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.

Keywords: GABAergic neuron; corticospinal tract; motor cortex; pyramidal neuron; transcranial magnetic stimulation.

Figure 1

A schematic view of the model of corticospinal volley generation based on canonical cortical circuit proposed by Douglas et al. (1989). This model includes the superficial population of excitatory pyramidal neurons of layers II and III (P2-P3), the large pyramidal tract neurons in layer V (P5), and the inhibitory GABA cells [modified from Figure 1.14 in “The Synaptic Organization of the Brain” (Shepherd, 2004)]. Electrical anodal stimulation activates the axons of P5 cells evoking a D wave. Magnetic stimulation with a latero-medial (LM) induced current in the brain produces a direct activation of the axons of corticospinal cells evoking the D wave followed by an I1 wave produced by monosynaptic activation of P5 cells by the axons of superficial pyramidal neurons, at high intensities it also produces a recurrent activity in the circuit composed of the layer II and III and layer V pyramidal neurons together with their connections with local GABAergic interneurons (red ellipse and arrows) evoking late I-waves. Magnetic stimulation with a posterior-anterior (PA) induced current in the brain evokes the I1 wave and, at higher intensities, late I-waves. Magnetic stimulation with an anterior-posterior (AP) induced current in the brain recruits small and delayed descending volleys with slightly different peak latencies and longer duration than those seen after posterior to anterior magnetic stimulation. It is proposed that this more dispersed descending activity is produced by a more complex circuit (green dotted ellipse and arrows) that might include cortico-cortical fibers originating from the premotor cortex and projecting upon the motor cortex circuits generating the I-waves.

Figure 2

Epidural volleys evoked by test magnetic stimulus alone (solid traces) and by test magnetic stimulus preceded by a subthreshold conditioning stimulus at 3 ms interstimulus interval (Short Interval Intracortical inhibition dotted trace) or by test magnetic stimulus preceded by a peripheral nerve stimulation to the median nerve at the wrist (Short Latency Afferent Inhibition dotted trace). Each trace is the average of 10 sweeps. The test stimulus activates the axons of pyramidal neurons of layers II and II (P2 and P3) that in turn activate pyramidal neurons of layer V (P5) and the GABA cells projecting upon the layer V pyramidal cells evoking multiple descending waves. In the short interval intracortical inhibition protocol a clear suppression of the late corticospinal volley is evident when test magnetic stimulus is preceded by the conditioning subthreshold stimulus. It is proposed that the conditioning stimulus enhances selectively the excitability of the GABAergic connections with a suppression of the late I waves. In SAI protocol clear suppression of the latest corticospinal volley is evident when test magnetic stimulus is preceded by the peripheral nerve conditioning stimulus. It is proposed that the peripheral nerve stimulation enhances the excitability of the GABAergic cells through the activation of thalamocortical projections.