. In studies with humans, the subjects were submitted to different PE protocols, including pilates, dance, and sports that demonstrated elevated serum and plasma BDNF levels that were evaluated by the ELISA method (Müller et al. [[40]]; Eftekhari and Etemadifar [[39]]; Rehfeld et al. [[42]]) (Table 4). However, when different cycling intensity patterns were used, no differences were observed on BNDF serum levels (Woost et al. [[43]]).

In human studies, only one study used a sample composed exclusively of women. The others used both sexes. The participants' ages ranged from 18 to 80 years old. Among the brain areas evaluated, three studies used magnetic resonance imaging (MRI) to analyze the hippocampus; one evaluated the dorsolateral prefrontal cortex, posterior cingulate, precuneus cortex, hand motor area, occipital lobe, and cerebellum. One of the studies did not report the assessed brain area (Eftekhari and Etemadifar [[39]]). Of the six selected studies, two studies used strength training, two studies performed dance activities, one study utilizes cycling, one used combined exercise (aerobic, balance, weightlifting, and yoga), and one study used balance and relaxation exercises.

The brain is characterized by having a high plastic capacity; it is necessary to elucidate how environmental factors, such as PE, can influence the production of neurotrophic factors providing improvements in brain functionality, through signaling, growth, and cell differentiation. The main aim of this systematic review is to evaluate the effects of different PE protocols on neuroplasticity components in a human and animal study. The second aim is to evaluate the effects of PE on the production of neurotrophic factors, signaling, cell growth and differentiation, and functional outcomes

Environmental stimuli throughout life can result in structural and functional changes in organs and tissues (Westneat et al. [[ 1]]). These changes are more propitious in structure that has plastic characteristics, as for example the brain, susceptible to changes from development to aging (Martínez-Morga et al. [[ 2]]). This process is called neuroplasticity and is defined as the capacity of the central nervous system to promote the neurogenesis and connections due to psychophysiological and environmental factors (Gulyaeva [[ 3]]). In this sense, neuroplasticity occurs with an increase in the production of neurotrophins that generate changes in the growth and differentiation of cell signaling (Kempermann et al. [[ 4]]).

Results. PE increases neuroplasticity via neurotrophic factors (BDNF, GDNF, and NGF) and receptor (TrkB and P75NTR) production providing improvements in neuroplasticity, and cognitive function (learning and memory) in human and animal models.

Methods. We conducted a systematic review process from November 2019 to January 2020 of the following databases: PubMed, ScienceDirect, SciELO, LILACS, and Scopus. A keyword combination referring to PE and neuroplasticity was included as part of a more thorough search process. From an initial number of 20,782 original articles, after reading the titles and abstracts, twenty-one original articles were included.

Objective. To evaluate the effects of different PE protocols on neuroplasticity components and brain function in a human and animal model.

Background. Physical exercise (PE) has been associated with increase neuroplasticity, neurotrophic factors, and improvements in brain function

The duration of each TENS treatment is 20 minutes. The intensity is raised carefully until the participant feels a slight pricklingsensation. The aim is to keep the intensity as minimal/low as possible (less than 10 niA). If the participant is adapted to thesensation, raising the intensity once is allowed

limitation is that progressively increasingthe intensity of the therapeutic exerciseregimen may temporarily causeincreased headache as a side effect.

We expected that the participants independently com mitted to the training athome and followed the 6 different training modules and the progression ofthe program, w hich may result inreduced headache.

Another limitation isthe m ulticenter setting com pared w ith asingle-center study. Multicenter studiesrequire careful m onitoring to ensure thatall study personnel follow the protocolexactly and that standardized assessmenttechniques are used in this study

The first limitation is the inability to perform blinding. A therapeutic exercisetraining regimen is easy to be recognizedas an active treatment; therefore, the participants cannot be blinded. The physicaltherapists w ho perform ed the carefulassessments w ere recruited on the basisof being the best in their field

e successive modules from 4 to 6 of the progressive training program, w e em phasized increasing the endurance of theneck muscles.

the first 3 modules of the therapeutic exercises w ere mainly aimed atimproving the participants’ awareness ofpostural control in the craniocervicaland cervicothoracic regions

Therefore, the first 2 THEX modulesw ere of very low intensity in order tominimize discontinuation of training andto maximize training adherence.

