운동의 신경생물학적 효과

운동의 신경생물학적 효과는 상당하여, 뇌구조(brain structure), 뇌기능(brain function), 인지(cognition)에 상관된 영향을 끼친다. 인간을 대상으로 한 대형 연구에서 하루 30분 정도의 지속적인 유산소 운동(aerobic exercise)는 인지 기능(cognitive function) 향상, 두뇌 유전자 발현(gene expression)의 건강한 대체, 신경가소성(neuroplasticity)과 행동 가소성(behavioral plasticity)에의 혜택을 유도한다. 장기적 효과로는 뉴런 성장(neuron growth) 증가, 신경 활동(neurological activity) 증가(예 : c-Fos 및 BDNF signaling), 스트레스 대처 향상, 행동의 인지적 통제(cognitive control of behavior) 고양, 서술 기억(declarative memory), 공간 기억(spatial memory), 작업 기억(working memory) 향상, 인지적 통제(cognitive control) 및 기억에 관한 뇌구조 및 신경경로(neural pathways) 개선이 있다. 인지에 끼치는 운동의 영향은 아동 및 대학생의 학업 성적(academic performance) 향상, 성인의 생산성(productivity) 향상, 노년의 인지기능(cognitive function) 유지, 특정 신경질환(neurological disorder) 예방 및 치료, 전반적 삶의 질(quality of life) 향상 등이 있다. 건강한 성인에게서, 유산소 운동(aerobic exercise)은 일정한 운동 이후에 인지에 순간적인 영향을 끼치며 몇 달 간 꾸준히 할 경우 지속적인 영향을 끼친다고 밝혀졌다. 런닝, 조깅, 빨리 걷기, 수영, 사이클 등 유산소 운동을 꾸준히 하는 사람들은 주의 조절(attentional control), 억제 조절(inhibitory control), 인지적 유연성(cognitive flexibility), 작업 기억의 갱신 및 수용 능력, 서술 기억, 공간 기억, 정보처리속도(information processing speed) 등 인지 기능을 측정하는 신경정신 기능 및 수행 검사(neuropsychological function and performance test)들에서 점수가 더 높다. 운동이 인지에 끼치는 순간적 영향으로는 주의력(attention), 작업기억, 인지적 유연성, 억제 조절, 문제 해결(problem solving), 의사 결정(decision making) 등 집행 기능(executive function) 대부분의 향상, 운동 후 최대 2시간 동안의 정보처리속도 상승이 있다. 긍정적 정서(positive affect)를 촉진시키고, 부정적 정서(negative affect)를 억제하며, 극심한 심리적 스트레스에 대한 생물학적 반응을 감소시킴으로써, 유산소 운동은 기분과 감정상태에 단기적 장기적 효과를 끼친다. 단기적으로 유산소 운동은 항우울제(antidepressant)이자 도취제(euphoriant)로 작용하지만, 반면 지속적인 운동은 기분과 자존감(self-esteem)을 향상시킨다. 꾸준한 유산소 운동은 다양한 중추신경계통 질환(central nervous system disorder) 관련 증상들을 개선시키고, 이러한 장애들을 위한 보조 치료(adjunct therapy)로 사용될 수 있다. 주요 우울 장애(major depressive disorder)와 주의력결핍 과잉행동장애(attention deficit hyperactivity disorder)에 대한 운동 치료 효과는 명백히 입증되었다. 미국 신경학회(American Academy of Neurology)의 경도인지장애(mild cognitive impairment) 환자를 위한 임상 실습 가이드라인(clinical practice guideline)에서는 실제 임상가들이 1주일에 2번씩 꾸준한 운동을 이 증상을 진단받은 환자들에게 권고할 것을 지시한다. 임상적 증거들에 대한 검토를 통해서도, 알츠하이머병(Alzheimer’s disease)이나 파킨슨병(Parkinson's disease)과 같은 특정 신경변성질환(neurodegenerative disorder)을 앓고 있는 환자들에게 보조치료로서 운동을 권고한다. 꾸준한 운동은 신경변성질환 발병율을 낮춘다고 알려져 있다. 임상전 증거(preclinical evidence)와 신생 임상 증거(emerging clinical evidence)들은 약물 중독(drug addiction) 치료 및 예방에 운동을 보조치료 수단으로 사용할 수 있다는 것을 보여준다. 또한 꾸준한 운동은 뇌암(brain cancer)의 보조치료 수단으로도 제안된다. 인지 기능 정동(affect) 긍정적 정서성 부정적 정서성 주의 조절 집행 기능 공간 기억 기획(planning) 문제 해결 서술 기억 억제 조절 의사결정 인지적 유연성 작업 기억 주의력 추론 Erickson KI, Hillman CH, Kramer AF (August 2015). “Physical activity, brain, and cognition”. 《Current Opinion in Behavioral Sciences》 4: 27–32. doi:10.1016/j.cobeha.2015.01.005. S2CID 54301951.  Paillard T, Rolland Y, de Souto Barreto P (July 2015). “Protective Effects of Physical Exercise in Alzheimer's Disease and Parkinson's Disease: A Narrative Review”. 《J Clin Neurol》 11 (3): 212–219. doi:10.3988/jcn.2015.11.3.212. PMC 4507374. PMID 26174783. Aerobic physical exercise (PE) activates the release of neurotrophic factors and promotes angiogenesis, thereby facilitating neurogenesis and synaptogenesis, which in turn improve memory and cognitive functions. ... Exercise limits the alteration in dopaminergic neurons in the substantia nigra and contributes to optimal functioning of the basal ganglia involved in motor commands and control by adaptive mechanisms involving dopamine and glutamate neurotransmission.  McKee AC, Daneshvar DH, Alvarez VE, Stein TD (January 2014). “The neuropathology of sport”. 《Acta Neuropathol.》 127 (1): 29–51. doi:10.1007/s00401-013-1230-6. PMC 4255282. PMID 24366527. The benefits of regular exercise, physical fitness and sports participation on cardiovascular and brain health are undeniable ... Exercise also enhances psychological health, reduces age-related loss of brain volume, improves cognition, reduces the risk of developing dementia, and impedes neurodegeneration.  Denham J, Marques FZ, O'Brien BJ, Charchar FJ (February 2014). “Exercise: putting action into our epigenome”. 