Fig. 2. Theoretical accounts for the site of activation for transcranial magnetic stimulation (TMS) in the precentral gyrus.

The figure displays a sagittal slice through the motor hand knob of the precentral gyrus with pyramidal cells occupying layer II/III. Inset A. Drawing of a single pyramidal cell. Displays a drawing of a single pyramidal cell with key anatomical features highlighted. Inset B. Activation of pyramidal cell in the crown or lip region. The panel depicts a pyramidal cell (Neuron A) located in the crown of the precentral gyrus. Possible sites of activation with a monophasic current (posterior-to-anterior direction) are highlighted in red for pyramidal cells modelled with and without axonal arborizations. Note that the axon terminals constitute primary targets when the pyramidal cell is modeled with arborizations. Neural excitation at the axon terminals will lead to propagation of action potentials in both orthodromic and antidromic directions. The orthodromic propagation leads to transsynaptic effects in downstream neurons (e.g. Neuron B). In contrast, when the neuron is modelled without axonal arborizations, activation is unlikely to take place in the crown region of the gyrus. This is in accordance with the phenomenological cortical column cosine theory (Fox et al., 2004) and demonstrated via modeling in Aberra et al., (2020). Inset C. Activation of a pyramidal cell in the lip region of the gyrus or in the sulcal wall. The panel shows a pyramidal cell located at the border between the lip region and the sulcal wall of the precentral gyrus. Possible sites of activation with a monophasic current (posterior-to-anterior current direction) are highlighted in red for cells modelled with and without axonal arborizations. Please note that activation at e.g. the axon terminal or the axon hillock can lead to both orthodromic and antidromic propagation of action potentials. The orthodromic activation will lead to transsynaptic effects. Induction of action potentials at the axon terminals (or axon hillocks, although this is less plausible from a biophysical modeling perspective) provides a key mechanism through which TMS exerts its neuronal effects. This does not, however, preclude other potential sites of activation such as excitation at axonal bends as discussed in the text.