Acute and Longitudinal Effects of High-density Theta Burst Stimulation on Rat Brain
Open Access
- Author:
- Li, Qiong
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 07, 2024
- Committee Members:
- Sri-Rajasekhar Kothapalli, Major Field Member
Xiao Liu, Major Field Member
Nanyin Zhang, Chair & Dissertation Advisor
Daniel Hayes, Program Head/Chair
Hanbing Lu, Special Member
Tao Zhou, Outside Unit & Field Member
Yihong Yang, Special Member - Keywords:
- TMS
fMRI
EMG
Animal models
Sex differences
Brain stimulation - Abstract:
- Transcranial magnetic stimulation (TMS) is a non-invasive and safe method that has been FDA-approved for treating psychological disorders. However, current TMS paradigms produce only modest effects in patients, partly due to an insufficient understanding of the physiological changes induced by TMS. By back-translating TMS to animal models, we can perform invasive manipulations that provide valuable insights into the TMS mechanisms and expedite the development of more effective paradigms. To achieve this goal, our group developed an animal model using a focal coil and subcutaneously implanted electrodes to study the aftereffects of TMS with high face validity. In this dissertation, we proposed a high-efficacy paradigm called High-Density Theta Burst Stimulation (hdTBS). This approach doubles the pulses per burst compared to conventional intermittent Theta Burst Stimulation (iTBS). Our results showed that hdTBS significantly enhances cortical excitability for 35 minutes after stimulation, compared to iTBS. We then evaluated the longitudinal effects (5-day stimulation) of hdTBS on the rat model using MEP and CBV-fMRI. The goal of this study was two-fold: 1) determine whether accelerated hdTBS (three sessions per day) can significantly enhance cortical excitability compared to single-session hdTBS, and 2) map the brain circuits affected by long-term hdTBS using CBV-fMRI. Results suggested that longitudinally applied accelerated hdTBS resulted in suppression of cortical excitability, whereas single-session hdTBS significantly facilitated cortical excitability. Additionally, we mapped the aftereffects of single session hdTBS on brain circuits. Our results revealed that CBV was enhanced in the primary motor cortex, somatosensory cortex of the hindlimb, somatosensory cortex of the forelimb, somatosensory barrel cortex, caudate putamen, amygdala, and visual cortex. In addition to this study, we aimed to develop a paradigm with the potential for focal stimulation of a deep brain region using TMS. Inspired by the temporal summation effects of repetitive TMS, we applied rTMS at ultra-high frequencies and subthreshold intensities to investigate whether they could induce a suprathreshold response. Our results suggest that sending a TMS pulse at 65% of the maximum machine stimulation (MSO) cannot elicit an MEP, but TMS pulses applied at 166 Hz and 250 Hz can. The first peak of the MEP consistently occurred after the third pulse, indicating the temporal summation effects. Finally, to better understand the sex-related factors when building the animal model, we used BOLD-fMRI to investigate sex differences in rat brains. The data suggested that female rats display stronger hypothalamus connectivity and stronger segregation between the cortical and sub-cortical regions, whereas male rats exhibit more prominent striatum-related connectivity and high cortico-subcortical connectivity. Taken together, this dissertation studied the physiological effects of new TMS paradigms on rat models, demonstrating their advantages compared to current paradigms and advancing our understanding of the mechanisms of TMS.