Effect of physical exercise on hippocampal volume in adults: Systematic review and meta-analysis

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REVIEW

Effect of physical exercise on hippocampal volume in adults: Systematic review and meta-analysis Effet de l’exercice physique sur le volume de l’hippocampe chez les adultes : une revue systématique et méta-analyse N. Feter a,b,∗, J.C. Penny b, M.P. Freitas a,b,c, A.J. Rombaldi a,b,c a

School of Physical Education, Federal University of Pelotas, 96055-630 Pelotas, Rio Grande do Sul, Brazil Exercise Physiology and Biochemistry Laboratory, Federal University of Pelotas, 96055-630 Pelotas, Rio Grande do Sul, Brazil c Physical Activity Epidemiology Study Group, Federal University of Pelotas, 96055-630 Pelotas, Rio Grande do Sul, Brazil b

Received 9 January 2018; accepted 28 February 2018

KEYWORDS Brain; Physical exercise; Interventions; Meta-analysis

∗

Summary Objectives. — To identify and evaluate the effect of different types of physical exercise (PE) and activity on hippocampal volume in humans. News. — The databases searched were MedLine/PubMed, Scopus, SPORTDiscus, Cochrane, Lilacs and Scielo. It was excluded during review process manuscripts that described: (i) nonexperimental studies, (ii) interventions without measurement of hippocampus volume at baseline and post-intervention period, or (iii) interventions that were not compound by physical exercise. After removing duplicates, applying exclusion criteria, and checking reference lists, 13 studies were added to this review. The random effect model was used to the meta-analysis of hippocampus volume. Moderate-intensity continuous training (MICT) was the most common PE adopted among the interventions, with most of them resulting in augmented hippocampus volume. Interventions based on concurrent training (resistance training + MICT) resulted in increase at same outcome in all cases, even though the target population was different. Regarding to meta-analysis, MICT [0.34 (0.10—0.58), P = 0.006] and resistance training (RT) [0.49 (0.09—0.89), P = 0.011] were associated with increased hippocampus volume. The heterogeneity was low in both MICT (I2 = 12.9%) and RT (I2 = 0.0%) interventions.

Corresponding author. Rua Dr. Miguel-Barcelos, 547, Pelotas, Rio Grande do Sul, Brazil. E-mail address: [email protected] (N. Feter).

https://doi.org/10.1016/j.scispo.2018.02.011 0765-1597/© 2018 Elsevier Masson SAS. All rights reserved.

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N. Feter et al. Conclusion. — The results suggest that MICT, RT and CT could potentially augment hippocampus volume, being its practice encouraged to both prevent and treat individuals with neurodegenerative disease as Alzheimer. © 2018 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Cerveau ; Activité physique ; Interventions ; Méta-analyse

Résumé Objectifs. — Identifier et évaluer l’effet des différents types d’activité physique (EP) sur le volume de l’hippocampe chez les humains. Informations. — Les sources de données recherchées étaient : Medline/PubMed, Scopus, SPORTDiscus, Cochrane, Lilacs et Scielo. Ont été exclus de l’analyse les articles qui décrivaient : (i) des études non expérimentales, (ii) des interventions sans mesure du volume de l’hippocampe au début et après l’intervention, ou (iii) des interventions qui ne consistaient pas en activité physique ou en exercice. Après la suppression des doublons, l’application des critères d’exclusion et la vérification des listes de référence, 13 études ont été incluses dans cette revue. Le modèle à effets aléatoires a été utilisé pour la méta-analyse du volume de l’hippocampe. L’entraînement continu à intensité modérée (MICT) était l’AP habituellement adoptée parmi les interventions: la plupart du temps elle entraînait une augmentation du volume de l’hippocampe. Les interventions basées sur des activités simultanées (entraînement en résistance + MCT) ont entraîné une augmentation analogue dans tous les cas, même si la population-cible était différente. En ce qui concerne la méta-analyse, le MICT [0,34 (0,10—0,58), p = 0,006] et l’entraînement en résistance (RT) [0,49 (0,09—0,89), p = 0,011] a été associée à l’augmentation du volume de l’hippocampe. L’hétérogénéité était faible dans les deux interventions MICT (I2 = 12,9 %) et RT (I2 = 0,0 %). Conclusion. — Les résultats suggèrent que le MICT, RT et CT augmentent le volume de l’hippocampe, et que leur pratique régulière devrait être encouragée dans le contexte de la prévention et du traitement des pathologies neurodégénératives comme la maladie d’Alzheimer. © 2018 Elsevier Masson SAS. Tous droits r´ eserv´ es.

