical literature regarding exercise as an intervention, both independently and in conjunction with other modalities, for brain injury rehabilitation. A key principle is the factor of timing of the initiation of exercise after mild traumatic brain injury, balancing potentially favorable and detrimental effects on recovery. PM R 2012;4:908-913 INTRODUCTION The benefits of exercise are thought to be ubiquitous in the short, intermediate, and long term [1]. A growing body of literature suggests that exercise has a positive impact on neurocognitive function. This potential positive impact of exercise is derived from basic science and from the animal translational literature that suggest upregulation of neurotro- phins and neurogenesis within the hippocampus. Exercise also may function in a pleiotro- pic manner and affect a broad array of cellular signaling systems. The role of exercise as a clinical intervention for severe, moderate, and mild traumatic brain injury (mTBI) has been enticing but not conclusively proven. Many of the studies are small, and the populations are ill defined. However, it appears likely that, in the future, we will be able to define subpopulations that may benefit most from exercise, optimize the timing of an exercise intervention, and understand the dosing of exercise that is most beneficial. In addition, exercise as an adjuvant therapy to various pharmacologic and nonpharmacologic treatments of TBI will be explored as a means to enhance the potential efficacy of such therapies. The specificity of the link between exercise and executive function has been observed in animal models. Rodent and nonhuman primate models have demonstrated preferential improvements in neural plasticity and cellular regeneration in the hippocampal dentate gyrus via various molecular and neurochemical mechanisms as a result of vigorous exercise after brain injury, which may lead to improved cognition, particularly in the domain of temporospatial memory and performance. The cognitive benefits of exercise have been demonstrated clinically among elderly persons and within the neurodegenerative popula- tion, and clinical trials among persons with TBI are under way [2,3]. In this review, we will summarize current knowledge regarding the impact of exercise on neurocognitive perfor- mance after TBI and will include both animal and human data. MECHANISTIC EFFECTS OF EXERCISE ON THE BRAIN AND NEUROCOGNITIVE FUNCTION The relationship between exercise and brain neurophysiology has been studied in animal models, and a number of mechanisms have been proposed. Churchill et al [4] presented evidence that persons with better cardiovascular fitness have increased cerebral blood flow, D.F. Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hos- pital, Harvard Medical School Disclosure: nothing to disclose R.Z. Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hos- pital, Massachusetts General Hospital, Har- vard Medical School. Address correspondence to: D.F., 125 Nashua St, Boston, MA 02114; e-mail: [email protected]. Disclosures related to this publication: grant (paid to institution), Department of Defense. Disclosures outside this publication: board membership (stipend), PM&R; board member- ship (no payment) ACRM, Journal of Neu- rotrauma, Neuroeng and Rehabil; expert testi- mony, US Department of Justice; grants/grants pending (paid to institution) NIH, DOD, NIDRR; royalties, demos – Brain Injury Medicine PM&R © 2012 by the American Academy of Physical Medicine and Rehabilitation 1934-1482/12/$36.00 Vol. 4, 908-913, November 2012 Printed in U.S.A. http://dx.doi.org/10.1016/j.pmrj.2012.09.028 908

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Page 1: Exercise to Enhance Neurocognitive Function After Traumatic Brain Injury

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Theme Issue: Exercise and Sports

Exercise to Enhance Neurocognitive Function AfteTraumatic Brain Injury

David Fogelman, MD, Ross Zafonte, DO

in manyormancerch havelain howticle willercise as

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Abstract: Vigorous exercise has long been associated with improved healthdomains. Results of clinical observation have suggested that neurocognitive perfalso is improved by vigorous exercise. Data derived from animal model–based reseabeen emerging that show molecular and neuroanatomic mechanisms that may expexercise improves cognition, particularly after traumatic brain injury. This arsummarize the current state of the basic science and clinical literature regarding exan intervention, both independently and in conjunction with other modalities,injury rehabilitation. A key principle is the factor of timing of the initiation of exermild traumatic brain injury, balancing potentially favorable and detrimental erecovery.

