Structural and Functional Brain Connectivity in Middle-Aged Carriers of Risk Alleles for Alzheimer\u27s Disease

Single nucleotide polymorphisms (SNPs) in APOE, COMT, BDNF, and KIBRA have been associated with age-related memory performance and executive functioning as well as risk for Alzheimer’s disease (AD). The purpose of the present investigation was to characterize differences in brain functional and structural integrity associated with these SNPs as potential endophenotypes of age-related cognitive decline. I focused my investigation on healthy, cognitively normal middle-aged adults, as disentangling the early effects of healthy versus pathological aging in this group may aid early detection and prevention of AD. The aims of the study were 1) to characterize SNP-related differences in functional connectivity within two resting state networks (RSNs; default mode network [DMN] and executive control network [ECN]) associated with memory and executive functioning, respectively; 2) to identify differences in the white matter (WM) microstructural integrity of tracts underlying these RSNs; and 3) to characterize genotype differences in the graph properties of an integrated functional-structural network. Participants (age 40-60, N = 150) underwent resting state functional magnetic resonance imaging (rs-fMRI), diffusion tensor imaging (DTI), and genotyping. Independent components analysis (ICA) was used to derive RSNs, while probabilistic tractography was performed to characterize tracts connecting RSN subregions. A technique known as functional-by-structural hierarchical (FSH) mapping was used to create the integrated, whole brain functional-structural network, or resting state structural connectome (rsSC). I found that BDNF risk allele carriers had lower functional connectivity within the DMN, while KIBRA risk allele carriers had poorer WM microstructural integrity in tracts underlying the DMN and ECN. In addition to these differences in the connectivity of specific RSNs, I found significant impairments in the global and local topology of the rsSC across all evaluated SNPs. Collectively, these findings suggest that integrating multiple neuroimaging modalities and using graph theoretical analysis may reveal network-level vulnerabilities that may serve as biomarkers of age-related cognitive decline in middle age, decades before the onset of overt cognitive impairment

The influence of acute aerobic exercise on excitability and rapid plasticity in the primary motor cortex

The aim of this thesis was to explore the influence of a single session of aerobic exercise on excitability changes and markers of short-term plasticity in the human primary motor cortex (M1). To that end, this thesis consists of 4 studies. In the first experiment, we explored whether acute exercise alone could modulate resting excitability in M1. We demonstrated that 20 minutes of moderate-intensity stationary biking could suppress intracortical inhibition and enhance intracortical facilitation in a non-exercised upper limb muscle for up to 30 minutes following exercise completion. Since decreases in inhibition are a necessary precursor to neuroplastic changes, we then investigated whether exercise could enhance the induction of rapid plasticity. We used paired-associative stimulation (PAS), a technique that reliably induces long-term potentiation (LTP)-like plasticity in M1 and found that a preceding bout of exercise enhanced the effectiveness of the intervention. Next, we examined whether these cortical changes were consistent across the entire cortical representation of the target muscle and if they were related to any measurable changes in motor performance. We paired exercise with a bimanual motor training task and observed that while performance was not enhanced compared to training alone, exercise facilitated training-related cortical excitability increases throughout the representation of the trained muscle. Finally, we demonstrated that exercise has opposite effects on the induction of long-term depression (LTD), suggesting that exercise is biased towards increasing excitability, and that this influence is evident even when exercise is performed following, rather than prior to, plasticity induction. This thesis demonstrates that aerobic exercise may optimize the conditions for experience-dependent plasticity to occur and provides a rationale for the use of exercise as an adjunct to interventions that aim to induce LTP in human motor cortex