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Cited by 798Parkinson's Disease Mechanisms and TreatmentsNeurological disorders and treatmentsMotor Control and Adaptation

Exercise-enhanced neuroplasticity targeting motor and cognitive circuitry in Parkinson's disease

Open access
Petzinger, Giselle M, Fisher, Beth E, McEwen, Sarah, Beeler, Jeff A, Walsh, John P, Jakowec, Michael W·2013·The Lancet Neurology
DOI 10.1016/s1474-4422(13)70123-6PMC PMC3690528
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Abstract

Exercise interventions in individuals with Parkinson's disease incorporate goal-based motor skill training to engage cognitive circuitry important in motor learning. With this exercise approach, physical therapy helps with learning through instruction and feedback (reinforcement) and encouragement to perform beyond self-perceived capability. Individuals with Parkinson's disease become more cognitively engaged with the practice and learning of movements and skills that were previously automatic and unconscious. Aerobic exercise, regarded as important for improvement of blood flow and facilitation of neuroplasticity in elderly people, might also have a role in improvement of behavioural function in individuals with Parkinson's disease. Exercises that incorporate goal-based training and aerobic activity have the potential to improve both cognitive and automatic components of motor control in individuals with mild to moderate disease through experience-dependent neuroplasticity. Basic research in animal models of Parkinson's disease is beginning to show exercise-induced neuroplastic effects at the level of synaptic connections and circuits.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that exercise, especially goal-based motor skill training combined with aerobic training, can promote neuroplasticity and improve motor and cognitive function in Parkinson’s disease. It synthesizes human and animal evidence for circuit-level effects involving dopaminergic and glutamatergic neurotransmission, brain health, and repair, while highlighting major gaps for advanced disease and mechanistic specificity.

Key findings

  • Exercise combining goal-based practice and aerobic training may improve both cognitive and automatic components of motor control. In early PD, 8 weeks (24 sessions) of body-weight-supported treadmill training at >3.0 METS and/or 75% of age-adjusted maximum heart rate improved gait and balance and increased cortical silent period duration on TMS; PET with [18F]fallypride showed increased DA-D2R binding potential in dorsal striatum.
  • Other goal-based modalities show benefits: 24 weeks of twice-weekly Tai Chi improved stride length and maximum excursion and reduced falls versus resistance training or stretching, with benefits retained at least 2 months; 12 months of Argentine tango improved balance, walking, and dual-task capability; forced cycling at pedaling rates 30% greater than preferred improved automatic manual dexterity and cortico-subcortical connectivity on fMRI.
  • In MPTP and 6-OHDA animal models, exercise improves motor performance and can preserve DA neurons or restore dopaminergic terminals, attributed to BDNF/GDNF increases and DAT downregulation. Neurorestoration studies show increased DA neurotransmission, reversal of dorsal striatal DA-D2R reduction, and restored AMPA receptor expression.
  • Exercise may also affect dendritic spines, cerebral blood flow/angiogenesis, immune modulation (e.g., IL-10, IL-6, M1-to-M2 macrophage conversion), and neurogenesis, though direct evidence in PD models is limited for several of these mechanisms.

Methods

  • Narrative review of published human exercise studies in Parkinson’s disease and animal models, including treadmill training, amplitude training, Tai Chi, tango, boxing, and forced cycling.
  • Animal evidence draws primarily on MPTP-lesioned mouse and 6-OHDA-lesioned rat toxin models of dopamine depletion.
  • Main analysis is a qualitative synthesis linking exercise-induced behavioral changes to proposed neuroplasticity mechanisms at circuits and synapses; no systematic search, meta-analysis, or risk-of-bias assessment is described.

Limitations

  • The paper states that future research is needed to discern the relative contribution of goal-based versus aerobic exercise alone or in combination on brain function, connectivity, and motor behavior, and that the role of exercise in advanced disease and severe cognitive impairment/dementia is a major gap.
  • The paper states that there are currently no studies supporting exercise effects on cerebral vasculature in animal models of PD, few reports directly addressing neurogenesis, exercise, and DA depletion, and it is not established whether exercise protects against age-related decline in DA neurotransmission in genetic models.
  • Evident from the text: as a narrative review, it lacks systematic search and quantitative synthesis; many cited human studies are small, pilot, or preliminary, and some treadmill studies showed no significant gait improvement, possibly due to differences in feedback/cognitive engagement or disease severity.