PM R 2012;4

INTRODUCTION

The benefits of exercise are thought to be ubiquitous in the short, intermediate,term [1]. A growing body of literature suggests that exercise has a positive imneurocognitive function. This potential positive impact of exercise is derived frscience and from the animal translational literature that suggest upregulation of nphins and neurogenesis within the hippocampus. Exercise also may function in apic manner and affect a broad array of cellular signaling systems.

The role of exercise as a clinical intervention for severe, moderate, and mild tbrain injury (mTBI) has been enticing but not conclusively proven. Many of the stsmall, and the populations are ill defined. However, it appears likely that, in the fuwill be able to define subpopulations that may benefit most from exercise, optitiming of an exercise intervention, and understand the dosing of exercise thabeneficial. In addition, exercise as an adjuvant therapy to various pharmacolnonpharmacologic treatments of TBI will be explored as a means to enhance theefficacy of such therapies.

The specificity of the link between exercise and executive function has been obanimal models. Rodent and nonhuman primate models have demonstrated primprovements in neural plasticity and cellular regeneration in the hippocampagyrus via various molecular and neurochemical mechanisms as a result of vigorousafter brain injury, which may lead to improved cognition, particularly in the dtemporospatial memory and performance. The cognitive benefits of exercise hdemonstrated clinically among elderly persons and within the neurodegenerativetion, and clinical trials among persons with TBI are under way [2,3]. In this reviewsummarize current knowledge regarding the impact of exercise on neurocognitivmance after TBI and will include both animal and human data.

MECHANISTIC EFFECTS OF EXERCISE ON THE BRAIN ANDNEUROCOGNITIVE FUNCTION

The relationship between exercise and brain neurophysiology has been studied imodels, and a number of mechanisms have been proposed. Churchill et al [4] p

evidence that persons with better cardiovascular fitness have increased cerebral blood fl

PM&R © 2012 by the American Ac1934-1482/12/$36.00

Printed in U.S.A.908

tatercisen ofbeenula-will

rfor-

imalnted

D.F. Department of Physical MRehabilitation, Spaulding Rehabpital, Harvard Medical SchoolDisclosure: nothing to disclose

R.Z. Department of Physical MRehabilitation, Spaulding Rehabpital, Massachusetts General Hvard Medical School. Address corto: D.F., 125 Nashua St, Boston,e-mail: [email protected] related to this publi(paid to institution), DepartmentDisclosures outside this publicmembership (stipend), PM&R; boship (no payment) ACRM, Jourotrauma, Neuroeng and Rehabil;mony, US Department of Justice;

ow,pending (paid to institution) NIH, DOD, NIDRR;royalties, demos – Brain Injury Medicine

ademy of Physical Medicine and RehabilitationVol. 4, 908-913, November 2012

http://dx.doi.org/10.1016/j.pmrj.2012.09.028

Page 2: Exercise to Enhance Neurocognitive Function After Traumatic Brain Injury

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909PM&R Vol. 4, Iss. 11, 2012

oxygen extraction, and glucose utilization. Exerciselarly cardiovascular conditioning, has been positeprove cognitive measures indirectly as a result of tphysiologic responses to increased physical activdence has emerged in animal models that demonsincrease in both neural plasticity and focal neurogthe hippocampus as a response to voluntary exercisevast majority of this research has involved rodentwith several findings corroborated in nonhuman prand human research [7]. This work has led to an unding of the direct mechanisms by which exercise mayaspects of cognitive performance after acquired braboth traumatic and ischemic, as well as protect againinsults.

