Concurrent TMS to the primary motor cortex augments slow motor learning

Abstract

Transcranial magnetic stimulation (TMS) has shown promise as a treatment tool, with one FDA approved use. While TMS alone is able to up- (or down-) regulate a targeted neural system, we argue that TMS applied as an adjuvant is more effective for repetitive physical, behavioral and cognitive therapies, that is, therapies which are designed to alter the network properties of neural systems through Hebbian learning. We tested this hypothesis in the context of a slow motor learning paradigm. Healthy right-handed individuals were assigned to receive 5 Hz TMS (TMS group) or sham TMS (sham group) to the right primary motor cortex (M1) as they performed daily motor practice of a digit sequence task with their non-dominant hand for 4 weeks. Resting cerebral blood flow (CBF) was measured by H2(15)O PET at baseline and after 4 weeks of practice. Sequence performance was measured daily as the number of correct sequences performed, and modeled using a hyperbolic function. Sequence performance increased significantly at 4 weeks relative to baseline in both groups. The TMS group had a significant additional improvement in performance, specifically, in the rate of skill acquisition. In both groups, an improvement in sequence timing and transfer of skills to non-trained motor domains was also found. Compared to the sham group, the TMS group demonstrated increases in resting CBF specifically in regions known to mediate skill learning namely, the M1, cingulate cortex, putamen, hippocampus, and cerebellum. These results indicate that TMS applied concomitantly augments behavioral effects of motor practice, with corresponding neural plasticity in motor sequence learning network. These findings are the first demonstration of the behavioral and neural enhancing effects of TMS on slow motor practice and have direct application in neurorehabilitation where TMS could be applied in conjunction with physical therapy.

Keywords: Digit sequence practice; Hebbian learning; Hyperbolic function; Motor learning; Motor learning network; Motor system; Primary motor cortex; Skill transfer; TMS.

Fig. 1

Individualized image guided TMS. TMS was applied to right M1_hand area identified by a left index finger adduction and abduction task during BOLD fMRI acquisition overlaid on the individual's anatomical MRI. The TMS treatment-planning tool determined the scalp location and the orientation of the TMS coil.

Fig. 2

Daily TMS/sham TMS treatment and digit sequence practice (DSP). The daily sitting consisted of 4 sessions of TMS/sham TMS interleaved with DSP. Each session consisted of six blocks of TMS/sham TMS with an inter-block interval (IBI) of 60 s. Each block included 5 trains of 5 Hz TMS with inter-train interval of 5 s. A train of TMS consisted of 10 s of 5 Hz TMS (50 pulses). DSP consisted of 4 min of practicing the training sequence as quickly and as accurately as possible.

Fig. 3

Performance over the course of training of digit sequence task in DSP + sham (open triangles) and DSP + TMS (open diamonds) groups. The solid lines indicate the modeled function for the two groups. Top panel A: First week of training. Both groups demonstrated significant improvement in performance from baseline. The DSP + TMS group had a significantly faster rate of learning, evidenced by a greater slope. Bottom panel B: Four weeks of training. Both groups demonstrated significant improvement in performance from baseline. The DSP + TMS group had a significantly faster rate of learning, evidenced by a significantly shorter model parameter R.

Fig. 4

Sequence time over the course of training of digit sequence task in DSP + sham (open triangles) and DSP + TMS (open diamonds) groups. Both groups demonstrated significant decreases in time taken to perform the sequences from baseline. The DSP + TMS groups had a significantly greater decrease (p = 0.0028).

Fig. 5

Transfer of motor skills in DSP + sham and DSP + TMS groups: A. Extrinsic transfer: The performance of the training sequence with the hand ipsilateral to the TMS stimulation (right hand). B. Intrinsic transfer-training hand: The performance of the mirrored sequence with the training hand (left hand). C. Intrinsic transfer-ipsilateral hand: The performance of the mirrored sequence with the hand ipsilateral to the TMS stimulation (right hand). All the three transfer sequences improved significantly over the training period in both the groups.

Fig. 6

Brain regions demonstrating increases in resting CBF after 4 weeks in DSP + sham group (regions in red) and DSP + TMS group (regions in blue). 1. Cingulate cortex (BA 24), 2. premotor cortex, 3. putamen, 4. amygdala, 5. caudate nucleus, 6. cingulate gyrus (BA23), 7. primary motor cortex, 8. parahippocampus, 9. thalamus, and 10. cerebellum. The PET data are overlaid on Colin Brain, and the coordinates are in Talairach system. The left hemisphere is on the left side of the image.

Fig. 7

Right: resting state CBF amplitude changes following 4 weeks of DSP + sham and DSP + TMS. TMS was applied to right M1_hand area. Significant increases in rsCBF were noted in right M1_hand, supplementary motor area (SMA), premotor cortex (PMd), and inferior parietal lobule (BA 40) in both groups after 4 weeks of DSP. The DSP + sham group demonstrated significant increases in the left M1_hand, and left BA 40 following training. Additional increases in rsCBF were noted in the right sided cingulate cortex, putamen, hippocampus, amygdala, as well as cerebellum in the DSP + TMS group. * = p < 0.05.