Discussion
breast cancers, breast cancer, cancer, cognitive difficulties, cognitive problems, volume loss
CANCER, RESOLUTION, BREAST CANCER
The PAM study is the first sufficiently powered randomized controlled trial designed to investigate the effects of a 6-month exercise intervention on cognitive functioning and brain structure/function in previously physically inactive breast cancers patients with cognitive problems. In the current study, we examined the effects on grey matter volumetric measures. At baseline, higher physical fitness levels were associated with larger total hippocampal volume, cortical thickness, and total grey matter volume. We observed no exercise effect on total hippocampal volume, our primary imaging outcome, and no effect on hippocampal subfield volumes, cortical thickness, and voxel-based grey matter volumes in chemotherapy-exposed breast cancer patients with cognitive problems. In highly fatigued patients, we observed an intervention effect on physical fitness of similar size. However, a significant reduction in hippocampal volume was found post-intervention, which was related to improved memory functioning. This was an unexpected finding and will be discussed below.In animal models beneficial effects of physical exercise on brain volume have been consistently found (Several explanations exist for the lack of intervention effects on brain volumes in our study. Wilckens et al. (Despite the lack of an effect of the physical exercise intervention on brain volumes, we did find, pre-intervention, a positive association between physical fitness levels and hippocampal volume. This kind of association has been reported previously in various populations, including breast cancer patients (In addition to environmental effects and the length of the intervention, timing of the intervention might also contribute to the intervention effect. Although we deliberately offered the intervention 2–4 years after diagnosis (when patients were post-acute and short-term cancer treatment effects, but still experienced difficulties in daily life), it is possible that the intervention might have been more effective when embedded shortly after treatment. Whether exercise during chemotherapy can contribute to prevention of (hippocampal) volume loss is also still unknown, but currently under investigation (In our recent article covering the exercise effects on cognition, an intervention effect was described in highly fatigued patients on learning and memory functioning, and processing speed (Hippocampal volume was thoroughly investigated, since it was examined at the subfield level. However, interpretability of the subfield segmentations is potentially limited. Resolution of the 3D T1-weighted MRI scan acquired with a 3 Tesla brain MRI scanner is considered low for (automated) hippocampal subfield segmentations (Strengths of the PAM study are the length (6 months), intensity (4 hrs/week) and type of intervention (aerobic, including high intensity interval training, and resistance training). Additionally, the intervention was partly supervised, and patients showed good adherence to the program, which subsequently resulted in improved physical fitness. To specifically target a relevant population, only relatively inactive patients who experienced and showed cognitive difficulties were selected for participation. Although the percentage of missing MRI data was relatively high due to COVID-19 measures, the current study is still one of the largest randomized controlled trials investigating the effects of physical exercise on grey matter volume.