Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment

In the paper

“In particular, AE has a potent impact on promoting the function of the hippocampus and stimulating neuroplasticity.”

In the paper

“Incorporating non-pharmacological interventions into clinical treatment may also have a number of other benefits to patient well being, such as limiting the risk of adverse side effects.”

In the paper

“Both schizophrenia and MDD are associated with hippocampal deterioration and cognitive dysfunctions, so we take these two conditions as examples to discuss the potential utility of AE-based interventions.”

In the paper

“Augmenting existing treatment approaches using AE based interventions may promote hippocampal function and alleviate cognitive deficits in various psychiatric disorders that currently remain untreated.”

In the paper

“Notably, many psychiatric and neurological disorders have been associated with hippocampal dysfunction, which may underlie the expression of certain symptoms common to these disorders, including (aspects of) cognitive dysfunction.”

• Also stated in: § Introduction · plain

  “The hippocampus is heavily involved in learning and memory processes and is particularly vulnerable to damage in various pathological conditions like major depressive disorder (MDD), Alzheimer’s disease and schizophrenia (Adriano et al., 2012; Bartsch and Wulff, 2015; Schmaal et al., 2016).”

What the sources say

• Not checked yetcites Adriano et al., 2012 source
• Not checked yetcites Bartsch and Wulff, 2015
• Not checked yetcites Schmaal et al., 2016 source

In the paper

“Meta-analyses have found AE interventions to improve cognitive performance across a variety of domains, including attention, executive functioning, processing speed, motor functioning, and memory in healthy young and middle aged adults (Etnier et al., 1997; Smith et al., 2010; Chang et al., 2012;”

What the sources say

• Not checked yetcites Colcombe and Kramer, 2003
• Not checked yetcites Angevaren et al., 2008 source
• Not checked yetcites Smith et al., 2010 source

In the paper

“As such, stimulating neuroplasticity is becoming a popular approach aimed to counteract pathological harm (Kays et al., 2012).”

What the sources say

• Not checked yetcites Kays et al., 2012 source

In the paper

“Cross-sectional data has also indicated that AE may also be beneficial to non-healthy individuals as higher levels of aerobic fitness have also been correlated with larger hippocampal volumes in patients with obesity (Bugg et al., 2012), anorexia (Beadle et al., 2015), mild cognitive impairments (Gates et al., 2013; Makizako et al., 2014), MDD (Travis et al., 2015), Alzheimer’s disease (Honea et”

What the sources say

• Not checked yetcites Bugg et al., 2012 source
• Not checked yetcites Beadle et al., 2015 source
• Not checked yetcites Gates et al., 2013 source

In the paper

“The dichotomous functioning of the hippocampus is thought to be reflected in its structure, with affective processing being largely attributed to the ventral hippocampus and learning and memory processes mostly occurring through the dorsal hippocampus (Moser and Moser, 1998).”

What the sources say

• Not checked yetcites Moser and Moser, 1998

In the paper

“Contextual memory is a process strongly related to episodic memory that is also highly dependent on the hippocampus and refers to the capacity for an animal to make associations with salient landmark objects and their environmental context (Eichenbaum et al., 2005).”

What the sources say

• Not checked yetcites Eichenbaum et al., 2005 source

In the paper

“AE increases the rate of hippocampal neurogenesis, i.e., both the rate of cell proliferation as well as the survival of newborn granule cells (Cotman et al., 2007; Kempermann et al., 2010; Lucassen et al., 2010; Vivar et al., 2013) and despite being difficult to study in humans (Manganas et al., 2007; Ho et al., 2013; Jessberger and Gage, 2014), AE may also stimulate cell proliferation and DG”

What the sources say

• Not checked yetcites Pereira et al., 2007 source
• Not checked yetcites Erickson et al., 2011 source
• Not checked yetcites Demirakca et al., 2014 source

In the paper

“While some RCTs have found that AE did not have an impact on hippocampal volume (Ruscheweyh et al., 2011; Scheewe et al., 2013; Krogh et al., 2014; Rosenbaum et al., 2015; Malchow et al., 2016), it is possible that such discrepancies are caused by a lack of consistency in AE protocols used (Prakash et al., 2015) or in the methods of calculating hippocampal volume (Niemann et al., 2014).”

