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Cited by 155Neurogenesis and neuroplasticity mechanismsMemory and Neural MechanismsPhysical Activity and Health

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

Open access
Kandola, Aaron, Hendrikse, Joshua, Lucassen, Paul J., Yücel, Murat·2016·Frontiers in Human Neuroscience
DOI 10.3389/fnhum.2016.00373PMC PMC4965462
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Abstract

Aerobic exercise (AE) has been widely praised for its potential benefits to cognition and overall brain and mental health. In particular, AE has a potent impact on promoting the function of the hippocampus and stimulating neuroplasticity. As the evidence-base rapidly builds, and given most of the supporting work can be readily translated from animal models to humans, the potential for AE to be applied as a therapeutic or adjunctive intervention for a range of human conditions appears ever more promising. 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. Augmenting existing treatment approaches using AE based interventions may promote hippocampal function and alleviate cognitive deficits in various psychiatric disorders that currently remain untreated. 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. This review incorporates both animal and human literature to comprehensively detail how AE is associated with cognitive enhancements and stimulates a cascade of neuroplastic mechanisms that support improvements in hippocampal functioning. Using the examples of schizophrenia and major depressive disorder, the utility and implementation of an AE intervention to the clinical domain will be proposed, aimed to reduce cognitive deficits in these, and related disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes animal and human evidence that aerobic exercise (AE) promotes hippocampal neuroplasticity and hippocampus-dependent cognition, and proposes AE as an adjunctive intervention for cognitive deficits in schizophrenia and major depressive disorder (MDD). It argues AE may enhance hippocampal structure and function via neurogenesis, synaptic plasticity, vasculature, and neurotrophic factors, but calls for more RCTs and standardized protocols.

Key findings

  • AE is associated with improved hippocampus-dependent cognition in humans, including episodic, spatial, contextual memory, and pattern separation, while less hippocampus-dependent tasks such as attention, verbal memory, or item recognition may not show the same effects; animal work consistently shows AE improves spatial and contextual memory.
  • Human imaging studies associate higher aerobic fitness and AE interventions with larger hippocampal or temporal lobe volumes; correlations between AE-induced hippocampal growth and spatial/contextual memory range from r = 0.12 to r = 0.36, with specific RCT correlations of r = 0.28 for a computerized spatial memory task and r = 0.37 for a complex figure test of spatial object recognition. Some RCTs found no effect of AE on hippocampal volume.
  • Proposed mechanisms include adult hippocampal neurogenesis, long-term potentiation and synaptic plasticity, angiogenesis/increased cerebral blood flow, and upregulation of BDNF, VEGF, and IGF-1; one 3-month AE study attributed improvements in hippocampus-dependent task performance and hippocampal volume predominantly to greater cerebral blood flow, while another found a 2% decrease in hippocampal volume with no change in NAA, suggesting the decline was unlikely due to neuronal loss.
  • In clinical examples, schizophrenia and MDD are associated with reduced hippocampal volume and cognitive deficits; AE has been shown to reduce positive and negative symptoms in schizophrenia and affective symptoms in MDD, in some cases as effectively as antidepressants, and early studies show cognitive improvements, though some null findings exist. AE is proposed as a low-risk adjunct to pharmacotherapy, with 10–30% of MDD patients potentially not responding to antidepressants alone.

Methods

  • Narrative review incorporating both animal and human literature on AE, hippocampal plasticity, cognition, and clinical application; no systematic search or meta-analytic pooling is described.
  • Uses schizophrenia and MDD as example conditions to discuss the utility and implementation of AE interventions for cognitive deficits.
  • Main analysis is a qualitative synthesis of cross-sectional studies, RCTs, animal models, neuroimaging, peripheral biomarker, and pharmacological treatment studies; no primary data collection is reported.

Limitations

  • The paper states that more RCTs are needed to establish a causal relationship between AE and neural/cognitive outcomes; there is a lack of consensus on optimal exercise type, intensity, or length; motivation and adherence are major obstacles, with high dropout rates in psychiatric AE studies; and there is a distinct lack of systematic investigations in psychiatric populations.
  • The paper notes that human imaging techniques directly assess only macro-scale changes and cannot determine the functional significance of volume changes; animal models cannot fully model complex disorders like schizophrenia; and human biomarker findings are mixed.
  • Evident from the text: as a narrative review, it does not systematically search or quantitatively synthesize the evidence, and conclusions are constrained by heterogeneous AE protocols and limited or inconsistent studies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fnhum.2016.00373

Cites

419 of 419 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

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  • Premisecitation

    The hippocampus has a high degree of endogenous neuroplasticity.

