Exploring the neural and behavioral correlates of cognitive telerehabilitation in mild cognitive impairment with three distinct approaches

background: currently, the impact of drug therapies on neurodegenerative conditions is limited. therefore, there is a strong clinical interest in non-pharmacological interventions aimed at preserving functionality, delaying disease progression, reducing disability, and improving quality of life for both patients and their caregivers. this longitudinal multicenter randomized controlled trial (RCT) applies three innovative cognitive telerehabilitation (TR) methods to evaluate their impact on brain functional connectivity reconfigurations and on the overall level of cognitive and everyday functions. methods: we will include 110 participants with mild cognitive impairment (MCI). fifty-five participants will be randomly assigned to the intervention group who will receive cognitive TR via three approaches, namely: (a) network-based cognitive training (NBCT), (b) Home-based cognitive rehabilitation (HomeCoRe), or (c) semantic memory rehabilitation training (SMRT). the control group (n = 55) will receive an unstructured home-based cognitive stimulation. the rehabilitative program will last either 4 (NBTC) or 6 weeks (HomeCoRe and SMRT), and the control condition will be adapted to each TR intervention. The effects of TR will be tested in terms of Delta connectivity change, obtained from high-density electroencephalogram (HD-EEG) or functional magnetic resonance imaging at rest (rs-fMRI), acquired before (T0) and after (T1) the intervention. all participants will undergo a comprehensive neuropsychological assessment at four time-points: baseline (T0), within 2 weeks (T1), and after 6 (T2) and 12 months (T3) from the end of TR. discussion: the results of this RCT will identify a potential association between improvement in performance induced by individual cognitive TR approaches and modulation of resting-state brain connectivity. the knowledge gained with this study might foster the development of novel TR approaches underpinned by established neural mechanisms to be validated and implemented in clinical practice.