1. Introduction Aging is often accompanied by declining in cognitive functioning, particularly on memory and executive function [1]. This process occurs as a result of atrophies in the key brain regions for these functions [2—5], such as the hippocampus and the cerebral cortex. The hippocampus, located in the cortical region, plays an important role in the limbic system, and it is involved in the formation of new memories, learning and emotions. It is found in both brain hemispheres, and whether some side is damaged, the ability to retain memories and generate neurons can be impaired. Then, strategies to prevent hippocampal volume reduction and memory impairment have become an important subject in recent years from both the scientific and public health perspectives. Physical exercise, especially the moderate intensity continuous training (MICT), emerged as a promising, low-cost non-pharmacological treatment to improve cognitive function. Physical exercise also develops learning and memory retention, which is accompanied by improved cell proliferation and survival at rodent hippocampus [6—8]; effects that are mediated in part by increased production and secretion of brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase (trkB) [9,10]. Furthermore, studies have reported positive results from MICT on control and reduction of atrophy at hippocampus [11], white and cortical gray matter [11] in adults.

BDNF and glial cell line-derived neurotrophic factors (GDNF) are small peptides that are distributed in different regions of the central nervous system (CNS) [12]. BDNF exhibits relevant role in brain development and plasticity [13]. The increase in its concentration, either peripheral or central, is directly related to reduction of apoptosis and degenerative atrophy of nerve cells [14], acting in prevention of neurological disorders such as Alzheimer’s disease and depression [15—17]. Furthermore, GDNF acts in the protection of dopaminergic and cortical motor neurons, performing a crucial role in defense of peripheral and central nervous system against Parkinson’s disease and amyotrophic lateral sclerosis [18—20]. Moreover, low concentrations of this neuropeptide are related to decreased muscle innervations and losses of myelinated nerve fibers [21], thus raising the incidence of falls in elderly humans [22]. However, the concentration of these neurotrophins may be affected by pro-inflammatory conditions, redox homeostasis, and physical exercise. In addition, hippocampus and median temporal lobe volume are larger in older adults with better physical fitness [23,24]. MICT further augments cerebral blood volume in humans [25] and in mice, where this improvement was associated with cardiopulmonary and cognitive function [26]. In same way, resistance training (RT) seems to develop and protect the CNS through increased insulin-like growth factor type 1 (IGF-1) [27,28]. This neurotrophic factor is secreted in hippocampus by microglia in situations involving cytotoxic

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Flow diagram of the studies selected for systematic review and meta-analysis.

damage, ischemia, spinal cord and cortical lesions [29], acting as an important neuroprotective molecule in the CNS [30]. Nevertheless, the literature presents inconsistencies on the effects of different forms of physical training on cerebral parameters, such as metabolism and brain plasticity. There is a body of studies in literature that suggests MICT has important neuroprotective capacity, being able to increase hippocampal volume [9], elevate concentration of neurotrophins [31], creation of neurons and blood vessels [32,33], support myelin sheath regeneration [34], and reduce oxidative stress in brain tissue [35]. However, there are still studies that adopted this training protocol and found opposite results when evaluating MICT in the hippocampal volume [36] and in the thickness of the myelin sheath [37]. Although its regular practice is able to raise IGF-1 levels [38—40], the ability of RT to improve neuroprotective capacity is not yet clear. Studies as ten Brinke et al. [11] and Best et al. [41] reported that this type of physical exercise was not able to increase hippocampal volume in the elderly. However, Mueller et al. [42] reported that the practice of RT combined with MICT was able to increase brain volume and BDNF concentration in obese individuals.

In relation to MICT, a study aimed to identify the effect of high-intensity interval training (HIIT) practice for six weeks on neurotrophins and in the inflammatory system of Wistar rats, and compare these results with those obtained through the MICT [31]. The study showed both training were able to generate neuroprotective responses, increasing the concentration of BDNF, GDNF, tumor necrosis factor alpha and H2 O2 . Still, the alterations found in the HIIT group were higher than those in the MICT group. Thus, it appears that HIIT is capable of generating greater neuroprotective effects when compared to the MICT. However, this was the first, and until that date, the only study that sought to compare the responses of these markers between different types of aerobic exercise. Thus, the main objective of the present study is to identify and evaluate the effect of different types of physical exercise and activity on hippocampal volume in humans.

2. Methods and materials This systematic review sought intervention studies aimed at identifying the effect of physical exercise on hippocampal plasticity. The survey comprised the period from February

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2017 to March 2017 and included the following databases and search language: MedLine/PubMed (English), Scopus (English), SPORTDiscus (English), Cochrane (English), Lilacs (Portuguese) and Scielo (Portuguese). In these databases, keywords related to physical activity (physical activity OR physical exercise OR motor activity) and cerebral plasticity (neurogenesis OR brain plasticity OR hippocampus OR gray matter OR dentate gyrus) were used during search in all fields of articles at all included databases. In addition, there were no language and year of publication limitations. All articles were included in this study and exported to EndNote X7 reference management software, where the duplicates were excluded. Then, titles and abstracts were analyzed, and the exclusion criteria were applied in each article. Finally, all references cited in the included manuscripts were checked in order to retrieve any other potential studies that should be examined for eligibility in this review. The exclusion criteria for title, abstracts and full text were:

since they matched inclusion criteria, while 9 articles were included at meta-analyses since provided necessary data to be quantitatively analyzed. Among the studies included in the systematic review, the samples were composed on average by 86.5 (± 81.9) individuals, ranging from 11 [26] to 319 subjects [47] (Table 1). Eight studies evaluated the response of physical exercise on brain volume in elderly [9,11,41,48—52] and the remaining with adults [26,47,53—55]. The mean intervention duration was 54.3 (± 56.1) weeks. Seven interventions adopted as a training protocol the MICT [9,11,49,50,52,54,55], two using concurrent training (MCIT + resistance training) [51,53] and two used resistance training (RT) [11,41]. Three physical exercise-based interventions resulted in improvements on different brain regions, such as cerebral cortex [48,53]. Regarding hippocampus volume, six studies found a positive response of physical exercise in that outcome, with four having exercised only with MCIT [9,11,50,55] and one using concurrent training protocol [53].