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

Integrity signals

Registry

Crossref · 10.1016/s1474-4422(13)70123-6

Cites

134 of 134 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 150 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Benefits of treadmill training transfer to improvements in Unified Parkinson's Disease Rating Scale motor score.

    “Interestingly benefits of treadmill training, a largely lower extremity task, have also been shown to transfer to improvements in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [28] Miyai, 2002, Long-term effect of body weight-supported treadmill training in Parkinson's disease: a randomized controlled trial, Arch Phys Med Rehabil source

      Not checked in the free run.

    • cites [29] Frazzitta, 2012, Effectiveness of intensive inpatient rehabilitation treatment on disease progression in Parkinsonian patients: a randomized controlled trial with 1-year follow-up, Neurorehabil Neural Repair source

      Not checked in the free run.

  • Premisecitation

    Treadmill exercise studies have shown that individuals with mild to moderate Parkinson's disease can improve gait performance, including velocity, stride length, cadence, postural stability, gait rhythmicity, and joint excursion.

    “Studies, using treadmill exercise (with or without body weight support typically used for the purpose of maintaining safety) have shown that through exercise practice individuals with mild to moderate stages of PD can improve gait performance, including velocity, stride length, cadence, postural stability, gait rhythmicity, and joint excursion 24, 25.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] Herman, 2007, Six weeks of intensive treadmill training improves gait and quality of life in patients with Parkinson's disease: a pilot study, Arch Phys Med Rehabil source

      Not checked in the free run.

    • cites [25] Herman, 2009, Treadmill training for the treatment of gait disturbances in people with Parkinson's disease: a mini-review, J Neural Transm source

      Not checked in the free run.

  • Interpretationcitation

    Retention of task benefits after a period without training is consistent with motor learning and underlying neuroplasticity.

    “The fact that individuals with PD show retention of task benefits (especially gait and balance) after a period of time without training is consistent with motor learning and underlying neuroplasticity 38.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Nieuwboer, 2002, Prediction of outcome of physiotherapy in advanced Parkinson's disease, Clin Rehabil source

      Not checked in the free run.

  • Interpretationcitation

    Differences in amount of feedback and cognitive engagement during practice may explain discrepant gait outcomes among treadmill studies.

    “One possible explanation for this discrepancy in gait outcomes may be due to differences in the amount of feedback and cognitive engagement during practice 26, 27.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Canning, 2012, Home-based treadmill training for individuals with Parkinson's disease: a randomized controlled pilot trial, Clin Rehabil source

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    • cites [27] Skidmore, 2008, Pilot safety and feasibility study of treadmill aerobic exercise in Parkinson disease with gait impairment, J Rehabil Res Dev source

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  • Premisecitation

    Tai Chi benefits were retained for at least 2 months.

    “These benefits were retained for at least 2 months 17.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Li, 2012, Tai chi and postural stability in patients with Parkinson's disease, N Engl J Med source

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  • Classified as probably not a substantial claim. 14
  • May combine two claims. 36

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

    Interpretationcitation

    Age, cognition, and disease severity could impact exercise effects on motor skill learning.

    “Other factors that could impact exercise effects on motor skill learning include age, cognition, and disease severity 35.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Rochester, 2010, Evidence for motor learning in Parkinson's disease: acquisition, automaticity and retention of cued gait performance after training with external rhythmical cues, Brain Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dopamine replacement therapy alleviates some motor features of Parkinson's disease but has less beneficial effects on cognitive function.

    “DA replacement therapy alleviates some motor features of PD, but with less beneficial effects observed on cognitive function 4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Schapira, 2009, Perspectives on recent advances in the understanding and treatment of Parkinson's disease, Eur J Neurol source

      Not checked in the free run.

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

    Premisenone given

    Basic research using animal models is beginning to reveal exercise-induced effects on neuroplasticity.