Cellular regeneration in the dentate gyrus ofpocampus is correlated with improved performancporospatial memory tasks [8,9]. This regeneration abe due to local upregulation of numerous neurosuch as brain-derived neurotrophic factor, synapsiinsulin-like growth factor I in the hippocampus, spthe dentate gyrus (see Figure 1). Voluntary exercisedemonstrated to upregulate proteins involved in signduction, synaptic trafficking, and transcriptional reExercise also has a role in upregulating receptorsatory neurotransmitters and downregulating receinhibitory neurotransmitters. It also has been shoproteins associated with glycolysis, adenosine tripsynthesis and transduction, and glutamate turnovecreased after a period of brief voluntary exercis[10-12]. A detailed discussion of the aforementioneular mechanisms is available in a prior review by De

Brain-derived neurotrophic factor

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EXERCISE AFTER mTBI

mTBI commonly is defined as a head injury, with orloss of consciousness, that results in a temporary dein brain function in the domains of physical, cand/or emotional symptoms. One hallmark of mTabsence of objective findings on standard neuroimasuch, it is regarded as a metabolic rather than an ainjury [14]. In this section, we chose to use mconcussion as similar terms. Although the pathophof mTBI is not fully understood, animal models havestrated that biomechanical trauma results in neurwhich leads to ionic fluxes and release of excitatrotransmitters into the extracellular space. This phenresults in increased metabolism of glucose as the bpends increased energy in neural healing and reestanormal intra- and extracellular ionic concentrationsCoupled with a concomitant decrease in cerebral blothe result is an energy mismatch.

DETRIMENTAL EFFECT OF EXERCISE ONRECOVERY FROM mTBI

Conventional wisdom has long suggested that an inriod of rest after mTBI in a broad population rangeficial. The duration of this rest period and its metabsocial consequences are as yet unclear. Exercise copotent therapy when timed correctly after the acuperiod. Pereira et al [17] demonstrated improved shmemory in uninjured young adults undergoing 12aerobic exercise and showed a relationship with

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Page 3: Exercise to Enhance Neurocognitive Function After Traumatic Brain Injury

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910 Fogelman and Zafonte EXERCISE, NEUROCOGNITIVE FUNCTION, AND TBI

after brain injury in humans continues to be awidespread investigation. In particular, exercise gafter mTBI recently have been a major topic of discusSimilar to other medical interventions, the paramoutions to be answered involve safety, efficacy, and com

The functional definition of what constitutes “resas its prescribed duration, is by no means agreedconsensus. Some practitioners prescribe a period orest, whereas others recommend bed rest; howeverto support bed rest are, at best, minimal. Physical inarecommended, at least initially, by most providers. Crest, including accommodations for reduced responschool or work, minimal or no computer usage, anance of exposure to loud noise, also is very much iyet few data support these recommendations [19].period also is vaguely defined and frequently is gduration of symptoms. As a result, this area of clindeserves further investigation.

Clinically, exercise may reproduce or exacerbatoms and thus is treated with caution by many pracThe potential of exercise to reproduce or exacerbatoms may be the rationale for recommendations agaexercise after mTBI [20]. This period of rest and/oavoidance is based on theoretical risks that undepathophysiology of acute mTBI and concern that nebolically taxing activity may hinder healing. Howclear linkage has been made between mild cognitiv(such as reading or watching a television program)acute injury period and enhanced metabolic or lobrain dysfunction. It is unlikely that this symptom etion is exclusively due to incomplete recovery anmismatch in the central nervous system because exebeen shown to bring about postconcussion symppatients who are removed from their injury fomonths and even years [21].

A very wide variability in symptom duration exmany postconcussive symptoms have been showpresent in persons with no history of mTBI [22].more, symptom burden appears to be influencedfactors outside of the injury itself, including the metto ascertain symptoms, motivation, and personalitpsychiatric factors. As more and more evidence is cit may be determined that prolonged rest is far momental than once believed after mTBI.

