Physical activity (PA) is known to maintain and improve neurocognitive health. However, there is still a poor understanding of the mechanisms by which PA exerts its effects on the brain and cognition in humans. Many of the most widely discussed mechanisms of PA are molecular and cellular and arise from animal models. While information about basic cellular and molecular mechanisms is an important foundation from which to build our understanding of how PA promotes cognitive health in humans, there are other pathways that could play a role in this relationship. For example, PA-induced changes to cellular and molecular pathways likely initiate changes to macroscopic properties of the brain and/or to behavior that in turn influence cognition. The present review uses a more macroscopic lens to identify potential brain and behavioral/socioemotional mediators of the association between PA and cognitive function. We first summarize what is known regarding cellular and molecular mechanisms, and then devote the remainder of the review to discussing evidence for brain systems and behavioral/socioemotional pathways by which PA influences cognition. It is our hope that discussing mechanisms at multiple levels of analysis will stimulate the field to examine both brain and behavioral mediators. Doing so is important, as it could lead to a more complete characterization of the processes by which PA influences neurocognitive function, as well as a greater variety of targets for modifying neurocognitive function in clinical contexts.

Background Accumulating evidence suggests that higher Mediterranean diet (MedDiet) adherence is associated with higher global cognitive performance and brain structural integrity as well as decreased risk of Alzheimer disease (AD) and vascular dementia (VaD). Objectives We directly examined cross-sectional associations between the MedDiet and cognitive and neuroimaging phenotypes associated with AD and VaD (separately) in a cohort of nondemented, nondepressed older adults. Methods Community-dwelling older adults (n = 82; aged ∼68.8 y; 50% female, 50% minority) underwent dietary (Block Food Frequency Questionnaire 2005) and neuropsychological assessments and neuroimaging. MedDiet scores were quantified with the use of published criteria, and participants were divided into High and Low (median split) adherence groups. We focused our neuropsychological investigation on cognitive phenotypes primarily associated with AD [i.e., learning and memory (L&M)] and VaD (i.e., information processing and executive functioning). AD neuroimaging phenotypes consisted of hippocampal and dentate gyrus volumes quantified using T1-weighted images and the FreeSurfer 6.0 segmentation pipeline (http://surfer.nmr.mgh.harvard.edu). The VaD neuroimaging phenotype consisted of total white matter hyperintensity (WMH) volumes quantified using combined T1-weighted and T2-fluid-attenuated inversion recovery images. Neuroimaging metrics were adjusted for total intracranial volume. Separate multivariable linear regression models controlling for age, sex, education, body mass index, and caloric intake examined the associations between MedDiet groups (High compared with Low) and cognitive and neuroimaging outcomes. Results When compared with the Low MedDiet group, the High MedDiet group was associated with better L&M performance and larger dentate gyri. MedDiet adherence was not associated with information processing, executive functioning, or WMH. Conclusion Results highlight the association between increasing MedDiet adherence and specific cognitive and neuroimaging phenotypes that, when altered, are associated with AD.

Objective Psychomotor slowing has been documented in depression. The digital Clock Drawing Test (dCDT) provides: i) a novel technique to assess both cognitive and motor aspects of psychomotor speed within the same task and ii) the potential to uncover subtleties of behavior not previously detected with non-digitized modes of data collection. Method Using digitized pen technology in 106 participants grouped by Age (younger/older) and Affect (euthymic/unmedicated depressed), we recorded cognitive and motor output by capturing how the clock is drawn rather than focusing on the final product. We divided time to completion (TTC) for Command and Copy conditions of the dCDT into metrics of percent of drawing (%Ink) versus non-drawing (%Think) time. We also obtained composite z-scores of cognition, including attention/ information processing (AIP), to explore associations of %Ink and %Think times to cognitive and motor performance. Results Despite equivalent TTC, %Ink and %Think Command times (Copy n.s.) were significant (AgeXAffect interaction:p=.03)—younger depressed spent a smaller proportion of time drawing relative to thinking compared to the older depressed group. Command %Think time negatively correlated with AIP in the older depressed group (r=−.46;p=.02). Copy %Think time negatively correlated with AIP in the younger depressed (r=−.47;p=.03) and older euthymic groups (r=−.51;p=.01). Conclusion The dCDT differentiated aspects of psychomotor slowing in depression regardless of age, while dCDT/cognitive associates for younger adults with depression mimicked patterns of older euthymics.

We investigated whether graphomotor organization during a digitized Clock Drawing Test (dCDT) would be associated with cognitive and/or brain structural differences detected with a tractography-derived structural connectome of the brain. 72 non-demented/non-depressed adults were categorized based on whether or not they used ‘anchor’ digits (i.e., 12,3,6,9) before any other digits while completing dCDT instructions to “draw the face of a clock with all the numbers and set the hands to 10 after 11”. ‘Anchorers’ were compared to ‘non-anchorers’ across dCDT, additional cognitive measures and connectome-based metrics. In the context of grossly intact clock drawings, anchorers required fewer strokes to complete the dCDT and outperformed non-anchorers on executive functioning and learning/memory/recognition tasks. Anchorers had higher local efficiency for the left medial orbitofrontal and transverse temporal cortices as well as the right rostral anterior cingulate and superior frontal gyrus versus non-anchorers suggesting better regional integration within local networks involving these regions; select aspects of which correlated with cognition. Results also revealed that anchorers’ exhibited a higher degree of modular integration among heteromodal regions of the ventral visual processing stream versus non-anchorers. Thus, an easily observable graphomotor distinction was associated with 1) better performance in specific cognitive domains, 2) higher local efficiency suggesting better regional integration, and 3) more sophisticated modular integration involving the ventral (‘what’) visuospatial processing stream. Taken together, these results enhance our knowledge of the brain-behavior relationships underlying unprompted graphomotor organization during dCDT.