Mild progression also wasimportant because of the potential risk ofexercise-induced headaches andmigraines, w hich often result indecreased training motivation later on

there is preliminary evidencethat patients with mild migraine maybenefit from aerobic training.1

Women with chronic headache are frequent clients of public health services,and they often visit several physiciansand other health care providers in orderto get relief for their headache, causing amajor burden to the health care system

The sample sizeof the trial was estimated based on thechange in headache intensity measuredby VAS in the study by Ylinen et al.-s Asample size of 49 people in each groupwas calculated to detect a decrease of 20mm in VAS scores in the THEX groupversus no change in the TENS group at 6months to achieve 90%

The participants randomly assigned tothe TENS group (control group) received6 individual 45-minute placebo treatment sessions at same time points as theTHEX group (Tab. 2), where TENS of lessthan 10 mA

, 3 supervised stretching exercises for the neck muscles were prescribed for the participants in bothgroups as home exercises (

Home training. After the supervisedsession at the beginning of the THEX M1to M4 sessions, the participants wereprescribed to perform the exercises athome. The exercises took place once aday, 6 days a week.

Supervised training sessions(Tab. 2). The first 2 sessions of theTHEX modules (Ml and M2 for posturalimprovement) included individual supervision. The interval between the sessionsfrom THEX Ml to M2 and from M2 to M3was 2 weeks, respectively. The remaining 4 THEX modules (M3-M6) were conducted for 6 weeks each, with one supervised group session at the beginning ofeach module.

The main goals ofthe therapeutic exercise program were(1) to improve postural and movementcontrol of the cervical spine and shoulder region and (2) to strengthen the muscles important for body posture. Twoexperienced physical therapists, one ateach study center, instructed and supervised the THEX program

Patients. The participants are women aged 18 to 60 years with chronic cervicogenicheadache or migraine

S e c o n d a ry o u tc o m e s . The HeadacheImpact Test-6 (HIT-6),20 w hich consistsof 6 items (pain, social functioning, rolefunctioning, vitality, cognitive functioning, and psychological distress), wasused to assess the im pact of headache ondaily life.

P rim a ry o u tc o m e . During the6-month training period, all participantsw ere requested to report each episode ofheadache every day, including its intensity, frequency, and duration (the timew hen the headache began and ended),using a diary. The intensity' of headachewas assessed using the VAS (0 -1 0 0 ).'819The duration of headaches was calculated as weekly minutes.

Our main hypothesis is that the specifictherapeutic exercise training programwill alleviate the intensity, frequency,and duration of headache. We also studyhow the therapeutic exercise programinfluences the function of the neck, theindividual’s quality of life, and the use ofmedication and other treatments.

16 The principles of therapeuticexercise in successfully treating patientswith chronic headache consist of low-load and low-intensity proprioceptivetraining at the first phase and specifichigh-load and high-intensity exercises inthe later phase of the program, or theformer or the latter throughout the treatment period.2

On the other hand, aerobictraining, relaxation therapy, and biofeedback have mainly been applied forpatients with migraine.

patients with cervicogenic headache andtension-type headache, several components of physical therapy have beenused, including ultrasound, transcutaneous electrical nerve stimulation (TENS),stretching, relaxation with active kineticcontrol movements, and manual treatment.

Headache is among the most common reasons for visits to primarycare physicians and physical therapists among working women.12 Headaches affect almost half of the adult population worldwide.3' 5 The estimatedcosts of migraine alone are €27 billion inEurope.5

The therapists are not blinded

Intervention. The treatment group’s exercise program consisted of 6 progressive therapeutic exercise modules, including proprioceptive low-load progressive craniocervical andcervical exercises and high-load exercises for the neck muscles. The participants in the controlgroup received 6 individually performed sham TENS treatment sessions

Design. A randomized controlled trial with 6-month intervention and follow-up was developed. The participants were randomly assigned to either a treatment group or a control group

Objective. The aim of this study is to investigate whether a progressive, group-basedtherapeutic exercise program decreases the intensity and frequency of chronic headacheamong women compared with a control group receiving a sham dose of transcutaneouselectrical nerve stimulation (TENS) and stretching exercises.

Background. Cervlcogenic headache and migraine are common causes of visits to physicians and physical therapists. Few randomized trials utilizing active physical therapy andprogressive therapeutic exercise have been previously published. The existing evidence onactive treatment methods supports a moderate effect on cervicogenic headache

Therapeutic Exercise Training toReduce Chronic Headache in WorkingWomen: Design of a RandomizedControlled Trial

BRAINFor years, it was thought that we stopped making fresh neurons (cells that send signals to and from the brain) in puberty. Yet it now transpires that this isn't the case. "The brain, like other organs in the body, is constantly trying to fix itself, just like the skin tries to heal itself after a nick or cut," says Norman Doidge, a US psychiatrist and author of The Brain That Changes Itself. Help it along: A study from Tufts University in Boston, US, has shown that exercise can induce neurogenesis - the formation of new neurons - which helps your memory and learning. So, aim for at least 30 minutes of exercise three times a week. And there's no need to feel guilty about your caffeine intake. The study, published in the Journal Of Neuroinflammation, found that just one cup of fresh coffee each morning could cut your risk of dementia by up to a third, by blocking damaging cholesterol that can affect your brain.

recent research has shown that the combination of time-restricted eating and HIIT may have additive effects on glycemic control and fat mass reduction in women with overweight/obesity.

