Transcranial and Transcutaneous Stimulation for Pain: What Have We Learned From the COVID-19 Pandemic Shutdown?

BACKGROUND: Transcranial magnetic stimulation (TMS) and transcutaneous magnetic stimulation (tMS) offer a novel noninvasive treatment option for chronic pain. While the recent COVID-19 pandemic caused by the SARS-CoV-2 virus resulted in a temporary interruption of the treatments for patients, it provided an excellent opportunity to assess the long-term sustainability of the treatment, and the feasibility of resuming the treatments after a brief period of interruption as no such data are available in current literature. METHODS: First, a list of patients whose pain/headache conditions have been stably controlled with either treatment for at least 6 months prior to the 3-month pandemic-related shutdown was generated. Those who returned for treatments after the shutdown were identified and their underlying pain diagnoses, pre- and posttreatment Mechanical Visual Analog Scale (M-VAS) pain scores, 3-item Pain, Enjoyment, and General Activity (PEG-3), and Patient Health Questionnaire-9 scores were assessed in 3 phases: Phase I (P1) consisted of a 6-month pre-COVID-19 period in which pain conditions were stably managed with either treatment modality; Phase II (P2) consisted of the first treatment visit period immediately after COVID-19 shutdown; and Phase III (P3) consisted of a 3-4 month post-COVID-19 shutdown period patients received up to 3 sessions of either treatment modality after the P2 treatment. RESULTS: For pre- and posttreatment M-VAS pain scores, mixed-effect analyses for both treatment groups demonstrated significant (P < 0.01) time interactions across all phases. For pretreatment M-VAS pain scores, TMS (n = 27) between-phase analyses indicated a significant (F = 13.572, P = 0.002) increase from 37.7 ± 27.6 at P1 to 49.6 ± 25.9 at P2, which then decreased significantly (F = 12.752, P = 0.001) back to an average score of 37.1 ± 24.7 at P3. Similarly, tMS (n = 25) between-phase analyses indicated the mean pretreatment pain score (mean ± standard deviation [SD]) increased significantly (F = 13.383, P = 0.003) from 34.9 ± 25.1 at P1 to 56.3 ± 27.0 at P2, which then decreased significantly (F = 5.464, P = 0.027) back to an average score of 41.9 ± 26.4 at P3. For posttreatment pain scores, the TMS group between-phase analysis indicated the mean posttreatment pain score (mean ± SD) increased significantly (F = 14.206, P = 0.002) from 25.6 ± 22.9 at P1 to 36.2 ± 23.4 at P2, which then significantly decreased (F = 16.063, P < 0.001) back to an average score of 23.2 ± 21.3 at P3. The tMS group between-phase analysis indicates a significant (F = 8.324, P = 0.012) interaction between P1 and P2 only with the mean posttreatment pain score (mean ± SD) increased from 24.9 ± 25.7 at P1 to 36.9 ± 26.7 at P2. The combined PEG-3 score between-phase analyses demonstrated similar significant (P < 0.001) changes across the phases in both treatment groups. CONCLUSIONS: Both TMS and tMS treatment interruptions resulted in an increase of pain/headache severity and interference of quality of life and functions. However, the pain/headache symptoms, patients' quality of life, or function can quickly be improved once the maintenance treatments were restarted.

Real world research on transcranial magnetic stimulation treatment strategies for neuropsychiatric symptoms with long-COVID in Japan.

The number of patients suffering from long-COVID is currently increasing rapidly, even after the acute symptoms of COVID-19 have improved. The objective of this study was to investigate the effects of a pilot transcranial magnetic stimulation (TMS) treatment on neuropsychiatric symptoms caused by long-COVID. In this study, we examined the efficacy of the TMS treatment protocol, which has been established to be effective in refractory depression, by applying it to patients who sought TMS treatment for neuropsychiatric symptoms caused by long-COVID at TMS clinics in Tokyo, Japan in the context of the real world TMS registry study in Japan. Of the 23 patients (13 females) with long-COVID included in this case series, the main neuropsychiatric symptoms were chronic fatigue (n = 12) and cognitive dysfunction (n = 11), but most patients also showed mild depressive symptoms. The mean score on the Montgomery-Åsberg Depression Rating Scale before TMS treatment was 21.2, which improved to 9.8 after treatment. Similarly, the score on the Performance Status, which assesses the degree of fatigue, improved from 5.4 to 4.2, and the score on the Perceived Deficits Questionnaire-Depression 5-item, which reflects cognitive function, improved from 10.0 to 6.3. Although a few patients complained of pain at the stimulation site during the TMS as a side effect, there were no serious adverse events. Despite the limitations of this open-label pilot study, the TMS protocol implemented in this study may have beneficial effects on neuropsychiatric symptoms caused by long-COVID, including depressive symptoms, chronic fatigue, and cognitive impairment. These preliminary findings warrant further validation in randomized controlled trials.