What the sources say

• Not checked yetcites Prakash et al., 2015 source
• Not checked yetcites Niemann et al., 2014 source

In the paper

“AE increases the rate of hippocampal neurogenesis, i.e., both the rate of cell proliferation as well as the survival of newborn granule cells (Cotman et al., 2007; Kempermann et al., 2010; Lucassen et al., 2010; Vivar et al., 2013) and despite being difficult to study in humans (Manganas et al., 2007; Ho et al., 2013; Jessberger and Gage, 2014), AE may also stimulate cell proliferation and DG”

What the sources say

• Not checked yetcites Cotman et al., 2007 source
• Not checked yetcites Kempermann et al., 2010 source
• Not checked yetcites Lucassen et al., 2010 source

In the paper

“Aerobic exercise has also been associated with certain morphological changes to the structure of neural cells, which may be important in facilitating hippocampal learning and memory (Lang et al., 2004).”

What the sources say

• Not checked yetcites Lang et al., 2004 source

In the paper

“Interestingly, these changes appear to be specific to the DG region and may be directly related to the stimulation of neurogenesis by AE (van Praag, 2008).”

What the sources say

• Not checked yetcites van Praag, 2008 source

In the paper

“Being hypersensitive to influence on their synaptic plasticity has led to the idea that these adult-born granule cells mediate the enhancement of LTP in the DG from AE (Voss et al., 2013a).”

What the sources say

• Not checked yetcites Voss et al., 2013a

In the paper

“These morphological changes are associated with higher rates of LTP induction and facilitate changes in dendritic strength (van Praag, 2008).”

What the sources say

• Not checked yetcites van Praag, 2008 source

In the paper

“AE has been demonstrated to stimulate LTP in young rodents and reverse the age-related decline of LTP within the DG of aged rodents compared to sedentary controls (van Praag, 2009; Voss et al., 2013a).”

What the sources say

• Not checked yetcites van Praag, 2009 source
• Not checked yetcites Voss et al., 2013a

In the paper

“Forming an episodic memory involves the association of an event or feature with a particular location in space and occurs through this LTP mechanism in the hippocampus (Bannerman et al., 2014).”

What the sources say

• Not checked yetcites Bannerman et al., 2014 source

In the paper

“Brain-derived neurotrophic factor (BDNF) is a centrally produced neurotrophin of particular interest due to its high concentration within the hippocampus and its integral role in supporting neuronal survival and growth, and synaptic plasticity (Cotman et al., 2007; Cowansage et al., 2010).”

What the sources say

• Not checked yetcites Cotman et al., 2007 source
• Not checked yetcites Cowansage et al., 2010 source

In the paper

“Increasing microvasculature density may be protective against white-matter hyperintensities, which itself may reduce gray-matter atrophy and cognitive dysfunction (Voss et al., 2013a).”

What the sources say

• Not checked yetcites Voss et al., 2013a

In the paper

“For example, some animal models have suggested that angiogenesis may underlie improvements in spatial memory tasks independent of other neuroplastic mechanisms (van Praag et al., 2007; Kerr et al., 2010), whereas others have found improvements in spatial learning to be driven by neurogenesis with no influence at all from angiogenesis (van Praag et al., 2005).”

What the sources say

• Not checked yetcites van Praag et al., 2005 source

In the paper

“The positive influence of improving vascularization may extend beyond a greater supply of oxygen and glucose through prompting the release of neurotrophic factors (the influence of which will be discussed below; Maass et al., 2015) or through facilitating other neuroplastic mechanisms like synaptic plasticity (Christie et al., 2008) or neurogenesis (Palmer et al., 2000; Pereira et al., 2007; Boe”

What the sources say

• Not checked yetcites Maass et al., 2015 source
• Not checked yetcites Christie et al., 2008 source
• Not checked yetcites Palmer et al., 2000 source

In the paper

“Cerebral blood flow is important in providing oxygen and essential nutrients that facilitate brain functioning.”

