Inhibitory effect of subthreshold transcranial magnetic stimulation on the stretch-evoked long latency response of forearm muscles

Abstract

The central nervous system controls human movements using multiple pathways that relay neural input to the muscles. The reticulospinal tract (RST) is a prominent secondary motor pathway, as it extends the function of the primary motor pathway, the corticospinal tract (CST). The RST is especially important for its involvement in locomotion, maintenance of posture, reaching, and grasping, which has considerable importance for recovery from corticospinal lesions such as stroke. There is currently a debate on whether increased reticulospinal function is necessary for recovery of motor function after severe lesions of the CST, or a sign of maladaptive plasticity. A primary reason for the unresolved debate is the lack of methods for measuring function of the reticular formation, a collection of nuclei in the brainstem that originate the RST. ☐ An important component of upper limbs movement mechanisms is the “long-latency response” (LLR), which is evident as a burst of muscle activity occurring 50–100 ms following an imposed limb displacement. Although the neural processing of these long latency responses through the cortical circuits has been roughly distinguished, it is still unclear how the RST circuits contributes to the LLR, independently from the cortical inputs. A possible method for decoupling the contribution of the CST and the RST to LLR would be to use the inhibitory TMS neuromodulation. Previous studies utilized TMS to study the neural substrates of LLR, demonstrating that the effects of TMS signal delivered over the motor cortex on the LLR amplitude (LLRa) are modulated by the signal intensity and arrival time relative to the EMG activity period. However, previous studies reported inconsistent findings of the effects of TMS on LLRa, reporting inconsistent inhibitory and excitatory LLR modulation. As such, the primary objective of this work was to develop a synchronized stimulation method including robotic perturbations, transcranial magnetic stimulation (TMS), and surface electromyography (EMG), which would allow to decouple the contributions of cortical and subcortical brain areas to LLRs. ☐ In part I, we present our developed novel synchronized Robot-TMS-EMG method which produces TMS pulses of controllable magnitude and timed to induce a motor-evoked response (MEP) at controlled time delays relative to the application of robotic perturbations of the wrist joint, while the LLRs are recorded from the muscles by surface EMG electrodes. In part II, we present the results of our experiments on 13 young healthy participants to quantify the effects of subthreshold TMS over the motor cortex, on two groups of healthy subjects, with two intensities of 90% and 95%AMT, which was applied with three different time delays for each group, as T1 (which induced MEPs evoked at the same time as the robot perturbations started), T2 (T1+20ms), and T3 (T1+50ms), on the amplitude of LLRs recorded through surface EMG signals from FCR muscle, which was stretched through the wrist extension perturbations. ☐ Our results identified two conditions (T2 and T3) that induced a significant inhibition of LLR activity in both groups, but no significant difference between groups was measured for any TMS delay levels inducing significant inhibition. Specifically, the T2 and T3 conditions resulted in a significant reduction of LLR amplitude (90% AMT group, T2: 20.3%, p=0.008; T3: 22.8%, p=0.002 – 95% AMT group, T2: 15.1%, p=0.017; T3= 25.3%, p<0.001), while condition T1 resulted in non-significant modulation of LLR amplitude (90% AMT group: 14.1% reduction, p=0.102; 95% AMT group: 3.5% increase, p=0.912). Moreover, TMS application which is timed to evoke MEPs 50ms before the stretch onset (condition T3) was found to have a greater inhibitory effect on the LLRa in both groups, with both the 90% and 95% subthreshold TMS intensity. This time delay condition likely inhibited the intracortical pathways contributed to the LLRa, which is a crucial finding to be applied for our future TMS-fMRI study, which, for the first time, would be the demonstration of a successful combination of TMS and fMRI to study causality of neural function in a distributed motor circuit, involving the primary motor cortex and the brainstem, with the aim of understanding and measuring the specific contribution of the RST to the long-latency responses.