ccPAS as a platform for biomarker-informed precision motor neurorehabilitation: a mini review

Inter-individual variability remains a major obstacle to translating non-invasive neuromodulation into rehabilitation. Cortico-cortical paired associative stimulation (ccPAS) is usually considered a tool for inducing pathway-specific plasticity, but its timing, direction and state dependence (and the possibility of measuring physiological responses during and after stimulation) may also make it useful for interrogating how an individual circuit responds. In this Mini Review, we examine ccPAS across applications to identify evidence relevant to biomarker-informed personalization, with a focus on premotor-motor pathways from the ventral premotor cortex (PMv) and supplementary/pre-supplementary motor area (SMA/preSMA) to primary motor cortex (M1). Our updated search identified 72 original reports applying repeated paired stimulation to two cortical (or cerebellar-cortical) sites, 25 of which targeted PMv → M1 or SMA/preSMA→M1 pathways. We synthesize evidence on spike-timing-dependent plasticity (STDP)-like effects, online physiological responses, transcranial magnetic stimulation–electroencephalography (TMS-EEG) and connectivity measures, structural pathway integrity, state dependence and dose. Rather than treating response variability only as a limitation, we ask whether measurable differences in pathway responsiveness could provide information for tailoring stimulation. Translational evidence remains predominantly mechanistic, although repeated SMA → M1 ccPAS has shown clinical and network-level effects after stroke. We propose a cautious framework in which baseline pathway assessment, a calibration stage, individualized stimulation parameters and post-intervention monitoring could support future precision motor neurorehabilitation.