    “Utilizing animal models, basic research is beginning to reveal exercise-induced effects on neuroplasticity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Feedback in exercise serves to challenge patients beyond self-selected levels of perceived capability, maintain motivation, and facilitate cognitive awareness of previously automatic movements.

    “Feedback serves several purposes including (i) challenging patients beyond self-selected levels of perceived capability, (ii) maintaining motivation, and (iii) facilitating the engagement of individuals to become cognitively aware of movements that were previously automatic and unconscious.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tango dancing for 12 months improves balance, walking, and dual tasking capability in individuals with Parkinson's disease.

    “Earhardt and colleagues showed that by the end of 12 months of Tango dancing individuals with PD had improved balance, walking, and dual tasking capability 34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Duncan, 2012, Randomized controlled trial of community-based dancing to modify disease progression in Parkinson disease, Neurorehabil Neural Repair source

      Not checked in the free run.

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

    Interpretationnone given

    Exercise-induced benefits on brain health (blood flow, trophic factors, immune system) may help create the optimal environmental milieu required for neuroplasticity in the injured brain.

    “Importantly, exercise-induced benefits on brain health (blood flow, trophic factors, immune system) may help to create the optimal environmental milieu required for neuroplasticity to occur in the injured brain.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Gait impairments involving reductions in speed and step length and increased stride length variability are common in Parkinson's disease and impact quality of life.

    “Gait impairments that involve reductions in speed and step length as well as increased stride length variability are common in PD and impact quality of life 23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Frenkel-Toledo, 2005, Effect of gait speed on gait rhythmicity in Parkinson's disease: variability of stride time and swing time respond differently, J Neuroengineering Rehabil source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tai Chi following 24 weeks of twice weekly sessions leads to improved stride length and maximum excursion and reduced falls compared to resistance training or stretching in Parkinson's disease.

    “Findings from these studies show that, following 24 weeks of twice weekly sessions, Tai Chi leads to improved stride length and maximum excursion as well as reduced falls compared to resistance training or stretching.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Li, 2012, Tai chi and postural stability in patients with Parkinson's disease, N Engl J Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Functional magnetic resonance imaging studies demonstrate that acquisition and learning of dual task training in Parkinson's disease is limited and occurs principally through compensatory cortical circuits.

    “Though studies point to preserved motor skill learning in individuals with early stage PD, fMRI studies demonstrate that the acquisition and learning of dual task training in PD is limited and occurs principally through compensatory cortical circuits.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Wu, 2007, Neural correlates of dual task performance in patients with Parkinson's disease, J Neurol Neurosurg Psychiatry

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The loss and restoration of automaticity in Parkinson's disease remains a difficult problem to solve.

    “the loss and restoration of automaticity in PD in general remains a difficult problem to solve.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Dopamine depletion predominant in the caudal basal ganglia of individuals with Parkinson's disease leads to aberrant habitual learning and loss of automatic motor control.

    “DA depletion predominant in the caudal basal ganglia of individuals with PD, leads to aberrant habitual learning and loss of automatic motor control.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The beneficial role of exercise, specifically incorporating aerobic training, may be to facilitate neuroplasticity and improve motor learning.

    “The beneficial role of exercise, and specifically incorporating aerobic training, may be to facilitate neuroplasticity and improve motor learning.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Forced cycling led to improved automatic manual dexterity and increased connectivity between cortico-subcortical regions involved in automatic control using functional magnetic resonance imaging.

    “This led to central changes as evidenced by improved automatic manual dexterity as well as increased connectivity between cortico-subcortical regions involved in automatic control using functional magnetic resonance imaging (fMRI).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Alberts, 2011, It is not about the bike, it is about the pedaling: forced exercise and Parkinson's disease, Exerc Sport Sci Rev source

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    • cites [22] Ridgel, 2009, Forced, not voluntary, exercise improves motor function in Parkinson's disease patients, Neurorehabil Neural Repair source

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  • May combine two claims.

    Premisecitation

    Alberts and colleagues forced individuals with Parkinson's disease to achieve pedaling rates 30% greater than their preferred rate, combining cognitive engagement with aerobic training.