• interventions without measurement of hippocampus volume at baseline and post-intervention period; • interventions did not compound by physical exercise; • studies that did not describe any intervention; • and literature review articles.

3.2. Evaluation of manuscript quality

Downs & Black (DB) scale [43] was used to evaluate the quality of the articles included in the study. This scale was designed to analyze randomized and non-randomized clinical trials and consists of 27 questions about reporting, external and internal validity and statistical power of the manuscripts, and generates scores ranging from zero to 32 points. Two researchers independently performed all the research and when there was disagreement between them, a third was consulted to reach a consensus. The review follows the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) [44]. Statistical analysis: the most studied outcomes (hippocampal volume in cm3 ) were quantified in a meta-analysis. The data was extracted and entered into Microsoft Excel software and then export to statistical software STATA 13.1, in which data analysis was performed. When a study had more than one intervention, the interventions were included in the analysis individually. The random effect model was adopted. Cochran’s Q test assessed the heterogeneity between the studies, while the I2 statistic quantified the amount of dispersion [45]. An I2 -value larger than 50% or a P-value equal or higher than 0.05 for the Q-statistic was considered to indicate significant heterogeneity [45]. Publication bias was assessed using Egger’s test [46].

3. Results 3.1. Systematic review We found 18,939 manuscripts in the databases, which were added to the library. After removing duplicates and applying the exclusion criteria in titles and abstracts, 54 original articles (Fig. 1) remained for full text reading. Next, 12 manuscripts were added to systematic review library

On the qualitative evaluation, the mean score obtained at DB scale by the studies added to the systematic review was 18.9 ± 4.2 points (Table 2). According to well-established classification used in systematic reviews [56,57], studies that do not reach scores above 50% of the maximum value have questionable methodological quality. Moreover, the maximum and minimum score reached between the evaluated ones was 28 [11] and 11 [53] points, respectively. Willems et al. [56] defined studies with a score ≥ 19 points should be considered of high methodological quality, reflecting two-thirds of the maximum achievable score. Thus, six studies [11,41,47—49,52,55] added to the review and the meta-analysis presented moderate or high methodological quality.

3.3. Meta-analysis All studies included in the systematic review evaluated the effect of physical exercise on hippocampal volume. Nevertheless, only 9 studies had enough data to be added to the meta-analysis. The outcome (hippocampal volume) was reported in cm3 . The effect of exercise on each side and total hippocampal volume was evaluated. The analysis shows that the group that performed physical exercise had volume of the right side of the hippocampus greater in 0.29 (95% CI: 0.10—0.49) cm3 (P = 0.003; I2 = 0.0%) when compared to the control group. In this sense, the same pattern was found when the left side was analyzed [0.20 (95% CI: 0.002—0.393); P = 0.047; I2 = 0.0%] (Fig. 3). Also, the total volume of the hippocampus reaches a value greater than 0.33 (95% CI: 0.16—0.50) cm3 (P < 0.001; I2 = 0.0%) when compared to the control group. Furthermore, the sensitivity analysis (Fig. 2) showed that when stratified for the type of physical training, MICT was able to increase total hippocampal volume by 0.34 (95% CI: 0.10—0.58) cm3 in a sample of 337 people (I2 = 12.9%, P = 0.006). In addition, the study group that adopted the intervention protocol RT also observed

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Sample/Age

Espeland et al. [47]

Intervention duration

Outcomes measured

Key findings

Conclusion

12 months 319 diabetic and overweight individuals/45—76 years

Physical activity promotion

Brain volume (cm3 )

The intervention did not increase hippocampal volume

Kleemeyer et al. [49]

52 healthy 6 months individuals/59—74 years

High and low intensity aerobic conditioning on indoor bike

CF, cognition and brain structure

The mean volume of hyperintensity of white matter was lower among participants in the intervention group. The mean volume of the ventricle was 9% lower No difference was found in CF and in the cerebral structure

Mueller et al. [53]

3 months 16 overweight/obese youths/27.2 ± 6.2 years

15 min of cycling and running, 30 min of individualized strength training and 15 min cool-down

CF, blood measurements and brain volume

Erickson et al. [9]

120 elderly/55—80 years old

6 months

Brain structure, CF, memory

Rosano et al. [51]

26 elderly/70—89 years

24 months

Wagner et al. [54]

