Critical Review Physical Exercise and Cognitive Recovery in Acquired Brain Injury: A Review of the Literature Jennifer M. Devine, MD, Ross D. Zafonte, DO Objective: Physical exercise has been shown to play an ever-broadening role in the maintenance of overall health and has been implicated in the preservation of cognitive function in both healthy elderly and demented populations. Animal and human studies of acquired brain injury (ABI) from trauma or vascular causes also suggest a possible role for physical exercise in enhancing cognitive recovery. Data Sources: A review of the literature was conducted to explore the current under- standing of how physical exercise impacts the molecular, functional, and neuroanatomic status of both intact and brain-injured animals and humans. Study Selection: Searches of the MEDLINE, CINHAL, and PsychInfo databases yielded an extensive collection of animal studies of physical exercise in ABI. Animal studies strongly tie physical exercise to the upregulation of multiple neural growth factor pathways in brain-injured animals, resulting in both hippocampal neurogenesis and functional improvements in memory. Data Extraction: A search of the same databases for publications involving physical exercise in human subjects with ABI yielded 24 prospective and retrospective studies. Data Synthesis: Four of these evaluated cognitive outcomes in persons with ABI who were involved in physical exercise. Three studies cited a positive association between exercise and improvements in cognitive function, whereas one observed no effect. Human exercise interventions varied greatly in duration, intensity, and level of subject supervision, and tools for assessing neurocognitive changes were inconsistent. Conclusions: There is strong evidence in animal ABI models that physical exercise facilitates neurocognitive recovery. Physical exercise interventions are safe in the subacute and rehabilita- tive phases of recovery for humans with ABI. In light of strong evidence of positive effects in animal studies, more controlled, prospective human interventions are warranted to better explore the neurocognitive effects of physical exercise on persons with ABI. INTRODUCTION The role of exercise in the maintenance of cardiovascular health has been well established. Epidemiological studies suggest that individuals who expend energy greater than 2000 kCal per week in some form of moderate-to-intense exercise significantly lower their risk of mortality from all causes [1] and decrease their cardiovascular morbidity when compared with those who exercise less intensely or frequently [2]. Further benefits of exercise include improvements in cardiovascular control [2], glycemic control [3], weight management [4], bone density [5], depression [6], and breast and colon cancer [7]. In light of this evidence, the American College of Sports Medicine and the American Heart Association currently recommend that all adults aged 18 to 65 years participate in 30 minutes of moderate-intense aerobic (endurance) physical activity per day at least 5 days per week [8]. Adding to the body of evidence showing its many established health benefits are findings that regular exercise may also have a positive impact on memory and cognition thus, investigational interest into the specific effects of exercise on cognitive function is growing. Numerous population-based studies suggest a decreased incidence of cognitive decline in individuals who participate in physically and cognitively stimulating activities later in life [9-13]. Friedland et al [13] further demonstrated that a decreased risk of cognitive delay is seen in elders who participated in cardiovascular conditioning throughout midlife. Finally, in an effort to further explore potential dose-dependency for this benefit, Larson et al [14] showed a decreased J.M.D. Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hos- pital, Harvard Medical School, Boston, MA Disclosure: nothing to disclose R.D.Z. Department of Physical Medicine & Re- habilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, 125 Nashua St, Bos- ton, MA 02214. Address correspondence to: R.D.Z. e-mail: rzafonte@partners.org Disclosure: 2A, BHR and Allergan 7A, Neuro- healing - Drug Phase II Study Cosponsored by FDA, Funded by Orphan Drug 8B, NIH, NIDRR, DOD-Supported Research Disclosure Key can be found on the Table of Contents and at www.pmrjournal.org Submitted for publication October 1, 2008 accepted March 29, 2009. PM&R �� 2009 by the American Academy of Physical Medicine and Rehabilitation 1934-1482/09/$36.00 Vol. 1, 560-575, June 2009 Printed in U.S.A. DOI: 10.1016/j.pmrj.2009.03.015 560

relative risk of dementia in elders who exercise more than 3 days per week. Most recent, Burns et al [15] showed that individuals with early stage Alzheimer dementia who had better cardiovas- cular fitness experienced less cortical loss than their less-fit counterparts. Although many investigators have focused their attention on older populations at risk for dementia, some evi- dence suggests that the connection between aerobic condition- ing and cognitive function may not be restricted to the elderly. A population-based study by Van Boxtel et al [16] showed a positive association between age- and gender-adjusted maxi- mum oxygen consumption (VO2max) �� levels and performance on tests of complex cognitive speed in a broad range of ages. Further evidence taken from the British 1946 birth cohort shows a positive impact of physical exercise on memory in mid-life [17]. Although the majority of the literature appears to focus on endurance training, resistance exercise also may have the potential to improve free recall and recognition [18]. To- gether, these findings have spurred questions about the exact role and mechanism of exercise as a prophylaxis against cogni- tive decline. There is broad speculation as to the possible mechanism by which exercise might impact cognition. Churchill et al [19] presented specific