MSc Brain and Cognitive Sciences
Behavioural Neuroscience
The Effects of Exercise on Structural and Functional Changes in the Brain: A Systematic Review Siel Hoornaert 12779385 January 2021 12 ECTS 3rd Period
Supervisor: Assessor: Examiner:
2 Literature Thesis S.L. Hoornaert
Abstract
Exercising is a popular way of improving general health and has been implicated to change the brain on a structural and functional level. Yet, to date, no systematic review has evaluated the effects of exercise on hippocampal volume, cortical thickness, hippocampal activity, or other changes in the brain using magnetic resonance imaging (MRI), within psychiatry. A search was conducted using PubMed, in which 18 randomised controlled trials (RCTs) were selected that included participants in three subcategories: (1) healthy, (2) depression, (3) schizophrenia. The present systematic review evaluated the effect of an exercise intervention on (f)MRI outcomes, including hippocampal volume, cortical thickness, depressive symptoms, schizophrenic symptoms, and functional changes in brain (i.e., GABA levels and hippocampal activity). There was no conclusive evidence that exercise increases hippocampal volume, however studies suggest that cortical thickness is increased following an exercise intervention. In addition to this, research indicates that depressive symptoms are significantly improved after exercise, although the evidence for symptom alleviation in schizophrenia is mixed. The RCTs were heterogeneous in methods and outcome measures, limiting the comparison of results. Future research should standardise the methods and neurobiological markers under investigation, in order to clarify which biological mechanisms of exercise may alter brain structure and function, both within healthy participants and/or patients suffering from a psychiatric disorder.
3 Literature Thesis S.L. Hoornaert
1 Introduction
It is widely known that exercise has a vast range of health benefits both physically and mentally, such as improving heart rate and blood pressure and reducing the risk of cognitive impairment (Erickson et al., 2011; Byrne & Byrne, 1993). Several lines of research suggest health benefits of exercise on the human brain; however, findings were often cross-sectional and much of this previous research was conducted on animals (Vaynman & Gomez-Pinilla, 2006; Hillman, Erickson & Kramer, 2008). Generally speaking, exercise has been found to induce both structural and functional changes in the brain (Erickson & Kramer, 2009). Aerobic exercise (also known as cardio- or cardiorespiratory exercise) has been found to improve memory performance, executive functioning, increase cerebral blood volume, increase hippocampal volume, enhance learning, and increase both grey and white matter volume in the prefrontal cortex, among others (Hillman, Erickson & Kramer, 2008; Colcombe et al., 2006). Animal studies performed on mice have corroborated these results, demonstrating a relationship between exercise training and hippocampal volume, and cell proliferation in the hippocampus (Van Praag et al., 2005). However, available evidence from human studies on linking exercise to the brain is often inconclusive (Engeroff et al., 2018; Gourgouvelis et al., 2017; Young et al., 2015).
It is hypothesised that exercise may have advantageous effects on the brain because of its capacity to facilitate neuroplasticity and reverse age-associated loss of volume in certain brain areas (Van Praag, Kempermann & Gage, 1999; Cotman & Berchtold, 2002). According to Parker and colleagues (2011), humans show loss of hippocampal volume both in normal aging and in disease pathologies (including schizophrenia and major depressive disorder). Both cross-sectional and longitudinal studies show that exercise stimulates the reverse: increased hippocampal volume, preserved grey matter volume, and improved cognitive functioning (Vaynman & Gomez-Pinilla, 2006; Hillman, Erickson & Kramer, 2008; Erickson et al., 2010).
4 Literature Thesis S.L. Hoornaert Rodent studies have shown that exercise leads to neuro-, synapto- and angiogenesis in the hippocampus, particularly in the dentate gyrus, in addition to hippocampal blood volume increases, which are in turn associated with improved cognitive functioning, such as learning and spatial memory (Pereira et al., 2007; Lopez-Lopez, LeRoith & Torres-Aleman, 2004; Voss
et al., 2013; Van Praag, 2008). Studies conducted in human populations also find increased
hippocampal volume, improved structural plasticity, and improved cerebrovascular integrity (Erickson et al., 2011; Colcombe et al., 2006; Thomas et al., 2016). However, to date, much of the evidence from human populations comes from cross-sectional studies, hampering causative interpretation of effects (Pajonk et al., 2010). The divergent results may be explained by the nature of the exercise intervention used in different studies (Papiol et al., 2019). Given that the existing literature studied different types, lengths, and intensities of exercise, it is important to analyse and assess these outcomes. The current literature thesis will therefore focus specifically on randomised controlled trials and clinical trials to examine the impact of exercise on the brain.
1.1 Depression and Schizophrenia
One of ways in which exercise RTCs might show particular utility is in psychiatric disorders, such as depression and schizophrenia. The present systematic review will therefore include these to study the effects that exercise can have on structural and functional changes in the brain. Depression is a psychiatric illness characterised by depressed mood or anhedonia, fatigue, loss of energy, or decreased concentration (among many other symptoms; Tolentino & Schmidt, 2018). Alternatively, people suffering from schizophrenia can experience hallucinations, negative symptoms (such as diminished emotional expression), and social dysfunction (among others; Glasheen, 2016).
