A Randomized Controlled Trial on the Effects of a 12-Week High- vs. Low-Intensity Exercise Intervention on Hippocampal Structure and Function in Healthy, Young Adults

Abstract

Physical exercise affects hippocampal structure and function, but the underlying neural mechanisms and the effects of exercise intensity remain incompletely understood. Therefore, we undertook a comprehensive, multi-modal 3T and 7T MRI randomized controlled trial (Netherlands Trial Register - NL5847) in which we randomized 52 young, non-athletic volunteers to a 12-week low- or high-intensity exercise program. Using state-of-the-art methods, we investigated changes in hippocampal volume, as well as changes in vasculature, neuro-metabolites, and peripheral growth factors as potential underpinnings. Cardiorespiratory fitness improved over time (p < 0.001), but no interaction with exercise intensity was found (p = 0.48). Accordingly, we did not observe significant interactions between exercise condition and time on MRI measures (all p > 0.06). However, we found a significant decrease in right hippocampal volume (p < 0.01), an increase in left hippocampal glutathione (p < 0.01), and a decrease of left hippocampal cerebral blood volume (p = 0.01) over time, regardless of exercise condition. Additional exploratory analyses showed that changes in brain-derived neurotrophic factor (p = 0.01), insulin-like growth-factor (p = 0.03), and dorsal anterior cingulate cortex N-acetyl-aspartate levels (p = 0.01) were positively associated with cardiorespiratory fitness changes. Furthermore, a trend toward a positive association of fitness and gray-matter cerebral blood flow (p = 0.06) was found. Our results do not provide evidence for differential effects between high-intensity (aerobic) and low-intensity (toning) exercise on hippocampal structure and function in young adults. However, we show small but significant effects of exercise on hippocampal volume, neurometabolism and vasculature across exercise conditions. Moreover, our exploratory results suggest that exercise might not specifically only benefit hippocampal structure and function, but rather has a more widespread effect. These findings suggest that, in agreement with previous MRI studies demonstrating moderate to strong effects in elderly and diseased populations, but none to only mild effects in young healthy cohorts, the benefits of exercise on the studied brain measures may be age-dependent and restorative rather than stimulatory. Our study highlights the importance of a multi-modal, whole-brain approach to assess macroscopic and microscopic changes underlying exercise-induced brain changes, to better understand the role of exercise as a potential non-pharmacological intervention.

Hippocampal blood flow rapidly and preferentially increases after a bout of moderate-intensity exercise in older adults with poor cerebrovascular health

“…Interestingly, post-exercise hippocampal blood flow never increased above baseline levels in individuals with high perfusion ( Figure 3 ). As we only tested a single type of exercise, it is possible that a different type of exercise stimulus, for example high intensity interval training, may elicit more robust vascular and neural plasticity in these individuals (Boyne et al, 2019; Kaiser et al, 2022; Neva et al, 2022; Weston et al, 2022). The present results provide preliminary evidence for the use of baseline cerebrovascular perfusion as a predictive biomarker for brain health benefit from exercise in aging populations.…”

Effects of Physical Exercise Training on Cerebral Blood Flow Measurements: A Systematic Review of Human Intervention Studies

“…Two studies found increases in either whole-brain CBF (Espeland et al, 2018) or gray-matter CBF (Robertson et al, 2017), while in eight other studies no differences were observed (Anazodo et al, 2016;Chapman et al, 2013Chapman et al, , 2016Chapman et al, , 2017Kaiser et al, 2021;Kleinloog et al, 2019;Maass et al, 2015;Moore et al, 2015;Steventon et al, 2021;van der Kleij et al, 2018). Studies that focused on differences in blood flow in brain lobes observed an increased CBF in the limbic (Espeland et al, 2018), occipital (Espeland et al, 2018), medial temporal (Moore et al, 2015), and parietal lobe (Robertson et al, 2017).…”