Functional magnetic resonance imaging studiescribed by Jantzen [23], have demonstrated that tinvolve working memory tasks of moderate difficultrecruitment of additional neural resources to mainformance during recovery from mTBI. For tasks odifficulty, there may be a lack of metabolic resourceity to maintain performance [23]. Yet the timing andof this metabolic mismatch are not clear, especiall

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Animal models suggest that exercise very earlyinitial injury has a negative impact on TBI. Griesb[24,25] found that neurotrophins in the brain (iderived neurotrophic factor and synapsin I) increashippocampus of experimental rats after TBI with iexercise beginning 1-2 weeks after injury but thatcrease was attenuated by early activation.

POSITIVE EFFECTS OF EXERCISE AFTER

The benefits of exercise that pertain to overall healthas neurologic function, have been exhaustively docfor a broad variety of diagnoses. The importance of rexercise as soon as possible may even be more pronothe setting of mTBI. A substantial number of mTBIsyounger people, many of whom are athletes whosmance in their sport of choice, as well as their moodcompromised by prolonged rest [26,27]. Exercisedemonstrated to have an antidepressant effect, pepart related to its impact on neurogenesis [28]. Horecent randomized trial failed to demonstrate effictreatment in depressed adults [29].

Prolonged caution in returning to strenuous noactivity is not necessarily supported by evidence. Aseveral of the studies have methodologic issues,regarding the results is observed. It also is of noteextent and type of vigorous activity after mTBI isspecified or could not be controlled in several of thevations. McCrea et al [30] demonstrated that early acollege-aged athletes did not negatively affect clincomes with respect to symptomatology, formal nchological testing, and balance. A recent retrospectiby Moser et al [31] noted significant improvement ocognitive testing and symptom scores when restscribed.

A retrospective study by Majerske et al [32] loocohort of teenaged student athletes after mTBIs sduring sports participation. The students were stracording to their activity level after injury on a 0-4scale; 0 is no activity and 4 is participation in schparticipation in a game, with neurocognitive testformed at follow-up in a concussion clinic up to 33 dinjury. The study found that students who returnederate levels of exertion during the first month, both pand cognitively (participation in school as well as molawn and/or light jogging) had the best outcomes ogroups. Impaired performance that was statisticallcant in the domains of visual memory and reactionobserved among students who returned to their spoas well as among students who took time away fromand did not engage in physical exercise at all [32].

A study by de Kruijk et al [33] observed 107 patiemTBI and found that 6 days of bed rest after injury c

no benefit in any of the 16 symptoms that were tracked at 3-
Page 4: Exercise to Enhance Neurocognitive Function After Traumatic Brain Injury

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911PM&R Vol. 4, Iss. 11, 2012

and 6-month follow-up. At 2 weeks after injury, onness was improved by bed rest, and this benefit disby 3 months.

When mTBI symptoms are long-standing, definesisting for more than 6 weeks, exercise can be benreducing symptom burden. A prospective study byal [34] included 6 athletes and 6 nonathletes, allunderwent graded treadmill exercise until the pointtom exacerbation was determined individually andcally. Each patient experienced improvement in hsymptoms, which was both statistically and clinicalicant, and no adverse events were reported. Similarlyby Gagnon et al [35] included 16 children and adwho remained symptomatic for more than 1 moinjury. This study demonstrated that a “gradual, clpervised active rehabilitation” strategy invoked a qprovement in symptom burden for all 16 participan

Although no clear guidance from randomized ctrials exists for post-mTBI resumption of activity,appear that graded resumption of activity guidedance and symptoms should be initiated in the daysately after injury. Persons with mTBI should be pfrom immediately engaging in sports and activitiesfer a high risk of reinjury. Avoidance of contact spothe patient is symptomatic and especially in the 7after initial injury, when repeated concussion is at it

Table 1. Human clinical studies of exercise intervent

Study, y Population

McMilan et al [38],2002

Single-blind RCT; 145 patientswith TBI, 3-12 mo afterinjury, who had self-reported problems withattention, as well asattention deficit onneuropsychological testing

