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Mol Psychiatry. 2016 Nov;21(11):1633-1642. doi: 10.1038/mp.2016.19. Epub 2016 Mar 22.

Therapeutically relevant structural and functional mechanisms triggered by physical and cognitive exercise.

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Regenerative Neuroscience Group, Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
Brain and Mental Health Laboratory, Monash Institute of Cognitive and Clinical Neuroscience, School of Psychological Sciences, Monash University, Clayton, VIC, Australia.
Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, NSW, Australia.
Exercise Health and Performance Faculty Research Group, Faculty of Health Sciences and Sydney Medical School, The University of Sydney, Lidcombe, NSW, Australia.
Hebrew SeniorLife and Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
Neuropsychiatric Institute, Prince of Wales Hospital, Sydney, NSW, Australia.
Dementia Collaborative Research Centre, University of New South Wales, Sydney, NSW, Australia.
Exercise Health and Performance Faculty Research Group, Faculty of Health Sciences, The University of Sydney, Lidcombe, NSW, Australia.
Department of Psychiatry, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
School of Exercise Science, Australian Catholic University, Strathfield, NSW, Australia.
Clinical and Rehabilitation Research Group, Faculty of Health Sciences, The University of Sydney, Lidcombe, NSW, Australia.
Department of Medicine and the Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.


Physical and cognitive exercise may prevent or delay dementia in later life but the neural mechanisms underlying these therapeutic benefits are largely unknown. We examined structural and functional magnetic resonance imaging (MRI) brain changes after 6 months of progressive resistance training (PRT), computerized cognitive training (CCT) or combined intervention. A total of 100 older individuals (68 females, average age=70.1, s.d.±6.7, 55-87 years) with dementia prodrome mild cognitive impairment were recruited in the SMART (Study of Mental Activity and Resistance Training) Trial. Participants were randomly assigned into four intervention groups: PRT+CCT, PRT+SHAM CCT, CCT+SHAM PRT and double SHAM. Multimodal MRI was conducted at baseline and at 6 months of follow-up (immediately after training) to measure structural and spontaneous functional changes in the brain, with a focus on the hippocampus and posterior cingulate regions. Participants' cognitive changes were also assessed before and after training. We found that PRT but not CCT significantly improved global cognition (F(90)=4.1, P<0.05) as well as expanded gray matter in the posterior cingulate (Pcorrected <0.05), and these changes were related to each other (r=0.25, P=0.03). PRT also reversed progression of white matter hyperintensities, a biomarker of cerebrovascular disease, in several brain areas. In contrast, CCT but not PRT attenuated decline in overall memory performance (F(90)=5.7, P<0.02), mediated by enhanced functional connectivity between the hippocampus and superior frontal cortex. Our findings indicate that physical and cognitive training depend on discrete neuronal mechanisms for their therapeutic efficacy, information that may help develop targeted lifestyle-based preventative strategies.

[Indexed for MEDLINE]
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Conflict of interest statement

The authors declare no conflict of interest. MJV has previously received honoraria for speaking at Pfizer and The Brain Department LLC-sponsored events, has received research funding from The Brain Department LLC for unrelated work and currently receives in-kind research support in the form of no-cost software from BrainTrain Inc (USA) and in-kind research support from NeuroNation for unrelated projects. HB has been an investigator for Pfizer, Novartis, Janssen, Lilly, Medivation, Sanofi and Servier; a sponsored speaker for Pfizer, Novartis, Janssen and Lundbeck; and is on advisory Boards for Pfizer, Novartis, Janssen, Lundbeck, Merck and Baxter. BTB is a member of advisory boards and/or gave presentations for the following companies, for which he received honoraria: AstraZeneca, Lundbeck, Pfizer, Servier and Wyeth. NG holds shares in HeadStrong Brain LLC New York although no dividends, gifts or royalties have ever been received and no work has been conducted for the company since 2007.

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