《Sports Med》 44 (2): 189–209. doi:10.1007/s40279-013-0114-1. PMID 24163284. S2CID 30210091. Aerobic physical exercise produces numerous health benefits in the brain. Regular engagement in physical exercise enhances cognitive functioning, increases brain neurotrophic proteins, such as brain-derived neurotrophic factor (BDNF), and prevents cognitive diseases [76–78]. Recent findings highlight a role for aerobic exercise in modulating chromatin remodelers [21, 79–82]. ... These results were the first to demonstrate that acute and relatively short aerobic exercise modulates epigenetic modifications. The transient epigenetic modifications observed due to chronic running training have also been associated with improved learning and stress-coping strategies, epigenetic changes and increased c-Fos-positive neurons ... Nonetheless, these studies demonstrate the existence of epigenetic changes after acute and chronic exercise and show they are associated with improved cognitive function and elevated markers of neurotrophic factors and neuronal activity (BDNF and c-Fos). ... The aerobic exercise training-induced changes to miRNA profile in the brain seem to be intensity-dependent [164]. These few studies provide a basis for further exploration into potential miRNAs involved in brain and neuronal development and recovery via aerobic exercise.  Gomez-Pinilla F, Hillman C (January 2013). 〈The influence of exercise on cognitive abilities〉. 《Comprehensive Physiology》. 《Compr. Physiol.》 3. 403–428쪽. doi:10.1002/cphy.c110063. ISBN 9780470650714. PMC 3951958. PMID 23720292.  Erickson KI, Leckie RL, Weinstein AM (September 2014). “Physical activity, fitness, and gray matter volume”. 《Neurobiol. Aging》. 35 Suppl 2: S20–528. doi:10.1016/j.neurobiolaging.2014.03.034. PMC 4094356. PMID 24952993.  Guiney H, Machado L (February 2013). “Benefits of regular aerobic exercise for executive functioning in healthy populations”. 《Psychon Bull Rev》 20 (1): 73–86. doi:10.3758/s13423-012-0345-4. PMID 23229442. S2CID 24190840.  Erickson KI, Miller DL, Roecklein KA (2012). “The aging hippocampus: interactions between exercise, depression, and BDNF”. 《Neuroscientist》 18 (1): 82–97. doi:10.1177/1073858410397054. PMC 3575139. PMID 21531985.  Buckley J, Cohen JD, Kramer AF, McAuley E, Mullen SP (2014). “Cognitive control in the self-regulation of physical activity and sedentary behavior”. 《Front Hum Neurosci》 8: 747. doi:10.3389/fnhum.2014.00747. PMC 4179677. PMID 25324754.  Cox EP, O'Dwyer N, Cook R, Vetter M, Cheng HL, Rooney K, O'Connor H (August 2016). “Relationship between physical activity and cognitive function in apparently healthy young to middle-aged adults: A systematic review”. 《J. Sci. Med. Sport》 19 (8): 616–628. doi:10.1016/j.jsams.2015.09.003. PMID 26552574. A range of validated platforms assessed CF across three domains: executive function (12 studies), memory (four studies) and processing speed (seven studies). ... In studies of executive function, five found a significant ES in favour of higher PA, ranging from small to large. Although three of four studies in the memory domain reported a significant benefit of higher PA, there was only one significant ES, which favoured low PA. Only one study examining processing speed had a significant ES, favouring higher PA. CONCLUSIONS: A limited body of evidence supports a positive effect of PA on CF in young to middle-aged adults. Further research into this relationship at this age stage is warranted. ... Significant positive effects of PA on cognitive function were found in 12 of the 14 included manuscripts, the relationship being most consistent for executive function, intermediate for memory and weak for processing speed.  Schuch FB, Vancampfort D, Rosenbaum S, Richards J, Ward PB, Stubbs B (July 2016). “Exercise improves physical and psychological quality of life in people with depression: A meta-analysis including the evaluation of control group response”. 《Psychiatry Res.》 241: 47–54. doi:10.1016/j.psychres.2016.04.054. PMID 27155287. S2CID 4787287. Exercise has established efficacy as an antidepressant in people with depression. ... Exercise significantly improved physical and psychological domains and overall QoL. ... The lack of improvement among control groups reinforces the role of exercise as a treatment for depression with benefits to QoL.  Pratali L, Mastorci F, Vitiello N, Sironi A, Gastaldelli A, Gemignani A (November 2014). “Motor Activity in Aging: An Integrated Approach for Better Quality of Life”. 