Cortico-cortical paired associative stimulation (ccPAS) over premotor-motor areas affects local circuitries in the human motor cortex via Hebbian plasticity
Sonia Turrini,
Francesca Fiori,
Emilio Chiappini,
Boris Lucero,
Emiliano Santarnecchi,
Alessio Avenanti
Affiliations
Sonia Turrini
Centro studi e Ricerche in Neuroscienze Cognitive, Dipartimento di Psicologia “Renzo Canestrari”, Alma Mater Studiorum Università di Bologna, Cesena Campus, Cesena 47521, Italy; Precision Neuroscience & Neuromodulation Program, Gordon Center for Medical Imaging, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, United States; Corresponding authors at: Centro studi e ricerche in Neuroscienze Cognitive, Dipartimento di Psicologia “Renzo Canestrari”, Alma Mater Studiorum Università di Bologna, Cesena Campus, Via Rasi Spinelli 176, Cesena 47521, Italy.
Francesca Fiori
Centro studi e Ricerche in Neuroscienze Cognitive, Dipartimento di Psicologia “Renzo Canestrari”, Alma Mater Studiorum Università di Bologna, Cesena Campus, Cesena 47521, Italy; NeXT: Neurophysiology and Neuro-Engineering of Human-Technology Interaction Research Unit, Campus Bio-Medico University, Rome 00128, Italy
Emilio Chiappini
Centro studi e Ricerche in Neuroscienze Cognitive, Dipartimento di Psicologia “Renzo Canestrari”, Alma Mater Studiorum Università di Bologna, Cesena Campus, Cesena 47521, Italy; Institut für Klinische und Gesundheitspsychologie, Universität Wien, Vienna 1010, Austria
Boris Lucero
Centro de Investigación en Neuropsicología y Neurociencias Cognitivas (CINPSI Neurocog), Universidad Católica Del Maule, Talca 346000, Chile
Emiliano Santarnecchi
Precision Neuroscience & Neuromodulation Program, Gordon Center for Medical Imaging, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, United States
Alessio Avenanti
Centro studi e Ricerche in Neuroscienze Cognitive, Dipartimento di Psicologia “Renzo Canestrari”, Alma Mater Studiorum Università di Bologna, Cesena Campus, Cesena 47521, Italy; Centro de Investigación en Neuropsicología y Neurociencias Cognitivas (CINPSI Neurocog), Universidad Católica Del Maule, Talca 346000, Chile; Corresponding authors at: Centro studi e ricerche in Neuroscienze Cognitive, Dipartimento di Psicologia “Renzo Canestrari”, Alma Mater Studiorum Università di Bologna, Cesena Campus, Via Rasi Spinelli 176, Cesena 47521, Italy.
Transcranial magnetic stimulation (TMS) studies have shown that cortico-cortical paired associative stimulation (ccPAS) can strengthen connectivity between the ventral premotor cortex (PMv) and the primary motor cortex (M1) by modulating convergent input over M1 via Hebbian spike-timing-dependent plasticity (STDP). However, whether ccPAS locally affects M1 activity remains unclear. We tested 60 right-handed young healthy humans in two studies, using a combination of dual coil TMS and ccPAS over the left PMv and M1 to probe and manipulate PMv-to-M1 connectivity, and single- and paired-pulse TMS to assess neural activity within M1. We provide convergent evidence that ccPAS, relying on repeated activations of excitatory PMv-to-M1 connections, acts locally over M1. During ccPAS, motor-evoked potentials (MEPs) induced by paired PMv-M1 stimulation gradually increased. Following ccPAS, the threshold for inducing MEPs of different amplitudes decreased, and the input-output curve (IO) slope increased, highlighting increased M1 corticospinal excitability. Moreover, ccPAS reduced the magnitude of short-interval intracortical inhibition (SICI), reflecting suppression of GABA-ergic interneuronal mechanisms within M1, without affecting intracortical facilitation (ICF). These changes were specific to ccPAS Hebbian strengthening of PMv-to-M1 connectivity, as no modulations were observed when reversing the order of the PMv-M1 stimulation during a control ccPAS protocol. These findings expand prior ccPAS research that focused on the malleability of cortico-cortical connectivity at the network-level, and highlight local changes in the area of convergent activation (i.e., M1) during plasticity induction. These findings provide new mechanistic insights into the physiological basis of ccPAS that are relevant for protocol optimization.
