Exercise, brain plasticity, and depression

Abstract Depression is a common mental disorder characterized by high incidence, high disability, and high fatality, causing great burden to the society, families, and individuals. The changes in brain plasticity may be a main reason for depression. Recent studies have shown that exercise plays a positive role in depression, but systematic and comprehensive studies are lacking on brain plasticity changes in depression. To further understand the antidepressive effect of exercise and the changes in brain plasticity, we retrieved related literatures using key words “depression,” “depressive disorder,” “exercise,” “brain plasticity,” “brain structure,” and “brain function” from the database of Web of Science, PubMed, EBSCO host, and CNKI, hoping to provide evidence for exercise in preventing and treating depression. Increase in exercise has been found negatively correlated with the risk of depression. Randomized controlled experiments have shown that aerobic exercise, resistance exercise, and mind‐body exercise can improve depressive symptoms and levels. The intensity and long‐term effect of exercise are now topical research issues. Exercise has been proven to reshape the brain structure of depression patients, activate the function of related brain areas, promote behavioral adaptation changes, and maintain the integrity of hippocampal and white matter volume, thus improving the brain neuroprocessing and delaying cognitive degradation in depression patients. Future studies are urgently needed to establish accurate exercise prescriptions for improving depressive symptoms, and studies on different depressive populations and studies using multimodal brain imaging combined with multiple analytical methods are also needed.

depression, but it is hindered by side effects, addiction, high price, and poor patient compliance. Drug treatment is overall not satisfactory, with the quality of life of patients being seriously affected.
Studies have confirmed that, as a nondrug way, exercise can help alleviate depressive symptoms, with comparable efficiency to drug therapy and other psychological interventions. 2,3 Exercise can also prevent other diseases, such as diabetes, osteoporosis, and obesity. 4,5 However, there have been different conclusions on the effect of different exercises on depression. Recently, more studies have shown structural and functional changes in certain parts of the central nervous system, which is the anatomical basis of depression. [6][7][8] Brain plasticity refers to the ability of brain to change its structure and function, which is also the physiological basis for psychological and behavioral adaptation. 9 With the advances in medical imaging, the changes in brain plasticity of depression patients have attracted wide attention. Researchers have done more studies at the molecular, cellular, behavioral, and structural network levels. However, there have been no systematic and comprehensive conclusions on brain plasticity change in exercise-induced antidepression.
Here, we summarized the effects of exercise on depression, analyzed different exercise modes in depressive people, and expounded the changes in brain plasticity in exercise-induced antidepression, hoping to provide more information on exercise-induced antidepression and brain plasticity theory, finally contributing to the design of precise exercise prescriptions for depression.

| Observational study
Exercise can not only enhance physical health, reduce diseases, but also promote psychological development. Salgureo et al 10 found that physical activity was significantly correlated with depression in 436 elderly Spanish people (60-98 years) (the Geriatric Depression Scale, GDS score), and more active physical activity was associated with lower depression level. Another study with 622 elderly people showed that low-intensity physical activity (<150 min/wk) increased the risk of depression (OR = 4.23) and led to lower cognitive function. 11 In a meta-analysis, Schuch et al 12 found that people with high levels of physical activity were less likely to suffer from depression (OR = 0.83), which was more prominent in the elderly. In addition, lower limb muscle strength, balance, and walking speed were found negatively correlated with depression level in the elderly, indicating that the motor function of the elderly was closely related to depression. 13 Long-term follow-up studies further revealed the association between exercise and depression. A recent 11-year follow-up study of 33 908 adults found that regular exercise has helped to reduce depression, with 1-hour exercise a week reducing the risk of depression by 12%. 2 After 2 years of follow-up, Li et al 14 found that every 10 MET-min/d decrease in physical activity level increased the risk of depression by 1.1% in boys and 2.1% in girls among college students, and every 10-s prolongation in running test increased the risk of depression by 1.5% in boys and 6.3% in girls; thus, the author believed that cardiopulmonary endurance played a mediating role in physical activity and depression risk. Improving physical activity and cardiopulmonary endurance can effectively reduce the risk of depression. Physical activity can also reduce the disability rate of depressed elderly. Lee 17 Hamer and Stamatakis 18 followed up 6359 elderly people for 2 years and found that moderate-intensity exercise at least once a week slowed down depression and improved speech fluency and memory.

