Transcranial Magnetic Stimulation and Neocortical Neurons: The Micro-Macro Connection

Understanding the operation of cortical circuits is an important and necessary task in both neuroscience and neurorehabilitation. The functioning of the neocortex results from integrative neuronal activity, which can be probed non-invasively by transcranial magnetic stimulation (TMS). Despite a clear indication of the direct involvement of cortical neurons in TMS, no explicit connection model has been made between the microscopic neuronal landscape and the macroscopic TMS outcome. Here we have performed an integrative review of multidisciplinary evidence regarding motor cortex neurocytology and TMS-related neurophysiology with the aim of elucidating the micro-macro connections underlying TMS. Neurocytological evidence from animal and human studies has been reviewed to describe the landscape of the cortical neurons covering the taxonomy, morphology, circuit wiring, and excitatory-inhibitory balance. Evidence from TMS studies in healthy humans is discussed, with emphasis on the TMS pulse and paradigm selectivity that reflect the underlying neural circuitry constitution. As a result, we propose a preliminary neuronal model of the human motor cortex and then link the TMS mechanisms with the neuronal model by stimulus intensity, direction of induced current, and paired-pulse timing. As TMS bears great developmental potential for both a probe and modulator of neural network activity and neurotransmission, the connection model will act as a foundation for future combined studies of neurocytology and neurophysiology, as well as the technical advances and application of TMS.