Repetitive transcranial magnetic stimulation (rTMS) is widely used in both research and clinical settings to modulate human brain function and behavior through the engagement of the mechanisms of plasticity. Based upon experiments using single-pulse TMS as a probe, the physiologic mechanism of these effects is often assumed to be via changes in cortical excitability, with 10 Hz rTMS increasing and 1 Hz rTMS decreasing the excitability of the stimulated region. However, the reliability and reproducibility of these rTMS protocols on cortical excitability across and within individual subjects, particularly in comparison to robust sham stimulation, have not been systematically examined.In a cohort of 28 subjects (39 ± 16 years), we report the first comprehensive study to (1) assess the neuromodulatory effects of traditional 1 Hz and 10 Hz rTMS on corticospinal excitability against both a robust sham control, and two other widely used patterned rTMS protocols (intermittent theta burst stimulation, iTBS; and continuous theta burst stimulation, cTBS), and (2) determine the reproducibility of all rTMS protocols across identical repeat sessions.At the group level, neither 1 Hz nor 10 Hz rTMS significantly modulated corticospinal excitability. 1 Hz and 10 Hz rTMS were also not significantly different from sham and both TBS protocols. Reproducibility was poor for all rTMS protocols except for sham. Importantly, none of the real rTMS and TBS protocols demonstrated greater neuromodulatory effects or reproducibility after controlling for potential experimental factors including baseline corticospinal excitability, TMS coil deviation and the number of individual MEP trials.These results call into question the effectiveness and reproducibility of widely used rTMS techniques for modulating corticospinal excitability, and suggest the need for a fundamental rethinking regarding the potential mechanisms by which rTMS affects brain function and behavior in humans.
Introduction Transcranial magnetic stimulation (TMS) mapping has become a critical tool for exploratory studies of the human corticomotor (M1) organization. Here, we propose to gather existing cutting-edge TMS-EMG and TMS-EEG approaches into a combined multi-dimensional TMS mapping that considers local and whole-brain excitability changes as well as state and time-specific changes in cortical activity. We applied this multi-dimensional TMS mapping approach to patients with Parkinson’s disease (PD) with Deep brain stimulation (DBS) of the sub-thalamic nucleus (STN) ON and OFF. Our goal was to identifying one or several TMS mapping-derived markers that could provide unprecedent new insights onto the mechanisms of DBS in movement disorders. Methods Six PD patients (1 female, mean age: 62.5 yo [59–65]) implanted with DBS-STN for 1 year, underwent a robotized sulcus-shaped TMS motor mapping to measure changes in muscle-specific corticomotor representations and a movement initiation task to probe state-dependent modulations of corticospinal excitability in the ON (using clinically relevant DBS parameters) and OFF DBS states. Cortical excitability and evoked dynamics of three cortical areas involved in the neural control of voluntary movements (M1, pre-supplementary motor area – preSMA and inferior frontal gyrus – IFG) were then mapped using TMS-EEG coupling in the ON and OFF state. Lastly, we investigated the timing and nature of the STN-to-M1 inputs using a paired pulse DBS-TMS-EEG protocol. Results In our sample of patients, DBS appeared to induce fast within-area somatotopic re-arrangements of motor finger representations in M1, as revealed by mediolateral shifts of corticomuscle representations. STN-DBS improved reaction times while up-regulating corticospinal excitability, especially during endogenous motor preparation. Evoked dynamics revealed marked increases in inhibitory circuits in the IFG and M1 with DBS ON. Finally, inhibitory conditioning effects of STN single pulses on corticomotor activity were found at timings relevant for the activation of inhibitory GABAergic receptors (4 and 20 ms). Conclusion Taken together, these results suggest a predominant role of some markers in explaining beneficial DBS effects, such as a context-dependent modulation of corticospinal excitability and the recruitment of distinct inhibitory circuits, involving long-range projections from higher level motor centers and local GABAergic neuronal populations. These combined measures might help to identify discriminative features of DBS mechanisms towards deep clinical phenotyping of DBS effects in Parkinson’s Disease and in other pathological conditions.