The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue.

Following an acute COVID-19 infection, a large number of patients experience persisting symptoms for more than four weeks, a condition now classified as Long-COVID syndrome. Interestingly, the likelihood and severity of Long-COVID symptoms do not appear to be related to the severity of the acute COVID-19 infection. Fatigue is amongst the most common and debilitating symptoms of Long-COVID. Other symptomes include dyspnoea, chest pain, olfactory disturbances, and brain fog. Fatigue is also frequently reported in many other neurological diseases, affecting a broad range of everyday activities. However, despite its clinical significance, limited progress has been made in understanding its causes and developing effective treatment options. Non-invasive brain stimulation (NIBS) methods offer the unique opportunity to modulate fatigue-related maladaptive neuronal activity. Recent data show promising results of NIBS applications over frontoparietal regions to reduce fatigue symptoms. In this current paper, we review recent data on Long-COVID and Long-COVID-related fatigue (LCOF), with a special focus on cognitive fatigue. We further present widely used NIBS methods, such as transcranial direct current stimulation, transcranial alternating current stimulation, and transcutaneous vagus nerve stimulation and propose their use as possible therapeutic strategies to alleviate individual pathomechanisms of LCOF. Since NIBS methods are safe and well-tolerated, they have the potential to enhance the quality of life in a broad group of patients.

Genetic Algorithm for TMS Coil Position Optimization in Stroke Treatment.

Transcranial magnetic stimulation (TMS), a non-invasive technique to stimulate human brain, has been widely used in stroke treatment for its capability of regulating synaptic plasticity and promoting cortical functional reconstruction. As shown in previous studies, the high electric field (E-field) intensity around the lesion helps in the recovery of brain function, thus the spatial location and angle of coil truly matter for the significant correlation with therapeutic effect of TMS. But, the error caused by coil placement in current clinical setting is still non-negligible and a more precise coil positioning method needs to be proposed. In this study, two kinds of real brain stroke models of ischemic stroke and hemorrhagic stroke were established by inserting relative lesions into three human head models. A coil position optimization algorithm, based on the genetic algorithm (GA), was developed to search the spatial location and rotation angle of the coil in four 4 × 4 cm search domains around the lesion. It maximized the average intensity of the E-field in the voxel of interest (VOI). In this way, maximum 17.48% higher E-field intensity than that of clinical TMS stimulation was obtained. Besides, our method also shows the potential to avoid unnecessary exposure to the non-target regions. The proposed algorithm was verified to provide an optimal position after nine iterations and displayed good robustness for coil location optimization between different stroke models. To conclude, the optimized spatial location and rotation angle of the coil for TMS stroke treatment could be obtained through our algorithm, reducing the intensity and duration of human electromagnetic exposure and presenting a significant therapeutic potential of TMS for stroke.

The Effect of Repetitive Transcranial Magnetic Stimulation on Suicidal Ideation in Treatment-Resistant Depression: A Meta-Analysis.

Objective: To quantitatively synthesize the literature on the effects of repetitive transcranial magnetic stimulation (rTMS) on suicidal ideation (SI) in patients with treatment-resistant depression.Data Sources: A literature search was conducted using PubMed, SCOPUS, Ovid, MEDLINE, Embase, and Web of Science from inception to January 11, 2021, for the keywords repetitive transcranial magnetic stimulation, suicidal ideation, suicidality, treatment-resistant depression, refractory depression, transcranial magnetic stimulation, and brain stimulation.Study Selection: A total of 16 publications were eligible for inclusion. Studies were included that investigated the effects of rTMS in adolescents and/or adults 16 years or older diagnosed with unipolar or bipolar depression with suicidal ideation data before and after rTMS intervention.Data Extraction: Data were extracted and managed using Covidence. Extracted data included authors, publication year, country of origin, study design, patient demographics, primary diagnosis, comorbidities, mean age, outcome assessment instruments, detailed stimulation parameters, sham control procedures, and any serious adverse events related to SI.Results: A quantitative analysis of effect size using Hedges g was calculated for both randomized controlled trials and all other uncontrolled trials. We found a decrease in SI scores in randomized controlled trials (g = 0.158, 95% confidence interval [CI] = -0.078 to 0.393, P = .191), although the effect was not significant. There was a significant decrease in suicidal ideation scores for uncontrolled trials (g = 0.692, 95% CI = 0.463 to 0.922, P < .001).Conclusions: Our findings suggest that rTMS may be an effective treatment for SI in individuals with treatment-resistant depression, although further investigation is warranted.

Two rTMS sessions per week: a practical approach for treating major depressive disorder.