| The research on experimental intervention
Cumulative randomized controlled trials and a number of systematic reviews have explored the impact of exercise on depression. Aerobic exercise, resistance exercise, and mind-body exercise were the most common exercise interventions. As early as 1984, McCann and his colleagues investigated the effect of aerobic exercise on depression. Forty-three depression patients were randomly assigned to an aerobic exercise treatment group, a relaxation therapy group, and a no-treatment group, and the results provided the first controlled evidence concerning the effects of aerobic exercise on depression. 19 Later, the interventions of aerobic exercise, such as walking and jogging, were found to improve the symptoms of depression. 20 Researchers also found that resistance exercise can be used alone or as an adjuvant treatment for depression. In 1997, Singh and his colleagues randomized 32 older adults with depression to either a resistance exercise group or a control group, and they found depression was significantly improved after resistance exercise. 21 In recent years, Taijiquan and Yoga, which can be regarded as mind-body exercise, have been accepted and loved by many people to relieve depression symptoms. 22,23 Here, we reviewed the antidepression effects of these three different types of exercise: aerobic exercise, resistance exercise, and mind-body exercise (Table 1).

| Aerobic exercise
Aerobic exercise is easy to engage and has great health benefits, and it is based on aerobic metabolism, big muscle group, longlasting time, and regular rhythm. 24 Many researches have revealed good antidepressant effect of aerobic exercise. Aerobic exercise can change monoamine neurotransmitters, increasing the levels of 5-HT and norepinephrine and reducing the cortisol level, leading to alleviation of depressive symptoms. 25 In addition, aerobic exercise was also associated with neuroactive substance concentration in the central nervous system of depressive rats and the activation of brain BDNF. 26 Active aerobic exercises also increase beta-endorphin. 27 Although many studies have shown that aerobic exercise has a better antidepressant effect than traditional medicine, the dose-response to aerobic exercise in people with depression remains equivocal. Systematic reviews have shown that moderate-intensity aerobic exercise for at least 9 weeks, 3-4 days a week, can effectively reduce the risk of depression. 28 Previous studies have shown that long-term exercise appears to be more effective as compared to short-term one. Nevertheless, one study showed that aerobic interval training intensity of 80% of maximum heart rate (MHR) in a short period of training (10 days) could substantially improve symptoms of depression. 29 Blumenthal and colleagues found that aerobic exercise with intensity of 70%-85% MHR, 30-minute sessions, three times a week for four months, had a similar effect with antidepressant. 30 Helgadttir et al 31

found that the Montgomery and Asberg
Depression Rating Scale (MADRS) scores of depressive patients (18-67 years) were significantly lower after low-intensity aerobic exercise compared with moderate-or high-intensity aerobic exercises (three times a week for 12 weeks); therefore, the author believed that moderate-and high-intensity aerobic exercises are more effective than the low-intensity one. Another study reported on shortterm (4 weeks, three times a week), high-intensity (80% VO 2max ), and low-intensity (60% VO 2max ) bicycling exercises in patients with unipolar depression, and found that the Beck Depression Inventory-II (BDI-II) score was decreased by 85% after high-intensity exercise. 32 Trivedi et al 33 explored the effects of 12-week high-intensity walking (16 kcal/kg/wk) and low-intensity walking (4 kcal/kg/wk) on depression, and the Hamilton Depression Scale (HDRS) showed that both of them achieved significant improvement in depression (P < .001), and intensive exercise was more conducive to reducing depression levels.
Current evidence indicates that high-intensity aerobic exercise is superior to the low-intensity one for depression treatment. Due to different forms of aerobic exercise and individual differences, the methods to evaluate exercise intensity are different between studies. There are absolute index (METs) and relative index (%HRR, %HRmax,%VO2max), and the ranges of low-, moderate-, and high-intensity exercise are also different, which makes it hard to provide significant insight into the effective exercise intensity for depression treatment. 34 So more accurate and rigorous limits are needed for aerobic exercise intensity in depression treatment, and systematic studies should be conducted to explore the dose-response effect of aerobic exercise intensity in depressive people.

| Resistance exercise
Resistance exercise is characterized by muscle against resistance, and it is an effective way to increase muscle strength, volume, and endurance. Resistance exercise can not only delay muscular degeneration, promote metabolism, and effectively reduce age-related falls and fractures, but also alleviate anxiety, inferiority, and other bad moods. 35,36 Compared with aerobic exercise, resistance exercise has been less studied for its role in depression treatment, but evidence was found that resistance exercise can be used separately or jointly for depression treatment. 37 Lecheminant et al 38  the CES-D scores of depressive patients were decreased, the plasma levels of 5-HT and the NE were increased, and the cortisol levels were decreased. Therefore, the change in monoamine transmitter is associated with exercise-induced improvement in depression.
Although resistance exercise has been proven to have antidepression effect, it is more difficult to implement resistance exercise in actual exercise plan than aerobic exercise. Resistance exercise requires high skill guidance and almost perfect equipment, which is a potential obstacle, and long-term follow-up studies and detailed descriptions of intensity and type of exercise are still needed for resistance exercise. Questionnaire-9 (PHQ-9) were decreased in both groups. One-year follow-up found significantly improved depression in patients involved in long-term regular yoga (P < .05). 50 Another latest research found no significant difference in moderately depressed women between 10-week yoga group and health education group (P = .36), but after 6 months, the PHQ-9 score was decreased by more than 50%

| Mind-body exercise
in 51% of the women in the yoga group. 51

| Changes in brain plasticity of depression patients
Increasingly more evidence revealed that depression is closely related to brain structure and functional changes. Functional magnetic resonance imaging (fMRI), event-related potentials (ERP), and spontaneous electroencephalograms (EEG) have identified structural and functional abnormalities in key brain regions of depression patients, including volume changes and functional damage. 57 Techniques such as voxel-based morphometry (VBM) and near-infrared spectroscopy (NIRS) have led to the availability of many useful methods for further identifying brain plasticity changes in depression patients.

