Motor Cortical Excitability Assessed by Transcranial Magnetic Stimulation in Psychiatric Disorders: A Systematic Review

BackgroundTranscranial magnetic stimulation (TMS) is a popular neurostimulation technique suitable for the investigation of inhibitory and facilitatory networks in the human motor system. In the last 20 years, several studies have used TMS to investigate cortical excitability in various psychiatric disorders, leading to a consequent improvement in pathophysiological understanding. However, little is known about the overlap and specificity of these findings across these conditions.ObjectiveTo provide a systematic review of TMS studies (1985–2013) focusing on motor cortical excitability in dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome (TS), substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)).MethodsSystematic literature-based review.ResultsAcross disorders, patients displayed a general pattern of cortical disinhibition, while the most consistent results of reduced short-interval intracortical inhibition could be found in schizophrenia, OCD and Tourette Syndrome. In dementia, the most frequently reported finding was reduced short-latency afferent inhibition as a marker of cholinergic dysfunction.ConclusionsThe results of this systematic review indicate a general alteration in motor cortical inhibition in mental illness, rather than disease-specific changes. Changes in motor cortical excitability provide insight that can advance understanding of the pathophysiology underlying various psychiatric disorders. Further investigations are needed to improve the diagnostic application of these parameters.     

Zonisamide Changes Unilateral Cortical Excitability in Focal Epilepsy Patients

Background and Purpose

To evaluate changes in cortical excitability induced by zonisamide (ZNS) in focal epilepsy patients.

Methods

Twenty-four drug-naїve focal epilepsy patients (15 males; overall mean age 29.8 years) were enrolled. The transcranial magnetic stimulation parameters obtained using two Magstim 200 stimulators were the resting motor threshold, amplitude of the motor-evoked potential (MEP), cortical silent period, short intracortical inhibition, and intracortical facilitation. These five transcranial magnetic stimulation parameters were measured before and after ZNS, and the findings were compared.

Results

All 24 patients were treated with ZNS monotherapy (200-300 mg/day) for 8-12 weeks. After ZNS, MEP amplitudes decreased (-36.9%) significantly in epileptic hemispheres (paired t-test with Bonferroni''s correction for multiple comparisons, p<0.05), whereas the mean resting motor threshold, cortical silent period, short intracortical inhibition, and intracortical facilitation were unchanged (p>0.05). ZNS did not affect cortical excitability in nonepileptic hemispheres.

Conclusions

These findings suggest that ZNS decreases cortical excitability only in the epileptic hemispheres of focal epilepsy patients. MEP amplitudes may be useful for evaluating ZNS-induced changes in cortical excitability.     

Investigating the Effect of Transcutaneous Auricular Vagus Nerve Stimulation on Cortical Excitability in Healthy Males

ObjectivesAs a potential treatment for epilepsy, transcutaneous auricular vagus nerve stimulation (taVNS) has yielded inconsistent results. Combining transcranial magnetic stimulation with electromyography (TMS-EMG) and electroencephalography (TMS-EEG) can be used to investigate the effect of interventions on cortical excitability by evaluating changes in motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs). The goal of this study is to objectively evaluate the effect of taVNS on cortical excitability with TMS-EMG and TMS-EEG. These findings are expected to provide insight in the mechanism of action and help identify more optimal stimulation paradigms.Materials and MethodsIn this prospective single-blind cross-over study, 15 healthy male subjects underwent active and sham taVNS for 60 min, using a maximum tolerated stimulation current. Single and paired pulse TMS was delivered over the right-sided motor hotspot to evaluate MEPs and TEPs before and after the intervention. MEP statistical analysis was conducted with a two-way repeated measures ANOVA. TEPs were analyzed with a cluster-based permutation analysis. Linear regression analysis was implemented to investigate an association with stimulation current.ResultsMEP and TEP measurements were not affected by taVNS in this study. An association was found between taVNS stimulation current and MEP outcome measures indicating a decrease in cortical excitability in participants who tolerated higher taVNS currents. A subanalysis of participants (n = 8) who tolerated a taVNS current ≥2.5 mA showed a significant increase in the resting motor threshold, decrease in MEP amplitude and modulation of the P60 and P180 TEP components.ConclusionstaVNS did not affect cortical excitability measurements in the overall population in this study. However, taVNS has the potential to modulate specific markers of cortical excitability in participants who tolerate higher stimulation levels. These findings indicate the need for adequate stimulation protocols based on the recording of objective outcome parameters.     

