Multipulse transcranial magnetic stimulation of human motor cortex produces short-latency corticomotor facilitation via two distinct mechanisms.

Single-pulse transcranial magnetic stimulation (TMS) of the precentral hand representation (M1HAND) can elicit indirect waves in the corticospinal tract at a periodicity of ∼660 Hz, called I-waves. These descending volleys are produced by transsynaptic excitation of fast-conducting corticospinal axons in M1HAND. Paired-pulse TMS can induce short-interval intracortical facilitation (SICF) of motor evoked potentials (MEPs) at interpulse intervals that match I-wave periodicity. This study examined whether short-latency corticospinal facilitation engages additional mechanisms independently of I-wave periodicity. In 19 volunteers, one to four biphasic TMS pulses were applied to left M1HAND with interpulse intervals adjusted to the first peak or trough of the individual SICF curve at different intensities to probe the intensity-response relationship. Multipulse TMSHAND at individual peak latency facilitated MEP amplitudes and reduced resting motor threshold (RMT) compared with single pulses. Multipulse TMSHAND at individual trough latency also produced a consistent facilitation of MEPs and a reduction of RMT. Short-latency facilitation at trough latency was less pronounced, but the relative difference in facilitation decreased with increasing stimulus intensity. Increasing the pulse number had only a modest effect. Two mechanisms underlie short-latency facilitation caused by biphasic multipulse TMSHAND. One intracortical mechanism is related to I-wave periodicity and engages fast-conducting direct projections to spinal motoneurons. A second corticospinal mechanism does not rely on I-wave rhythmicity and may be mediated by slower-conducting indirect pyramidal tract projections from M1HAND to spinal interneurons. The latter mechanism deserves more attention in studies of the corticomotor system and its link to manual motor control using the MEP.NEW & NOTEWORTHY TMS pairs evoke SICF at interpulse intervals (IPIs) that match I-wave periodicity. Biphasic bursts with IPIs at the latency of the first peak facilitate MEPs and reduce corticomotor threshold. Bursts at the latency of the first trough facilitate MEPs and reduce corticomotor threshold to a lesser extent. TMS bursts facilitate corticomotor excitability via two mechanisms: SICF-dependently via fast-conducting direct projections from M1HAND to spinal motoneurons and SICF-independently, probably through slower-conducting indirect pyramidal tract projections.

Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper.

Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.