In the paper

“Changes in vasculature may indeed stimulate other neuroplastic mechanisms like synaptogenesis or neurogenesis and promote hippocampal tissue growth (Kleemeyer et al., 2015), but a greater investigation is required to outline the direct relationship between vascularization and enhancements in hippocampal functioning stimulated by AE (Davenport et al., 2012).”

What the sources say

• Not checked yetcites Kleemeyer et al., 2015 source

In the paper

“For example, some animal models have suggested that angiogenesis may underlie improvements in spatial memory tasks independent of other neuroplastic mechanisms (van Praag et al., 2007; Kerr et al., 2010), whereas others have found improvements in spatial learning to be driven by neurogenesis with no influence at all from angiogenesis (van Praag et al., 2005).”

What the sources say

• Not checked yetcites van Praag et al., 2007 source
• Not checked yetcites Kerr et al., 2010 source

In the paper

“It has been demonstrated in animal models that AE stimulates the sprouting of new capillaries (angiogenesis) and improves vasculature within the hippocampus (Trejo et al., 2001; van Praag et al., 2005).”

What the sources say

• Not checked yetcites Trejo et al., 2001 source
• Not checked yetcites van Praag et al., 2005 source

In the paper

“Through generating a greater influx of adult-born granule cells that have an enhanced propensity for LTP and fine-grained morphological changes, AE stimulates an environment within the hippocampus that promotes LTP and facilitates improvements in hippocampus-dependent cognition (Boecker et al., 2012).”

What the sources say

• Not checked yetcites Boecker et al., 2012 source

In the paper

“Neither antipsychotics nor antidepressants have been consistently shown to induce any lasting neuroplastic changes in the brain (Rief et al., 2015).”

What the sources say

• Not checked yetcites Rief et al., 2015 source

In the paper

“Vascular endothelial derived growth factor (VEGF) and insulin growth factor 1 (IGF-1) are growth factors that are produced peripherally and are implicated in both angiogenesis and neurogenesis (Gomez-Pinilla and Hillman, 2013).”

What the sources say

• Not checked yetcites Gomez-Pinilla and Hillman, 2013

In the paper

“Cognitive dysfunction in human patients with schizophrenia is rapidly being considered amongst the most debilitating aspects of schizophrenia (Nuechterlein et al., 2011) and the severity of cognitive dysfunction is a key determinant of the functional outcome following treatment (Goldberg and Green, 2002).”

What the sources say

• Not checked yetcites Nuechterlein et al., 2011 source
• Not checked yetcites Goldberg and Green, 2002

In the paper

“both molecules are known to cross the blood brain barrier and interact with hippocampal cells (Ding et al., 2006; Tang et al., 2010).”

What the sources say

• Not checked yetcites Ding et al., 2006 source
• Not checked yetcites Tang et al., 2010 source

In the paper

“Similarly, human patients with MDD have consistently demonstrated clinically relevant deficits in domains of executive functioning, psychomotor speed, attention, and memory (McDermott and Ebmeier, 2009; Lee R.S. et al., 2012; McIntyre et al., 2013; Rock et al., 2013).”

What the sources say

• Not checked yetcites McDermott and Ebmeier, 2009 source
• Not checked yetcites Lee R.S. et al., 2012
• Not checked yetcites McIntyre et al., 2013 source

In the paper

“Indeed, the inhibition of VEGF or IGF-1 has been demonstrated to impair the promotional impact of AE on the rate of neurogenesis (Trejo et al., 2001; Fabel et al., 2003; Ding et al., 2006) and spatial memory performance (Ding et al., 2006).”

