What have We Learned from "Perturbing" the Human Cortical Motor System with Transcranial Magnetic Stimulation?

Abstract

The purpose of this paper is twofold. First, we will review different approaches that one can use with transcranial magnetic stimulation (TMS) to study both its effects on motor behavior and on neural connections in the human brain. Second, we will present evidence obtained in TMS-based studies showing that the dorsal premotor area (PMd), the ventral premotor area (PMv), the supplementary motor area (SMA), and the pre-supplementary motor area (pre-SMA) each have different roles to play in motor behavior. We highlight the importance of the PMd in response selection based on arbitrary cues and in the control of arm movements, the PMv in grasping and in the discrimination of bodily actions, the SMA in movement sequencing and in bimanual coordination, and the pre-SMA in cognitive control. We will also discuss ways in which TMS can be used to chart "true" cerebral reorganization in clinical populations and how TMS might be used as a therapeutic tool to facilitate motor recovery after stroke. We will end our review by discussing some of the methodological challenges and future directions for using this tool in basic and clinical neuroscience.

Keywords: effective connectivity; functional connectivity; functional neuroimaging; motor system; premotor area; stroke recovery; supplementary motor area; transcranial magnetic stimulation.

Figure 1

Motor areas in the frontal lobe. The premotor cortex on the lateral surface of the brain can be divided into the dorsal and ventral premotor areas (PMd and PMv) and the supplementary motor cortex on the medial wall of the brain can be divided into the supplementary motor and pre-supplementary motor areas (SMA and pre-SMA). Premotor cortex below the superior frontal sulcus is typically considered PMv whereas premotor cortex above this anatomical landmark is typically considered PMd. The vertical anterior-commissural line is often used to denote the boundary between SMA and pre-SMA. One can further divide PMd according to a rostral subdivision located along the superior frontal gyrus and a caudal subdivision located along the precentral gyrus. However, one cannot dissociate these two subdivisions with TMS easily and we therefore do not discuss them separately. There also exists two cingulate motor areas (RCZa and RZp) anterior to the vertical anterior-commissural line and one cingulate motor area (CCZ) posterior to the vertical anterior-commissural line. This parcellation of non-primary motor areas in the human was proposed by Picard and Strick (1996, 2001). We have arbitrarily drawn boundaries on a surface-rendered cortical surface loosely based on definitions proposed by Picard and Strick (1996, 2001).

Figure 2

Dual-site TMS approach. Dual-site TMS approach can be used to examine the time course of interactions in a particular neural circuit containing a non-primary motor area and M1. The idea is to stimulate a non-primary motor area with a conditioning pulse to examine its effect on a subsequent supra-threshold test pulse to M1. Changes in M1 can be inferred by measuring any possible changes in its motor excitability on a hand muscle using electromyography.

Figure 3

TMS/PET study on M1 and PMd effective connectivity. In a combined TMS/PET study, we mapped networks of brain regions in which changes in cerebral blood flow correlated with changes in the motor excitability of the left M1 after applying repetitive TMS over either the left PMd or the left M1 (Chouinard et al., 2003). We interpreted these correlations as an index of neural modulation induced by the repetitive TMS. Although repetitive stimulation at the two adjacent cortical sites produced the same effects on motor excitability, statistical maps of correlations between the magnitude of MEP suppression and changes in cerebral blood flow revealed two distinct patterns of distal neural modulation. Abbreviations: MIP = medial intraparietal area; DL-PFC = dorsolateral prefrontal cortex; AIP = anterior intra-parietal area; VL-PFC = ventrolateral prefrontal cortex; VL Thalamus = ventrolateral thalamus.

Figure 4

TMS/PET studies of M1 effective connectivity on normal volunteers and stroke patients. (A) Paus et al. (1998) applied sub-threshold 10-Hz repetitive TMS over M1 and varied the number of TMS trains delivered during each block of PET scanning. In doing so, the CBF response correlated negatively with the number of stimulus trains delivered both at the site of stimulation and in several distal brain regions. Given the success of this protocol in normal volunteers, we carried out the same procedures before and after the stroke patients had their CI therapy. (B) In one analysis, we asked whether or not correlations between CBF and TMS trains differed for any brain regions after CI therapy from those seen before CI therapy. This analysis revealed that both the stimulated ipsilesional M1 and a more distal ipsilesional CMA reverted back to the more normal inverse relationship between CBF and TMS trains. (C) In another analysis, we examined the relationship between motor improvement and changes in the CBF response to TMS between the two PET sessions. This analysis revealed an inverse relationship locally in the stimulated ipsilesional M1, which suggests that the observed changes in M1 were adaptive.