Long-term cognitive training enhances fluid cognition and brain connectivity in individuals with MCI

Abstract

Amnestic mild cognitive impairment (aMCI) is a risk factor for Alzheimer's disease (AD). Multi-domain cognitive training (CT) may slow cognitive decline and delay AD onset. However, most work involves short interventions, targeting single cognitive domains or lacking active controls. We conducted a single-blind randomized controlled trial to investigate the effect of a 6-month, multi-domain CT on Fluid Cognition, functional connectivity in memory and executive functioning networks (primary outcomes), and white matter microstructural properties (secondary outcome) in aMCI. Sixty participants were randomly assigned to either a multi-domain CT or crossword training (CW) group, and thirty-four participants completed the intervention. We found a significant group-by-time interaction in Fluid Cognition (p = 0.007, F (1,28) = 8.26, Cohen's d = 0.38, 95% confidence interval [CI]: 2.45-14.4), with 90% of CT patients showing post-intervention improvements (p < 0.01, Cohen's d = 0.7). The CT group also showed better post-intervention Fluid Cognition than healthy controls (HCs, N = 45, p = 0.045). Functional connectivity analyses showed a significant group-by-time interaction (Cohen's d ≥ 0.8) in the dorsolateral prefrontal cortex (DLPFC) and inferior parietal cortex (IPC) networks. Specifically, CT displayed post-intervention increases whereas CW displayed decreases in functional connectivity. Moreover, increased connectivity strength between the left DLPFC and medial PFC was associated with improved Fluid Cognition. At a microstructural level, we observed a decline in fiber density (FD) for both groups, but the CT group declined less steeply (1.3 vs. 2%). The slower decline in FD for the CT group in several tracts, including the cingulum-hippocampus tract, was associated with better working memory. Finally, we identified regions in cognitive control and memory networks for which baseline functional connectivity and microstructural properties were associated with changes in Fluid Cognition. Long-term, multi-domain CT improves cognitive functioning and functional connectivity and delays structural brain decline in aMCI (ClinicalTrials.gov number: NCT03883308).

Fig. 1

CONSORT diagram.

Fig. 2. Changes in cognitive functioning and functional connectivity in response to intervention.

a Cognitive Fluid Intelligence for each group and time point. The error bars represent the mean value and standard error. b Functional brain connections between the left DLPFC (Area 46), right DLPFC (Area 8BL) and medial PFC (Area s6-8), and between the left intraparietal sulcus (Area IP0) and right anterior PFC (Area 9-46v) showing a significant group-by-time interaction effect (${\mathrm{p}}_{\mathrm{FDR}}<0.05$). c Association between change in Fluid Cognition standard scores and connectivity strength between the left DLPFC (Area 46) and right medial PFC (Area s6-8) across the groups. d Box plots of functional connectivity strengths between the left DLPFC (Area 46), right DLPFC (Area 8BL), and right medial PFC (Area s6-8), and between the left intraparietal sulcus (Area IP0) and right anterior PFC (Area 9-46v) for each group across timepoints. The line between dark green and light green states the median value of connectivity strength in each group.

Fig. 3. Changes in white matter microstructure in response to intervention.

a Fixels showing a significant group-by-time interaction effect projected onto the group white matter FOD template. Significant regions are represented as fixels color-coded by FWE-corrected p-value. b Mean FD changes for each group and time point. The line between dark green and light green states the median value of the mean FD changes in each group. c Association between changes in FD and changes in List Sorting Working Memory (LSWM) standard scores across the groups.