evidence showing that improved aerobic fit- ness increased cerebral blood flow, oxygen extraction, and glu- cose utilization. Other investigators have proposed that the apparent cognitive benefits of physical exercise were likely the byproduct of other physiologic responses to exercise [20-23]. However, early work by Cotman and Berchtold [24] also showed that exercise improved neural plasticity, suggesting that cardiovascular conditioning itself may improve cognition by way of specific changes to the neurochemical microenviron- ment that may ultimately lead to neurogenesis. Focal neurogenesis in the adult brain, the pursuit of modulatory factors that encourage it, and the question of whether new cells confer function are all areas of active investigation in the neuroscientific community. Histopatho- logic evidence in animals [25,26] and humans [27] docu- ments neurogenesis in the adult hippocampus, a region of the brain involved in spatial and temporal memory. In animals, several studies have shown that proliferative activity in this area is enhanced by voluntary exercise, and that this phe- nomenon correlates directly with improved performances on temporospatial memory tasks [28-30].Given these findings, there is understandable question and interest into whether the human brain holds similar capacity for focal neurogenesis and whether physical exercise may confer similar neurocog- nitive benefits to humans. In humans with brain injury caused by trauma or cerebro- vascular events, memory and cognitive impairments can limit function. Given the strong need for new therapies to address these deficits, there is understandable interest in the possible role that physical exercise may play in cognitive recovery. However, people with acquired brain injury (ABI) can also show a decreased capacity for exercise because of the periph- eral and central sequelae of their injuries. Spasticity, paresis, and peripheral sensory and central balance disturbances can raise concerns about the ability of persons with ABI to safely and effectively exercise at the same intensity as recom- mended for the general population. Recent studies of con- temporary stroke rehabilitation programs, for example, find that traditional inpatient stroke therapy is not sufficiently intense to induce a cardiovascular training effect [31]. Add- ing to the physical impediments to exercise, external barriers to participation and safety concerns can further decrease access to and compliance with cardiovascular conditioning regimens in people with brain injuries [32]. A recent Cochrane review of cardiorespiratory training in people with traumatic brain injury (TBI) concluded that aerobic conditioning is a safe intervention when applied in the rehabil- itation phase of moderate-to-severe ABI [33]. However, because only a subset of these investigators followed markers of exercise efficacy, such as peak VO2, �� authors could not fully characterize the physiologic benefit of the exercise intervention. In addition, although several of the studies included in the analysis found a positive effect of exercise on mood and social integration, none conducted a rigorous assessment of the possible role of aerobic conditioning on cognitive function. Meta-analyses of cardiovas- cular conditioning for stroke sufferers also support the safety of such interventions and suggest other benefits on mood and the ability to perform activities of daily living [34]. Nonetheless, direct evidence of the role of controlled physical exercise specif- ically on cognitive function in ABI is not well represented in the literature. Along with concerns about overall musculoskeletal safety and efficacy of physical exercise come questions about the metabolic demands it may make on damaged areas of the brain. Specifically, there is legitimate concern that the in- creased overall oxidative stress of exercise might attenuate recovery from the neurometabolic cascade of TBI. Current understanding of the pathophysiology of brain injury sug- gests that biomechanical trauma to the brain causes the indiscriminate release of excitatory neurotransmitters, which in turn acutely increases glucose metabolism and decreases cerebral blood flow, creating an energy mismatch. Although it is during this period, hours to days after injury, when the brain is thought to be least able to respond to secondary insults, there is also evidence that decreased cerebral blood flow, decreased glycolysis, mitochondrial dysfunction, and intracellular calcium accumulation may persist for weeks, rendering the recovering brain persistently more sensitive to the metabolic demands, such as those made by physical exercise [35-37]. Clinical evidence to support this has been reported in athletes with postconcussive syndromes, in which the increased oxidative stress of aggressive physical exercise in the days after injury was shown to worsen neuro- cognitive outcomes [38]. Additional studies in animal mod- els of TBI suggest that hippocampal plasticity-related protein expression is curtailed in animals exercised acutely after the induction of injury, and that this change corresponds to poorer performance on functional memory tasks [39,40]. Thus, there is legitimate reason for concern about the overall safety of physical exercise for people in recovery from ABI. The goals of this review are 3-fold. First, it will introduce the reader to the current literature on how physical exercise 561 PM&R Vol. 1, Iss. 6, 2009

