Translational Neuromodulation: Approximating Human Transcranial Magnetic Stimulation Protocols in Rats

Objective: Transcranial magnetic stimulation (TMS) is a well‐established clinical protocol with numerous potential therapeutic and diagnostic applications. Yet, much work remains in the elucidation of TMS mechanisms, optimization of protocols, and in development of novel therapeutic applications. As with many technologies, the key to these issues lies in the proper experimentation and translation of TMS methods to animal models, among which rat models have proven popular. A significant increase in the number of rat TMS publications has necessitated analysis of their relevance to human work. We therefore review the essential principles for the approximation of human TMS protocols in rats as well as specific methods that addressed these issues in published studies. Materials and Methods: We performed an English language literature search combined with our own experience and data. We address issues that we see as important in the translation of human TMS methods to rat models and provide a summary of key accomplishments in these areas. Results: An extensive literature review illustrated the growth of rodent TMS studies in recent years. Current advances in the translation of single, paired‐pulse, and repetitive stimulation paradigms to rodent models are presented. The importance of TMS in the generation of data for preclinical trials is also highlighted. Conclusions: Rat TMS has several limitations when considering parallels between animal and human stimulation. However, it has proven to be a useful tool in the field of translational brain stimulation and will likely continue to aid in the design and implementation of stimulation protocols for therapeutic and diagnostic applications.     

重复经颅磁刺激抗癎作用及其机制研究进展

重复经颅磁刺激（rTMS）是一门新兴的电生理技术。近年来,实验和临床研究显示rTMS具有潜在抗癎作用。本文对rTMS抗癎的安全性、有效性及可能存在的抗癎机制予以阐述。     

Multimodal Elements of Suicidality Reduction After Transcranial Magnetic Stimulation

ObjectivesRepetitive transcranial magnetic stimulation (TMS) is a promising treatment for suicidality, but it is underlying neural mechanisms remain poorly understood. Our prior findings indicated that frontostriatal functional connectivity correlates with the severity of suicidal thoughts and behaviors. In this secondary analysis of data from an open label trial, we evaluated whether changes in frontostriatal functional connectivity would accompany suicidality reductions following TMS. We also explored the relationship between frontostriatal connectivity change and underlying white matter (WM) organization.Materials and MethodsWe conducted seed-based functional connectivity analysis on participants (N = 25) with comorbid post-traumatic stress disorder and depression who received eight weeks of 5 Hz TMS to left dorsolateral prefrontal cortex. We measured clinical symptoms with the Inventory of Depressive Symptomatology-Self Report (IDS-SR) and the PTSD Checklist for DSM-5 (PCL-5). We derived suicidality from IDS-SR item 18. Magnetic resonance imaging data were collected before TMS, and at treatment end point. These data were entered into analyses of covariance, evaluating the effect of suicidality change across treatment on striatal and thalamic functional connectivity. Changes in other PTSD and depression symptoms were included as covariates and results were corrected for multiple comparisons. Diffusion connectometry in a participant subsample (N = 17) explored the relationship between frontal WM integrity at treatment baseline and subsequent functional connectivity changes correlated with differences in suicidality.ResultsSuicidal ideation decreased in 65% of participants. Reductions in suicidality and functional connectivity between the dorsal striatum and frontopolar cortex were correlated (p-False Discover Rate-corrected < 0.001), after covariance for clinical symptom change. All other results were nonsignificant. Our connectometry results indicated that the integrity of frontostriatal WM may circumscribe functional connectivity response to TMS for suicide.ConclusionsTargeted reduction of fronto-striatal connectivity with TMS may be a promising treatment for suicidality. Future research can build on this multimodal approach to advance individualized stimulation approaches in high-risk patients.     

Transcranial Random Noise Stimulation Acutely Lowers the Response Threshold of Human Motor Circuits

Transcranial random noise stimulation (tRNS) over cortical areas has been shown to acutely improve performance in sensory detection tasks. One explanation for this behavioral effect is stochastic resonance (SR), a mechanism that explains how signal processing in nonlinear systems can benefit from added noise. While acute noise benefits of electrical RNS have been demonstrated at the behavioral level as well as in in vitro preparations of neural tissue, it is currently largely unknown whether similar effects can be shown at the neural population level using neurophysiological readouts of human cortex. Here, we hypothesized that acute tRNS will increase the responsiveness of primary motor cortex (M1) when probed with transcranial magnetic stimulation (TMS). Neural responsiveness was operationalized via the well-known concept of the resting motor threshold (RMT). We showed that tRNS acutely decreases RMT. This effect was small, but it was consistently replicated across four experiments including different cohorts (total N = 81, 46 females, 35 males), two tRNS electrode montages, and different control conditions. Our experiments provide critical neurophysiological evidence that tRNS can acutely generate noise benefits by enhancing the neural population response of human M1.SIGNIFICANCE STATEMENT A hallmark feature of stochastic resonance (SR) is that signal processing can benefit from added noise. This has mainly been demonstrated at the single-cell level in vitro where the neural response to weak input signals can be enhanced by simultaneously applying random noise. Our finding that transcranial random noise stimulation (tRNS) acutely increases the excitability of corticomotor circuits extends the principle of noise benefits to the neural population level in human cortex. Our finding is in line with the notion that tRNS might affect cortical processing via the SR phenomenon. It suggests that enhancing the response of cortical populations to an external stimulus might be one neurophysiological mechanism mediating performance improvements when tRNS is applied to sensory cortex during perception tasks.     