经颅重频磁刺激对大鼠脑缺血再灌流损伤早期运动皮层兴奋性和神经功能的影响

目的 观察经颅重频磁刺激（rTMS）对大鼠脑缺血再灌流损伤早期运动皮层兴奋性和神经功能的影响。方法测定Wistar大鼠右后肢运动阚值（MT）．制作左侧大脑中动脉栓塞（MCAO）再灌流模型．给予rTMS（1次／d）。再灌流72h处死取脑。比较大鼠MCAO再灌流损伤不同时间MT、神经功能评分，脑梗死体积的变化及rTMS的影响。结果MCAO再灌流损伤使大鼠出现局灶性梗死灶，MT升高；神经功能障碍且其程度随损伤时间延长而愈加明显．表现为功能评分升高；rTMS可改善大鼠MCAO再灌流损伤72h的MT和功能障碍程度。减小梗死体积。尤其改善神经功能障碍的程度与对照组比较差异有显著性（P=0．004）。结论rTMS可能对早期缺血脑组织有保护作用．对缺血性脑卒中有进一步研究、应用前景。     

Effect of levetiracetam on cortical excitability: a transcranial magnetic stimulation study

Background and purpose:  We studied the effect of levetiracetam (LEV), an anticonvulsant with a novel mechanism of action, on cortical excitability, measured using transcranial magnetic stimulation (TMS). For this purpose, 38 healthy volunteers were assessed in two TMS sessions, before and after an oral dose of 3000 mg LEV.
Methods:  Resting motor threshold (RMT), intracortical facilitation (ICF) and intracortical inhibition (ICI), cortical silent period (CSP) threshold and duration and motor-evoked potential (MEP) amplitude were calculated.
Results:  After treatment with LEV, RMT was increased (mean ± SD: 63 ± 14% of the maximum stimulator output) compared with baseline (58 ± 11%). CSP threshold was decreased after LEV (54 ± 10%; baseline, 57 ± 11%). CSP duration was increased after LEV (116 ± 37 ms; baseline: 102 ± 33 ms). LEV did not affect ICF or ICI or mean MEP amplitude significantly.
Conclusions:  Our results indicate that LEV modulates some aspects of cortical excitability. Whereas the increase in the RMT most probably reflects the effect of LEV on ion channel activity, effects on the CSP might represent a modulation of GABA receptors at cortical and spinal level.     

Visual cortex excitability in migraine before and after valproate prophylaxis: a pilot study using TMS

We examined the effect of standard migraine prophylaxis with sodium valproate on repeated measures of occipital excitability using transcranial magnetic stimulation (TMS). We predicted that, comparing pre- and post-treatment assessments, a reduction in clinical migraine parameters would be paralleled by a decrease in excitability measurements.A total of 31 migraine patients enrolled in the study, for assessment prior to and 1 month after commencement of sodium valproate prophylaxis. At each assessment, we used a standardized protocol to stimulate the occipital cortex with a 90-mm circular (coil A) and 70 mm figure-of-eight (coil B) coil. We recorded the threshold stimulation intensity at which subjects just perceived phosphenes. Subjects kept detailed records of headache parameters 1 month before and also during the study period.Valproate therapy significantly improved headache indexes, as expected. In MA subjects assessed with coil B, phosphene thresholds were significantly higher post-treatment than pre-treatment, but those for MO did not change. Modest correlations were observed in MA patients between increase in phosphene threshold and decrease in headache index. Although preliminary, the findings with coil B lend some support to the notion that effective migraine prophylaxis may be achieved through lowering cortical excitability by gamma-aminobutyric acid (GABA)-ergic intervention. Further investigation of the effect of sodium valproate or other similarly acting substances on cortical excitability in migraine is warranted.     

Brain-Derived Neurotrophic Factor Polymorphism Influences Response to Single-Pulse Transcranial Magnetic Stimulation at Rest