4

Grealy et al [39],1999

RCT; 26 subjects withmoderate TBI �6 wk afterinjury, with 25 controlsubjects matched for age,severity, and time sinceinjury

4

Gagnon et al [35],2009

16 teenaged athletes withmTBI sustained duringsport, slow recovery (�1mo symptomatic)

G

Leddy et al [34],2010

12 patients with mTBI, aged13-22 years, 6 athletes and6 nonathletes, withrefractory postconcussivesymptoms at rest (�6 wk)

T

TBI � traumatic brain injury; RCT � randomized controlled trial

risk, appears reasonable. Further studies that focus on

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timing and efficacy of exercise as an intervention afare warranted (see Table 1).

EXERCISE AFTER MODERATE-TO-SEVER

In general, vigorous exercise involves 2 notable risks: mskeletal injury and sudden cardiac death. The sequelaeerate to severe TBI, such as hemiparesis and spasticpredispose this population to increased risk of muscuinjury. Sudden cardiac death is an exceedingly rare ction of exercise and is even less likely with increasedactivity in the general population. The most common esudden cardiac death during exercise is ventricular arra complication that is more likely to occur in the prcoronary artery disease. Analysis of data has demonstrsurvivors of TBI have an elevated heart rate response toAlthough this fact may theoretically increase the rate ocomplication, a recent Cochrane review showed that nevents were observed in 303 patients with chronicbegan varied exercise programs in inpatient, outpatcommunity settings in the chronic phase, defined as myears after injury [36].

As far as the efficacy of exercise programs for a broadpersons with TBI, statistically significant evidence in thprospective data that link exercise to improved cogthese diagnoses is still emerging. Retrospective data rep

ter TBI

Intervention Findings

roup 1: audiotape attentionalrol therapy, 5 � 45 min; group 2:5 min supervised exercise with

otape-based physical fitnessing; group 3: no therapy

Both intervention groups haself-reported cognitive fabaseline and experiencesignificant reduction in sereported cognitive failuresignificant differences wein cognitive function inintervention groups immeor at 12 mo after the inte

tervention; group 1: 3 � 25 min/xercise at 10-12 on the Borg; group 2: a single session ase

Group 1 showed improvedand visual learning

d rehabilitation, beginning withaximal aerobic training,asing according to symptomsasymptomatic

Improvement in balance,coordination, and postcosymptoms in 100% of part

ill test to ST, with 5-6 d/wk ofmill exercise at 80% heart rate

, treadmill test repeated every 3

Improvement in exercise toreturn to sport and/or wopatients; in the rate ofsymptomatic improvemerelated to peak exerciseathletes improved fasternonathletes

symptom threshold; HR � heart rate; mTBI � mild TBI.

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Page 5: Exercise to Enhance Neurocognitive Function After Traumatic Brain Injury

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912 Fogelman and Zafonte EXERCISE, NEUROCOGNITIVE FUNCTION, AND TBI

TBI into exercisers (those who jog, bike, or swim for 30or longer 3 or more times weekly within the 6 months binterview) and nonexercisers and made a similar dichgrouping for nondisabled individuals. Self-reportedsymptoms assessments were fewer in TBI exercisernonexercisers, and improvement in Beck Depression Ialso was noted among exercisers [37].

Clinical trials that evaluate exercise as an intervensevere and moderate TBI are needed in the subachronic periods after injury. Although adaptationsto be made in the type and intensity of exercise interthe potential for clinical improvements among thmoderate and severe TBI is substantial.

SUMMARY

Exercise has the potential to enhance recovery ofand motor function after mild, moderate, and severeclear that further studies are needed to understandcific timing of exercise intervention, subpopulationmost likely to respond, and nonpharmacologic or phlogic responses that enhance the exercise responseSpecifically, exercise may enhance neurocognitivevia neurogenesis, neurotrophin upregulation, or aized impact on health. Most compelling early studiethose with TBI have shown a beneficial effect onsymptoms and postconcussive sequelae.

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