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Low-intensity focused ultrasound with continuous theta burst stimulation induces human primary motor cortex functional connectivity changes
Wei-Chih Yang1, Kai-Hsiang Stanley Chen2, Yih-Chih Jacinta Kuo2, Yan-Siou Dong2, Gin-Shin Chen3, and Yao-Chia Shih1
1Graduate Institute of Medicine, Yuan Ze University, Taoyuan City, Taiwan, 2Department of Neurology, National Taiwan University Hospital Hsin-Chu Branch, Hsin-Chu, Taiwan, 3Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan

Synopsis

Keywords: Other Interventional, fMRI (resting state)

Motivation: Combining low-intensity transcranial focused ultrasound stimulation (TUS) akin to continuous theta burst stimulation (cTBS) setting (ctbTUS) with cTBS over M1 can be a potential strengthening non-invasive neuromodulatory method.

Goal(s): To understand the neuroplasticity in response to ctbTUS or simultaneous ctbTUS+cTBS.

Approach: Resting-state fMRI with seed-based analysis with seeds of M1 and its first dorsal interosseous (FDI) muscle representation (M1FDI) was used to assess functional connectivity (FC) changes due to cTBS, ctbTUS, or ctbTUS+cTBS.

Results: We replicated M1-FC degradations in ipsilateral sensorimotor regions due to cTBS, and verified the potential synergic effect of ctbTUS+cTBS on M1-FC decreases in supplementary motor area.

Impact: Our study is the first to use resting-state fMRI to investigate FC changes within motor network due to either cTBS, ctbTUS, or ctbTUS+cTBS stimulations on left M1. The results help understand the potential of ctbTUS+cTBS to be a novel therapy.

Introduction

Previous studies have shown that applying repetitive Transcranial Magnetic Stimulation (rTMS) over the primary motor cortex (M1) can modify the cortical plasticity in either facilitatory or inhibitory response according to different paradigm. A specific mode of rTMS, continuous theta burst stimulation (cTBS) on the first dorsal interosseous (FDI) muscle representation in the ipsilateral M1 (M1FDI) only takes 40 seconds to produce the prolonged motor evoked potential (MEP) suppression in the contralateral FDI muscle, lasting about 60 minutes.1,2 However, rTMS is limited to the depth-focality trade-off, leading to therapeutic inefficiency. In contrast, the low-intensity transcranial focused ultrasound stimulation (TUS) with deeper brain penetration has shown great efficacy for reversing neural dysfunctions without adverse events3,4 but its neuromodulatory mechanisms across different protocols remain controversial. Therefore, the present study using the resting-state fMRI (rsfMRI) aimed to (1) understand whether the low-intensity tTUS following cTBS sequence (ctbTUS) setting on left M1 can induce long-term functional connectivity (FC) changes within sensorimotor network similar to cTBS neuromodulation, (2) and examine whether the synergic effect of simultaneous ctbTUS+cTBS exist if both interventions are hypothesized to have the similar neuromodulatory influences on FC (i.e., decreased FC in M1 in parallel to suppressed MEP).

Methods and Materials

Twenty participants (11 males, age: 31.5±5.8 years) underwent 3 different study protocols of interventions as follows: cTBS with sham ctbUS, ctbTUS with sham cTBS, and simultaneous ctbTUS+cTBS (details described in Fig. 1&2). A single-pulse TMS was performed to navigate the exact hotspot on each participant’s M1FDI before performing study protocols. MRI acquisition: Two MRI scans were respectively performed before and after stimulations for each participant on a 3-T MRI scanner (Skyra, Siemens, Erlangen, Germany) with 20-channel head coil. Each scan included a high-resolution T1-weighted (T1W) MPRAGE sequence (voxel size=1×1×1 mm3) and a blood-level-oxygen-dependent rsfMRI acquisition using the 2D gradient EPI sequence (TR/TE=2500/25 ms, voxel size=3×3×3 mm3, and 180 measures). MRI analysis: The rsfMRI data were preprocessed and analyzed using a MATLAB CONN toolbox5, including quality control, slice timing correction, head motion correction, nuisance regression, bandpass filtering (0.01-0.1 Hz), denoising, co-registration between rsfMRI and T1W images, tissue segmentation, spatial normalization to the MNI152 template, and spatial smoothing with 6-mm FWHM. The seed-based analysis using a bivariate correlation weighted by hemodynamic-response-function was performed to calculate voxel-wise FC between the seed and other brain regions. The anatomical M1 and spherical M1FDI (with radius=5 mm) seeds respectively obtained from Harvard-Oxford atlas6 and the centered coordinate of [-38.4,-20.6,60.7] in the MNI space.7 The group comparison of FC between pre- and post-stimulation rsfMRI scans in each protocol was conducted by a multivariate linear regression analysis adjusted for age and gender. The following region-of-interest (ROI) analysis using paired-t test was applied to assess the significance and effect size of FC changes in sensorimotor regions.