According to the World Health Organisation, 264 million people worldwide suffer from depression today (James et al., 2018 in: WHO, 2020). People with depression frequently suffer
5 Literature Thesis S.L. Hoornaert from memory impairment, which can persist even after taking antidepressants (Gourgouvelis
et al.,2017). The hippocampal region is therefore thought to play an important role and has
been shown to significantly reduce in volume during major depressive disorder (MDD; Schmaal et al., 2016). Previous research points to decreased neurogenesis as an explanation for the observed decreases in hippocampal volume (Krogh et al., 2014). Additional hypotheses include the GABA hypothesis, in which imaging studies have found that deficits in GABA (gamma-aminobutyric acid, a prominent neurotransmitter) and depressive symptoms are related (Luscher, Shen & Sahir, 2011).
Schizophrenia (SCZ) is another chronic and severe psychiatric disease, associated with impaired cognitive functioning and brain deficits (Kuperberg & Heckers, 2000; Honea et al., 2005). People with SCZ also show reduced hippocampal volume, dysfunction of neural plasticity, impairment of adult neurogenesis, and cortical grey matter deficits (e.g., Honea et
al., 2005; Weiss et al., 2005; Adriano, Caltagirone & Spalletta, 2012). The structural changes
in SCZ, particularly the smaller hippocampal volume, correlate with the severity and deficits of the disease, such as impaired functioning of declarative memory (Papiol et al., 2019; Malchow et al., 2016). According to Scheewe et al., (2013) brain volume reductions and disease symptoms could be explained and enhanced by lack of physical exercise, especially considering antipsychotic medications often include side effects such as weight gain and adverse cardiometabolic effects (Protopopova et al., 2011).
Exercise is thought to be an efficacious treatment of psychiatric disorders such as depression and schizophrenia for a number of reasons: (1) physical activity can be accessible and relatively, (2) physical activity does not have a wide range of physical and cognitive side effects (excluding potential injuries), unlike many pharmacological treatments, (3) exercise has been found to improve symptoms for both SCZ and depression, (4) medication alone is not considered a successful treatment of depression for everyone, as almost half of the individuals
6 Literature Thesis S.L. Hoornaert do not achieve remission, and it is more effective for some than others (5) management of SCZ symptoms is only partly successful with the current antipsychotic medication available, (6) exercise has been found to be successful in targeting neural volume increase in the brain (Colcombe et al., 2006; Van Praag, 2008; Vancampfort et al., 2011 in: Woodward et al., 2018; Pereira et al., 2007). It is hypothesised that neuroplasticity in the hippocampus could improve symptoms in SCZ, a process that can be stimulated by physical activity (Papiol et al., 2019). Similarly, individuals with depression show structural abnormalities (e.g., in the hippocampus), which in turn overlap with the effects of exercising in the brain (Gujral et al., 2017; Gujral et al., 2019). There is a clear motive to study exercise as a potential treatment (additional to others, e.g. pharmacological strategies), for individuals who suffer from both depression and SCZ. However, much is unknown regarding the neural mechanisms of this symptom-alleviating potential of exercise. The primary aim of this literature review is therefore to examine the direct impact of exercise RCTs on brain structure and function.
2. Methods
2.1 Literature Search
One author conducted the literature search using the PubMed database from November to December 2020. The following search terms were used: (((("exercise" OR "physical activity")) AND ("depress*" OR "anxiety" or "schizophrenia" OR "bipolar" OR "obsessive compulsive disorder" OR "OCD" OR "psychiatry")) AND ("cortical thickness" OR "magnetic resonance imaging" OR "MRI" OR "resting state" OR "subcortical" OR "cortical")) NOT ("mice" OR "rat" OR "hamster" OR "traumatic brain injury" OR "arthritis" OR "stroke" OR "fibromyalgia" OR "diabetes" OR "cancer" OR "kidney" OR "coronary artery disease" OR "asthma" OR "parkins*" OR "HIV" OR "multiple sclerosis" OR "Alzheimer*" OR "chronic heart failure" OR "Spine*" OR "Spinal" OR "epilepsy" OR "COPD" OR "bowel" OR "pain")). A filter was used to select randomised controlled trials and clinical trials using human subjects.
7 Literature Thesis S.L. Hoornaert Reference lists of studies that were found using the above term were also used to find eligible articles (“snowballing”). However, it should be noted that due to time constraints, it was not
feasible to methodically check every single reference in the included papers.
2.2 Study Selection
Articles were initially reviewed at the title and abstract level for potential eligibility. The inclusion criteria were: (1) study involved subjects from healthy and/or patient populations healthy, (2) published in English, (3) used (f)MRI for brain outcome measures, both structural or functional, (3) included a longitudinal exercise-based intervention (i.e., not a single exercise session).
Articles that measured brain changes not measured using an MRI machine were excluded (e.g., serum brain derived neurotrophic factor; BDNF). Other exclusion criteria included lack of a control group compared to the patient group, other cognitive impairments/comorbidities (e.g., mild cognitive impairment; MCI, Alzheimer’s disease,
diabetes, etc.), outcomes that were only measured during a specific task (e.g., one paper looked at the activation of a specific region only during the observation of sports-related activities, which was deemed too specific and non-generalisable for this study; Takahashi et al, 2012).
The data extracted from the selected studies included: participant information (sample size, diagnosis, average age and sex), intervention information (type of exercise, length of intervention, frequency of intervention), outcome information (MRI measures, depression symptoms, SCZ symptoms).