6 weeks 34 students/25.0 ± 3.3 years

Intervention: 10 min/session + 5 minutes per week until week 7; 40 min/session, in all remaining sessions. Control: training program for flexibility Intervention: Moderate walking, resistance exercises for lower extremities, balance, stretching and behavioral counseling. Control: stretching and elongation of upper limbs 3 days a week, 60 min. p/day @ 85% of the maximum power

Carlson et al. [48]

111 elderly/67.2 (6.1)

Intervention for productive social engagement

24 months

Brain structure and CF

Blood tests, CF, BDNF and brain structure

Brain structure

Participants increased BDNF concentration. Changes in BMI and serum BDNF were related to an increase in gray matter density in the left hippocampus, the insular cortex, and the left cerebellar lobe Aerobic training increased anterior hippocampal volume, leading to improvements in spatial memory and reversing age-related volume loss in 1 to 2 years There were differences between the groups at hippocampus. The results were similar to adjustment for dementia-related factors The intervention group improved CF and BDNF levels and decrease hippocampal volume The intervention did increase hippocampal volume in men

The intervention did not increase hippocampal volume The intervention did increase hippocampal volume

The intervention did increase hippocampal volume

The intervention did increase hippocampal volume

The intervention did reduce hippocampal volume. The intervention did increase hippocampal volume

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Description of the studies included in the systematic review.

Effect of physical exercise on hippocampus volume

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Table 1

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Sample/Age

Intervention duration

Type of intervention

Outcomes measured

Key findings

Conclusion

Best et al. [41]

155 elderly/65—75 years

12 months

RT: 40 min/session; 2 sets of 6—8 repetitions; (1) 1×/week, (2) 2×/week, and control group

Cognition, muscle power and brain volume

The intervention did not increase hippocampal volume

Niemann et al. [50]

91 elderly/62—79 years

12 months

3×/week; 45—60 min/session; @75—80% HRmax

CF, motor fitness, and hippocampal volume

ter Brinke et al. [11]

29 elderly/70—80 years

6 months

2×/week; RT: 2 sets of 6—8 RM MICT: @70—80% HRmax

Hippocampal volume, learning and verbal memory

Morris et al. [52]

68 elderly/> 55 years old

26 weeks

MICT: 3—5×/week: 150 min/session @60—75% HRR; Control: stretching

Executive function, memory, depression symptoms, brain volume

Pajonk et al. [55]

24 schizophrenic adults/20—51 years

12 weeks

Group Ex and ExSch: 3×/week; 30 min/session; @ HR corresponding to the blood lactate concentration at 1.5—2 mmol/L (± 10 bpm). Control group: table football

Memory, cognitive function and brain volume

One year after the intervention, both training frequencies improved executive function compared to the control group. Group 2 enhanced memory, reduced white matter cortical atrophy, and increased maximal muscle power at the 2-year follow-up in relation to the control group Motor fitness was associated with hippocampal volume. After intervention period, both training groups led to increases in hippocampal volume Compared to control group, MICT group increased right, left and total hippocampal volume. The RT group did not increase the volume in any region of hippocampus MICT did not result in significant changes in hippocampal volume. However, improvement in CF was associated with bilateral hippocampal volume changes Ex and ExSch groups increased hippocampal volume, a result not observed in the control group. CF correlated with changes in hippocampal volume

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The intervention did increase hippocampal volume. The intervention did increase hippocampal volume

The intervention did not increase hippocampal volume

The intervention did increase hippocampal volume

N. Feter et al.

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Table 1

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Effect of physical exercise on hippocampus volume Table 2

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Quality evaluation of the studies included in the review (Downs and Black Scale).

Articles

Reporting

External validity

Bias

Confounding variables

Power

Total score

Best et al. [41] Carlson et al. [48] Erickson et al. [9] Espeland et al. [47] Kleemeyer et al. [49] Morris et al. [52] Mueller et. al. [53] Niemann et al. [50] Pajonk et al. [55] Rosano et al. [51] ten Brinke et al. [11] Wagner et al. [54]

8/10 8/10 8/10 9/10 9/10 9/10 5/10 8/10 7/10 8/10 10/10 9/10

0/3 1/3 0/3 2/3 2/3 2/3 1/3 0/3 2/3 2/3 3/3 0/3

6/7 6/7 4/7 3/7 3/7 4/7 3/7 3/7 4/7 4/7 5/7 4/7

6/6 5/6 5/6 5/6 5/6 3/6 2/6 4/6 5/6 4/6 6/6 3/6

0/5 0/5 0/5 0/5 0/5 5/5 0/5 5/5 5/5 0/5 0/5 0/5

20/32 20/32 17/32 19/32 19/32 24/32 11/32 15/32 21/32 18/32 28/32 16/32

Figure 2 Meta-analysis on the association of physical exercise with total hippocampal volume compared to the control group and stratified by type of physical training. MICT: moderate-intensity continuous training; CT: concurrent training; RT: resistance training (n = 547).

statistically significant changes in the same outcome, with RT being able to increase hippocampal volume by 0.49 (95% CI: 0.06—0.89) cm3 (I2 = 0.0%, P = 0.015, n = 105). Only one study among those added in the meta-analysis adopted a concurrent training protocol [51].