    “Using a stationary tandem bicycle Alberts and colleagues “forced” individuals with PD to achieve pedaling rates that were 30% greater than their preferred rate thus combining aspects of cognitive engagement with aerobic training.21, 22”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Alberts, 2011, It is not about the bike, it is about the pedaling: forced exercise and Parkinson's disease, Exerc Sport Sci Rev source

      Not checked in the free run.

    • cites [22] Ridgel, 2009, Forced, not voluntary, exercise improves motor function in Parkinson's disease patients, Neurorehabil Neural Repair source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Animal models provide an important tool to investigate mechanisms by which exercise induces neuroplasticity in the mammalian brain.

    “Animal models provide an important tool to investigate the mechanisms by which exercise induces neuroplasticity in the mammalian brain.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    These studies reported improvement in motor function, along with preservation of dopamine neurons and restoration of dopaminergic terminals, using tyrosine hydroxylase immunostaining, within the striatum.

    “These studies have reported improvement in motor function, along with the preservation of DA neurons and the restoration of dopaminergic terminals, using tyrosine hydroxylase (TH) immunostaining, within the striatum.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dopamine depletion in the striatum induces hyper-excitability in the indirect pathway in response to alterations in glutamatergic expression and underlies critical aspects of motor impairment in Parkinson's disease.

    “DA depletion in the striatum induces hyper-excitability in the indirect pathway in response to alterations in glutamatergic expression (receptors and neurotransmitter release) and underlies critical aspects of motor impairment in PD 84.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Real, 2013, BDNF receptor blockade hinders the beneficial effects of exercise in a rat model of Parkinson s disease, Neuroscience source

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

    Premisecitation

    Two commonly used models of dopamine depletion include the MPTP-lesioned mouse and the 6-OHDA-lesioned rat.

    “Two commonly used models of DA-depletion include the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse and the 6-hydroxydopamine (6-OHDA)-lesioned rat models.71”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Tanaka, 2009, Benefits of physical exercise on executive functions in older people with Parkinson's disease, Brain Cogn source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    While motor learning may be limited or impaired in Parkinson's disease, exercise may improve both goal-directed motor skill practice and ultimately automaticity through repair of the basal ganglia and its connections.

    “First that while motor learning may be limited or impaired in PD, exercise may improve both goal directed motor skill practice and ultimately through repair of the basal ganglia and its connections, automaticity.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    These models have utility in investigating underlying molecular mechanisms involved in exercise-induced neuroplasticity in both neuroprotection and neurorestoration studies.

    “These models have utility in investigating the underlying molecular mechanisms involved in exercise-induced neuroplasticity in both neuroprotection and neurorestoration studies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Other factors that may influence neuroprotective effects of exercise include the relative time frame of exercise initiation to toxin administration, as well as the extent of toxin-induced injury.

    “Importantly, other factors that may influence neuroprotective effects of exercise include the relative time frame of exercise initiation to toxin administration, as well as the extent (severe versus mild) of the toxin-induced injury.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Both MPTP and 6-OHDA toxins lead to destruction of nigrostriatal dopamine neurons and subsequent depletion of dopamine in the dorsal striatum.

    “Both toxins lead to the destruction of nigrostriatal DA neurons and the subsequent depletion of DA in the dorsal striatum.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Tanaka, 2009, Benefits of physical exercise on executive functions in older people with Parkinson's disease, Brain Cogn source

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  • May combine two claims.

    Premisenone given

    Exercise can increase post-lesion dopamine neurotransmission by enhancing vesicular release of dopamine and increasing synaptic occupancy and decreasing dopamine clearance through reduced DAT expression.

    “These studies have shown that exercise can increase post-lesion DA neurotransmission by enhancing the vesicular release of DA and increasing synaptic occupancy and decreasing DA clearance through reduced DAT expression.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    It has not yet been established if exercise can provide protection from age-related decline in dopamine neurotransmission in genetic models of familial Parkinson's disease.

    “While genetic models of familial forms of PD are now available it has not yet been established if exercise can provide protection from age-related decline in DA neurotransmission.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Glutamate and its receptors contribute to neuroplasticity and synaptic strengthening during learning.