2.3 Outcome Measures
To begin with, an overview of participant characteristics will be given (i.e., sample size, mean age, sex, and diagnosis), in addition to an overview of the nature (i.e., type, frequency, length) of the exercise intervention. The primary outcome measure of this review is structural brain changes as seen on MRI scans, including hippocampal volume and cortical thickness as
8 Literature Thesis S.L. Hoornaert the main measures. Several papers also reported on measures such as cerebral small vein integrity and total intracranial volume, but these will not be the focus of this paper. An additional MRI outcome measure that will be analysed is functional changes in the brain, including thalamic GABA levels, prefrontal cortex (PFC) activity, and hippocampal activity. The third and fourth outcome measures that will be discussed are depressive and schizophrenia symptoms, pre-post testing. Lastly, this literature review will make note of MRI technical parameters and pre-processing software used by the included studies.
3 Results
3.1 Characteristics of Included Studies & Samples
After filtering the search results from PubMed, 18 studies were included in this systematic review (Engeroff et al., 2018; Erickson et al., 2011; Goldin et al., 2013; Gourgouvelis et al., 2017; Gujral et al., 2019; Krogh et al., 2014; Malchow et al., 2016; Pajonk et al., 2010; Papiol
et al., 2019; Paker et al., 2011; Rektorova et al., 2020; Rogge et al., 2018; Scheewe et al.,
2013; Shaaban et al., 2019; Stern et al., 2019; Streeter et al., 2020; Wagner et al., 2015; Woodward et al., 2019). All 18 studies investigated the neural response to an exercise intervention using an MRI machine (for an overview of MRI specifications, see Appendix A), in three subsets of populations: (1) healthy populations (8 studies), (2) participants with depression (5 studies), (3) participants with schizophrenia (5 studies). See the table below for an overview of participant characteristics of the samples included for review (Table A). The table shows sample size (M = 62.72, SD = 44.29), participant age (M = 42.58, SD = 15.99), and participant sex (percentage of female participants; M = 52.29, SD = 25.62) per study included in the systematic review. All included papers had a longitudinal exercise intervention; no acute effects or cross-sectional studies were included. The various interventions are described in the section titled “Exercise Interventions” below.
9 Literature Thesis S.L. Hoornaert *Note: Gujral et al., 2019 included two age groups: old and young
3.2 Exercise Interventions
As stated previously, the exercise interventions employed by different studies vary greatly in type, length, and duration. The effects of exercise were compared to control conditions (which included no exercise or stretching or low impact/intensity exercise). Below is an overview of the different aspects of the interventions listed by study (Table B). The most predominant type of exercise was aerobic exercise, used in 14 of the 18 studies (78%; see Table B). For one study, data on the exercise frequency was unavailable, but in 13/18 studies, participants exercised three times per week (M = 3.18, SD = 1.04). The average length of the intervention was 15.78 weeks (SD = 10.56).
Table A: Overview of Participant Characteristics
Study Diagnosis Sample
Size (N)
Mean Age Sex (% Female)
Rogge et al., 2018 Healthy 59 43.9 63
Enegeroff et al., 2018 Healthy 50 75 N/A
Rektorova et al., 2020 Healthy 62 67.2 68
Shaaban et al., 2019 Healthy 24 74.3 87
Stern et al., 2019 Healthy 132 41.5 71
Wagner et al., 2015 Healthy 34 25 0
Erickson et al., 2010 Healthy 120 67.6 73
Parker et al., 2011 Healthy 13 34 38
Goldin et al., 2013 Depression 56 32 50
Gourgouvelis et al., 2017 Depression 16 37 85
Gujral et al., 2019 Depression 15 28.6 / 67.5* 50 / 50*
Krogh et al., 2014 Depression 79 41.3 67
Streeter et al., 2020 Depression 28 34 80
Malchow et al., 2016 Schizophrenia 64 36.3 50 “matched”
Pajonk et al., 2010 Schizophrenia 24 32.9 0
Papiol et al., 2019 Schizophrenia 64 37.3 40
Scheewe et al., 2013 Schizophrenia 118 28.5 23
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3.3 Psychiatric Symptoms
3.3.1 Depressive Symptoms
This study included five papers that investigated the brain changes as a result of physical activity in people with depression. Three of these papers included a scale to measure depressive symptoms (Gourgouvelis et al., 2017; Gujral et al., 2019; Streeter et al., 2020). In the remaining two, depressive symptom data was only available prior to the intervention (Krogh et al., 2014) or was only measured during a cognitive reappraisal task, in which case it is not possible to say whether the intervention directly impacted depressive symptoms (Goldin et al., 2013). The cognitive assessments used by the five papers are listed below (see Table C). It should be noted that Goldin and colleagues (2013) included patients with social anxiety disorder (SAD) as classified by the DSM-V, but focused on negative emotions and self-beliefs, which is why it was included in this study (in general, 56% of SAD patients have a depressive disorder as well, in addition to 75% of patients with a lifetime diagnosis of SAD having had major depression at least 1 year prior to the diagnosis; Keller, 2003).
