An Investigation of Short-Term Plasticity in Human Motor Cortex

Transcranial magnetic stimulation (TMS) produces a transient magnetic field that activates underlying cortical tissue by eliciting an electrical discharge of the neurons in the targeted area. Repetitive TMS (rTMS) uses patterns of repetitive TMS pulses and has been reliably shown to produce changes in the state of cortical excitability outlasting the time of stimulation. One such protocol that has demonstrated states of increased excitability is intermittent theta burst stimulation (iTBS). This method applies high-frequency bursts (50Hz) of pulses every 200 ms in trains of ten bursts. The effects of and differences between rTMS protocols have been investigated since gaining popularity in the 1990’s, however, there are still many unknowns regarding the neurophysiological changes that accompany this plasticity. Much research on these effects takes place in motor cortex due to reliable and quantifiable measures of cortical excitability observed there. Here, I sought to further investigate the effects of iTBS on inter-hemispheric changes in in motor cortex using EEG simultaneously recorded with TMS pulses. That is, I examined if iTBS conducted over right motor cortex would lead to measureable changes in excitability indices of left motor cortex. I quantified changes in right and left motor cortex excitability with measurements of TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs) elicited through blocks of single pulse TMS immediately following iTBS and 30 minutes post-iTBS. I compared the effects of the iTBS condition to those found in a control condition where a sham version of iTBS was administered. Results indicate differential modulations of cortical TEPs between hemispheres, including an initial enhancement of the P30 in right hemisphere, coinciding with sustained suppression in left hemisphere, and an enhancement of the P190 during left hemisphere stimulation

Investigation of brain networks for personalized rTMS in healthy subjects and patients with major depressive disorder: A translational study

Depression is a complex psychiatric disorder with emotional dysregulation at its core. The first line of treatment includes cognitive behaviour therapy and pharmacological antidepressants. However, up to one third of patients with depression fail to respond to these treatment interventions. The past decades have seen an increasing use of repetitive Transcranial Magnetic Stimulation (rTMS) in clinical studies, as an alternative treatment for depression. Several large-scale, multicentre randomized controlled trials have led the Food and Drugs Administration (FDA), USA to approve two rTMS protocols for clinical application in the treatment of depression - 10 Hz rTMS and intermittent Theta Burst Stimulation (iTBS). However, only 30-50% of patients receiving rTMS respond to the treatment. The large variability in response to rTMS likely stems from multiple reasons, one being the targeting method currently employed for delivering rTMS at the left dorsolateral prefrontal cortex (DLPFC). Previous functional connectivity studies have shown that stimulation at left DLPFC targets with larger negative correlation to the subgenual anterior cingulate cortex (sgACC) may result in greater therapeutic response than those with lower negative correlation. However, current use of rTMS ignores functional connectivity in choosing the left DLPFC target, thus largely discarding functional architectural differences of the brain across subjects. Furthermore, despite widespread clinical use of rTMS, the basic network mechanisms behind these rTMS protocols remain elusive. This work presents a novel personalization method of left DLPFC target selection based on their negative functional connectivity to the sgACC. The default mode network (DMN) is a large-scale brain network commonly involved in self-referential thought processing and plays an essential role in the pathophysiology of depression. I use the novel personalization method and identical study designs to delineate DMN mechanisms from a single session of 10 Hz rTMS and iTBS in healthy subjects. Arguably, an understanding of basic mechanisms of clinically relevant rTMS protocols in healthy subjects will help improve the current therapeutic effect of rTMS, and possibly expand the therapeutic role of rTMS. My work shows, for the first time, strong but different modulations of DMN connectivity by single personalized sessions of 10 Hz rTMS and iTBS. Such modulations can be predicted using the personality trait harm avoidance (HA). Given that initial results show that the method is robust and reproducible, its adaptation to patient cohorts is likely to result in improved therapeutic benefits. Therefore, the novel method of personalization is translated to clinical setting by using accelerated iTBS (aiTBS) in patients with depression. Additionally, a comparison is made between effects resulting from personalized and nonpersonalized (10-20 EEG system F3 position) aiTBS in patients with depression. By evaluating the DMN, and heart rate variability, I show precise modulatory effects of personalized aiTBS, which is not seen in the standard aiTBS group. The work presented here introduces an important method to reduce variability and increase precision in rTMS modulation by personalizing the left DLPFC target selection. Even though DMN and cardiac effects already point towards the advantage of personalization, the still preliminary analysis fails to show significant differences in treatment response. Lack of greater therapeutic benefits viii from personalized aiTBS in this ongoing study probably stems from a still limited sample size. In case personalization proves clinically advantageous to standard iTBS by the final sample size, this work can sediment the first step towards systems medicine in the field of psychiatry.2022-02-0

Theta-burst stimulation and frontotemporal regulation of cardiovascular autonomic outputs : the role of state anxiety