What the sources say

• Not checked yetcites Trejo et al., 2001 source
• Not checked yetcites Fabel et al., 2003 source
• Not checked yetcites Ding et al., 2006 source

In the paper

“Firstly, a number of psychiatric and neurological disorders seem to have a particularly potent influence on hippocampal structure (Bartsch and Wulff, 2015) and its deterioration may underlie certain aspects of their symptomatology.”

What the sources say

• Not checked yetcites Bartsch and Wulff, 2015

In the paper

“In humans, AE is associated with increases in hippocampal volume and some indirect indicators of neuroplasticity (e.g., increased cerebral blood flow or BDNF serum concentration), which correlate with improved performances on hippocampus dependent tasks, indicative of an enhanced hippocampal functioning.”

In the paper

“N-acetylaspartate (NAA) is a metabolite indicative of neuronal integrity and a number of AE studies have demonstrated that the growth in hippocampal volume (Pajonk et al., 2010; Erickson et al., 2012; Gonzales et al., 2013; Wagner et al., 2015) and in some cases, improvements in working memory performance (Erickson et al., 2011) are both correlated with higher concentrations of NAA.”

What the sources say

• Not checked yetcites Pajonk et al., 2010 source
• Not checked yetcites Erickson et al., 2012 source
• Not checked yetcites Gonzales et al., 2013 source

In the paper

“A reduced hippocampal volume is one of the most consistently reported structural abnormalities in patients of MDD (Schmaal et al., 2016) and of schizophrenia (Ellison-Wright and Bullmore, 2010; Adriano et al., 2012).”

What the sources say

• Not checked yetcites Schmaal et al., 2016 source
• Not checked yetcites Ellison-Wright and Bullmore, 2010 source
• Not checked yetcites Adriano et al., 2012 source

In the paper

“These findings suggest that AE can stimulate hippocampal neuroplasticity and promote the regions functioning in humans in a similar way to that which has been demonstrated using animal models.”

In the paper

“By facilitating vascularization in this way, particularly within the DG (Clark et al., 2009), the molecule also supports the AE induced stimulation of neurogenesis (Gomez-Pinilla and Hillman, 2013).”

What the sources say

• Not checked yetcites Clark et al., 2009 source
• Not checked yetcites Gomez-Pinilla and Hillman, 2013

In the paper

“Similarly, IGF-1 is known to support alterations in vascularization that are induced by AE (Lopez-Lopez et al., 2004) and promotes the proliferation and survival of newborn neural cells (Gomez-Pinilla and Hillman, 2013).”

What the sources say

• Not checked yetcites Lopez-Lopez et al., 2004 source
• Not checked yetcites Gomez-Pinilla and Hillman, 2013

In the paper

“Targeting neuroplasticity has recently become an important approach in treating psychiatric symptoms (Kays et al., 2012) and may be useful in counteracting this hippocampal harm to remediate cognitive deficits.”

What the sources say

• Not checked yetcites Kays et al., 2012 source

In the paper

“However, several large-scale meta-analyses have recently suggested that the effectiveness of antipsychotic and antidepressant medications is only marginally different from that of a placebo (Leucht et al., 2009; Rief et al., 2009), and neither have been able to successfully remediate cognitive dysfunction (Keefe et al., 2013, 2014; Solé et al., 2015).”

What the sources say

• Not checked yetcites Leucht et al., 2009 source
• Not checked yetcites Rief et al., 2009 source
• Not checked yetcites Keefe et al., 2013 source

In the paper

“with some AE studies findings a positive correlation between hippocampal volume or connectivity changes and serum concentrations of BDNF, VEGF, and IGF-1 (Erickson et al., 2011; Coelho et al., 2013; Voss et al., 2013b), while others have failed to replicate such findings (Maass et al., 2016).”