Table B: Overview of Exercise Interventions
Study Exercise Type Exercise Frequency
(times per week)
Exercise Duration (weeks)
Rogge et al., 2018 Balance Training 2 12
Engeroff et al., 2018 Aerobic Exercise 3 12
Rektorova et al., 2020 Dance Exercise 3 24
Shaaban et al., 2019 Aerobic Exercise 3 24
Stern et al., 2019 Aerobic Exercise 4 24
Wagner et al., 2015 Aerobic Exercise 3 8
Erickson et al., 2010 Aerobic Exercise N/A 52
Parker et al., 2011 Aerobic Exercise 3 10
Goldin et al., 2013 Aerobic Exercise 3 8
Gourgouvelis et al., 2017 Aerobic Exercise 3 8
Gujral et al., 2019 Aerobic Exercise 3 12
Krogh et al., 2014 Aerobic Exercise 3 12
Streeter et al., 2020 Yoga (high intensity) 7 12
Malchow et al., 2016 Aerobic Exercise 3 6
Pajonk et al., 2010 Aerobic Exercise 3 12
Papiol et al., 2019 Aerobic Exercise 3 12
Scheewe et al., 2013 Cardiorespiratory Exercise 2 24
11 Literature Thesis S.L. Hoornaert Of the papers that assessed depressive symptoms prior to and following the exercise intervention, all three studies found a significant improvement in depressive symptoms. Gourgouvelis et al., (2017) found a group X time interaction in which the depressive group had a greater reduction in depressive symptoms (f (1,15) = 30.42, p < 0 0001). Gujral et al., (2019) found that participants from both groups had significantly reduced depressive scores, in addition to the exercise group having a “more efficient trajectory of decline in depressive symptoms ... (i.e., remitted after a shorter treatment duration relative to the MED group)”
(Gujral et al., 2019). Finally, Streeter et al., (2020) found significant improvements in BDI-II (Beck Depression Inventory) scores for both groups, meaning scores decreased, with p < 0.05. In sum, of the studies that included a scale for depressive symptoms, all found an improvement following the exercise intervention.
3.3.2 Schizophrenic Symptoms
Similar to the depressive studies, five papers were included that investigated the effect of exercise on the brain in patients suffering from schizophrenia. Three papers measured schizophrenic symptoms pre- and post-intervention (Malchow et al., 2016; Pajonk et al., 2010; Woodward et al., 2019), and for the two remaining studies, no data was available for schizophrenia related symptoms (Papiol et al., 2019; Scheewe et al., 2013). The results of the schizophrenia assessments varied. For an overview of the cognitive assessments, see Table D below.
Table C: Overview of Diagnostic Instrument used to Ascertain Depression/Assessments of Depression
Study Assessment
Goldin et al., 2013 Anxiety Disorders Interview Schedule (SAD diagnosis) Gourgouvelis et al., 2017 Montreal Cognitive Assessment & Beck Depression Inventory Gujral et al., 2019 Montgomery Asberg Depression Rating Scale
Krogh et al., 2014 Mini International Neuropsychiatric Interview Streeter et al., 2020 Beck Depression Inventory
12 Literature Thesis S.L. Hoornaert One paper found that there were no significant effects of an exercise intervention for group nor time (Malchow et al., 2016), whereas two papers found that there was an improvement in symptom severity for schizophrenic patients (Pajonk et al., 2010; Woodward et al., 2019). Firstly, Pajonk et al., (2019) found that the symptom severity for schizophrenia decreased in the exercise group by 9% and moreover, symptoms increased for the control participants by 13% (i.e., those who were not in the exercise intervention group; SCZ table-football group & healthy participants). The time X group interaction was significant (F1,14=6.76; p = .02; Pajonk et al., 2010). Secondly, two scales for social functioning were
found to improve significantly in the study conducted by Woodward et al., (2019; t(16) = 4.4, p.
= 0.0004). Overall, two papers found that exercise interventions alleviated schizophrenic symptoms.
3.4 MRI Outcomes: Structural
3.4.1 Hippocampal Volume
Of the 18 papers that were included in this systematic review, 11 examined hippocampal volume as an outcome measure, and among those, 7 found no significant effect of exercise training on hippocampal volume. This included three papers analysing healthy populations (Rogge et al., 2018; Wagner et al., 2015; Parker et al., 2011), one paper analysing populations with depression (Krogh et al., 2014), and finally, three papers with schizophrenic participants (Malchow et al., 2016; Pajonk et al., 2010; Scheewe et al., 2013).
