It is unclear whether Hebbian-like learning occurs at the level of long-range white matter connections in humans, i.e., where measurable changes in structural connectivity (SC) are correlated with changes in functional connectivity. However, the behavioral changes observed after deep brain stimulation (DBS) suggest the existence of such Hebbian-like mechanisms occurring at the structural level with functional consequences. In this rare case study, we obtained the full network of white matter connections of one patient with Parkinson’s disease (PD) before and after long-term DBS and combined it with a computational model of ongoing activity to investigate the effects of DBS-induced long-term structural changes. The results show that the long-term effects of DBS on resting-state functional connectivity is best obtained in the computational model by changing the structural weights from the subthalamic nucleus (STN) to the putamen and the thalamus in a Hebbian-like manner. Moreover, long-term DBS also significantly changed the SC towards normality in terms of model-based measures of segregation and integration of information processing, two key concepts of brain organization. This novel approach using computational models to model the effects of Hebbian-like changes in SC allowed us to causally identify the possible underlying neural mechanisms of long-term DBS using rare case study data. In time, this could help predict the efficacy of individual DBS targeting and identify novel DBS targets.

MLK is supported by the TrygFonden Charitable Foundation and ERC Consolidator Grant: CAREGIVING (n. 615539). TZ is supported by the Medical Research Council, Norman Collisson Foundation, Charles Wolfson Charitable Trust, and NIHR Biomedical Research Centre. GD is supported by the ERC Advanced Grant: DYSTRUCTURE (n. 295129), by the Spanish Research Project SAF2010-16085, by the CONSOLIDER-INGENIO 2010 Programme CSD2007–00012, by the FP7-ICT BrainScales and by the Brain Network Recovery Group through the James S. McDonnell Foundation.