In this regard, a considerable number of studies support that afternoon/evening exercise may be more effective than morning exercise to improve several metabolic outcomes, such as glycemic control, blood pressure, or lipid profile.

exercise timing may play an important role in the management of different metabolic conditions, such as obesity, T2DM, dyslipidemia, or hypertension.

As different exercise modalities, as well as distinct frequency, intensity, or duration of exercise, may lead to different metabolic effects, specific training programs should be prescribed.

it is important to take into account that inter-individual differences in the preferred circadian pattern of activity and sleep–wake cycles (i.e., different chronotypes) could imply distinct responses to morning/evening exercise.

it is important to keep in mind that mitochondrial activity and dynamics follow a circadian pattern,79, 121 and disrupted circadian oscillations in different metabolic diseases, such as T2DM, are related to an altered mitochondrial metabolism.

It is noteworthy that exercise training is able to induce beneficial mitochondrial adaptations, including enhanced mitochondrial content, protein synthesis, oxidative capacity, or biogenesis, as well as the more efficient removal of dysfunctional/damaged mitochondria, with derived benefits in metabolic health.

The systemic response to exercise also involves the activation of the immune system, which plays an important role in the modulation of metabolism.

Beyond the skeletal muscle, exercise timing can elicit time-dependent effects on additional tissues, such as adipose tissue.

physical exercise is known to be a key zeitgeber and acts as an essential regulator of circadian clock machinery in the skeletal muscle, with important implications in metabolic health.

the alterations of circadian systems may lead to metabolic disease.96 Thus, circadian disruption has been postulated to be involved in alterations in glucose metabolism/insulin sensitivity and the development of T2DM, obesity, and dyslipidemia.

, trials evaluating the role of timing of HIIT (or multimodal programs including HIIT) in glycemic response showed greater effects of afternoon/evening exercise,39, 41 whereas studies including moderate-intensity aerobic physical activity/exercise in training programs showed conflicting findings

Age might be another potential clinical factor involved in the variability of response to the timing of physical activity/exercise.

(women exercising in the morning experienced greater reductions in body fat and blood pressure, whereas men exercising in the evening achieved greater reductions in blood pressure, as well as a significant increase in fat oxidation).

sex differences may play a role in the potential effects of timing of physical exercise on blood pressure.

Accordingly, several clinical variables, such as sex, age, health status, training status prior to the intervention, exercise modality, or chronotype (discussed in following sections), may explain some of these results

Therefore, a recent randomized trial including healthy volunteers found that 12 weeks of multimodal exercise in the morning led to a stronger decrease in blood pressure in women, whereas a decrease in blood pressure levels was observed in men following evening exercise.

it is known that endogenous circadian clocks have a major influence on blood pressure regulation,76, 77 and the modulation of clock-mediated target genes by time-of-day-based exercise might play a role in these results.

lipid metabolism (including triglyceride and cholesterol synthesis) is under the influence of circadian rhythms, with a peak at night-time,72 and the potential lipid-lowering effects of exercise might be time dependent, similar to other time-based therapeutic strategies (e.g., the use of statins)

Also, a trial conducted in 54 healthy postmenopausal women demonstrated that 2-h moderate-intensity acute exercise performed 1 h after meals was more effective in reducing insulin resistance than exercise performed 1 h before meals.

In fact, a growing body of evidence suggests that the interaction between exercise timing and the timing of food intake may play an important role in the modulation of the circadian clock and the prevention of metabolic diseases, such as T2DM

Physical exercise is a key modulator of metabolism and exerts protective effects against the development and progression of metabolic diseases.

In a cross-sectional analysis including more than 7000 older women from the Women's Health Study, the lowest quartile of physical activity in the morning (measured by percent accelerometer counts before 12 p.m. according to total accelerometer counts per day) was associated with a higher risk of obesity.