What the sources say

• Not checked yetcites Erickson et al., 2011 source
• Not checked yetcites Coelho et al., 2013 source
• Not checked yetcites Voss et al., 2013b

In the paper

“5-HT transmission in the hippocampus is disrupted in schizophrenia and MDD (Naughton et al., 2000; Middlemiss et al., 2002) and this 5-HT dysfunction is likely to contribute deficits in learning and memory in these disorders (Meeter et al., 2006; Gray and Roth, 2007).”

What the sources say

• Not checked yetcites Naughton et al., 2000 source
• Not checked yetcites Middlemiss et al., 2002 source
• Not checked yetcites Meeter et al., 2006 source

In the paper

“In humans, AE has been shown to stimulate hippocampal neuroplasticity and successfully counteract deteriorating hippocampal function caused by aging or Alzheimer’s disease (Intlekofer and Cotman, 2013).”

What the sources say

• Not checked yetcites Intlekofer and Cotman, 2013

In the paper

“The impact of AE on the monoamine system has largely been discussed in terms of its antidepressant properties (Christie et al., 2008; van Praag, 2009), but it is possible that this interaction may also contribute toward cognitive enhancement.”

What the sources say

• Not checked yetcites Christie et al., 2008 source
• Not checked yetcites van Praag, 2009 source

In the paper

“While its therapeutic potential has only been explored very recently, AE has been demonstrated to counteract pathologically induced hippocampal harm and improve the region’s functioning in a range of animal disease models including fetal alcohol spectrum disorders, traumatic brain injury, stroke, and Parkinson’s, Alzheimer’s and Huntington’s diseases (Patten et al., 2015).”

What the sources say

• Not checked yetcites Patten et al., 2015 source

In the paper

“Just one human study has sought to assess macro-scale structural changes and found no association between an AE intervention and hippocampal volume or neurotrophin circulation (Krogh et al., 2014). However, participant attendance rate to AE sessions was very low in this study, at less than half (one session per week) the attendance rate recorded by studies in other psychiatric populations who did”

What the sources say

• Not checked yetcites Krogh et al., 2014 source

In the paper

“In animal models of stress/MDD, certain micro-scale changes have been recorded which demonstrate that AE can promote hippocampal neurogenesis, vascularization, BDNF expression (both brain-wide and within the hippocampus), IGF-1 expression, VEGF expression, and hippocampal synaptic plasticity (Adlard and Cotman, 2004; Zheng et al., 2006; Bjørnebekk et al., 2010; Nakajima et al., 2010; Sartori et al”

What the sources say

• Not checked yetcites Adlard and Cotman, 2004
• Not checked yetcites Zheng et al., 2006 source
• Not checked yetcites Bjørnebekk et al., 2010 source

In the paper

“It is possible that pharmacotherapy may eventually develop a comprehensive treatment for cognitive dysfunction, but non-pharmacological approaches like AE have a number of distinct benefits to the patient (discussed below), which make these interventions worthy of further investigation by future research.”

In the paper

“For example, in patients with schizophrenia a 12-week AE intervention has led to increased hippocampal volume, hippocampal NAA concentration and improved performances on short-term memory and working memory tasks (Pajonk et al., 2010; Lin et al., 2015; McEwen et al., 2015).”

What the sources say

• Not checked yetcites Pajonk et al., 2010 source
• Not checked yetcites Lin et al., 2015 source
• Not checked yetcites McEwen et al., 2015 source

In the paper

“Importantly, AE appears to be able to stimulate neuroplasticity and promote hippocampal functioning in brains with both healthy and pathologically deteriorated hippocampi.”

In the paper

“The inclusion of AE interventions into current treatment approaches could be useful to counteract hippocampal harm and alleviate cognitive dysfunctions caused by psychiatric disorders.”

In the paper

“It is plausible that AE interventions could be used to counteract hippocampal harm caused by disorders that profoundly impact upon hippocampal functioning, and through this approach, aid in the alleviation of certain aspects of cognitive dysfunction.”