    “Glutamate and its receptors are known to contribute to neuroplasticity and synaptic strengthening during the learning process.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cognition is affected early and progresses with disease severity and involves dopaminergic, serotoninergic, noradrenergic, and cholinergic systems.

    “Cognition is affected early and progresses with disease severity and involves a number of neurotransmitter systems including dopaminergic, serotoninergic, noradrenergic, and cholinergic 60, 61.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Ekman, 2012, Functional brain activity and presynaptic dopamine uptake in patients with Parkinson's disease and mild cognitive impairment: a cross-sectional study, Lancet Neurol source

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    • cites [61] Godefroy, 2010, Dysexecutive syndrome: diagnostic criteria and validation study, Ann Neurol source

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

    Premisecitation

    Exercise leads to cognitive improvement in normal aging and Alzheimer's disease.

    “It is well established that exercise leads to cognitive improvement in normal aging and Alzheimer’s disease 62–64.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Yeterian, 1991, Prefrontostriatal connections in relation to cortical architectonic organization in rhesus monkeys, J Comp Neurol source

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    • cites [63] Lewis, 2003, Cognitive impairments in early Parkinson's disease are accompanied by reductions in activity in frontostriatal neural circuitry, J Neurosci source

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    • cites [64] Ray, 2012, The neurobiology and neural circuitry of cognitive changes in Parkinson's disease revealed by functional neuroimaging, Mov Disord source

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    Premisecitation

    Spine loss occurs predominantly on DA-D2R-containing medium spiny neurons of the indirect pathway, reflecting dysfunction in neurotransmission in this circuitry.

    “Spine loss occurs predominantly on DA-D2R-containing MSNs of the indirect pathway, reflecting the dysfunction in neurotransmission in this circuitry 92, 93.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Ingham, 1993, Morphological changes in the rat neostriatum after unilateral 6-hydroxydopamine injections into the nigrostriatal pathway, Exp Brain Res source

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    • cites [93] Cheng, 1997, Differential spine loss and regrowth of striatal neurons following multiple forms of deafferentation: a Golgi study, Exp Neurol source

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  • May combine two claims.

    Interpretationcitation

    Long-term exercise elicits change in regional blood perfusion of underlying motor circuits that may contribute to changes in brain connectivity related to synaptogenesis but also enhance synaptic function.

    “Long-term exercise elicits change in regional blood perfusion of underlying motor circuits that may contribute to changes in brain connectivity related to synaptogenesis but also enhance synaptic function 102.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [102] Cotman, 2007, Exercise builds brain health: key roles of growth factor cascades and inflammation, Trends Neurosci source

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    Premisecitation

    Exercise has been shown to induce conversion of M1-type to M2-type myeloid cells in adipose tissue macrophages and inhibit M1-type macrophage infiltration.

    “The fact that exercise has been shown to induce a conversion of M1-type to M2-type myeloid cells in adipose tissue macrophages coupled with inhibition of M1-type macrophage infiltration support this hypothesis.120”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Perry, 2004, The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease, Brain Behav Immun source

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    Premisecitation

    Studies in healthy rodents have shown that exercise can alter hippocampal cerebral blood flow and elevate hippocampal, striatal, and substantia nigra levels of vascular endothelial growth factor.

    “While there are currently no studies supporting the effects of exercise on the cerebral vasculature in animal models of PD, studies in healthy rodents have shown that exercise can alter hippocampal cerebral blood flow and elevate hippocampal, striatal, and substantia nigra levels of VEGF,99–101”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [99] Cotman, 2002, Exercise: a behavioral intervention to enhance brain health and plasticity, Trends Neurosci source

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    • cites [100] Swain, 2003, Prolonged exercise induces angiogenesis and increases cerebral blood volume in primary motor cortex of the rat, Neuroscience source

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    • cites [101] Secher, 2008, Cerebral blood flow and metabolism during exercise: implications for fatigue, J Appl Physiol source

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    Premisecitation

    Exercise-induced IL-6 elicits an anti-inflammatory response including elevated expression of IL-10 and IL-1RA and inhibition of TNF-alpha.