ObjectivesThe ability of noninvasive brain stimulation to modulate corticospinal excitability and plasticity is influenced by genetic predilections such as the coding for brain-derived neurotrophic factor (BDNF). Otherwise healthy individuals presenting with BDNF Val66Met (Val/Met) polymorphism are less susceptible to changes in excitability in response to repetitive transcranial magnetic stimulation (TMS) and paired associative stimulation paradigms, reflecting reduced neuroplasticity, compared to Val homozygotes (Val/Val). In the current study, we investigated whether BDNF polymorphism influences “baseline” excitability under TMS conditions that are not repetitive or plasticity-inducing. Cross-sectional BDNF levels could predict TMS response more generally because of the ongoing plasticity processes.Materials and MethodsForty-five healthy individuals (23 females; age: 25.3 ± 7.0 years) participated in the study, comprising two groups. Motor evoked potentials (MEP) were collected using single-pulse TMS paradigms at fixed stimulation intensities at 110% of the resting motor threshold in one group, and individually-derived intensities based on MEP sizes of 1 mV in the second group. Functional variant Val66Met (rs6265) was genotyped from saliva samples by a technician blinded to the identity of DNA samples.ResultsTwenty-seven participants (60.0%) were identified with Val/Val, sixteen (35.5%) with Val/Met genotype, and two with Met/Met genotype. MEP amplitudes were significantly diminished in the Val/Met than Val/Val individuals. These results held independent of the single-pulse TMS paradigm of choice (p = 0.017110% group; p = 0.035 1 mV group), age, and scalp-to-coil distances.ConclusionsThe findings should be further substantiated in larger-scale studies. If validated, intrinsic differences by BDNF polymorphism status could index response to TMS prior to implementing plasticity-inducing protocols.     

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.     

Effectiveness of Repetitive Transcranial Magnetic Stimulation on Fibromyalgia Patients Responding to a First Repetitive Transcranial Magnetic Stimulation Induction Course After Six Months of Maintenance Treatment: A Randomized Pilot-Controlled Study

BackgroundFibromyalgia is a chronic painful condition without real, effective treatment. The administration of repetitive transcranial magnetic stimulation (rTMS) has been shown to have a therapeutic effect on pain, but there are still questions about the maintenance of its effect over time. Continuation of the treatment upon clinical response through maintenance sessions is promising and merits further exploration.Materials and MethodsWe conducted a randomized, parallel-group, controlled study involving 78 patients to evaluate the effect of rTMS vs sham stimulation after a three-week induction treatment and six months of maintenance treatment (three-week periodicity) on 22 patients who presented a clinical response to the induction treatment. The clinical response was defined as a ≥30% decrease of the baseline visual analog scale (VAS) for pain and a score for the Patient Global Impression of Change (PGIC) >5. The clinic global impression, fibromyalgia impact questionnaire, symptom severity score, and Beck’s depression inventory were also studied.ResultsA significant clinical response to treatment with rTMS was observed after the induction phase and maintained over six months, particularly as measured by the PGIC parameter of pain, as well as of the intensity of fatigue and depression, with an absence of adverse effects induced by this method.ConclusionA three-week rTMS treatment, characterized by a reduction in pain, as evaluated by VAS, should be continued with the administration of rTMS maintenance sessions for an additional six months to maintain the best possible long-term effects.     

Cortical Disinhibition Drives Freezing of Gait in Parkinson's Disease and an Exploratory Repetitive Transcranial Magnetic Stimulation Study

Background

Dysfunction of the primary motor cortex, participating in regulation of posture and gait, is implicated in freezing of gait (FOG) in Parkinson's disease (PD).

Objective

The aim was to reveal the mechanisms of “OFF-period” FOG (OFF-FOG) and “levodopa-unresponsive” FOG (ONOFF-FOG) in PD.

Methods

We measured the transcranial magnetic stimulation (TMS) indicators and gait parameters in 21 healthy controls (HCs), 15 PD patients with ONOFF-FOG, 15 PD patients with OFF-FOG, and 15 PD patients without FOG (Non-FOG) in “ON” and “OFF” medication conditions. Difference of TMS indicators in the four groups and two conditions and its correlations with gait parameters were explored. Additionally, we explored the effect of 10 Hz repetitive TMS on gait and TMS indicators in ONOFF-FOG patients.

Results

In “OFF” condition, short interval intracortical inhibition (SICI) exhibited remarkable attenuation in FOG patients (both ONOFF-FOG and OFF-FOG) compared to Non-FOG patients and HCs. The weakening of SICI correlated with impaired gait characteristics in FOG. However, in “ON” condition, SICI in ONOFF-FOG patients reduced compared to OFF-FOG patients. Pharmacological treatment significantly improved SICI and gait in OFF-FOG patients, and high-frequency repetitive TMS distinctly improved gait in ONOFF-FOG patients, accompanied by enhanced SICI.

Conclusions

Motor cortex disinhibition, represented by decreased SICI, is related to FOG in PD. Refractory freezing in ONOFF-FOG patients correlated with the their reduced SICI insensitive to dopaminergic medication. SICI can serve as an indicator of the severity of impaired gait characteristics in FOG and reflect treatments efficacy for FOG in PD patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.