    “One brain region with a high degree of endogenous neuroplasticity is the hippocampus (Bavelier and Neville, 2002).”
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    • cites Bavelier and Neville, 2002 source

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  • Interpretationreasoning

    Aerobic exercise represents a promising therapeutic target for a range of brain pathologies.

    “Given its general benefits to ones physical health, low risk profile and relative ease of implementation, AE represents a promising therapeutic target for a range of brain pathologies.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Aerobic exercise has a low risk profile and is relatively easy to implement.
    • Rests on an assumption: Aerobic exercise has general benefits to physical health.
  • Premisecitation

    Some randomized controlled trials have suggested aerobic exercise had no significant impact on cognition at all.

    “Some RCTs have stipulated that AE influences divergent cognitive domains, whereas others have suggested AE had no significant impact on cognition at all (Etnier et al., 2006; van Uffelen et al., 2008; Snowden et al., 2011; Gates et al., 2013; Kelly et al., 2014; Young et al., 2015).”
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  • Premisecitation

    Aerobic exercise may also be a promising approach for various psychiatric disorders like schizophrenia or major depressive disorder.

    “AE has been suggested as a promising approach in remediating hippocampal harm and cognitive deficits caused by neurodegenerative disorders like AD (Intlekofer and Cotman, 2013), but AE may also be a promising approach for various psychiatric disorders like schizophrenia or MDD (Oertel-Knöchel et al., 2014).”
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  • Premisecitation

    Findings have been consistent in demonstrating that aerobic exercise has a strong, positive influence on the structure of the hippocampus, which is not seen to the same extent in any other brain regions.

    “On a neural level, findings have been consistent in demonstrating that AE has a strong, positive influence on the structure of the hippocampus, which is not seen to the same extent in any other brain regions (Gomez-Pinilla and Hillman, 2013).”
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    Interpretationnone given

    Aerobic exercise has a potent impact on promoting the function of the hippocampus and stimulating neuroplasticity.

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

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

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

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    Both schizophrenia and major depressive disorder are associated with hippocampal deterioration and cognitive dysfunctions.

    “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.”
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    Interpretationreasoning

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

    “Augmenting existing treatment approaches using AE based interventions may promote hippocampal function and alleviate cognitive deficits in various psychiatric disorders that currently remain untreated.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cognitive deficits in various psychiatric disorders currently remain untreated.

  • May combine two claims.

    Premisecitation

    Many psychiatric and neurological disorders are associated with hippocampal dysfunction, which may underlie cognitive symptoms including cognitive dysfunction.

    “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).”
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    Premisecitation

    Meta-analyses have found aerobic exercise interventions improve cognitive performance mostly in older age groups.

    “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;”
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    Premisecitation

    Stimulating neuroplasticity is becoming a popular approach aimed to counteract pathological harm.

    “As such, stimulating neuroplasticity is becoming a popular approach aimed to counteract pathological harm (Kays et al., 2012).”
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    Higher levels of aerobic fitness have been correlated with larger hippocampal volumes in patients with obesity, anorexia, mild cognitive impairments, major depressive disorder, Alzheimer's disease, and multiple sclerosis.

    “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”
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    Premisecitation

    Affective processing is largely attributed to the ventral hippocampus and learning and memory processes mostly occur through the dorsal hippocampus.

    “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).”
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    Premisecitation

    Contextual memory is a process strongly related to episodic memory that is also highly dependent on the hippocampus.

    “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).”
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    Premisecitation

    Aerobic exercise may also stimulate cell proliferation and dentate gyrus volume growth in the human brain.

    “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”
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    Interpretationcitation

    Discrepancies in aerobic exercise effects on hippocampal volume may be caused by a lack of consistency in aerobic exercise protocols used or in methods of calculating hippocampal volume.

    “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).”
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    Premisecitation

    Aerobic exercise increases the rate of hippocampal neurogenesis, including both the rate of cell proliferation and the survival of newborn granule cells.

    “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”
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    • cites Cotman et al., 2007 source

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    Premisecitation

    Aerobic exercise is associated with morphological changes to the structure of neural cells, which may be important in facilitating hippocampal learning and memory.

    “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).”
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    Interpretationcitation

    The changes in long-term potentiation appear to be specific to the dentate gyrus region and may be directly related to the stimulation of neurogenesis by aerobic exercise.

    “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).”
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    • cites van Praag, 2008 source

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    Interpretationreasoning

    Adult-born granule cells mediate the enhancement of long-term potentiation in the dentate gyrus from aerobic exercise.

    “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).”
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    Premisecitation

    These morphological changes are associated with higher rates of long-term potentiation induction and facilitate changes in dendritic strength.

