Learning sculpts microstructure in real time: evidence from dense temporal sampling of diffusion MRI

Learning induces rapid microstructural plasticity in the human brain, yet the precise temporal dynamics of these changes remain unclear. Using dense temporal sampling of diffusion-weighted MRI (DW-MRI) combined with task-based fMRI, we assessed microstructural changes throughout a declarative learning paradigm and subsequent rest. Seventy-four participants (36 females) learned image-location associations across four encoding-retrieval repetitions while undergoing interleaved functional and DW-MRI acquisitions. A matched control group (N=37, 21 females) underwent a similar imaging protocol without learning. Dense sampling of DW-MRI acquisitions (k=2146 across 22 time points in 127 min) revealed that learning-induced mean diffusivity (MD) decreases emerged shortly after learning onset and continued to develop during post-learning rest. The most robust and spatially consistent change was localized to the left middle occipital/temporal gyrus, a region also showing functional activation during encoding and retrieval. Linear mixed-effects modeling further confirmed a significant group-by-time interaction, with MD reductions in the left middle occipital/temporal gyrus emerging as early as {approx}7 min after learning onset, becoming robust by {approx}35-40 min, and persisting throughout the extended post-learning period, while controls showed no changes. Our findings demonstrate that learning-related microstructural plasticity unfolds continuously from encoding to offline consolidation, with learning-induced structural changes emerging in functionally engaged regions. Dense temporal sampling of DW-MRI offers a powerful approach to bridge functional activation and structural remodeling, providing evidence of when and where experience-dependent plasticity occurs during memory formation.