“…Finally, 45 original intervention studies were identified, of which 16 used MRI (10 of these studies used arterial spin labeling, two studies used gadolinium as a contrast agent, and one study used PET), 20 transcranial Doppler ultrasound, and eight NIRS. Twenty-six RCTs were included (MRI: n = 10 [ Chapman et al, 2013;Espeland et al, 2018;Kaiser et al, 2021;Kaufman et al, 2021;Kleinloog et al, 2019;Maass et al, 2015;Maffei et al, 2017;Moore et al, 2015;Small et al, 2006;van der Kleij et al, 2018]; transcranial Doppler ultrasound: n = 12 [Akazawa et al, 2012;Bailey, Cable, Aziz, Atkinson, et al, 2016;Cho & Roh, 2019;Green et al, 2021;Hata et al, 1998;Heli et al, 2013;Ivey et al, 2011;Lee et al, 2021;Miller et al, 2022;Northey et al, 2019;Thomas et al, 2021;Tomoto, Liu, et al, 2021]; and NIRS: n = 4 [Fu et al, 2013;Hamasaki et al, 2019;Tsai et al, 2016;Wang et al, 2010]) that involved a control group, which performed no exercise or performed activities not affecting fitness levels (e.g., yoga or stretching). The remaining 18 studies (MRI: n = 6 [Alfini et al, 2019;Anazodo et al, 2016;Burdette et al, 2010;Pereira et al, 2007;Robertson et al, 2017;Steventon et al, 2021]; transcranial Doppler ultrasound: n = 8 [Akazawa et al, 2018;Bailey, Cable, Miller, et al, 2016;Drapeau et al, 2019;…”

“…The type of intervention and the study population are detailed in Table 1 for MRI studies, in Table 2 for transcranial Doppler ultrasound studies and in Table 3 for NIRS studies. The exercise training arms included continuous exercise (MRI: n = 8 [Alfini et al, 2019;Burdette et al, 2010;Chapman et al, 2013;Kaiser et al, 2021;Kaufman et al, 2021;Kleinloog et al, 2019;Pereira et al, 2007;van der Kleij et al, 2018]; transcranial Doppler ultrasound: n = 14 [Akazawa et al, 2012[Akazawa et al, , 2018Bailey, Cable, Aziz, Atkinson, et al, 2016;Bailey, Cable, Miller, et al, 2016;Green et al, 2021;Hata et al, 1998;Ivey et al, 2011;Lake et al, 2022;Miller et al, 2022;Murrell et al, 2013;Northey et al, 2019;Stanek et al, 2011;Thomas et al, 2021;Tomoto, Liu, et al, 2021]; and NIRS: n = 3 [Fu et al, 2013;Tsai et al, 2016;Wang et al, 2010]) or high-intensity interval training (HIIT; MRI: n = 1 [Maass et al, 2015]; transcranial Doppler ultrasound: n = 2 [Drapeau et al, 2019;Northey et al, 2019]; and NIRS: n = 3 [Caen et al, 2019;Fu et al, 2013;Tsai et al, 2016]) or a combination of different types of exercise (MRI: n = 7 [Anazodo et al, 2016;Espeland et al, 2018;Maffei et al, 2017;<...…”

“…In contrast, studies that imaged the entire brain may be more susceptible for partial volume effects due to larger voxel size. Another explanation for these differences may be the different statistical approaches that were used such as region of interest (Burdette et al, 2010;Chapman et al, 2013;Espeland et al, 2018;Kaiser et al, 2021;Kaufman et al, 2021;Maass et al, 2015;Maffei et al, 2017;Moore et al, 2015;Pereira et al, 2007;Steventon et al, 2021;van der Kleij et al, 2018), or voxel-wise analyses (Alfini et al, 2019;Anazodo et al, 2016;Chapman et al, 2013;Kleinloog et al, 2019;Small et al, 2006). The latter approach is more sensitive as it permits statistical inferences at voxel level after normalization to a reference atlas and is not limited to predefined brain regions (Astrakas & Argyropoulou, 2010).…”