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

    Aerobic exercise stimulates long-term potentiation in young rodents and reverses the age-related decline of long-term potentiation within the dentate gyrus of aged rodents compared to sedentary controls.

    “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).”
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    Premisecitation

    Forming an episodic memory involves the association of an event or feature with a particular location in space and occurs through the long-term potentiation mechanism in the hippocampus.

    “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).”
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    Premisecitation

    Brain-derived neurotrophic factor 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.

    “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).”
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    Interpretationcitation

    Increasing microvasculature density may be protective against white-matter hyperintensities, which itself may reduce gray-matter atrophy and cognitive dysfunction.

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

    Other animal models have found improvements in spatial learning to be driven by neurogenesis with no influence at all from angiogenesis.

    “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).”
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    Interpretationcitation

    The positive influence of improving vascularization may extend beyond a greater supply of oxygen and glucose through prompting the release of neurotrophic factors or through facilitating other neuroplastic mechanisms like synaptic plasticity or neurogenesis.

    “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”
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    Premisenone given

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

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

    Changes in vasculature may stimulate other neuroplastic mechanisms like synaptogenesis or neurogenesis and promote hippocampal tissue growth.

    “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).”
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    Some animal models have suggested that angiogenesis may underlie improvements in spatial memory tasks independent of other neuroplastic mechanisms.

    “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).”
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    Premisecitation

    Aerobic exercise stimulates the sprouting of new capillaries (angiogenesis) and improves vasculature within the hippocampus in animal models.

    “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).”
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    Interpretationcitation

    Through generating a greater influx of adult-born granule cells that have an enhanced propensity for long-term potentiation and fine-grained morphological changes, aerobic exercise stimulates an environment within the hippocampus that promotes long-term potentiation and facilitates improvements in hippocampus-dependent cognition.

    “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).”
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    Premisecitation

    Neither antipsychotics nor antidepressants have been consistently shown to induce any lasting neuroplastic changes in the brain.

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

    VEGF and IGF-1 are growth factors produced peripherally and implicated in both angiogenesis and neurogenesis.

    “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).”
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    Premisecitation

    Cognitive dysfunction in human patients with schizophrenia is considered amongst the most debilitating aspects of schizophrenia, and its severity is a key determinant of functional outcome following treatment.

    “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).”
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    VEGF and IGF-1 cross the blood brain barrier and interact with hippocampal cells.

    “both molecules are known to cross the blood brain barrier and interact with hippocampal cells (Ding et al., 2006; Tang et al., 2010).”
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    Human patients with MDD have consistently demonstrated clinically relevant deficits in executive functioning, psychomotor speed, attention, and memory.

    “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).”
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    Premisecitation

    Inhibition of VEGF or IGF-1 impairs the promotional impact of AE on the rate of neurogenesis and spatial memory performance.

    “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).”
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    Premisecitation

    A number of psychiatric and neurological disorders have a particularly potent influence on hippocampal structure, and its deterioration may underlie certain aspects of their symptomatology.

    “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.”
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    Premisereasoning

    In humans, AE is associated with increases in hippocampal volume and some indirect indicators of neuroplasticity, which correlate with improved performances on hippocampus dependent tasks.

    “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.”
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    Premisecitation

    Growth in hippocampal volume and, in some cases, improvements in working memory performance are correlated with higher concentrations of NAA.

    “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.”
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    Premisecitation

    Reduced hippocampal volume is one of the most consistently reported structural abnormalities in patients with MDD and in patients with schizophrenia.

    “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).”
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    Interpretationreasoning

    These findings suggest that AE can stimulate hippocampal neuroplasticity and promote the region's functioning in humans in a similar way to that demonstrated using animal models.

    “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.”
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    Premisecitation

    VEGF facilitates vascularization, particularly within the dentate gyrus (DG), and thereby supports AE-induced stimulation of neurogenesis.

    “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).”
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    Premisecitation

    IGF-1 supports alterations in vascularization induced by AE and promotes the proliferation and survival of newborn neural cells.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lopez-Lopez et al., 2004 source

      Not checked in the free run.

    • cites Gomez-Pinilla and Hillman, 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Targeting neuroplasticity has recently become an important approach in treating psychiatric symptoms and may be useful in counteracting hippocampal harm to remediate cognitive deficits.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kays et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Large-scale meta-analyses suggest that the effectiveness of antipsychotic and antidepressant medications is only marginally different from placebo, and neither has successfully remediated cognitive dysfunction.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Leucht et al., 2009 source

      Not checked in the free run.

    • cites Rief et al., 2009 source

      Not checked in the free run.