    “Specifically, IL-6, which originates in skeletal muscle, has been shown with exercise to elicit an anti-inflammatory response that includes elevated expression of a number of factors including IL-10 and IL-1RA, and as well as inhibition of factors like tumor necrosis factor alpha (TNF-alpha).113–115”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [113] Streit, 2002, Microglia as neuroprotective, immunocompetent cells of the CNS, Glia source

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    • cites [114] Huang, 2012, Aspects of innate immunity and Parkinson's disease, Front Pharmacol source

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    • cites [115] Scalzo, 2010, Serum levels of interleukin-6 are elevated in patients with Parkinson's disease and correlate with physical performance, Neurosci Lett source

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    Premisecitation

    These morphological changes reflect loss of synapses and reduction in neurotransmission in Parkinson's disease and a wide spectrum of brain disorders including Alzheimer's disease and Fragile-X syndrome.

    “These morphological changes reflect the loss of synapses and hence reduction in neurotransmission not only in PD but a wide spectrum of brain disorders including Alzheimer’s disease and Fragile-X syndrome 91.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [91] Ingham, 1989, Spine density on neostriatal neurones changes with 6-hydroxydopamine lesions and with age, Brain Res source

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    Premisecitation

    Exercise (cycling) can increase plasma levels of the anti-inflammatory cytokine IL-10 in individuals with PD and improve motor performance.

    “Reports have shown that exercise (cycling) can increase plasma levels of the anti-inflammatory cytokine IL-10 in individuals with PD along with improved motor performance.111, 112”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [111] Schwartz, 2003, Macrophages and microglia in central nervous system injury: are they helpful or harmful?, J Cereb Blood Flow Metab source

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    • cites [112] Schwartz, 2006, Microglial phenotype: is the commitment reversible?, Trends Neurosci source

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

    Premisecitation

    There is a strong immune component in Parkinson's disease.

    “Yet it is well recognized that there is a strong immune component in PD 110.”
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    • cites [110] Marchetti, 2005, To be or not to be (inflamed)—is that the question in anti-inflammatory drug therapy of neurodegenerative disorders?, Trends Pharmacol Sci source

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  • May combine two claims.

    Interpretationcitation

    Exercise can alter the storage and release of glutamate in presynaptic terminals that may improve circuit function and diminish the increased inhibitory drive of the dopamine depleted striatum.

    “In addition to its receptors, exercise can also alter the storage and release of glutamate in presynaptic terminals that may also improve circuit function and diminish the increased inhibitory drive of the DA depleted striatum 41–44.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [41] Cameron, 2010, Executive impairment in Parkinson's disease: response automaticity and task switching, Neuropsychologia source

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    • cites [42] Smith, 1998, Microcircuitry of the direct and indirect pathways of the basal ganglia, Neuroscience

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    • cites [43] DeLong, 2010, Changing views of basal ganglia circuits and circuit disorders, Clin EEG Neurosci source

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    • cites [44] Calabresi, 1997, Synaptic plasticity and physiological interactions between dopamine and glutamate in the striatum, Neurosci Biobehav Rev source

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    Premisecitation

    CNS resident microglia and perivascular macrophages form an integrated network in close proximity with neurons, suggesting they interact with numerous CNS cell types and circuits.

    “The large number of CNS resident microglia and perivascular macrophages form an integrated network in close proximity with neurons suggesting that these cells interact with numerous CNS cell types and circuits.118”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [118] Pedersen, 2005, Muscle-derived interleukin-6—a possible link between skeletal muscle, adipose tissue, liver, and brain, Brain Behav Immun source

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    Premisecitation

    Rats learning new motor skills have a greater number of synapses per neuron within the motor cortex, without an increase in capillary density.

    “Conversely, rats learning new motor skills have a greater number of synapses per neuron within the motor cortex, without an increase in capillary density.96, 103, 104”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [96] Day, 2006, Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models, Nat Neurosci source

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    • cites [103] Fabel, 2003, VEGF is necessary for exercise-induced adult hippocampal neurogenesis, Eur J Neurosci source

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    • cites [104] Ding, 2006, Cerebral angiogenesis and expression of angiogenic factors in aging rats after exercise, Curr Neurovasc Res source

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    Premisecitation

    Rats that have undergone aerobic exercise have an increase in density of capillaries in cerebral motor regions, without an increase in number of synapses, but display improved cortical related behaviors.