Also, the sensitivity analysis showed that when the response in different hippocampal hemispheres was evaluated, only MICT (Figs. 3 and 4) was able to increase the volume of the right side of this brain region (0.36 cm3 , 95% CI: 0.08—0.63, P = 0.011, n = 203). The volume of the left side of the hippocampus showed positive responses to brain

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Figure 3 Meta-analysis on the association of physical exercise with right hippocampal volume compared to the control group and stratified by the type of physical training. MICT: moderate-intensity continuous training; CT: concurrent training; RT: resistance training (n = 492).

physical exercise (0.25 cm3 , 95% CI: 0.03—0.46, P = 0.027, I2 = 0.0%, n = 203), but not it was possible to determine what type of exercise is due to this increase.

3.4. Publication bias It was not observed any evidence of publication bias when analyzed studies with data from total (P = 0.095), left (P = 0.991), and right (P = 0.749), hippocampus volume (Supplementary files).

4. Discussion The results obtained in the present study suggest that physical exercise, especially MICT, is capable of inducing changes in hippocampal volume in humans. Likewise, other brain regions, such as cerebral cortex could be improved by physical exercise. This finding is important in view of the high prevalence of physical inactivity [58] and mental illnesses, such as dementia [59]. Thus, the study and discussion of this type of action becomes essential for a better

improvement of the quality of interventions in different cultural and economic contexts. When compared to the control group, interventions were able to increase total hippocampal volume by 0.32 (95% CI: 0.15—0.49) cm3 . Among the evaluated studies, two adopted concurrent training protocol (MICT + RT) [51,53] and both observed a positive response from exercise in this outcome. Two other interventions [11,41] with RT alone showed that this type of physical exercise generated a significant increase in hippocampal volume. Although RT-induced response on BDNF levels appears to be inconsistent [60—62], RT raises concentrations of insulin-like growth factor-1 (IGF1) [27,28], which was directly related to the neuronal creation and protection, besides synaptic plasticity [29,40]. According to O’Kusky and Ye [63], IGF-1 is still responsible for the development of oligodendrocytes, also promoting cerebral myelination. The remaining studies evaluated the effect of low to moderate intensity aerobic training protocols, and found a statistically significant increase in hippocampus. Studies such as this of Erickson et al. [9,64] have shown that exercise was able to increase hippocampal volume, mainly in response to increased neurotrophins concentration in this

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Figure 4 Meta-analysis on the association of physical exercise with left hippocampus volume compared to the control group and stratified by type of physical training. MICT: moderate-intensity continuous training; CT: concurrent training; RT: resistance training (n = 413).

region, such as BDNF, which is directly linked to neurogenesis. Trivi˜ no-Paredes et al. [65] reported that interventions composed by intense training, despite also producing BDNF, even in a higher concentration than in continuous training of moderate intensity [31], increase the production of the hormone corticosterone, which impairs the phases of creation of new neurons. According to a report by Alzheimer’s Disease International [59] it is estimated that the annual worldwide expenditure on dementia in 2018 reaches the mark of US$ 1 trillion, and in 2030 that figure is expected to double. In Brazil, it is estimated that there are 1.2 million cases. Public policies should encourage people, especially as young people, to adopt an active lifestyle. Thus, exercise may act as a neuroprotective factor, triggering pathways of neuronal protection, such as increase in BDNF concentration, reduction of oxidative stress and infiltration of inflammatory cells in the hippocampus, in order to prevent cognitive and functional loss, guaranteeing the individual a healthy aging. Through the meta-analysis, both MICT and RT were able to generate a statistically significant increase in the total volume of the human hippocampus. Conversely, when the sides were analyzed separately using sensitivity analysis,

neither one could generate augments at left side of hippocampus. In a study of Niemann et al. [50], the group that underwent coordinative training presented greater volume in the right side than in the left side of hippocampus. However, according to Goto et al. [66] and Shipton et al. [67], this dissociation between the volume of the hippocampal hemispheres is critical in the memory acquisition and retention process. Shipton et al. [67] suggested that this difference is not only a reflection in the linguistic learning process, but also a fundamental feature in the function of the hippocampus in mammals. Moreover, Bergess, Maguire and O’Keefe [68] and Piekema et al. [69] further propose that the left side of the hippocampus would be responsible for episodic and autobiographical memories, while the right side would be responsible for the ability to relate an object to environmental factors. Among the studies analyzed in the systematic review, three [9,53,54] evaluated the concentration of BDNF in plasma. Among them, two [9,53] used the MICT in the protocol, and the results of these manuscripts showed that this type of physical exercise was capable of produce a significant increase in the concentration of neurotrophins, and thus, induce plasticity in brain tissue, especially in

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10 the hippocampus. In another study that measured this neurotrophin, Best et al. [41] adopted RT in their intervention protocol and did not observe a rise in BDNF concentration in the blood plasma sample.