T2DM, a randomized trial including 25 men with overweight and obesity and no T2DM found that 5-day evening training (HIIT and moderate-intensity cycling), but not morning training, improved nocturnal glycemic control (assessed by CGM) after a short-term high-fat diet

resistance-based exercises [12–18 repetitions]) conducted in 40 adults with overweight with and without T2DM showed no significant differences between morning/evening exercises with regard to glycemic outcomes (HbA1c, fasting glucose, and postprandial glucose).36 Indeed, no differences in the circadian rhythm of wrist skin temperature (which could be used as proxy for the rhythmicity in the central clock),64 in response to training (evaluated >24 h after the final training session, compared with pre-intervention), were observed, although the authors argued that a higher exercise intensity/duration might have resulted in greater shifts in the circadian rhythms and glucose metabolism

Moreover, as glucose tolerance and insulin sensitivity exhibit circadian oscillations, the alignment of circadian clocks with specific time-of-day-based exercise bouts may induce greater effects on glucose metabolism.63

A randomized crossover trial of 11 men with T2DM that underwent 2 weeks of morning/afternoon HIIT (3 sessions/week) demonstrated that afternoon HIIT resulted in the improvement of glucose levels measured by continuous glucose monitoring (CGM) compared with morning HIIT.

differences in meal timing in relation to exercise were not assessed in most studies evaluated in this section.

a recent trial showed that acute evening exercise prompted greater post-exercise ad libitum energy intake than morning exercise

Thus, it has been postulated that timing of exercise may involve a different release of signals and appetite-related hormones, which might have an influence on appetite regulation and energy intake

it should be mentioned that only a few studies have evaluated the effects of exercise timing on weight loss/changes in body composition in other potentially effective modalities, such as HIIT or resistance training.

l, a reduction in dietary intake is considered as a key element in weight loss, whereas exercise may facilitate weight loss maintenance,54 a fact that should be considered in the aforementioned studies.

Although Brooker et al. did not find significant differences in weight loss in a 12-week randomized trial (100 inactive adults with overweight/obesity, 76% women) between morning/evening self-paced aerobic exercises (250 min/week), a greater proportion of participants in the evening group achieved clinically meaningful weight loss (>5%).38

contrast, in an interventional study conducted in 42 sedentary postmenopausal women with BMI ≥ 25 kg/m2, evening walking led to greater reductions in fat mass than morning walking.

but not in men, with no changes in the self-reported dietary intake during a 12-week intervention of multimodal training regimen (resistance, high-intensity interval training [HIIT], stretching, and endurance exercise).

10-month Midwest Exercise Trial 2, including 88 physically inactive young adults with overweight/obesity, the predominant completion of aerobic training sessions between 7:00 and 11:59 a.m. was associated with greater weight loss than 3:00 and 7:00 p.m. (−7.2 ± 1.2% vs. −2.1 ± 1.0%, respectively), although no significant differences in terms of en

Despite the fact that no differences related to overall appetite scores between groups were found, the morning group presented a higher satiety and a decrease in calorie intake during the intervention, which might explain, in part, these results.

Time-of-day-based exercise could be useful for the management of obesity. In this regard, in a 6-week randomized control trial including 48 adult women with overweight, 30 min of moderate- to high-intensity morning treadmill running (3 sessions/week) resulted in greater reductions in body weight, body mass index (BMI), and abdominal circumference than the evening group

Physical exercise performed at different times of the day may result in diverse health outcomes. In the following subsections, we explore the impact of exercise timing on the prevention and treatment of the main components of metabolic syndrome, including obesity, insulin resistance/T2DM, dyslipidemia, and hypertension

, we summarize the current knowledge on the role of exercise timing in metabolic health and discuss the potential mechanisms involved in time-dependent metabolic outcomes related to physical exercise.

the timing of food intake, as well as the distribution of calorie consumption through the day, can result in different effects on weight loss and distinct metabolic parameters.

the disruption of circadian rhythms may lead to the development of metabolic diseases.

Circadian rhythms are essential processes in human physiology and play a central role in a wide range of molecular mechanisms involved in metabolism and energy homeostasis.

physical exercise acts as a key modifier in the development and progression of several chronic diseases, including obesity and related metabolic disorders

imbalance between energy intake and expenditure, including unhealthy dietary habits and a sedentary lifestyle, has been demonstrated to be a decisive factor in the pathophysiology of metabolic diseases

this article, we review the role of exercise timing in metabolic health and discuss the potential mechanisms that could drive the metabolic-related benefits of physical exercise performed in a time-dependent manner.

s. Similar to other time-based interventions, including nutritional therapy or drug administration, time-of-day-based exercise may become a useful approach for the management of metabolic disorders.

exercise training includes different modalities, with variable intensity, duration, volume, or frequency, which may have a distinct impact on several characteristics related to metabolic syndrome, the potential effects of exercise timing on metabolic health are yet to be fully elucidated.