    “Interestingly, rats that have undergone aerobic exercise have an increase in the density of capillaries in the cerebral motor regions, without an increase in the number of synapses, but display improved cortical related behaviors52.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52] Fisher, 2013, Treadmill exercise elevates striatal dopamine D2 receptor binding potential in patients with early Parkinson's disease, NeuroReport source

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    Premisecitation

    Exercise increases neurogenesis in the hippocampus and subventricular zone.

    “The fact that exercise increases neurogenesis in the hippocampus and subventricular zone does not necessarily translate into the potential role of exercise in increasing neuron numbers in important basal ganglia circuitry within the striatum, cortex, or thalamus 123.”
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    • cites [123] Tremblay, 2011, A role for microglia in synaptic plasticity?, Commun Integr Biol source

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    Premisecitation

    The adult mammalian brain, including humans, displays a high degree of neurogenesis.

    “It is well established that the adult mammalian brain including humans displays a high degree of neurogenesis, the birth of newborn cells.”
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    • cites Feliciano, 2013 #43937 source

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  • May combine two claims.

    Premisecitation

    Exercise and environmental enrichment in normal rodents increase the rate of newborn cell numbers, the fraction that differentiate into neurons, and the proportion that incorporate into neuronal circuits.

    “Exercise and environmental enrichment in normal rodents have been shown to have a number of important influences on neurogenesis including increasing (i) the rate of newborn cell numbers, (ii) the fraction that differentiate into neurons, and (iii) the proportion that incorporate into neuronal circuits 122.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [122] Wake, 2012, Functions of microglia in the central nervous system—beyond the immune response, Neuron Glia Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combining goal-based with aerobic training may improve automatic and cognitive motor control and reduce the attentional demands of consciously processing behaviors such as walking.

    “More importantly, studies suggest that combining goal based with aerobic training the possibility for improving automatic with cognitive motor control may be possible and thus reduce the attentional demands of consciously processing behaviors such as walking.126”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Feliciano, 2013, Newborn cortical neurons: only for neonates?, Trends Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neurogenesis is limited by age and to a very limited number of anatomical sites including regions adjacent to the lateral ventricle and hippocampus.

    “However, neurogenesis is limited by both age and to a very limited number of anatomical sites including the regions adjacent to the lateral ventricle and hippocampus {Feliciano, 2013 #43937}.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Feliciano, 2013 #43937 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Based on published studies in both animals and individuals with PD, exercise improves motor function in PD and facilitates neuroplasticity.

    “Based on published studies in both animals and individuals with PD, exercise has been shown to be important in improving motor function in PD and to facilitate neuroplasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exercise incorporating goal-based motor skill learning improves motor skill performance in PD, and this may be enhanced through cognitive engagement.

    “The general idea is that exercise incorporating goal based motor skill learning improves motor skill performance in PD and that this may be enhanced through cognitive engagement.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Kleim, 2008, Principles of experience-dependent neural plasticity: implications for rehabilitation after brain damage, J Speech Lang Hear Res source

      Not checked in the free run.

    • cites [125] Vivar, 2012, All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis, Curr Top Behav Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Exercise can restore important circuits in motor behavior by modulating DA and glutamate neurotransmission and by influencing general brain health.

    “Exercise can restore important circuits in motor behavior by modulating DA and glutamate neurotransmission as well as influencing general brain health.”
    Quote in the paperNot a substantial claim
47 of 47

  • The paper relies on this without support.

    Findings from toxin models of Parkinson’s disease are applicable to human Parkinson’s disease and to genetic models of familial Parkinson’s disease.

    “It is anticipated that much of what we learn in toxin models will be applicable to many of the current genetic models.”

  • The paper relies on this without support.

    Animal model findings on exercise-induced neuroplasticity can guide and translate to studies in humans with Parkinson’s disease.

    “In the following sections we draw from the basic research literature to show how animal models provide insights and create a framework that can guide translational studies in humans with disease.”

  • The paper relies on this without support.

    There are very few studies exploring the relationship between exercise and the immune system in individuals with PD.