5. Conclusion Thus, the present study suggests that the regular practice of physical exercise has a neuroprotective function, acting and inducing the increase of hippocampal volume. Relating to MICT, a capacity of this type of exercise to increase the volume of the region in the right hemisphere and total volume of the hippocampus was evidenced. This result can be explained by the capacity of this type of physical exercise to increase BDNF concentration, responsible for neuroprotection, cerebral plasticity, and neurogenesis. Regarding RT, this form of physical exercise was able to generate positive responses in the total hippocampal volume, and this effect may be due to the exercise-induced high concentration of IGF-1, playing an important role in the creation and protection of neurons [29,40]. However, it is suggested that more studies are necessary to identify the response of other forms of physical exercises, such as high-intensity interval training, and behaviors such as sedentary and daily physical activity, in the plasticity and protection of the hippocampus.

Contributors N.F. contributed to the design of the study, the literature search, data screening and extraction, conducted all statistical analyses, and managed all aspects of manuscript preparation and submission. J.C.P. contributed to the design of the study, provided methodological input. M.P.F. contributed to the design and writing of the study. A.J.R. contributed to writing and editing of the manuscript.

Disclosure of interest The authors declare that they have no competing interest.

Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10. 1016/j.scispo.2018.02.011.

References [1] Bugg JM, Head D. Exercise moderates age-related atrophy of the medial temporal lobe. Neurobiol Aging 2011;32(3):506—14. [2] Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, Williamson A, et al. Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 2005;15(11):1676—89. [3] Salat DH, Tuch DS, Greve DN, van der Kouwe AJ, Hevelone ND, Zaleta AK, et al. Age-related alterations in white matter microstructure measured by diffusion tensor imaging. Neurobiol Aging 2005;26(8):1215—27. [4] van Praag H, Shubert T, Zhao C, Gage FH. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci 2005;25(38):8680—5.

N. Feter et al. [5] Walhovd KB, Fjell AM, Reinvang I, Lundervold A, Dale AM, Eilertsen DE, et al. Effects of age on volumes of cortex, white matter and subcortical structures. Neurobiol Aging 2005;26(9):1261—70 [discussion: 75—8]. [6] Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002;25(6):295—301. [7] Creer DJ, Romberg C, Saksida LM, van Praag H, Bussey TJ. Running enhances spatial pattern separation in mice. Proc Natl Acad Sci U S A 2010;107(5):2367—72. [8] Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 2004;20(10):2580—90. [9] Erickson K, Voss M, Prakash R, Basak C, Szabo A, Chaddock L, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S 2011;108(7):3017—22 from: http://www.onlinelibrary.wiley.com/o/ [Available cochrane/clcentral/articles/434/CN-00778434/frame.html ; Internet]. [10] Li Y, Luikart BW, Birnbaum S, Chen J, Kwon CH, Kernie SG, et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 2008;59(3):399—412. [11] ten Brinke LF, Bolandzadeh N, Nagamatsu LS, Hsu CL, Davis JC, Miran-Khan K, et al. Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: a 6-month randomised controlled trial. Br J Sports Med 2015;49(4):248—54. [12] Siamilis S, Jakus J, Nyakas C, Costa A, Mihalik B, Falus A, et al. The effect of exercise and oxidant-antioxidant intervention on the levels of neurotrophins and free radicals in spinal cord of rats. Spinal Cord 2009;47(6):453—7. [13] Weishaupt N, Blesch A, Fouad K. BDNF: the career of a multifaceted neurotrophin in spinal cord injury. Exp Neurol 2012;238(2):254—64. [14] Nagahara AH, Tuszynski MH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 2011;10(3):209—19. [15] Cotman CW, Berchtold NC, Christie L-A. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 2007;30(9):464—72. [16] Ogonovszky H, Berkes I, Kumagai S, Kaneko T, Tahara S, Goto S, et al. The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain. Neurochem Int 2005;46(8):635—40. [17] Radak Z, Toldy A, Szabo Z, Siamilis S, Nyakas C, Silye G, et al. The effects of training and detraining on memory, neurotrophins and oxidative stress markers in rat brain. Neurochem Int 2006;49(4):387—92. [18] Lau YS, Patki G, Das-Panja K, Le WD, Ahmad SO. Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration. Eur J Neurosci 2011;33(7):1264—74. [19] McCullough MJ, Gyorkos AM, Spitsbergen JM. Short-term exercise increases GDNF protein levels in the spinal cord of young and old rats. Neuroscience 2013;240:258—68. [20] Ma X, Hamadeh MJ, Christie BR, Foster JA, Tarnopolsky MA. Impact of treadmill running and sex on hippocampal neurogenesis in the mouse model of amyotrophic lateral sclerosis. PLOS One 2012;7(4):e36048. [21] Johnson H, Hokfelt T, Ulfhake B. Expression of p75(NTR), trkB and trkC in nonmanipulated and axotomized motoneurons of aged rats. Brain Res Mol Brain Res 1999;69(1):21—34. [22] Fries JF, Singh G, Morfeld D, Hubert HB, Lane NE, Brown Jr BW. Running and the development of disability with age. Ann Internal Med 1994;121(7):502—9. [23] Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E, et al. Aerobic exercise training increases brain

Please cite this article in press as: Feter N, et al. Effect of physical exercise on hippocampal volume in adults: Systematic review and meta-analysis. Sci sports (2018), https://doi.org/10.1016/j.scispo.2018.02.011

