Baseline Neurochemical Excitability and Individual Differences in Motor Learning and Non-Invasive Brain Stimulation Outcomes

Motor skill acquisition arises from complex interactions between inhibitory and excitatory neurotransmission in sensorimotor circuits. While non-invasive neuromodulation via transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) can influence motor learning, the underlying neurochemical determinants of this remain poorly defined. Using ultra-high field (7 T) magnetic resonance spectroscopy (MRS) in eighty human participants of both sexes (53-70 participants after exclusions), we quantified GABA and glutamate concentrations (together providing E/I balance) in M1, prefrontal cortex and the intraparietal sulcus (IPS). We then assessed TMS-based corticomotor excitability measures and evaluated motor sequence learning with and without M1-targeted tDCS. Our findings revealed that baseline neurochemical profiles and ensuing excitation/inhibition (E/I) balance in M1 and IPS related to individual variability in motor sequence learning and its modulation by tDCS. In the absence of tDCS, higher M1 E/I balance correlated with greater sequence-specific learning, indicating that baseline neurochemistry shapes intrinsic motor performance gains. Under active tDCS, individuals with elevated M1 excitability and greater IPS E/I balance exhibited pronounced learning disruption relative to sham, suggesting distinct mechanisms for skill acquisition when neuromodulation is applied. Further, M1 E/I balance was related to TMS-derived excitability indices, linking the two measures. These findings establish direct relationships between MRS-defined neurochemical states, TMS-based excitability measures, and motor learning trajectories. They reveal that E/I balance in motor-relevant regions not only influences learning capacity but also governs susceptibility to tDCS-induced modulation, paving the way for precision-targeted interventions to optimize motor rehabilitation and skill development.