can impact the molecular, functional, and neuroanatomic status of intact animals and those with ABI from a variety of causes. This will include a discussion of the molecular mech- anisms by which physical exercise is thought to impact cellular regeneration in the adult brain and the possible pathways by which this process can affect cognitive function. Animal models of ABI are useful and relevant to the study of human ABI rehabilitation because they provide investigators the opportunity to obtain information, specimens, and data that are largely unobtainable from humans with brain injury. Specifically, animal studies can be carefully controlled and data can be gathered as a function of time after the induction of the brain injury itself. Animal models for ABI also allow investigators to simultaneously consider the molecular, ana- tomic, and functional sequelae of brain injuries without other potentially confounding comorbidities, such as concomitant disease or pharmacologic interference. Although not directly analogous to human disease, the findings obtained under these carefully controlled conditions can provide valuable information as well as suggest possible future paths of inquiry and intervention in the treatment of humans. A discussion of this literature is especially vital for the clinically oriented reader, as it provides the necessary background to appreciate the rationale for physical exercise studies in humans with ABI. The second goal of this article is to review the available literature showing the impact of physical exercise on persons with ABI. Because this literature is limited, a discussion of all existing studies involving physical exercise interventions in people with brain injury, as well as retrospective surveys of the exercise habits of brain-injured individuals as they relate to cognitive function, will come first. This review will further present the subset of these exercise studies in which mea- sures of cognitive function were made and discuss the find- ings of these measures, with special attention to the metrics used to assess cognitive function. Finally, the implications of these data for future therapeutic interventions in people with ABI will be summarized and discussed. METHODS For the purpose of this review, exercise is defined as physical movement designed to improve cardiovascular conditioning or global musculoskeletal strength. Other forms of exercise, such as cognitive exercises, physical and occupational ther- apy, skill- or task-specific exercises or therapy, meditation, stretching, and relaxation are not discussed, unless they were compared directly with interventions in which physical ex- ercise was used. Papers discussed in this article were obtained through searches of MEDLINE, Cochrane, CINAHL, and PsychINFO databases. For all searches, articles included were published between 1965 and 2008 in English. For the results section on animal studies, the search was limited to animal studies the results section on human studies was limited to studies of human subjects. After limiting the search to animal studies, literature reviewed in the results section on animal studies was collected using the most effective search terms, which included [brain injury, TBI, cerebrovascular accident (CVA), stroke, focal cerebral ischemia, global isch- emia] and [exercise, running wheel, memory, hippocampus]. All studies in which physical exercise interventions were given to animals with ABI are included in this discussion. To provide readers the most current understanding of the mo- lecular, anatomic, and behavioral sequelae of ABI, additional studies of brain-injured animals were also included if these studies were thought to provide novel or relevant informa- tion to this discussion. Human studies were obtained using the following terms: [brain injury, brain damage, CVA, stroke] and [exercise, aerobic, fitness, physical activity] and [cognition, cognitive function, memory], which were identi- fied as the most effective search terms. Although searches were not restricted to original research, review articles were not included per se in the evaluation. Rather, studies refer- enced in all review articles were checked for relevance and included in the discussion if appropriate. Because the data- base of human studies of physical exercise and cognition was not extensive, all studies involving physical exercise inter- ventions in humans with ABI are presented in this review. Those studies that measured cognitive outcomes specifically in this population are discussed individually. Reference lists of all included studies were mined for previously unidenti- fied relevant studies. RESULTS Animal Studies The neuroscientific community has long pursued rodent mod- els as a means of understanding the cellular and anatomic physiology of the brain, both in its native state and under changing environmental conditions. Rodent studies were among the first to demonstrate a capacity for neurogenesis in specific areas of the adult brain [41], prompting similar discov- eries in nonhuman primates [42] and humans [27]. These findings raised immediate questions about the factors responsi- ble for stimulating neurogenesis and the functional role new cells might play in the adult brain. Subsequent work with rodents showed that environmental enrichment���a multifacto- rial stimulus that includes physical activity, a larger, more varied living space, and social interactions with other rodents���helped to stimulate neurogenesis specifically in the adult hippocampus [43]. Van Praag et al [25] further analyzed the components of environmental enrichment and found that voluntary exercise alone was more effective in stimulating hippocampal neurogen- esis than were all other factors of environmental enrichment. Further studies suggested this neurogenesis was associated with the upregulation of brain-derived neurotrophic factor (BDNF), a ubiquitous central nervous system (CNS) growth factor, in the dentate gyrus region of the rodent hippocampus and that this phenomenon was linked to improved performance on tempo- rospatial memory tasks [28,30]. The link between cellular re- generation and improved function generated significant interest in the signaling pathways by which exercise stimulates cell growth in the hippocampus and in the potential capacity for new neurons to function in the setting of traumatic cell loss. This 562 Devine and Zafonte PHYSICAL EXERCISE AND COGNITIVE RECOVERY IN ACQUIRED BRAIN INJURY