《International Scholarly Research Notices》 2014: 257248. doi:10.1155/2014/257248. PMC 4897547. PMID 27351018. Research investigating the effects of exercise on older adults has primarily focused on brain structural and functional changes with relation to cognitive improvement. In particular, several cross-sectional and intervention studies have shown a positive association between physical activity and cognition in older persons [86] and an inverse correlation with cognitive decline and dementia [87]. Older adults enrolled in a 6-month aerobic fitness intervention increased brain volume in both gray matter (anterior cingulate cortex, supplementary motor area, posterior middle frontal gyrus, and left superior temporal lobe) and white matter (anterior third of corpus callosum) [88]. In addition, Colcombe and colleagues showed that older adults with higher cardiovascular fitness levels are better at activating attentional resources, including decreased activation of the anterior cingulated cortex. One of the possible mechanisms by which physical activity may benefit cognition is that physical activity maintains brain plasticity, increases brain volume, stimulates neurogenesis and synaptogenesis, and increases neurotrophic factors in different areas of the brain, possibly providing reserve against later cognitive decline and dementia [89, 90].  Mandolesi, Laura; Polverino, Arianna; Montuori, Simone; Foti, Francesca; Ferraioli, Giampaolo; Sorrentino, Pierpaolo; Sorrentino, Giuseppe (2018년 4월 27일). “Effects of Physical Exercise on Cognitive Functioning and Wellbeing: Biological and Psychological Benefits”. 《Frontiers in Psychology》 9: 509. doi:10.3389/fpsyg.2018.00509. PMC 5934999. PMID 29755380.  Basso JC, Suzuki WA (March 2017). “The Effects of Acute Exercise on Mood, Cognition, Neurophysiology, and Neurochemical Pathways: A Review”. 《Brain Plasticity》 2 (2): 127–152. doi:10.3233/BPL-160040. PMC 5928534. PMID 29765853. 요약문 – Can A Single Exercise Session Benefit Your Brain? (2017년 6월 12일). A large collection of research in humans has shown that a single bout of exercise alters behavior at the level of affective state and cognitive functioning in several key ways. In terms of affective state, acute exercise decreases negative affect, increases positive affect, and decreases the psychological and physiological response to acute stress [28]. These effects have been reported to persist for up to 24 hours after exercise cessation [28, 29, 53]. In terms of cognitive functioning, acute exercise primarily enhances executive functions dependent on the prefrontal cortex including attention, working memory, problem solving, cognitive flexibility, verbal fluency, decision making, and inhibitory control [9]. These positive changes have been demonstrated to occur with very low to very high exercise intensities [9], with effects lasting for up to two hours after the end of the exercise bout (Fig. 1A) [27]. Moreover, many of these neuropsychological assessments measure several aspects of behavior including both accuracy of performance and speed of processing. McMorris and Hale performed a meta-analysis examining the effects of acute exercise on both accuracy and speed of processing, revealing that speed significantly improved post-exercise, with minimal or no effect on accuracy [17]. These authors concluded that increasing task difficulty or complexity may help to augment the effect of acute exercise on accuracy. ... However, in a comprehensive meta-analysis, Chang and colleagues found that exercise intensities ranging from very light (<50% MHR) to very hard (>93% MHR) have all been reported to improve cognitive functioning [9].  Cunha GS, Ribeiro JL, Oliveira AR (June 2008). “[Levels of beta-endorphin in response to exercise and overtraining]”. 《Arq Bras Endocrinol Metabol》 (포르투갈어) 52 (4): 589–598. doi:10.1590/S0004-27302008000400004. PMID 18604371. Interestingly, some symptoms of OT are related to beta-endorphin (beta-end(1-31)) effects. Some of its effects, such as analgesia, increasing lactate tolerance, and exercise-induced euphoria, are important for training.  