There were four papers that found a significant effect of an exercise intervention on hippocampal volume, where hippocampal volume increased following exercise (healthy: Engeroff et al., 2018; Erickson et al., 2010; Schizophrenia: Papiol et al., 2019; Woodward et
Table D: Overview of Cognitive Assessments for Schizophrenia
Study Cognitive and Functional Assessment: Clinical Diagnosis
Malchow et al., 2016 ICD-10 criteria & MINI-plus interview Pajonk et al., 2010 ICD-10 & DSM-5
Papiol et al., 2019 ICD-10 criteria & MINI-plus interview
Scheewe et al., 2013 Comprehensive Assessment of Schizophrenia and History (CASH) Woodward et al., 2019 DSM-5 criteria
13 Literature Thesis S.L. Hoornaert
al., 2019). Engeroff et al., (2018) conducted a correlational analysis between hippocampal
volume and maximum workload, which is a measure of aerobic- and anaerobic capacity, measured in watts, and found that there was a significant correlation for right hippocampal volume and maximum volume (p = 0.44). The second study with a significant finding found a significant time X group interaction for both the left and right hippocampus (left [F(2,114) = 8.25;
P < 0.001; ηp2 = 0.12] & right [F(2,114) = 10.41; P < 0.001; ηp2 = 0.15]), whereas the hippocampal
volume declined in the control group (Erickson et al., 2010). This was specifically found in the anterior hippocampus, as no significant volume changes were found in the posterior hippocampus (p > 0.10 for left & right; Erickson et al., 2010). Two remaining studies reported significant findings in schizophrenic samples. Firstly, Woodward et al., (2019) found a significant increase in total hippocampal volume (t(16) = −2.54, p. = 0.02). Secondly, Papiol
et al., (2019) looked at hippocampal volume change in correlation with genetic risk burden and
found that these were significantly correlated in the left Ca4/DG subfield for which a threshold of p = .01 was used. Overall, findings are mixed regarding hippocampal volume, as over half of the RCTs did not find a significant interaction between exercise, (time,) and hippocampal volume. However, in the studies that found a significant interaction, exercise increased hippocampal volume.
3.4.2 Cortical Thickness
Findings were relatively homogeneous regarding cortical thickness changes as a result of exercise intervention. In total, 5 papers had cortical thickness as an outcome measure (Rogge
et al., 2018; Rektorova et al., 2020; Stern et al., 2019; Gujral et al., 2019; Scheewe et al., 2013).
Only one paper did not find a significant effect (main or interaction) for cortical thickness changes (schizophrenic sample; Scheewe et al., 2013). One paper with a depressed sample found a significant negative correlation between depression severity and cortical thickness in several brain areas using a Spearman’s rho correlation: (1) anterior cingulate cortex (r = -0.75;
14 Literature Thesis S.L. Hoornaert df = 8; p = 0.01; R2 = 0.56), (2) right medial orbitofrontal cortex (r = -0.78; df = 8; p = 0.008;
R2 = 0.61), (3) right parahippocampal gyrus (r = -0.93; df = 8; p <0.001; R2 = 0.86; Gujral et
al., 2019). The remaining three papers found significant cortical thickness changes in samples
with healthy participants. Firstly, Rogge et al., (2018) found a time X group interaction in a whole brain analysis for cortical thickness in the exercise group in numerous brain regions (i.e., “the superior temporal gyrus extending into the circular insular sulcus, the superior transverse
occipital sulcus, the superior frontal sulcus of the left hemisphere, and the posterior cingulate of the right hemisphere; p < .05, FDR-corrected”). Secondly, Rektorova et al., (2020) also found a significant increase in cortical thickness in the exercise group in a time X group interaction in the right inferior temporal, fusiform and lateral occipital regions (linear effects model: b = 0.032; t(53) = 2.91; P = .005). Lastly, a significant effect of exercise was found on
cortical thickness in the left frontal region (Stern et al., 2019). Taken together, cortical thickness seems to be positive influenced by the exercise intervention, in which the majority of RCTs found increases in cortical thickness.
3.5 MRI Outcomes: Functional
There were two papers that investigated the effect of exercise on brain function, namely on hippocampal activity (Gourgouvelis et al., 2017) and on thalamic GABA levels (Streeter et
al., 2020). An exercise intervention was found to have a small, but significant, effect of time
on hippocampal activity pre-post testing (Gourgouvelis et al., 2017). This was found using a repeated measures ANOVA, in which the main effect of time was significant (F (1,15) = 3.3, p
= 0 09), but there was no group effect or group X time interaction present. Streeter et al., (2020) did not find a significant difference of GABA levels between the low- and high-dose exercise group.
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4 Discussion
The aim of this systematic review was to evaluate the effect of exercise on the human brain, with papers including samples of healthy participants and with those psychiatric illnesses, specifically depression and schizophrenia. An overview of the current state of the literature was made. The results of the participant characteristics and exercise interventions varied, as did the findings regarding psychiatric symptoms, hippocampal volume, cortical thickness, and cognitive function. The present systematic review found evidence for decrease in depressive symptoms and increase in cortical thickness as a result of the exercise interventions used by the different RCTs. However, the evidence is limited and complex, and will be elaborated on below.
4.1 Participant Characteristics & Exercise Interventions
The samples that were included in this systematic review had a very wide range of age groups, with the average age being 42 years (despite much of the previous literature on exercise and brain health – including other outcomes not analysed by the present paper – being conducted in older populations). The sex distribution of participants was 52% female on average, though there was a widespread range between different papers, whereas when looking only at participants in studies with depression, this was 66.4% (SD = 14.62). Worldwide, there is a higher prevalence of depression within women (Salk et al., 2017), which explains the overrepresentation of women in the sample, as it more accurately represents the global population. When looking at the 9 studies that had significant results for brain outcome measures, either structural (i.e., hippocampal volume or cortical thickness) or functional (i.e., hippocampal activity), 8 of these were found in samples that had a mean age of 37 or higher. Despite that the age of diagnosis was not reported, it seems that the effect of exercise on the brain is found especially in older participants. This could be because exercise is not effective in enlarging the hippocampus (early in life or early in disease stage), or in targeting other signs
16 Literature Thesis S.L. Hoornaert of deterioration in the brain, but is only effective once the hippocampus has shrunk as a result of age or psychiatric illness (i.e., ‘reversing’ this change, but not simply ‘growing’ the hippocampus). There may be a certain age or period of disease progression that is necessary for the brain to show deterioration structurally and functionally, before which it is working ‘optimally’ and, thus, is not significantly affected by exercise.
