Exercise effects on brain health and learning from minutes to months: The brain EXTEND trial

Abstract

Despite evidence that aerobic exercise benefits the aging brain, in particular the hippocampus and memory, controlled clinical trials have not comprehensively evaluated effects of aerobic exercise training on human memory in older adults. The central goal of this study was to determine chronic effects of moderate-to-vigorous intensity aerobic exercise on the hippocampus and memory in non-demented, inactive adults ages 55-80 years. We determine effects of aerobic exercise training with a 6-month randomized controlled trial (RCT) comparing 150 min/week of home-based, light intensity exercise with progressive moderate-to-vigorous intensity aerobic exercise. For the first time in a large trial, we examined temporal mechanisms by determining if individual differences in the rapid, immediate effects of moderate intensity exercise on hippocampal-cortical connectivity predict chronic training-related changes over months in connectivity and memory. We examined physiological mechanisms by testing the extent to which chronic training-related changes in cardiorespiratory fitness are a critical factor to memory benefits. The Exercise Effects on Brain Connectivity and Learning from Minutes to Months (Brain-EXTEND) trial is conceptually innovative with advanced measures of hippocampal-dependent learning and memory processes combined with novel capture of the physiological changes, genetic components, and molecular changes induced by aerobic exercise that change hippocampal-cortical connectivity. Given that hippocampal connectivity deteriorates with Alzheimer's and aerobic exercise may contribute to reduced risk of Alzheimer's, our results could lead to an understanding of the physiological mechanisms and moderators by which aerobic exercise reduces risk of this devastating and costly disease.

Keywords: Aerobic exercise; Blood biomarkers; Brain; Cardiorespiratory fitness; Cognitive aging; Learning and memory; Physical activity.

Figure 1:. Overall study premise.

The study is designed to test the proposal that moderate-to-vigorous intensity aerobic exercise acutely affects hippocampal function through the mechanisms shown within the feedback loop, and this, in turn, affects hippocampal-cortical network functional connectivity. The medial frontal-parietal network is shown as comprised of three subnetworks, including a medialtemporal subnetwork that integrates the hippocampus into the cortical network. Chronic aerobic training adaptations are proposed to accumulate through the extended mechanisms that result from repeated acute effects that stimulate growth and recovery for functional adaptations in metabolism, brain structure, and perfusion, which are proposed to result in stable functional connectivity increases among the same Medial Temporal Lobe (MTL) subnetwork. Cellular, molecular, metabolic, and vascular measures listed in orange are primarily derived from animal models, and together comprise the potential biological mechanisms for changes in fMRI-derived functional connectivity examined in this trial. Additionally, we test how these hippocampal and MTL network changes from long-term training relate to changes in three types of hippocampal-dependent learning that have been shown to improve from exercise in animal models.

Figure 2:. Overall study design and fidelity.

A) Timeline of acute exercise paradigm completed preceding the chronic exercise training intervention. t=time in minutes preceding the start of exercise (EX) that is either light (L, Light) or moderate-to-vigorous (M, ModVig) intensity. The order of L and M intensities was counter-balanced with randomization. Following the functional MRI (fMRI) scans, a T1 and FLAIR structural MR image always occurred on day 1, and a diffusion-weighted image (DWI) and T1ρ always occurred on day 2. B) Timeline of the chronic exercise intervention, with randomization to chronic training group following the conclusion of pre-testing that included the acute exercise paradigm. See Table 2 for a full listing of measurements for each assessment. C) %HRR for acute cross-over design, HR was measured continuously and each timepoint reflects an average of the preceding 5-min. D) %HRR for each of the three phases of the chronic training intervention. Raw HR (bpm) for each exercise session was recorded continuously and summarized as median HR per session; the point estimate for each training phase reflects the average HR of all sessions within the phase.

Figure 3.

Study Consort diagram