Boecker H, Sprenger T, Spilker ME, Henriksen G, Koppenhoefer M, Wagner KJ, Valet M, Berthele A, Tolle TR (2008). “The runner's high: opioidergic mechanisms in the human brain”. 《Cereb. Cortex》 18 (11): 2523–2531. doi:10.1093/cercor/bhn013. PMID 18296435. The runner's high describes a euphoric state resulting from long-distance running.  Josefsson T, Lindwall M, Archer T (2014). “Physical exercise intervention in depressive disorders: meta-analysis and systematic review”. 《Scand J Med Sci Sports》 24 (2): 259–272. doi:10.1111/sms.12050. PMID 23362828. S2CID 29351791.  Rosenbaum S, Tiedemann A, Sherrington C, Curtis J, Ward PB (2014). “Physical activity interventions for people with mental illness: a systematic review and meta-analysis”. 《J Clin Psychiatry》 75 (9): 964–974. doi:10.4088/JCP.13r08765. PMID 24813261. This systematic review and meta-analysis found that physical activity reduced depressive symptoms among people with a psychiatric illness. The current meta-analysis differs from previous studies, as it included participants with depressive symptoms with a variety of psychiatric diagnoses (except dysthymia and eating disorders). ... This review provides strong evidence for the antidepressant effect of physical activity; however, the optimal exercise modality, volume, and intensity remain to be determined. ... Conclusion Few interventions exist whereby patients can hope to achieve improvements in both psychiatric symptoms and physical health simultaneously without significant risks of adverse effects. Physical activity offers substantial promise for improving outcomes for people living with mental illness, and the inclusion of physical activity and exercise programs within treatment facilities is warranted given the results of this review.  Szuhany KL, Bugatti M, Otto MW (October 2014). “A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor”. 《J Psychiatr Res》 60C: 56–64. doi:10.1016/j.jpsychires.2014.10.003. PMC 4314337. PMID 25455510. Consistent evidence indicates that exercise improves cognition and mood, with preliminary evidence suggesting that brain-derived neurotrophic factor (BDNF) may mediate these effects. The aim of the current meta-analysis was to provide an estimate of the strength of the association between exercise and increased BDNF levels in humans across multiple exercise paradigms. We conducted a meta-analysis of 29 studies (N = 1111 participants) examining the effect of exercise on BDNF levels in three exercise paradigms: (1) a single session of exercise, (2) a session of exercise following a program of regular exercise, and (3) resting BDNF levels following a program of regular exercise. Moderators of this effect were also examined. Results demonstrated a moderate effect size for increases in BDNF following a single session of exercise (Hedges' g = 0.46, p < 0.001). Further, regular exercise intensified the effect of a session of exercise on BDNF levels (Hedges' g = 0.59, p = 0.02). Finally, results indicated a small effect of regular exercise on resting BDNF levels (Hedges' g = 0.27, p = 0.005). ... Effect size analysis supports the role of exercise as a strategy for enhancing BDNF activity in humans.  Lees C, Hopkins J (2013). “Effect of aerobic exercise on cognition, academic achievement, and psychosocial function in children: a systematic review of randomized control trials”. 《Prev Chronic Dis》 10: E174. doi:10.5888/pcd10.130010. PMC 3809922. PMID 24157077. This omission is relevant, given the evidence that aerobic-based physical activity generates structural changes in the brain, such as neurogenesis, angiogenesis, increased hippocampal volume, and connectivity (12,13). In children, a positive relationship between aerobic fitness, hippocampal volume, and memory has been found (12,13). ... Mental health outcomes included reduced depression and increased self-esteem, although no change was found in anxiety levels (18). ... This systematic review of the literature found that [aerobic physical activity (APA)] is positively associated with cognition, academic achievement, behavior, and psychosocial functioning outcomes. Importantly, Shephard also showed that curriculum time reassigned to APA still results in a measurable, albeit small, improvement in academic performance (24).  ... The actual aerobic-based activity does not appear to be a major factor; interventions used many different types of APA and found similar associations. In positive association studies, intensity of the aerobic activity was moderate to vigorous. The amount of time spent in APA varied significantly between studies; however, even as little as 45 minutes per week appeared to have a benefit.  Mura G, Moro MF, Patten SB, Carta MG (2014). “Exercise as an add-on strategy for the treatment of major depressive disorder: a systematic review”. 《CNS Spectr》 19 (6): 496–508. doi:10.1017/S1092852913000953. PMID 24589012. S2CID 32304140. Considered overall, the studies included in the present review showed a strong effectiveness of exercise combined with antidepressants. ... Conclusions This is the first review to have focused on exercise as an add-on strategy in the treatment of MDD. Our findings corroborate some previous observations that were based on few studies and which were difficult to generalize.41,51,73,92,93 Given the results of the present article, it seems that exercise might be an effective strategy to enhance the antidepressant effect of medication treatments. Moreover, we hypothesize that the main role of exercise on treatment-resistant depression is in inducing neurogenesis by increasing BDNF expression, as was demonstrated by several recent studies.  Den Heijer AE, Groen Y, Tucha L, Fuermaier AB, Koerts J, Lange KW, Thome J, Tucha O (July 2016). “Sweat it out? The effects of physical exercise on cognition and behavior in children and adults with ADHD: a systematic literature review”. 《J. Neural Transm. (Vienna)》 124 (Suppl 1): 3–26. doi:10.1007/s00702-016-1593-7. PMC 5281644. PMID 27400928.  Kamp CF, Sperlich B, Holmberg HC (July 2014). “Exercise reduces the symptoms of attention-deficit/hyperactivity disorder and improves social behaviour, motor skills, strength and neuropsychological parameters”. 《Acta Paediatr.》 103 (7): 709–14. doi:10.1111/apa.12628. PMID 24612421. S2CID 45881887. The present review summarises the impact of exercise interventions (1–10 weeks in duration with at least two sessions each week) on parameters related to ADHD in 7-to 13-year-old children. We may conclude that all different types of exercise (here yoga, active games with and without the involvement of balls, walking and athletic training) attenuate the characteristic symptoms of ADHD and improve social behaviour, motor skills, strength and neuropsychological parameters without any undesirable side effects. Available reports do not reveal which type, intensity, duration and frequency of exercise is most effective in this respect and future research focusing on this question with randomised and controlled long-term interventions is warranted.  Petersen RC, Lopez O, Armstrong MJ, Getchius T, Ganguli M, Gloss D, Gronseth GS, Marson D, Pringsheim T, Day GS, Sager M, Stevens J, Rae-Grant A (January 2018). “Practice guideline update summary: Mild cognitive impairment – Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology”. 《Neurology》. Special article 90 (3): 126–135. doi:10.1212/WNL.0000000000004826. PMC 5772157. PMID 29282327. 요약문 – Exercise may improve thinking ability and memory (2017년 12월 27일). In patients with MCI, exercise training (6 months) is likely to improve cognitive measures and cognitive training may improve cognitive measures. ... Clinicians should recommend regular exercise (Level B). ... Recommendation For patients diagnosed with MCI, clinicians should recommend regular exercise (twice/week) as part of an overall approach to management (Level B).  Farina N, Rusted J, Tabet N (January 2014). “The effect of exercise interventions on cognitive outcome in Alzheimer's disease: a systematic review”. 