Neurochemical predictors of generalised learning induced by brain stimulation and training.

Methods of cognitive enhancement for humans are most impactful when they generalise across tasks. However, the extent to which such "transfer" is possible via interventions is widely debated. In addition, the contribution of excitatory and inhibitory processes to such transfer is unknown. Here, in a large-scale neuroimaging individual differences study with humans (both sexes), we paired multitasking training and non-invasive brain stimulation (transcranial direct current stimulation; tDCS) over multiple days and assessed performance across a range of paradigms. In addition, we varied tDCS dosage (1.0 mA and 2.0 mA), electrode montage (left or right prefrontal regions), and training task (multitasking versus a control task) and assessed GABA and glutamate concentrations via ultra-high field 7T magnetic resonance spectroscopy. Generalised benefits were observed in spatial attention, indexed by visual search performance, when multitasking training was combined with 1.0 mA stimulation targeting either the left or right prefrontal cortex. This transfer effect persisted for ∼30 days post-intervention. Critically, the transferred benefits associated with right prefrontal tDCS were predicted by pre-training concentrations of glutamate in the prefrontal cortex. Thus, the effects of this combined stimulation and training protocol appears to be linked predominantly to excitatory brain processes.Significance statement Despite the general public's fascination with cognitive training, performance benefits rarely extend beyond the trained task, i.e., 'transfer'. Our study examines the impact of combining executive function training and transcranial direct current stimulation (tDCS) on human cognitive performance and identifies a functional neural metabolite marker (glutamate concentrations in prefrontal cortex assessed via 7 T MR Spectroscopy) that predicts outcomes. In the largest study of its kind to date (178 individuals), we find generalised performance benefits induced by frontal tDCS for an untrained spatial attention task. Further, the degree of transfer correlated with concentrations of glutamate in the frontal cortex. Thus, excitatory neural processes in this region are implicated in the transfer of paired stimulation and training benefits.