    • cites Keefe et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some AE studies found a positive correlation between hippocampal volume or connectivity changes and serum concentrations of BDNF, VEGF, and IGF-1, while others failed to replicate such findings.

    “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).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Erickson et al., 2011 source

      Not checked in the free run.

    • cites Coelho et al., 2013 source

      Not checked in the free run.

    • cites Voss et al., 2013b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5-HT transmission in the hippocampus is disrupted in schizophrenia and MDD, and this dysfunction is likely to contribute to deficits in learning and memory in these disorders.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Naughton et al., 2000 source

      Not checked in the free run.

    • cites Middlemiss et al., 2002 source

      Not checked in the free run.

    • cites Meeter et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, AE has been shown to stimulate hippocampal neuroplasticity and successfully counteract deteriorating hippocampal function caused by aging or Alzheimer's disease.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Intlekofer and Cotman, 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    It is possible that AE's interaction with the monoamine system may contribute toward cognitive enhancement.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Christie et al., 2008 source

      Not checked in the free run.

    • cites van Praag, 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AE has been demonstrated to counteract pathologically induced hippocampal harm and improve the region's functioning in a range of animal disease models.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Patten et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One human study found no association between an AE intervention and hippocampal volume or neurotrophin circulation in MDD, but participant attendance was very low and participants showed no reduction in depressive symptoms.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Krogh et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In animal models of stress/MDD, AE can promote hippocampal neurogenesis, vascularization, BDNF expression, IGF-1 expression, VEGF expression, and hippocampal synaptic plasticity.

    “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”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Adlard and Cotman, 2004

      Not checked in the free run.

    • cites Zheng et al., 2006 source

      Not checked in the free run.

    • cites Bjørnebekk et al., 2010 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    Non-pharmacological approaches like AE have a number of distinct benefits to the patient that make them worthy of further investigation.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Pajonk et al., 2010 source

      Not checked in the free run.

    • cites Lin et al., 2015 source

      Not checked in the free run.

    • cites McEwen et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

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

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

  • May combine two claims.

    Interpretationreasoning

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

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

  • May combine two claims.

    Interpretationreasoning

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

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Long-term antipsychotic treatment in humans may be linked to a reduction in both global gray- and white-matter volumes as well as region-specific reductions in hippocampal volume.

    “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).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Navari and Dazzan, 2009

      Not checked in the free run.

    • cites Ho et al., 2011

      Not checked in the free run.

    • cites Vernon et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Psychiatric patients have previously reported having a favorable perspective of AE treatment, but this is not necessarily reflected in actual AE engagement.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Stanton and Reaburn, 2014

      Not checked in the free run.

    • cites Vancampfort et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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 effectiveness and reduces harms associated with pharmacological interventions.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

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

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    A combined pharmacotherapy/AE approach may have an additive impact on symptom alleviation, meaning patients may reach remission at a faster rate.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Fiuza-Luces et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AE is known to be preventative of cardiovascular, metabolic and respiratory dysfunction.

    “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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Caemmerer et al., 2012 source

      Not checked in the free run.

    • cites Vancampfort et al., 2014 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Developing further pharmacological interventions that effectively alleviate cognitive symptoms in medicated psychiatric populations could elevate the risk of adverse side effects for the patient.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    AE has the potential to directly combat adverse side effects of pharmacotherapy and contribute toward remediation of cognitive deficits and other psychiatric symptoms that may be related to hippocampal dysfunction.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    AE interventions could improve the treatment of schizophrenia and MDD and could have a broader application in mental health such as in treating substance abuse.

    “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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Zschucke et al., 2012 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

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

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other forms of exercise such as yoga or weight training may also be beneficial in promoting brain health and cognition.

    “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.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lin et al., 2015 source

      Not checked in the free run.

    • cites Suo et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Hippocampal damage is a significant factor underlying the symptomatology of disorders that AE may treat.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Exercise intensities may vary depending on the purpose of the intervention; improving cognitive performance may require high-intensity interval training, while preserving cognitive function in an aging brain may require a lower intensity, more continuous protocol.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Duzel et al., 2016 source

      Not checked in the free run.

70 of 70

  • The paper relies on this without support.

    Aerobic exercise has a low risk profile and is relatively easy to implement.

    “Given its general benefits to ones physical health, low risk profile and relative ease of implementation, AE represents a promising therapeutic target for a range of brain pathologies.”

  • The paper relies on this without support.

    Most of the supporting work on aerobic exercise can be readily translated from animal models to humans.

    “As the evidence-base rapidly builds, and given most of the supporting work can be readily translated from animal models to humans, the potential for AE to be applied as a therapeutic or adjunctive intervention for a range of human conditions appears ever more promising.”