The most common type of exercise used in the RCTs was aerobic exercise (used in 78% of the included studies), with an average length of 15.78 weeks, and took place roughly 3 times per week. While there are deviations from this, such as studies using a dance- or yoga-based intervention (Rektorova et al., 2020; Streeter et al., 2020, respectively), aerobic exercise has been found to have cognitive benefits and increased cortical thickness, however this is limited largely to observational studies (Stern et al., 2019). Moreover, animal and some human studies have shown (aerobic) exercise to increase hippocampal volume, which normally decreases with age, and more so with disease pathologies such as depression and schizophrenia (Parker et al., 2011). However, only 22% of the studies used an exercise intervention other than aerobic exercise. Whether other types of exercise therapies are similarly or more effective therefore remains an open question. One study investigated dance exercise as an intervention, but this type of exercise involves an extra dimension of sensorimotor integration, and includes aspects of rhythm and melody, for example. Therefore, it is difficult to say whether the effects on the brain were due to the exercise alone (Rektorova et al., 2020). Exercise is a promising method for inducing positive changes in the brain (such as increases in hippocampal volume and cortical thickness, or increased hippocampal activity), improving cognitive function, and reducing psychiatric symptoms because it is low-cost and accessible (i.e., it can be done with little to no equipment in almost any environment) and can be adapted to each person’s individual needs and abilities. There are some disadvantages of exercise, such as a risk of injury, in addition to the fact that it is often carried out alone which makes it difficult to verify
17 Literature Thesis S.L. Hoornaert whether participants really completed the exercise to the full extent (i.e., participant compliance). Exercise is also not necessarily cheaper than medication in all cases, such as when an individual needs to have a personal trainer and schema made up tailored to their specific needs, for example. It should also be noted that while the current literature review focused on depression and schizophrenia, findings may also generalise to other (non-clinical) populations. Regarding the length of the intervention, it is possible that ~16 weeks is not a long enough time for changes induced by aerobic exercise to manifest themselves properly and be visible in the brain, as proposed by Jonasson et al., (2007). The only study in this systematic review with an intervention longer than 6 months showed a significant increase in hippocampal volume, in which participants exercised for a full year (Erickson et al., 2010). The other three studies that found significant findings for hippocampal volume had 12-week interventions, and significant findings for cortical thickness were found after 12 weeks (Rogge et al., 2018; Gujral et al., 2019) and 24 weeks (Rektorova et al., 2020; Stern et al., 2019). Based on these findings, it is not possible to say how long an ideal intervention is but it should be at least 12 weeks, given that anything less than this might be too short to measure the brain’s dynamic response to
exercise of both structure and function. Despite this, it is not known whether the results can be attributed solely to the length of the intervention, or whether the type of exercise might (in part) determine the brain’s response.
4.2 Psychiatric Symptoms
4.2.1 Depression
Out of the five studies with a depressed sample, three RCTs found significant improvement of disease symptoms after the exercise intervention. The remaining two studies did not include a scale for symptom severity, meaning that we cannot conclude that there was a reduction in symptoms or an absence of an effect, simply that it was not measured. One of the studies that did not include a scale of depressive symptoms was by Goldin and colleagues
18 Literature Thesis S.L. Hoornaert (2013). As was noted earlier, this study did not specifically include a depressed sample, but rather, participants with social anxiety disorder. This anxiety disorder also falls under our psychiatry category and was included in our search strategy, in addition to the fact that this paper focuses on negative emotions and negative emotion regulation. When considering exercise as a viable addition to (or perhaps even replacement of) common treatments for depression, the current research suggests it is effective in reducing symptom severity. However, future research should specifically test the efficacy of exercise versus antidepressants such as SSRI’s. In all five studies with depressed samples, the intervention was carried out alone, but
two studies had an additional weekly group session as well. The results, however, do not consistently show that group exercise therapy is more effective in reducing depressive symptoms than exercising alone, or vice versa. All three studies that measured symptom severity found significant improvements, where two studies had individual exercise therapies and one had a combination of individual and group-based exercise. It is therefore not possible to say at this stage whether a social component of the therapy influenced the effectiveness of exercise on symptom alleviation. Exercise could target other neurotrophic factors which alleviate depressive symptoms, in addition to the fact that exercise affects the hippocampus – which is involved in emotional regulation, especially in response to positive stimuli (Zhu et al., 2019).
4.2.2 Schizophrenia
Two of the five papers that looked at schizophrenia did not look at the symptom alleviation (or exacerbation), indicating a gap in the research in this field. Of the remaining three studies, two found improvements in schizophrenia symptoms, whereas one found no significant effect. It is promising that two studies did find an alleviation of symptoms, especially considering that research finds that antipsychotic drug treatments typically is not effective on negative or cognitive symptoms (Dauwan et al., 2016). The two studies that found
19 Literature Thesis S.L. Hoornaert improvements in schizophrenic symptom severity had 3 sessions of weekly exercise for a duration of 12 weeks, but were not the only studies with this design, meaning it is difficult to attribute the effects to frequency and duration of the intervention. They also had very different participant groups: the first had no female participants and a sample size of 24, whereas the second study had almost half (44%) females and a sample size of 171 (Pajonk et al., 2010; Woodward et al., 2019, respectively). These characteristics are very different from each other, which means we cannot draw conclusions from this with regards to the symptom outcomes. Moreover, considering that schizophrenia also results in weight gain and reduction of physical activity, these results are optimistic. However, there is no treatment or cure for schizophrenia, so we should not look towards the results from the RCTs as a possible cure or alternate treatment for this chronic disease, but rather at the capacity of exercise to alleviate symptoms to some degree.
