Investigating the effects of cortico-cortical paired associative stimulation in the human brain: A systematic review and meta-analysis.

Recent decades have witnessed a rapid development of novel neuromodulation techniques that allow direct manipulation of cortical pathways in the human brain. These techniques, known as cortico-cortical paired stimulation (ccPAS), apply magnetic stimulation over two cortical regions altering interregional connectivity. This review evaluates ccPAS's effectiveness to induce plastic changes in cortical pathways in the healthy brain. A systematic database search identified 41 studies investigating the effect of ccPAS on neurophysiological or behavioural measures, and a subsequent multilevel meta-analysis focused on the standardized mean differences to assess ccPAS's efficacy. Most studies report significant neurophysiological and behavioural changes from ccPAS interventions across several brain networks, consistently showing medium effect sizes. Moderator analyses revealed limited influence of experimental manipulations on effect sizes. The multivariate approach and lack of small-study bias suggest reliable effect estimates. ccPAS is a promising tool to manipulate neuroplasticity in cortical pathways, showing reliable effects on brain cortical networks. Important areas for further research on the influence of experimental procedures and the potential of ccPAS for clinical interventions are highlighted.