《Int Psychogeriatr》 26 (1): 9–18. doi:10.1017/S1041610213001385. PMID 23962667. S2CID 24936334. Six RCTs were identified that exclusively considered the effect of exercise in AD patients. Exercise generally had a positive effect on rate of cognitive decline in AD. A meta-analysis found that exercise interventions have a positive effect on global cognitive function, 0.75 (95% CI = 0.32–1.17). ... The most prevalent subtype of dementia is Alzheimer’s disease (AD), accounting for up to 65.0% of all dementia cases ... Cognitive decline in AD is attributable at least in part to the buildup of amyloid and tau proteins, which promote neuronal dysfunction and death (Hardy and Selkoe, 2002; Karran et al., 2011). Evidence in transgenic mouse models of AD, in which the mice have artificially elevated amyloid load, suggests that exercise programs are able to improve cognitive function (Adlard et al., 2005; Nichol et al., 2007). Adlard and colleagues also determined that the improvement in cognitive performance occurred in conjunction with a reduced amyloid load. Research that includes direct indices of change in such biomarkers will help to determine the mechanisms by which exercise may act on cognition in AD.  Rao AK, Chou A, Bursley B, Smulofsky J, Jezequel J (January 2014). “Systematic review of the effects of exercise on activities of daily living in people with Alzheimer's disease”. 《Am J Occup Ther》 68 (1): 50–56. doi:10.5014/ajot.2014.009035. PMC 5360200. PMID 24367955. Alzheimer’s disease (AD) is a progressive neurological disorder characterized by loss in cognitive function, abnormal behavior, and decreased ability to perform basic activities of daily living [(ADLs)] ... All studies included people with AD who completed an exercise program consisting of aerobic, strength, or balance training or any combination of the three. The length of the exercise programs varied from 12 weeks to 12 months. ... Six studies involving 446 participants tested the effect of exercise on ADL performance ... exercise had a large and significant effect on ADL performance (z = 4.07, p < .0001; average effect size = 0.80). ... These positive effects were apparent with programs ranging in length from 12 wk (Santana-Sosa et al., 2008; Teri et al., 2003) and intermediate length of 16 wk (Roach et al., 2011; Vreugdenhil et al., 2012) to 6 mo (Venturelli et al., 2011) and 12 mo (Rolland et al., 2007). Furthermore, the positive effects of a 3-mo intervention lasted 24 mo (Teri et al., 2003). ... No adverse effects of exercise on ADL performance were noted. ... The study with the largest effect size implemented a walking and aerobic program of only 30 min four times a week (Venturelli et al., 2011).  Mattson MP (2014). “Interventions that improve body and brain bioenergetics for Parkinson's disease risk reduction and therapy”. 《J Parkinsons Dis》 4 (1): 1–13. doi:10.3233/JPD-130335. PMID 24473219.  Grazina R, Massano J (2013). “Physical exercise and Parkinson's disease: influence on symptoms, disease course and prevention”. 《Rev Neurosci》 24 (2): 139–152. doi:10.1515/revneuro-2012-0087. PMID 23492553. S2CID 33890283.  van der Kolk NM, King LA (September 2013). “Effects of exercise on mobility in people with Parkinson's disease”. 《Mov. Disord.》 28 (11): 1587–1596. doi:10.1002/mds.25658. PMID 24132847. S2CID 22822120.  Tomlinson CL, Patel S, Meek C, Herd CP, Clarke CE, Stowe R, Shah L, Sackley CM, Deane KH, Wheatley K, Ives N (September 2013). “Physiotherapy versus placebo or no intervention in Parkinson's disease”. 《Cochrane Database Syst Rev》 9 (9): CD002817. doi:10.1002/14651858.CD002817.pub4. PMC 7120224. PMID 24018704.  Blondell SJ, Hammersley-Mather R, Veerman JL (May 2014). “Does physical activity prevent cognitive decline and dementia?: A systematic review and meta-analysis of longitudinal studies”. 《BMC Public Health》 14: 510. doi:10.1186/1471-2458-14-510. PMC 4064273. PMID 24885250. Longitudinal observational studies show an association between higher levels of physical activity and a reduced risk of cognitive decline and dementia. A case can be made for a causal interpretation. Future research should use objective measures of physical activity, adjust for the full range of confounders and have adequate follow-up length. Ideally, randomised controlled trials will be conducted. ... On the whole the results do, however, lend support to the notion of a causal relationship between physical activity, cognitive decline and dementia, according to the established criteria for causal inference.  Carroll ME, Smethells JR (February 2016). “Sex Differences in Behavioral Dyscontrol: Role in Drug Addiction and Novel Treatments”. 