4.3 MRI Outcomes: Structural
4.3.1 Hippocampal Volume
The present systematic review did not find convincing evidence that exercise significantly increases hippocampal volume; only 4 studies established a link, whereas 7 did not. We see that all 4 papers that found evidence for the fact that exercise increases hippocampal volume had aerobic exercise as the intervention type, with 3/4 training participants 3 times per week, for 12 weeks (data for the frequency of exercise in the last paper was unavailable, but the intervention lasted for 52 weeks; Erickson et al., 2010). The studies that found this link also included healthy (Engeroff et al., 2018; Erickson et al., 2010) and schizophrenic samples (Papiol et al., 2019; Woodward et al., 2019). The RCT by Woodward and colleagues (2019) also included a scale for symptom severity, which improved, suggesting that exercise may trigger the biological mechanism by which hippocampal volume increases, resulting in an alleviation of schizophrenic symptoms. While the increase in hippocampal
20 Literature Thesis S.L. Hoornaert volume is important in all three populations to counteract the cognitive impairment as a result of aging, depression, or schizophrenia, the fact that the majority of papers found no significant link means that we cannot say that exercise has been shown to increase hippocampal volume. This does mean, however, that we also cannot state the opposite. Additionally, it is hypothesised that the increase in hippocampal volume is mediated by other neurotrophins such as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and Insulin-like growth factor 1 (IGF-1; Krogh et al., 2014). Clearly, more research is warranted in order to investigate the influence of exercise on hippocampal growth, potentially mediated by the abovementioned factors. Given that it is hypothesised that hippocampal volume growth is mediated at least in part by neurotrophins, future studies should ideally examine the effect of physical exercise on levels of neurotrophins such as BDNF in humans with different psychiatric pathologies, as a potential mediator for its effect on hippocampal volume, for example (Voss et al., 2013; Huang et al., 2014).
4.3.2 Cortical Thickness
Most consistent evidence was found for an effect of exercise on cortical thickness (CT), with only one RCT who did not find a significant increase in CT following the intervention. Four studies did establish this relationship, of which three had samples with healthy participants and one investigated a depressed sample. This supports literature that states that exercise can alter our neural anatomy. The brain regions in which CT increased overlapped in the four studies, including the frontal and occipital regions, strengthening the findings. Previous research has established increases in frontal and occipital regions in response to exercise training within healthy controls of a schizophrenia study (Falkai et al., 2013). Frontal and occipital regions are involved in movement – which is logical given that these are affected by exercise – but also in memory formation, motivation, mediating socially appropriate behaviour, and is connected to the limbic system, which deals with emotion and memory (Burruss et al.,
21 Literature Thesis S.L. Hoornaert 2000; Rehman & Al Kalili, 2019). This can perhaps explain an improvement in symptoms of psychiatric illnesses, as these functions are closely related to the disease pathology. However, taken together with the fact that the 3 studies that found this effect studied healthy samples, this indicates that the effect of exercise on CT may be limited to healthy brains.
4.4 MRI Outcomes: Functional
It is difficult to draw conclusions about the effects of exercise on functional changes in the brain because only 2 studies included this as an outcome measure of their RCT. Moreover, one study did not find a significant relationship between brain function (i.e., GABA levels), leaving only one finding: hippocampal activity increased between pre- and post-testing following an exercise intervention (Gourgouvelis et al., 2017). As there were no other RCTs that included functional measures as outcome variables, it is not yet possible to draw conclusions about the capacity of exercise to influence these until further research is conducted in this field. However, research on the functional mechanisms of the brain and how these are potentially affected by exercise is valuable, since there are behavioural changes that come about from these interventions (as seen in the scales for depression and schizophrenia symptoms). For both healthy and psychiatric populations it is important to understand whether hippocampal activity, which deteriorates over time and with psychiatric diseases, can be targeted by physical exercise. It should also be noted that the studies included in this systematic review were not selected based on the functional outcomes, but rather predominantly on structural findings.
