The Role of Functional Brain Connectivity in Intervention Success: A Secondary Analysis from the SYNERGIC Trial

ABSTRACT Purpose Functional (brain) connectivity, or brain regions that are anatomically separate but temporally synchronized, is crucial for executing complex functions and is sensitive for identifying covert but meaningful differences in clinical populations. We aimed to determine if pre-intervention functional connectivity and executive function differ between “responders” and “non-responders” in a randomized controlled trial. Methods Participants diagnosed with mild cognitive impairment completed combined physical exercise (i.e., aerobic and resistance training) with or without cognitive training and/or vitamin D3 supplementation three times per week for 20-weeks. We assessed pre-intervention functional connectivity using a seed-to-voxel approach and executive function using the (normalized) Trail Making Test. We defined responders as those who achieved the minimal clinically important difference in tests of physical performance (i.e., cardiovascular fitness, muscle strength, and muscle power) by the end of the intervention. Results Our 67 participants were mostly male, with an average age of 74.51 ± 6.44 years. For cardiovascular fitness, responders demonstrated stronger functional connectivity between the medial prefrontal cortex and right frontal pole (cluster: size = 352 p -FDR < 0.05). Similarly, for muscle strength, responders demonstrated stronger functional connectivity between the left amygdala and right cerebellum (cluster: size = 268 p -FDR < 0.05). There was no link between functional connectivity and executive function. Conclusions Responders to a physical exercise intervention possess stronger pre-intervention functional connectivity between regions implicated in higher-order cognitive and behavioural processing. Functional connectivity may delineate who is primed for intervention success and who may require alternative strategies before beginning. Future research should aim to determine if pre-intervention functional connectivity can help optimize intervention resources and enhance the precision of personalized exercise recommendations.