Dysregulation of autonomic cardiovascular homeostasis is an important cardiological and neurological risk factor. Cortical regions including the prefrontal and insular cortices exert tonic control over cardiovascular autonomic functions. Transcranial Magnetic Stimulation (TMS) may be a suitable approach for studying top-down control of visceromotor processes. However, there is inconsistent evidence as to whether TMS can modify cardiovascular autonomic states. One reason for the inconsistency may arise from the lack of studies accounting for the acute affective states of participants with respect to the stimulation procedures. To gain more insights into these processes, we evaluated the effects of intermittent and continuous theta-burst stimulation (TBS) to the right frontotemporal cortex on state anxiety and cardiovascular responses in a preliminary study. State anxiety significantly increased for both intermittent and continuous TBS relative to sham. Intermittent TBS also significantly increased heart-rate variability (HRV) at natural and slow-paced breathing rates. The effect of intermittent TBS on vagally-mediated HRV was attenuated after accounting for stimulation-induced anxiety, suggesting that increased HRV after stimulation may reflect a response to a transient stressor (i.e., the stimulation itself), rather than TBS effects on visceromotor networks. In contrast, continuous TBS increased pulse transit time latency across breathing rates, an effect that was enhanced after accounting for state anxiety. TMS is a promising approach to study cortical involvement in cardiovascular autonomic regulation. The findings show that TBS induces effects on visceromotor networks, and that analysis of state covariates such as anxiety can be important for increasing the precision of these estimates. Future non-invasive brain stimulation studies of top-down neurocardiac regulation should account for the potential influence of non-specific arousal or anxiety responses to stimulation

Brain Circuits Involved in the Development of Chronic Musculoskeletal Pain: Evidence From Non-invasive Brain Stimulation

It has been well-documented that the brain changes in states of chronic pain. Less is known about changes in the brain that predict the transition from acute to chronic pain. Evidence from neuroimaging studies suggests a shift from brain regions involved in nociceptive processing to corticostriatal brain regions that are instrumental in the processing of reward and emotional learning in the transition to the chronic state. In addition, dysfunction in descending pain modulatory circuits encompassing the periaqueductal gray and the rostral anterior cingulate cortex may also be a key risk factor for pain chronicity. Although longitudinal imaging studies have revealed potential predictors of pain chronicity, their causal role has not yet been determined. Here we review evidence from studies that involve non-invasive brain stimulation to elucidate to what extent they may help to elucidate the brain circuits involved in pain chronicity. Especially, we focus on studies using non-invasive brain stimulation techniques [e.g., transcranial magnetic stimulation (TMS), particularly its repetitive form (rTMS), transcranial alternating current stimulation (tACS), and transcranial direct current stimulation (tDCS)] in the context of musculoskeletal pain chronicity. We focus on the role of the motor cortex because of its known contribution to sensory components of pain via thalamic inhibition, and the role of the dorsolateral prefrontal cortex because of its role on cognitive and affective processing of pain. We will also discuss findings from studies using experimentally induced prolonged pain and studies implicating the DLPFC, which may shed light on the earliest transition phase to chronicity. We propose that combined brain stimulation and imaging studies might further advance mechanistic models of the chronicity process and involved brain circuits. Implications and challenges for translating the research on mechanistic models of the development of chronic pain to clinical practice will also be addressed

Developing a Brain‐Based, Non‐Invasive Treatment for Pain

Chronic pain cost society more than $500 billion each year and contributes to the ongoing opioid overdose crisis. Substantial risks and low efficacy are associated with opiate usage for chronic pain. This dissertation seeks to fill the urgent need for a new pain treatment using a neural-circuit based approach in healthy controls and chronic pain patients. First, we performed a single-blind study examining the causal effects of transcranial magnetic stimulation (TMS), compared to a well-matched control condition. Using interleaved TMS/fMRI we explored brain activation in response to dorsolateral prefrontal cortex (DLPFC) stimulation in 20 healthy controls. This study tested the hypothesis that the TMS evoked responses would be in frontostriatal locations. Consistent with this hypothesis active TMS, compared to the control, led to significantly greater activity in the caudate, thalamus and anterior cingulate cortex (ACC). Building on these findings, we developed a single-blind, sham-controlled study examining two TMS strategies for analgesia in 45 healthy controls. We completed an fMRI thermal pain paradigm before and after modulatory repetitive TMS at either the DLPFC or the medial prefrontal cortex (MPFC). Despite a role in pain processing, the MPFC has not yet been explored as a target for analgesia. Only MPFC stimulation significantly improved behavioral pain measures. These effects were associated with increased motor and parietal cortex activity during the pain task. We then supplement these findings by testing the hypothesis that chronic pain patients who use opioids (n=14) would have elevated brain responses to thermal pain relative to healthy controls (n=14). Despite indistinguishable self-report measures, we found increased brain activity in the ACC and sensory areas in patients which were positively correlated with opioid dose. We conclude by evaluating the feasibility of these approaches in chronic pain patients, reporting preliminary findings from a pilot study examining the two treatment strategies tested previously in controls. Collectively, our findings support a circuits-first approach to pain treatment. Though MPFC stimulation was effective in reducing pain in healthy controls, further work is required to confirm these results in a chronic pain population, as chronic pain and opioid usage alter how the brain processes the pain experience