The contribution of transcranial magnetic stimulation in the functional evaluation of microcircuits in human motor cortex

Abstract

Although transcranial magnetic stimulation (TMS) activates a number of different neuron types in the cortex, the final output elicited in corticospinal neurones is surprisingly stereotyped. A single TMS pulse evokes a series of descending corticospinal volleys that are separated from each other by about 1.5 ms (i.e., ~670 Hz). This evoked descending corticospinal activity can be directly recorded by an epidural electrode placed over the high cervical cord. The earliest wave is thought to originate from the direct activation of the axons of fast-conducting pyramidal tract neurones (PTN) and is therefore termed “D” wave. The later waves are thought to originate from indirect, trans-synaptic activation of PTNs and are termed “I” waves. The anatomical and computational characteristics of a canonical microcircuit model of cerebral cortex composed of layer II and III and layer V excitatory pyramidal cells, inhibitory interneurons, and cortico-cortical and thalamo-cortical inputs can account for the main characteristics of the corticospinal activity evoked by TMS including its regular and rhythmic nature, the stimulus intensity-dependence and its pharmacological modulation. In this review we summarize present knowledge of the physiological basis of the effects of TMS of the human motor cortex describing possible interactions between TMS and simple canonical microcircuits of neocortex. According to the canonical model, a TMS pulse induces strong depolarization of the excitatory cells in the superficial layers of the circuit. This leads to highly synchronized recruitment of clusters of excitatory neurons, including layer V PTNs, and of inhibitory interneurons producing a high frequency (~670 Hz) repetitive discharge of the corticospinal axons. The role of the inhibitory circuits is crucial to entrain the firing of the excitatory networks to produce a high-frequency discharge and to control the number and magnitude of evoked excitatory discharge in layer V PTNs. In summary, simple canonical microcircuits of neocortex can explain activation of corticospinal neurons in human motor cortex by TMS.

Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease

“…In the 6-hydroxydopamine rat model of PD, direct activation of layer V pyramidal neurons through antidromic activation of the hyperdirect pathway with STN stimulation has been demonstrated (Li et al, 2007;Dejean et al, 2009;Gradinaru et al, 2009). It has been proposed that layer II and III neurons are activated by TMS (Amassian et al, 1987;Huerta and Volpe, 2009;Di Lazzaro and Ziemann, 2013;Di Lazzaro and Rothwell, 2014), which in turn excites the pyramidal neurons in layer V. The possibility of collision between TMSevoked M1 volleys and DBS-induced antidromic volleys should also be considered. However, TMS activates corticospinal and other corticofugal neurons indirectly via an interneuron with a …”

“…latency of ϳ1.5 ms (Di Lazzaro and Ziemann, 2013). Therefore, the time from STN stimulation to activation of corticofugal neurons is ϳ4.5 ms (3 Ϯ 1.5 ms).…”

Canonical cortical circuits: current evidence and theoretical implications

“…An alternative way of assessing the effects of TMS is to directly record the synaptic activity evoked by stimulation of M1 from epidural electrodes implanted chronically in the spinal cord for relief from pain. From 1998 onward, Di Lazzaro and Ziemann 34 have performed an extensive series of studies using this approach.…”

Assessment and modulation of cortical inhibition using transcranial magnetic stimulation

“…In both cases, inhibition of the test MEP amplitude can be observed. While the fundamental network mechanisms still remain elusive (Di Lazzaro and Ziemann, 2013), it is assumed that the initial pulse is responsible for a characteristic (direct or indirect) activation of inhibitory interneurons, triggering a quantifiable reduction of the test MEP. Meanwhile, pharmacological studies indicate that SICI reflects the influence of ionotropic GABA A receptors, whereas LICI is rather attributed to metabotropic GABA B receptors .…”

“…Functional experiments of intra-and intercortical inhibition in the motor cortex of the human brain are mainly based on TMS-studies (Di Lazzaro and Ziemann, 2013). In recent years, several specific double-pulse protocols have been established in this context: the so-called 'short-interval intracortical inhibition' (SICI) is based on application of a subthreshold conditioning TMS pulse, which does not induce MEPs itself, followed by a suprathreshold test pulse within a short interval (1-5 ms).…”