+Model SCISPO-3205; No. of Pages 12

ARTICLE IN PRESS

Effect of physical exercise on hippocampus volume

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32] [33]

[34]

[35] [36]

[37]

[38]

[39]

[40]

[41]

volume in aging humans. J Gerontol A Biol Sci Med Sci 2006;61(11):1166—70. Erickson KI, Prakash RS, Voss MW, Chaddock L, Hu L, Morris KS, et al. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus 2009;19(10):1030—9. Honea RA, Thomas GP, Harsha A, Anderson HS, Donnelly JE, Brooks WM, et al. Cardiorespiratory fitness and preserved medial temporal lobe volume in Alzheimer disease. Alzheimer Dis Assoc Disord 2009;23(3):188—97. Pereira AC, Huddleston DE, Brickman AM, Sosunov AA, Hen R, McKhann GM, et al. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus. Proc Natl Acad Sci U S A 2007;104(13):5638—43. Luo L, Lu AM, Wang Y, Hong A, Chen Y, Hu J, et al. Chronic resistance training activates autophagy and reduces apoptosis of muscle cells by modulating IGF-1 and its receptors, Akt/mTOR and Akt/FOXO3a signaling in aged rats. Exp Gerontol 2013;48(4):427—36. Madzima TA, Ormsbee MJ, Schleicher EA, Moffatt RJ, Panton LB. Effects of resistance training and protein supplementation in breast cancer survivors. Med Sci Sports Exerc 2017;49(7):1283—92. Morel GR, León ML, Uriarte M, Reggiani PC, Goya RG. Therapeutic potential of IGF-I on hippocampal neurogenesis and function during aging. Neurogenesis 2017;4(1):e1259709. Breese CR, D’Costa A, Rollins YD, Adams C, Booze RM, Sonntag WE, et al. Expression of insulin-like growth factor-1 (IGF-1) and IGF-binding protein 2 (IGF-BP2) in the hippocampus following cytotoxic lesion of the dentate gyrus. J Comp Neurol 1996;369(3):388—404. Afzalpour ME, Chadorneshin HT, Foadoddini M, Eivari HA. Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain. Physiol Behav 2015;147:78—83. Cotman CW, Engesser-Cesar C. Exercise enhances and protects brain function. Exerc Sport Sci Rev 2002;30(2):75—9. Lista I, Sorrentino G. Biological mechanisms of physical activity in preventing cognitive decline. Cell Mol Neurobiol 2010;30(4):493—503. Feter N, Freitas MP, Gonzales NG, Umpierre D, Cardoso RK, Rombaldi AJ. Effects of physical exercise on myelin sheath regeneration: a systematic review and meta-analysis. Sci Sports 2017;33:8—21. Andersen JK. Oxidative stress in neurodegeneration: cause or consequence? Nat Med 2004:10. Morris JK, Vidoni ED, Johnson DK, Van Sciver A, Mahnken JD, Honea RA, et al. Aerobic exercise for Alzheimer’s disease: a randomized controlled pilot trial. PloS One 2017;12(2):e0170547. Oliveira L, Sobral L, Takeda S, Betini J, Guirro R, Somazz M, et al. Electrical stimulation and swimming in the acute phase of axonotmesis: their influence on nerve regeneration and functional recovery. Revista Neurol 2007;47(1):11—5. Borst SE, De Hoyos DV, Garzarella L, Vincent K, Pollock BH, Lowenthal DT, et al. Effects of resistance training on insulinlike growth factor-I and IGF binding proteins. Med Sci Sports Exerc 2001;33(4):648—53. LLorens-Martin M, Torres-Aleman I, Trejo JL. Reviews: mechanisms mediating brain plasticity: IGF1 and adult hippocampal neurogenesis. Neurosci 2009;15(2):134—48. Nieto-Estévez V, Defterali C ¸ , Vicario-Abejón C. IGF-I: a key growth factor that regulates neurogenesis and synaptogenesis from embryonic to adult stages of the brain. Front Neurosci 2016:10. Best JR, Chiu BK, Liang Hsu C, Nagamatsu LS, Liu-Ambrose T. Long-term effects of resistance exercise training on cognition

11

[42]

[43]

[44]