INTRODUCTION: Depression is one of the leading causes of disability in the world, and a disease that contributes greatly to the global burden of disease. Repetitive transcranial magnetic stimulation (rTMS) has proven to be a well-tolerated, effective treatment for depression. The present study was designed to evaluate the efficacy of an rTMS treatment scheme with a fewer number of sessions per week. METHODS: In total 91 adult university students with major depressive disorder (MDD). This was a double-blind, randomized clinical trial in which 15 sessions of rTMS were given to each one of two treatment groups made up of adults with active MDD. One treatment group received two sessions per week, the other received five. The study protocol included their respective sham rTMS groups. The patients who received active rTMS also participated in a follow-up procedure that consisted of two sessions of active rTMS per month for three more months. RESULTS: Measurements by the Hamilton Rating Scale for Depression (HAMD) showed that the groups which received active rTMS had higher percentages of antidepressant response at 96 and 95.5% for five and two sessions/week, respectively, compared to the sham rTMS groups: 27.3 and 4.5% for five and two sessions/week, respectively. Observations at the end of the 3-month follow-up phase showed that the improvements in HAMD scores were maintained in both groups. CONCLUSION: This study contributes to demonstrating that rTMS with a more practical schedule of two sessions/week is an effective antidepressant treatment that could be considered the first choice for managing symptoms of depression.

Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS. METHOD: We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019-related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured. RESULTS: Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output (P < .01). Change could be detected in the larger 4 mg group (P = .02), but not in the smaller 8 mg dose group (P = .1). No side effects were reported after single dose exposure. DISCUSSION: This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.

Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19.

OBJECTIVE: A high proportion of patients experience fatigue and impairment of cognitive functions after coronavirus disease 2019 (COVID-19). Here we applied transcranial magnetic stimulation (TMS) to explore the activity of the main inhibitory intracortical circuits within the primary motor cortex (M1) in a sample of patients complaining of fatigue and presenting executive dysfunction after resolution of COVID-19 with neurological manifestations. METHODS: Twelve patients who recovered from typical COVID-19 pneumonia with neurological complications and complained of profound physical and mental fatigue underwent, 9 to 13 weeks from disease onset, a psychometric evaluation including a self-reported fatigue numeric-rating scale (FRS, Fatigue Rating Scale) and the Frontal Assessment Battery (FAB). Intracortical activity was evaluated by means of well-established TMS protocols including short-interval intracortical inhibition (SICI), reflecting GABAA-mediated inhibition, long-interval intracortical inhibition (LICI), a marker of GABAB receptor activity, and short-latency afferent inhibition (SAI) that indexes central cholinergic transmission. TMS data were compared to those obtained in a control group of ten healthy subjects (HS) matched by age, sex and education level. RESULTS: Post-COVID-19 patients reported marked fatigue according to FRS score (8.1 ± 1.7) and presented pathological scores at the FAB based on Italian normative data (12.2 ± 0.7). TMS revealed marked reduction of SICI, and disruption of LICI as compared to HS. SAI was also slightly diminished. CONCLUSIONS: The present study documents for the first time reduced GABAergic inhibition in the M1 in patients who recovered from COVID-19 with neurological complications and manifested fatigue and dysexecutive syndrome. SIGNIFICANCE: TMS may serve as diagnostic tool in cognitive disturbances and fatigue in post-COVID-19 patients.

Measuring latency distribution of transcallosal fibers using transcranial magnetic stimulation.

BACKGROUND: Neuroimaging technology is being developed to enable non-invasive mapping of the latency distribution of cortical projection pathways in white matter, and correlative clinical neurophysiological techniques would be valuable for mutual verification. Interhemispheric interaction through the corpus callosum can be measured with interhemispheric facilitation and inhibition using transcranial magnetic stimulation. OBJECTIVE: To develop a method for determining the latency distribution of the transcallosal fibers with transcranial magnetic stimulation. METHODS: We measured the precise time courses of interhemispheric facilitation and inhibition with a conditioning-test paired-pulse magnetic stimulation paradigm. The conditioning stimulus was applied to the right primary motor cortex and the test stimulus was applied to the left primary motor cortex. The interstimulus interval was set at 0.1 ms resolution. The proportions of transcallosal fibers with different conduction velocities were calculated by measuring the changes in magnitudes of interhemispheric facilitation and inhibition with interstimulus interval. RESULTS: Both interhemispheric facilitation and inhibition increased with increment in interstimulus interval. The magnitude of interhemispheric facilitation was correlated with that of interhemispheric inhibition. The latency distribution of transcallosal fibers measured with interhemispheric facilitation was also correlated with that measured with interhemispheric inhibition. CONCLUSIONS: The data can be interpreted as latency distribution of transcallosal fibers. Interhemispheric interaction measured with transcranial magnetic stimulation is a promising technique to determine the latency distribution of the transcallosal fibers. Similar techniques could be developed for other cortical pathways.