Testing a Neurobiological Model of Depersonalization Disorder Using Repetitive Transcranial Magnetic Stimulation

BackgroundDepersonalization disorder (DPD) includes changes in subjective experiencing of self, encompassing emotional numbing. Functional magnetic resonance imaging (fMRI) has pointed to ventrolateral prefrontal cortex (VLPFC) inhibition of insula as a neurocognitive correlate of the disorder.ObjectiveWe hypothesized that inhibition to right VLPFC using repetitive transcranial magnetic stimulation (rTMS) would lead to increased arousal and reduced symptoms.MethodsPatients with medication-resistant DSM-IV DPD (N = 17) and controls (N = 20) were randomized to receive one session of right-sided rTMS to VLPFC or temporo-parietal junction (TPJ). 1Hz rTMS was guided using neuronavigation and delivered for 15 min. Co-primary outcomes were: (a) maximum skin conductance capacity, and (b) reduction in depersonalization symptoms (Cambridge Depersonalisation Scale (CDS) [state version]). Secondary outcomes included spontaneous fluctuations (SFs) and event-related skin conductance responses.ResultsIn patients with DPD, rTMS to VLPFC led to increased electrodermal capacity, namely maximum skin conductance deflections. Patients but not controls also showed increased SFs post rTMS. Patients who had either VLPFC or TPJ rTMS showed a similar significant reduction in symptoms. Event-related electrodermal activity did not change.ConclusionsA single session of right-sided rTMS to VLPFC (but not TPJ) significantly increased physiological arousal capacity supporting our model regarding the relevance of increased VLPFC activity to emotional numbing in DPD. rTMS to both sites led to reduced depersonalization scores but since this was independent of physiological arousal, this may be a non-specific effect. TMS is a potential therapeutic option for DPD; modulation of VLPFC, if replicated, is a plausible mechanism.     

重复经颅磁刺激治疗卒中后认知障碍的研究进展

认知障碍是卒中后常见并发症,严重影响患者康复进程及生活质量。重复经颅磁刺激（repetitive transcranial magnetic stimulation,rTMS）作为一种新型的非侵入性神经电生理技术,通过改变神经细胞动作电位影响脑内代谢和神经电活动,近年来逐渐被用于卒中后认知障碍的治疗。目前rTMS在卒中后执行功能、记忆功能、语言能力及视空间能力的康复应用中均取得了较为积极的疗效,且在指南推荐的治疗参数范围内操作基本是安全的,但仍缺乏大样本、多中心、高质量的随机对照试验进一步明确其最佳刺激参数与治疗效果。rTMS治疗卒中后认知障碍的研究仍处于探索阶段,未来有望进行更深入的机制研究,为rTMS治疗卒中后认知功能障碍提供更切实有力的依据。     

Static Field Influences on Transcranial Magnetic Stimulation: Considerations for TMS in the Scanner Environment

BackgroundTranscranial magnetic stimulation (TMS) can be combined with functional magnetic resonance imaging (fMRI) to simultaneously manipulate and monitor human cortical responses. Although tremendous efforts have been directed at characterizing the impact of TMS on image acquisition, the influence of the scanner's static field on the TMS coil has received limited attention.Objective/hypothesisThe aim of this study was to characterize the influence of the scanner's static field on TMS. We hypothesized that spatial variations in the static field could account for TMS field variations in the scanner environment.MethodsUsing an MRI-compatible TMS coil, we estimated TMS field strengths based on TMS-induced voltage changes measured in a search coil. We compared peak field strengths obtained with the TMS coil positioned at different locations (B₀ field vs fringe field) and orientations in the static field. We also measured the scanner's static field to derive a field map to account for TMS field variations.ResultsTMS field strength scaled depending on coil location and orientation with respect to the static field. Larger TMS field variations were observed in fringe field regions near the gantry as compared to regions inside the bore or further removed from the bore. The scanner's static field also exhibited the greatest spatial variations in fringe field regions near the gantry.ConclusionsThe scanner's static field influences TMS fields and spatial variations in the static field correlate with TMS field variations. Coil orientation changes in the B0 field did not result in substantial TMS field variations. TMS field variations can be minimized by delivering TMS in the bore or outside of the 0–70 cm region from the bore entrance.     

Effect of Transcranial Static Magnetic Field Stimulation Over the Sensorimotor Cortex on Somatosensory Evoked Potentials in Humans

BackgroundThe motor cortex in the human brain can be modulated by the application of transcranial static magnetic field stimulation (tSMS) through the scalp. However, the effect of tSMS on the excitability of the primary somatosensory cortex (S1) in humans has never been examined.ObjectiveThis study was performed to investigate the possibility of non-invasive modulation of S1 excitability by the application of tSMS in healthy humans.MethodstSMS and sham stimulation over the sensorimotor cortex were applied to 10 subjects for periods of 10 and 15 min. Somatosensory evoked potentials (SEPs) following right median nerve stimulation were recorded before and immediately after, 5 min after, and 10 min after tSMS from sites C3′ and F3 of the international 10-20 system of electrode placement. In another session, SEPs were recorded from 6 of the 10 subjects every 3 min during 15 min of tSMS.ResultsAmplitudes of the N20 component of SEPs at C3′ significantly decreased immediately after 10 and 15 min of tSMS by up to 20%, returning to baseline by 10 min after intervention. tSMS applied while recording SEPs every 3 min and sham stimulation had no effect on SEP.ConclusionstSMS is able to modulate cortical somatosensory processing in humans, and thus might be a useful tool for inducing plasticity in cortical somatosensory processing. Lack of change in the amplitude of SEPs with tSMS implies that use of peripheral nerve stimulation to cause SEPs antagonizes alteration of the function of membrane ion channels during exposure to static magnetic fields.