[45] [46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

and brain volume in older women: results from a randomized controlled trial. J Int Neuropsychol Soc 2015;21(10):745—56. Mueller K, Möller HE, Horstmann A, Busse F, Lepsien J, Blüher M, et al. Physical exercise in overweight to obese individuals induces metabolic-and neurotrophic-related structural brain plasticity. Front Hum Neurosci 2015:9. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 1998;52(6):377—84. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6(7):e1000097. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Br Med J 2003;327(7414):557. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315(7109):629—34. Espeland MA, Erickson K, Neiberg RH, Jakicic JM, Wadden TA, Wing RR, et al. Brain and white matter hyperintensity volumes after 10 years of random assignment to lifestyle intervention. Diabetes Care 2016;39(5):764—71. Carlson MC, Kuo JH, Chuang YF, Varma VR, Harris G, Albert MS, et al. Impact of the Baltimore Experience Corps Trial on cortical and hippocampal volumes. Alzheimers Dement 2015;11(11):1340—8. Kleemeyer MM, Kühn S, Prindle J, Bodammer NC, Brechtel L, Garthe A, et al. Changes in fitness are associated with changes in hippocampal microstructure and hippocampal volume among older adults. NeuroImage 2016;131:155—61. Niemann C, Godde B, Voelcker-Rehage C. Not only cardiovascular, but also coordinative exercise increases hippocampal volume in older adults. Front Aging Neurosci 2014;6 from: http://www.onlinelibrary.wiley.com/o/ [Available cochrane/clcentral/articles/577/CN-01002577/frame.html ; Internet]. Rosano C, Guralnik J, Pahor M, Glynn NW, Newman AB, Ibrahim TS, et al. Hippocampal response to a 24-month physical activity intervention in sedentary older adults. Am J Geriatr Psychiatry 2016;25:209—17. Morris JK, Vidoni ED, Johnson DK, Van Sciver A, Mahnken JD, Honea RA, et al. Aerobic exercise for Alzheimer’s disease: a randomized controlled pilot trial. PLoS One 2017;12(2):e017547. Mueller K, Moller HE, Horstmann A, Busse F, Lepsien J, Bluher M, et al. Physical exercise in overweight to obese individuals induces metabolic- and neurotrophic-related structural brain plasticity. Front Hum Neurosci 2015;9:372. Wagner G, Herbsleb M, De La Cruz F, Schumann A, Brünner F, Schachtzabel C, et al. Hippocampal structure, metabolism, and inflammatory response after a 6-week intense aerobic exercise in healthy young adults: a controlled trial. Cereb Blood Flow Metab 2015;35(10):1570—8. Pajonk FG, Wobrock T, Gruber O, Scherk H, Berner D, Kaizl I, et al. Hippocampal plasticity in response to exercise in schizophrenia. Arch Gen Psychiatry 2010;67(2):133—43. Willems LM, Vriezekolk JE, Schouffoer AA, Poole JL, Stamm TA, Bostrom C, et al. Effectiveness of nonpharmacologic interventions in systemic sclerosis: a systematic review. Arthritis Care Res (Hoboken) 2015;67(10):1426—39. Häfele CA, Freitas MP, Rombaldi AJ. Efeitos do exercicio fisico na epilepsia em humanos: uma revisao sistemática. Revista Neurociências 2015;23(3):8. Andersen LB, Mota J, Di Pietro L. Update on the global pandemic of physical inactivity. Lancet 2016;388(10051): 1255—6.

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+Model SCISPO-3205; No. of Pages 12

ARTICLE IN PRESS

12 [59] Prince M, Wimo A, Guerchet M, Ali G, Wu Y, Prina M. World Alzheimer Report 2015. The global impact of dementia. An analysis of prevalence, incidence, cost & trends; 2015. [60] Gomes FGN, Fernandes J, Campos DV, Cassilhas RC, Viana GM, D’Almeida V, et al. The beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling is impaired by anabolic androgenic steroids. Psychoneuroendocrinology 2014;50:106—17. [61] Correia PR, Pansani A, Machado F, Andrade M, Silva ACd, Scorza FA, et al. Acute strength exercise and the involvement of small or large muscle mass on plasma brain-derived neurotrophic factor levels. Clinics 2010;65(11):1123—6. [62] Church DD, Hoffman JR, Mangine GT, Jajtner AR, Townsend JR, Beyer KS, et al. Comparison of high-intensity vs. high-volume resistance training on the BDNF response to exercise. J Appl Physiol 2016;121(1):123—8. [63] O’Kusky J, Ye P. Neurodevelopmental effects of insulinlike growth factor signaling. Front Neuroendocrinol 2012;33(3):230—51.

N. Feter et al. [64] Erickson KI, Gildengers AG, Butters MA. Physical activity and brain plasticity in late adulthood. Dialogues Clin Neurosci 2013;15(1):99—108. [65] Trivino-Paredes J, Patten AR, Gil-Mohapel J, Christie BR. The effects of hormones and physical exercise on hippocampal structural plasticity. Front Neuroendocrinol 2016;41:23—43. [66] Goto K, Kurashima R, Gokan H, Inoue N, Ito I, Watanabe S. Leftright asymmetry defect in the hippocampal circuitry impairs spatial learning and working memory in iv mice. PLoS One 2010;5(11):e15468. [67] Shipton OA, El-Gaby M, Apergis-Schoute J, Deisseroth K, Bannerman DM, Paulsen O, et al. Left-right dissociation of hippocampal memory processes in mice. Proc Natl Acad Sci U S A 2014;111(42):15238—43. [68] Burgess N, Maguire EA, O’Keefe J. The human hippocampus and spatial and episodic memory. Neuron 2002;35(4):625—41. [69] Piekema C, Kessels RP, Mars RB, Petersson KM, Fernandez G. The right hippocampus participates in short-term memory maintenance of object-location associations. NeuroImage 2006;33(1):374—82.

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