In the paper

“Evidence is also accumulating to suggest that long-term antipsychotic treatment in humans may be linked to a reduction in both global gray- and white-matter volumes (Navari and Dazzan, 2009; Ho et al., 2011; Vernon et al., 2011; Fusar-Poli et al., 2013) as well as region-specific reductions in hippocampal volume (Panenka et al., 2007).”

What the sources say

• Not checked yetcites Navari and Dazzan, 2009
• Not checked yetcites Ho et al., 2011
• Not checked yetcites Vernon et al., 2011 source

In the paper

“The use of AE as an adjunctive treatment to traditional antidepressant medication may have a synergising impact on neuroplasticity potentially resulting in a more effective approach toward remediating psychiatric symptoms.”

In the paper

“Psychiatric patients have previously reported having a favorable perspective of AE treatment (Stanton and Reaburn, 2014), however, this is not necessarily reflected in actual AE engagement (Vancampfort et al., 2016).”

What the sources say

• Not checked yetcites Stanton and Reaburn, 2014
• Not checked yetcites Vancampfort et al., 2016 source

In the paper

“AE interventions are unlikely to represent a viable standalone treatment for cognitive dysfunction, but may make an important, low-risk adjunctive treatment to pharmacotherapy that promotes the effectiveness and reduces the harms associated with pharmacological interventions.”

In the paper

“Thereby, the inclusion of AE interventions may also reduce the total time a patient is exposed to pharmacotherapy, lowering their risk of any adversities associated with long-term use.”

In the paper

“In addition, the aforementioned potential for a combined pharmacotherapy/AE approach to have an additive impact on symptom alleviating may mean that patients reach remission at a faster rate.”

In the paper

“Contrastingly, AE is known to elicit comparatively few adverse side effects and is associated with improvements in the social, physical and affective well being of individuals with psychiatric disorders (Fiuza-Luces et al., 2013).”

What the sources say

• Not checked yetcites Fiuza-Luces et al., 2013 source

In the paper

“Moreover, AE is known to be preventative of cardiovascular, metabolic and respiratory dysfunction, which suggests that the inclusion of an AE intervention may be useful in stemming the risk of psychiatric patients developing these severe conditions (Caemmerer et al., 2012; Vancampfort et al., 2014).”

What the sources say

• Not checked yetcites Caemmerer et al., 2012 source
• Not checked yetcites Vancampfort et al., 2014 source

In the paper

“Developing further pharmacological interventions that effectively alleviate cognitive symptoms in medicated psychiatric populations will undoubtedly provide a more comprehensive treatment approach, but it could also elevate the risk of adverse side effects for the patient.”

In the paper

“AE has the potential to directly combat these adverse side effects as well as contributing toward the remediation of cognitive deficits, as well as various other psychiatric symptoms that may be related to hippocampal dysfunction.”

In the paper

“This paper has highlighted two promising examples of how AE interventions could improve the treatment of schizophrenia and MDD, but AE interventions could well have a broader application in mental health such as in treating substance abuse (Zschucke et al., 2012).”

What the sources say

• Not checked yetcites Zschucke et al., 2012 source

In the paper

“Research demonstrating the potential for AE to promote hippocampal structure and function is growing at an impressive rate as more and more work is translated from animal to human models.”

In the paper

“Although most of the current literature has focussed on AE, other forms of exercise such as yoga (Lin et al., 2015) or weight training (Suo et al., 2016) may also be beneficial in promoting brain health and cognition.”

What the sources say

• Not checked yetcites Lin et al., 2015 source
• Not checked yetcites Suo et al., 2016 source

In the paper

“AE interventions represent an effective method of promoting hippocampal neuroplasticity and function that encompasses few risks and several additional benefits to the patient, such as combating pharmacologically induced side effects.”

In the paper

“It is possible that exercise intensities may vary depending on the purpose of the intervention, for example it has been suggested that improving cognitive performance may require high-intensity, interval training but preserving cognitive function in an aging brain may require a lower intensity, more continuous protocol (Duzel et al., 2016).”

What the sources say

• Not checked yetcites Duzel et al., 2016 source