The use of TMS-EEG coupling as a neuroimaging tool for the functional exploration of the human brain recently gained strong interest. If this tool directly inherits the fine temporal resolution from EEG, its spatial counterpart remains unknown. In this study, we explored the spatial resolution of TMS-EEG coupling by evaluating the minimal distance between two stimulated cortical sites that would significantly evoke different response dynamics. TMS evoked responses were mapped on the sensorimotor region in twenty participants. The stimulation grid was composed of nine targets separated between 10 and 15 mm on average. The dynamical signatures of TMS evoked activity were extracted and compared between sites using both local and remote linear regression scores and spatial generalized mixed models. We found a significant effect of the distance between stimulated sites on their dynamical signatures, neighboring sites showing differentiable response dynamics. Besides, common dynamical signatures were also found between sites up to 25-30 mm from each other. This overlap in dynamical properties decreased with distance and was stronger between sites within the same Brodmann area. Our results suggest that the spatial resolution of TMS-EEG coupling might be at least as high as 10 mm. Furthermore, our results reveal an anisotropic spatial resolution that was higher across than within the same Brodmann areas, in accordance with the TMS induced E-field modeling. Common cytoarchitectonic leading to shared dynamical properties within the same Brodmann area could also explain this anisotropy. Overall, these findings suggest that TMS-EEG benefits from the spatial resolution of TMS, which makes it an accurate technique for meso-scale brain mapping.
Abstract Background Cortical excitability is elevated in Alzheimer’s disease (AD). Transcranial magnetic stimulation‐evoked responses on electromyography (EMG) and electroencephalography (EEG) have captured this increased excitability in motor brain regions. However, it is not yet known if increased excitability is also present in the parietal lobe or the extent to which excitability is related to cognition. Method TMS‐EEG data from 29 participants with biomarker‐confirmed AD (CDR 0.5‐1, age 57‐81, 45% female) and 38 cognitively unimpaired older controls (CDR 0, age 57‐89, 59% female) were analyzed. Single‐pulse TMS was applied to left motor cortex (M1) and inferior parietal lobule (IPL) at 120% of resting motor threshold (RMT) and 135% of RMT (in 12 AD and 22 controls). The early (15‐40 msec) TMS‐evoked local mean field amplitude (LMFA) was assessed from electrodes near each TMS target. Group differences in LMFA were assessed separately for each site and intensity, controlling for age, sex, and scalp‐to‐cortex distance. A subset of AD participants had cognitive testing scores available for the Assessment Scale‐Cognitive subscale (ADAS‐Cog, n=10) and a Parietal Composite Score (averaged z‐scores of Benton Judgement of Line Orientation, ADAS‐Cog Maze 3 time, and WRAT 4 Math, n=13). Cognitive scores were related to LMFA at each site and intensity using separate linear models. Result In M1, 135% RMT evoked a larger LMFA in AD than in older controls (R 2 adj=0.17, p=0.036). Visual inspection of the M1 135% RMT evoked responses also revealed higher local responses in AD (Figure 1). There were no between‐group differences for other conditions (p‐values > 0.100). In AD, higher M1 LMFA at 135% RMT was related to worse global cognition on the ADAS‐Cog (R 2 adj=0.68, p=0.002, Figure 2a), but not the Parietal Composite Score. Higher IPL LMFA at 120% RMT was related to worse performance on the Parietal Composite Score (R 2 adj =0.38, p=0.015, Figure 2b), but not the ADAS‐Cog. Conclusion TMS‐EEG reveals elevated motor‐area excitability in AD. Excitability measures showed a double‐dissociation with cognition: motor excitability is related to global cognition and parietal excitability is related to parietal function. TMS‐EEG may be useful to measure target engagement for future therapies seeking to restore normal neuronal excitability in AD.