| Changes in brain structure
In patients with depression, brain structure changes are closely associated with certain parts of the nervous system, including the frontal lobe, cingulate gyrus, hippocampus, striatum, and white matter. 58 Reductions in brain volume (including structural brain changes such as neuronal loss and decreased neurotrophic factor) are related to de-

| Changes in brain function
There are a wide range of brain dysfunction and asymmetry in the patients with depression during the resting state. Abnormal spontaneous neuronal activity was observed in multiple brain regions at resting state in depression patients. 68

| Exercise rebuilds brain structure
Exercise is closely related to certain brain structures, and it may affect depressive emotion by rebuilding brain structure. Animal exper-

| Exercise activates function of related brain regions
Exercise can promote brain function in patients with depression, affect brain function, and promote generation of positive emotions.
ERP and EEG studies have revealed the differences in functional activation of brain regions associated with exercise. Many  and β1 rhythms were increased in both high and low anxiety groups, indicating that anxiety has been converted into mind and body relaxation and emotional stability after Taijiquan exercises. 86  In summary, appropriate exercise can induce positive changes in EPR and EEG, and activate brain function in patients with depression.
However, related studies on exercise and neuroimaging in depression are rarely reported. The related studies should be strengthened, and exercise-induced activation of depression-related brain regions should be comprehensively examined. Depression can lead to brain structure changes and affect brain function. Exercise can effectively protect brain plasticity and promote brain health. Furthermore, appropriate exercise has positive impact on maintaining the integrity of hippocampal volume and white matter volume, promoting the regeneration of hippocampus, activating the function of prefrontal cortex, and eventually improving the brain neuroprocessing efficiency and delaying cognitive degradation in depression patients. 3. Depression patients have different degrees of impairment in brain structure and function, as reflected in the changes in hippocampal structure, frontal lobe, temporal lobe, cerebellum, and other regional functions. A variety of neuroimaging techniques (represented by BOLD-fMRI and NIRS) and neuroelectrophysiological techniques (represented by EEG and ERP) have revealed brain plasticity changes in depression.

Exercise has a positive effect on brain plasticity in patients with
depression. It can rebuild brain structure, activate related brain regions, and promote adaptive changes in behavior; it also has a positive effect on maintaining hippocampal volume and white matter volume integrity, thus improving brain nerve processing efficiency and delaying degradation of cognitive function. The neuroprotective and brain activation effects of exercise have been revealed from a mechanistic perspective.

| To establish accurate exercise prescriptions for depressive symptoms
Researchers have designed many exercise intervention programs, but the existing studies are mainly based on the recommendations of the American Sports Medicine Society, and consider only the general functions of exercises, so they are not fully applicable for depressive population. Besides, the relevant intensities of aerobic exercise, resistance exercise, and mind-body exercise are not clearly defined. And the specific mechanisms of different exercise patterns against depression remain unclear. Therefore, the brain plasticity of different exercise patterns needs to be further clarified, and the load, frequency, and duration of exercises should be seriously designed to formulate more accurate exercise prescriptions.

| To emphasize studies of different depressive populations
Existing research has mainly focused on depressive adults around 60 years old. With the increase in age, brain plasticity and cognitive function will decline; therefore, it is easier to judge the effects of exercise interventions. However, fewer studies have focused on young people and children. At present, depression is more frequently found in younger people, with the incidence in adolescents being 5%-8%.
Children and adolescents are in a sensitive period of mind-body development, which gives it especial significance to prevent and treat depression through exercise. Future studies on antidepression exercise should consider different age groups.

| To combine multimodal brain imaging with multiple analytical methods
Single-modality and single-analysis methods have limitations in identifying the brain plasticity mechanisms underlying the involvement of exercise in depression. Multimodal brain imaging combined with multiple analytical methods can approach the effect of exercise on brain structure and function in a more comprehensive way and from different aspects. In future studies, techniques such as fMRI, VBM, ERP, EEG, and NIRS should be used comprehensively to collect data, eventually contributing to the early diagnosis and exercise intervention of depression.

ACK N OWLED G M ENTS
The results of the study are presented clearly, honestly, and without fabrication, or inappropriate data manipulation.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.