《Front. Psychiatry》 6: 175. doi:10.3389/fpsyt.2015.00175. PMC 4745113. PMID 26903885. There is accelerating evidence that physical exercise is a useful treatment for preventing and reducing drug addiction ... In some individuals, exercise has its own rewarding effects, and a behavioral economic interaction may occur, such that physical and social rewards of exercise can substitute for the rewarding effects of drug abuse. ... The value of this form of treatment for drug addiction in laboratory animals and humans is that exercise, if it can substitute for the rewarding effects of drugs, could be self-maintained over an extended period of time. Work to date in [laboratory animals and humans] regarding exercise as a treatment for drug addiction supports this hypothesis. ... However, a RTC study was recently reported by Rawson et al. (226), whereby they used 8 weeks of exercise as a post-residential treatment for METH addiction, showed a significant reduction in use (confirmed by urine screens) in participants who had been using meth 18 days or less a month. ... Animal and human research on physical exercise as a treatment for stimulant addiction indicates that this is one of the most promising treatments on the horizon. [emphasis added]  Lynch WJ, Peterson AB, Sanchez V, Abel J, Smith MA (September 2013). “Exercise as a novel treatment for drug addiction: a neurobiological and stage-dependent hypothesis”. 《Neurosci Biobehav Rev》 37 (8): 1622–1644. doi:10.1016/j.neubiorev.2013.06.011. PMC 3788047. PMID 23806439.  Olsen CM (December 2011). “Natural rewards, neuroplasticity, and non-drug addictions”. 《Neuropharmacology》 61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC 3139704. PMID 21459101. Similar to environmental enrichment, studies have found that exercise reduces self-administration and relapse to drugs of abuse (Cosgrove et al., 2002; Zlebnik et al., 2010). There is also some evidence that these preclinical findings translate to human populations, as exercise reduces withdrawal symptoms and relapse in abstinent smokers (Daniel et al., 2006; Prochaska et al., 2008), and one drug recovery program has seen success in participants that train for and compete in a marathon as part of the program (Butler, 2005). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al., 2006; Aiken, 2007; Lader, 2008).  Linke SE, Ussher M (2015). “Exercise-based treatments for substance use disorders: evidence, theory, and practicality”. 《Am J Drug Alcohol Abuse》 41 (1): 7–15. doi:10.3109/00952990.2014.976708. PMC 4831948. PMID 25397661. The limited research conducted suggests that exercise may be an effective adjunctive treatment for SUDs. In contrast to the scarce intervention trials to date, a relative abundance of literature on the theoretical and practical reasons supporting the investigation of this topic has been published. ... numerous theoretical and practical reasons support exercise-based treatments for SUDs, including psychological, behavioral, neurobiological, nearly universal safety profile, and overall positive health effects.  Zhou Y, Zhao M, Zhou C, Li R (July 2015). “Sex differences in drug addiction and response to exercise intervention: From human to animal studies”. 《Front. Neuroendocrinol.》 40: 24–41. doi:10.1016/j.yfrne.2015.07.001. PMC 4712120. PMID 26182835. Collectively, these findings demonstrate that exercise may serve as a substitute or competition for drug abuse by changing ΔFosB or cFos immunoreactivity in the reward system to protect against later or previous drug use. ... As briefly reviewed above, a large number of human and rodent studies clearly show that there are sex differences in drug addiction and exercise. The sex differences are also found in the effectiveness of exercise on drug addiction prevention and treatment, as well as underlying neurobiological mechanisms. The postulate that exercise serves as an ideal intervention for drug addiction has been widely recognized and used in human and animal rehabilitation. ... In particular, more studies on the neurobiological mechanism of exercise and its roles in preventing and treating drug addiction are needed.  Cormie P, Nowak AK, Chambers SK, Galvão DA, Newton RU (April 2015). “The potential role of exercise in neuro-oncology”. 《Front. Oncol.》 5: 85. doi:10.3389/fonc.2015.00085. PMC 4389372. PMID 25905043.