Results

Multivariate linear regression analyses with a statistical threshold of cluster-level FDR-p<0.05 detected decreased FC due to cTBS in the precuneus, left precentral gyrus (preCG) and bilateral postcentral gyrus (postCG), increased FC due to ctbTUS in the bilateral occipital pole as well as decreased FC in the supplementary motor area (SMA) and paracingulate gyrus and increased FC in the preCG/postCG due to simultaneous ctbTUS+cTBS. However, the following ROI analysis only confirmed significant FC reductions in the SMA, with a moderate effect size (p=0.01, Cohen’s d=-0.61), and the rest findings in sensorimotor regions were insignificant (Fig. 3). When seeding on left M1FDI, FC decreases (cluster-level FDR-p<0.05) were seen in the cerebellum VIII after cTBS, in the left preCG/postCG and precuneus after ctbTUS (with voxel-level uncorrected-p=0.001), in the bilateral occipital pole after simultaneous ctbTUS+cTBS (Fig. 4). However, the above findings were absent in ROI analyses.

Discussion

To our best knowledge, this study is the first to use rsfMRI to investigate the neuroplasticity in response to either cTBS, ctbTUS, or ctbTUS+cTBS stimulations on left M1. The patterns of FC changes due to cTBS and ctbTUS were different, regardless of which seed region we placed. cTBS caused M1-FC reductions in the preCG/postCG consistent with previous findings,8 but had no significant influence on M1FDI FC. In contrast, ctbTUS only degrades M1FDI-FC to the left preCG/postCG. It suggests that cTBS might require a wider neuromodulatory coverage than ctbTUS to achieve the effective neurovascular influences. The synergic effect of ctbTUS+cTBS might exist, and be more evident in reduced FC in the SMA, which is associated with the control of distal/proximal limbs and complex movements.9

Conclusion

This pilot study could help understand the potential of ctbTUS or simultaneous ctbTUS+cTBS for developing novel neuromodulatory therapies in Parkinson's disease.

Acknowledgements

Funding for this project was obtained from the National Health Research Institutes (NHRI-112-H01).

References

  1. Huang YZ, Edwards MJ, Rounis E, et al. Theta burst stimulation of the human motor cortex. Neuron 2005;45:201-206
  2. Huang YZ, Rothwell JC, Chen RS, et al. The theoretical model of theta burst form of repetitive transcranial magnetic stimulation. Clin Neurophysiol 2011;122:1011-1018
  3. Baek H, Pahk KJ, Kim H. A review of low-intensity focused ultrasound for neuromodulation. Biomed Eng Lett2017;7:135-142
  4. Fomenko A, Chen KS, Nankoo JF, et al. Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior. Elife 2020;9
  5. Whitfield-Gabrieli S, Nieto-Castanon A. Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connect 2012;2:125-141
  6. Desikan RS, Ségonne F, Fischl B, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 2006;31:968-980
  7. Diekhoff S, Uludağ K, Sparing R, et al. Functional localization in the human brain: Gradient-Echo, Spin-Echo, and arterial spin-labeling fMRI compared with neuronavigated TMS. Hum Brain Mapp 2011;32:341-357
  8. Kirkovski M, Donaldson PH, Do M, et al. A systematic review of the neurobiological effects of theta-burst stimulation (TBS) as measured using functional magnetic resonance imaging (fMRI). Brain Struct Funct 2023;228:717-749
  9. Tanji J. The supplementary motor area in the cerebral cortex. Neurosci Res 1994;19:251-268

Figures

Fig. 1: For each participant, three experiments were conducted at three different timepoints, >1 week apart. There were two MRI examinations before and after an interventional protocol within each experiment. Within three experiments, cTBS, ctbTUS, and ctbTUS+cTBS were assigned to participants by the randomized order. A single-pulse TMS was performed to navigate the exact hotspot on each participant’s M1FDI before performing study protocols.

Fig. 2: (a) Photograph of the custom TUS-TMS delivery apparatus, which provides the option to apply ctbTUS and TMS either separately or concurrently. (b) Diagram depicting the cTBS and ctbTUS intervention protocol. For the cTBS, burst duration = 40ms, pulse repetition interval = 200 ms, total duration = 40s and giving a total of 600 pulses. The fundamental frequency of ctbTUS is set at 0.5MHz with pulse repetition frequency at 5Hz, and duty cycle is 20%. 3 different study protocols of interventions as follows : cTBS with sham ctbTUS, ctbTUS with sham cTBS, and simultaneous ctbTUS+cTBS


Fig. 3: Changes due to neuromodulatory interventions of functional connectivity (FC) seeding by left PreCG (M1). (a) Results of multivariate linear regression analyses with a statistical threshold of cluster-level FDR-p < 0.05. The color scale represents FC strength by t-value. Results of region-of-interest (ROI) analyses: (b) comparisons of beta values (FC strength) between pre- and post-cTBS in left preCG/postCG; (c) FC changes between pre- and post-ctbTUS+cTBS in motor-related ROIs. * indicates a statistical level of p = 0.01.

Fig. 4: Changes due to neuromodulatory interventions of functional connectivity (FC) seeding by M1FDI. (a) Results of multivariate linear regression analyses with a statistical threshold of cluster-level FDR-p < 0.05. The color scale represents FC strength by t-value. The warmer and colder colors respectively indicate stronger and weaker FC after interventions. (b) Comparisons of beta values (FC strength) between pre- and post-ctbTUS in left preCG/postCG.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
1284
DOI: https://doi.org/10.58530/2024/1284