4.5 Limitations
The RCTs that were included in the present systematic review were extremely heterogeneous, meaning that there was little overlap of methods, outcome measures, and participant characteristics. As a result, there is a substantial amount of missing information when trying to form a coherent overview of the research that is available at this point about this
22 Literature Thesis S.L. Hoornaert topic. Missing information from papers in this review includes evaluating symptom severity, frequency of intervention, CT, or functional activity. An additional aspect that was absent and not standardised from many studies were the control groups, which varied from study to study. While all studies included a disease + exercise treatment group, the control groups varied much more: some included no control, some had a healthy exercise group, and some included a disease + no exercise group, whereas a healthy + no exercise group was absent from the included samples. It is the opinion of the researcher that in order to best compare effects of the intervention, the controls should be standardised to some degree. Furthermore, ‘exercise’ is a
very broad term, which leaves room for interpretation. While most studies used a form of aerobic exercise, there were few who used other types of exercise: dance exercise, yoga, stretching/weigh-bearing. Different forms of exercise may have different effects on the brain and its structural and functional changes, and its different aspects are difficult to isolate (e.g., within dance exercise, an individual uses sensorimotor integration, motor skills, and needs to take into account rhythm, which may all influence the brain differently than walking would). Like the control groups, it would be beneficial to the field if the definition of exercise was streamlined, in order to be sure that RCTs are researching the same effects when building upon previous research. Similarly, the secondary outcome measures of the studies (secondary to MRI structural/functional changes) varied greatly. Some included a task (e.g., memory), some tested BDNF, maximum oxygen uptake, or maximum workload. Consequently, there were many findings that were correlations between the abovementioned factors and brain changes, rather than looking at structural changes alone, for example. Finally, another issue that was not addressed is the lack of control for confounders, such as diet, additional activity, social contact, and mental activity, for example. These could potentially enhance or inhibit the effects of exercise, or influence other secondary changes in the brain, and the surveillance for these factors was superficial (e.g., asking participants if they had a “sedentary lifestyle”). These study
23 Literature Thesis S.L. Hoornaert limitations make it difficult to make an overall conclusion about the effect of exercise on structural and functional changes in the brain.
4.6 Future Research
There is abundant room for further progress in determining and evaluating the beneficial effects that exercise can have on healthy, depressed, and schizophrenic brains. Researchers should, for example, consider that major depressive disorder is extremely heterogeneous, and several treatment strategies exist. It is important to investigate the effect of exercise on the brain as it compares to current antidepressant medication or therapy, to evaluate whether exercise could be an effective and targeted alternative for mainstream treatments. In the same way, it is important to understand the relationship between the psychological and biological mechanisms of depression, including how exercise may affect this relationship, in order to better understand and treat the condition. There are also different levels of “functionality” and fitness among people suffering from psychiatric diseases such as
depression, so it would be valuable if exercise is as effective for everyone, and which aspect of the intervention is most effective at creating (lasting) changes in the brain that make a pathology more manageable and increase overall quality of life. Additionally, given that psychiatric illnesses rarely show the same prevalence, disease severity and age of onset for both sexes, it is important for future research on the topic to include sex aggregates in order to determine potential differences in the changes in male and female brains resulting from exercise (Li et al., 2016; Salk et al., 2017).
Despite promising results regarding changes in both subjective symptoms and the brain, future research is required to establish the viability of exercise as a way to counteract hippocampal volume and CT decreases as a result of aging, depression, and schizophrenia, in which researchers focus on how long effects of exercise last in the brain. Not only is the length of intervention important in determining whether a significant effect is found, but also how
24 Literature Thesis S.L. Hoornaert long afterwards follow-up scans are made to see whether the effect is still present despite the termination of the intervention. Valuable insights could also come from investigating whether the exercise needs to be ongoing, and whether we would then continue seeing effects, or whether they level off (or revert) once exercise/participation stops. Related to this is also the nature of the exercise, and whether the participants exercised individually or in groups, which may influence results given the benefit of social contact for motivation, for example.
Finally, to answer remaining questions, future research should focus on age differences and whether exercise results in more or less structural and functional changes in the brain or symptom alleviation in the case of depressed or schizophrenic patients, if it is done early on, or later in life/disease progression. For example, the greatest changes in hippocampal volume are seen in regions that typically show the greatest declines in late adulthood (Erickson et al., 20110). This suggests that the timing of the intervention can have implications for how effective it is, or which changes it may elicit. Exercise affects our brain on a structural and functional level, but these changes are not consistently shown in the existing research. Hence, it is important for further research to investigate the potential that exercise therapy can have in treatments for psychiatric illnesses, such as depression or schizophrenia, and for well-being in healthy populations.
25 Literature Thesis S.L. Hoornaert
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32 Literature Thesis S.L. Hoornaert 6 Appendix A Study MRI characteristics Preprocessing Software Engeroff et al., 2018 3T SPM 8
Erickson et al., 2010 3T Oxford Centre for Functional MRI of the Brain
(FMRIB)’s Integrated Registration and
Segmentation Tool in FMRIB’s Software Library version 4.1
Goldin et al., 2013 3T Analysis of functional neuroimages (AFNI)
software (Cox, 1996)
Gourgouvelis et al., 2017 3T SPM12 methods (Statistical Parametric Mapping, Wellcome Department of Cognitive Neurology, London, UK within MatLab 8.3
Gujral et al., 2019 7T FreeSurfer 6.0
Krogh et al., 2014 3T N/A
Malchow et al., 2016 3T FreeSurfer 5.3
Pajonk et al., 2010 1.5T Analyze & SPM99
Papiol et al., 2019 3T FreeSurfer 5.3
Parker et al., 2011 3T Custom Graphics Software
Rektorova et al., 2020 3T FreeSurfer 6.0
Rogge et al., 2018 3T FreeSurfer 6.0
Scheewe et al., 2013 3T UMCU Network
Shaaban et al., 2019 7T N/A
Stern et al., 2019 3T FreeSurfer Longitudinal Pipeline
Streeter et al., 2020 4T N/A
Wagner et al., 2015 3T FreeSurfer