    “Currently there are very few studies exploring the relationship between exercise and the immune system in individuals with PD.”

  • The paper relies on this without support.

    There are few reports in the literature directly addressing the interactions of neurogenesis, exercise, and DA-depletion in animal models.

    “Currently, there are few reports in the literature directly addressing the interactions of neurogenesis, exercise, and DA-depletion in animal models.”

  • The paper relies on this without support.

    There are no reports supporting elevated neurogenesis in the basal ganglia with exercise.

    “While decreased gliosis is observed in these regions with exercise there are no reports supporting elevated neurogenesis in the basal ganglia with exercise.”
5 of 5

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?

  • Exercise and massage alleviate Parkinsonian symptoms and enhance well-being in PD.

    “This supports research showing that both alleviate Parkinsonian symptoms and enhance well-being in PD49,50.”

    From The experience of Anxiety for people with Parkinson’s disease (2023) · cites this paper as [50]

    The Overall Conclusions and Impact on Clinical Care section says exercise improves motor function in PD, and the Goal-Based plus Aerobic Exercise section reports improvements in some cognitive functions. These passages support symptom improvement from exercise, but our copy does not establish that massage alleviates symptoms or that either intervention enhances well-being. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Exercise improves motor performance in individuals with Parkinson's disease, lowers disability in multiple sclerosis, improves functionality in individuals with motor neuron disease, and improves cognitive, mood and motor recovery from TBI.

    “exercise also improves motor performance in individuals with Parkinson’s disease [153], lowers disability in multiple sclerosis [161], improves functionality in individuals with motor neuron disease [46], and improves cognitive, mood and motor recovery from TBI, although the precise timing and intensity of the beneficial exercise after TBI remain to be determined [62, 197].”

    From The neuropathology of sport (2014) · cites this paper as [153]

  • Exercise effects can be enhanced by increasing subjects' cognitive engagement with practice through the provision of cueing or biofeedback in Parkinson's disease.

    “Also, it has been suggested that exercise effects can be enhanced by increasing subjects' cognitive engagement with practice through the provision of cueing or biofeedback in PD [4, 5].”

    From Feasibility and effects of home-based smartphone-delivered automated feedback training for gait in people with Parkinson's disease: A pilot randomized controlled trial (2016) · cites this paper as [4]

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Smith, 1998, Microcircuitry of the direct and indirect pathways of the basal ganglia, Neuroscience, 86, 353

Cited by

Sorted by citations

Related

Authors
Petzinger, G. M., Fisher, B. E., McEwen, S., Beeler, J. A., Walsh, J. P., & Jakowec, M. W.
Affiliations
  • University of Southern California (US)
  • University of California, Los Angeles (US)
  • University of Chicago (US)
Corresponding author
Petzinger, Giselle M
ORCID
Venue
The Lancet Neurology
Publisher
Elsevier BV
Published
2013-07
Volume
12
Issue
7
Pages
716-726
ISSN
1474-4422 (ISSN-L)
DOI
10.1016/s1474-4422(13)70123-6
PMC
PMC3690528
OpenAlex
W2143978324
Cited by
798
References
134
Citations by year
2026: 67 · 2025: 83 · 2024: 88 · 2023: 55 · 2022: 79 · 2021: 71 · 2020: 58 · 2019: 56 · 2018: 53 · 2017: 57 · 2016: 41 · 2015: 48 · 2014: 33 · 2013: 8
FWCI
27.50
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (UL1TR000130)
  • National Institute of Mental Health (K01MH099431)
  • National Institute of Neurological Disorders and Stroke (R01NS044327)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Neurology › Neurological disorders and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Motor Control and Adaptation
Keywords
Parkinson's disease, physical activity, neuroplasticity, motor learning, cognitive function, aerobic exercise, physiotherapy, motor control, experience-dependent plasticity, synaptic connectivity, animal models
MeSH terms
Animals, Cognition, Disease Models, Animal, Exercise Therapy, Goals, Health Status, Humans, Neural Pathways, Neuronal Plasticity, Parkinson Disease, Exercise, MPTP Poisoning, Dendritic Spines, Neurogenesis

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.

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