  • The paper relies on this without support.

    Cognitive deficits in various psychiatric disorders currently remain untreated.

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

  • The paper relies on this without support.

    Aerobic exercise has general benefits to physical health.

    “Given its general benefits to ones physical health, low risk profile and relative ease of implementation, AE represents a promising therapeutic target for a range of brain pathologies.”

  • The authors state this as an assumption.

    Low mean diffusivity is indicative of increased gray-matter tissue density.

    “based on the assumption that a low mean diffusivity is indicative of an increased gray-matter tissue density (Kleemeyer et al., 2015).”

  • The paper relies on this without support.

    NAA is a metabolite indicative of neuronal integrity.

    “N-acetylaspartate (NAA) is a metabolite indicative of neuronal integrity”

  • The paper relies on this without support.

    Comparatively little attention has been afforded to the potential application of AE in treating psychiatric disorders that have a similarly deleterious impact on the hippocampus and are associated with severe cognitive deficits.

    “Comparatively little attention has been afforded to the potential application of AE in treating psychiatric disorders that have a similarly deleterious impact on the hippocampus and are associated with severe cognitive deficits.”

  • The paper relies on this without support.

    Cognitive dysfunctions in psychiatric disorders remain largely untreated.

    “targeting cognitive dysfunctions that remain largely untreated.”

  • The paper relies on this without support.

    Hippocampal damage is a significant factor underlying the symptomatology of disorders that AE may treat.

    “disorders in which hippocampal damage is a significant factor that underlies its symptomatology.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Physical activity stimulates neurogenic processes important for brain functioning, such as up-regulating brain-derived neurotrophic factor and stimulating neurogenesis and angiogenesis.

    “PA also stimulates a broad range of neurogenic processes important for proper brain functioning, such as up-regulating growth factors like brain-derived neurotrophic factor (BDNF), and stimulating neurogenesis and angiogenesis [74, 75]⁠.”

    From Moving to Beat Anxiety: Epidemiology and Therapeutic Issues with Physical Activity for Anxiety (2018) · cites this paper as [74]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • A 12-month exercise trial is cited as a review

    Minor

    The cited Voss et al. (2013b) entry is a review about bridging animal and human models, not the 12-month trial described here. The reference list assigns the one-year exercise intervention to Voss et al. (2013a).

1 of 1

Cites

Flagged first, then by citations

10 of the 429 references couldn’t be matched to a known paper.

Research works printed but not linked: 4

  1. CMR International, 2015, CMR International 2015 Pharmaceutical R&D Factbook.
  2. Goldberg, 2002, Neurocognitive functioning in patients with schizophrenia: an overview, Neuropsychopharmacology: The Fifth Generation of Progress
  3. Moser, 1998, Functional differentiation in the hippocampus., Hippocampus, 8, 608, 10.1002/(sici)1098-1063(1998)8:6608::aid-hipo33.0.co;2-7 · DOI
  4. Sexton, 2015a, Physical activity and anterior hippocampal volume in older adults., Proc. Physiol. Soc., 33

Cited by

Sorted by citations

Related

Authors
Kandola, A., Hendrikse, J., Lucassen, P. J., & Yücel, M.
Affiliations
  • Monash University (AU)
  • University of Amsterdam (NL)
Corresponding author
  • Kandola, Aaron
  • Yücel, Murat
ORCID
Venue
Frontiers in Human Neuroscience
Publisher
Frontiers Media SA
Published
2016-07-29
Volume
10
Pages
373-373
ISSN
1662-5161 (ISSN-L)
DOI
10.3389/fnhum.2016.00373
PMC
PMC4965462
OpenAlex
W2498750904
Semantic Scholar
7fd8145dec185001dd53aad3279ccfa546b0ca86
Cited by
155
References
429
Citations by year
2026: 18 · 2025: 11 · 2024: 17 · 2023: 15 · 2022: 12 · 2021: 15 · 2020: 17 · 2019: 15 · 2018: 18 · 2017: 15 · 2016: 2
FWCI
2.07
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Human Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion, cc-by)
  • Monash University Research Portal (Monash University) (submittedVersion, other-oa)
  • UvA-DARE (University of Amsterdam) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
National Health and Medical Research Council (APP1021973)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Health Sciences › Medicine › Physiology › Physical Activity and Health
Keywords
aerobic exercise, hippocampus, neuroplasticity, cognitive enhancement, psychotherapy, schizophrenia, major depressive disorder, cognitive impairment, non-pharmacological treatment, adjunctive therapy, hippocampal dysfunction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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