How does TMS “engage” the human cortex? Insights from structural and functional mapping of the precentral motor hand knob

Abstract

Abstract Background: TMS of the primary motor hand area (M1-HAND) can probe the function of fast corticomotor connections to the contralateral hand. TMS gives rise to indirect (transsynaptic) excitation of large pyramidal tract (PT) neurons in M1-HAND that make monosynaptic connections with spinal motoneurons in the cervical cord. Other cell types are effectively excited by TMS as well. Yet, it is still unclear which neuronal elements (e.g. axon terminals or axon hillock), which cell types (e.g. PT neurons, intra-telencephalic (IT) neurons, or inhibitory interneurons), and which sites in the precentral hand knob (e.g. crown, lip, or sulcus region) are preferentially depolarized by the TMS-induced electrical field in the precentral gyrus. Objective: To address whether non-invasive neuroimaging in human volunteers can help to pinpoint the primary targets for TMS of M1-HAND. Methods: Structural and functional neuroimaging (MRI and PET) were employed in a series of experiments to target the M1-HAND. Structural MRI was used for shaped-based TMS mapping, electrical field modelling, and mapping of cortical myelin content. Functional MRI and PET were used to localize clusters in the precentral hand knob that are functionally activated by focal TMS of M1-HAND. Results: Inter-individual differences in precentral cortical myelin content account for interindividual differences in rostro-caudal “motor hotspot” location, linking cortical myelination to TMS target engagement. Functional brain mapping reveals different peak target sites in the precentral hand knob and indicates that PT and IT neurons as well as inhibitory interneurons are effectively excited by TMS. Discussion: Structural and functional neuroimaging can help to elucidate how TMS engages its local cortical targets in the precentral gyrus. Causal interpretation of the results needs to consider the potential and pitfalls inherent to the neuroimaging method and the physiological implications of the TMS protocol (e.g. intensity, number of stimuli, online-offline TMS). Keywords: Transcranial magnetic stimulation, Motor cortex, Magnetic resonance imaging, Positron emission tomography