Enhancing Transcranial Magnetic Stimulation Comfort: The Role of Electrical Stimulation in Pain Reduction

Dear Editor,

Transcranial Magnetic Stimulation (TMS) has emerged as a promising therapeutic tool for various neurological and psychiatric conditions [1–3]. However, despite its potential benefits, TMS is not without its discomfort issues [4, 5], which are mainly related to target location, stimulus intensity, and treatment duration. The discomfort associated with TMS arises from several factors, including the physical sensations experienced during the procedure and potential adverse effects on the scalp and surrounding tissues. The discomfort includes a tapping or tingling sensation, loud and disruptive sound, localized pain at the stimulation site, sensations of burning, itching, or pressure, particularly with higher intensity stimulation, as well as side effects such as headaches, dizziness, or nausea, which can occur either during or after the procedure. Repeated sessions of TMS over time can lead to cumulative discomfort, with up to 40% of patients experiencing pain or discomfort, as reported in a meta-analysis [6]. This can pose challenges for patients undergoing long-term TMS treatment regimens, particularly if they experience discomfort that interferes with their daily activities or quality of life. In this letter, we introduce a novel way of reducing pain during TMS by applying Transcranial Electrical Stimulation (TES) at the TMS stimulation site. It is low-cost, convenient, and ready to use in clinical settings.

The most common and limiting discomfort is pain at the stimulation site. Stimulus intensity is a factor of discomfort, which is usually determined as a percentage of either resting motor threshold (RMT) or active motor threshold (AMT). The stimulation site is another major factor in TMS discomfort. Some individuals may experience jaw discomfort or mild sensations in the facial muscles during TMS sessions, particularly if the stimulation is targeted near the motor cortex responsible for controlling facial muscles. This discomfort is typically temporary and should not have any lasting effects on dental health or structure. However, some sites are more intolerable, for example, the ventrolateral prefrontal cortex, which has been much less frequently used as a target, most likely due to some subjects being intolerant. Han et al. reported that half of the subjects were intolerant to single-pulse stimulation at 120% RMT or theta-burst stimulation (TBS) at 80% AMT at the stimulation site F8 defined in the 10–20 system [7]. They concluded that a larger sample size is needed for ventrolateral than dorsolateral prefrontal TMS to account for potential drop-out caused by intolerability.

Pain poses multifaceted challenges to effective treatment. Firstly, it hampers adherence, making it challenging for individuals to consistently follow treatment plans, thereby compromising outcomes. In addition, pain can induce physiological changes, altering the body’s responsiveness to treatment, and potentially diminishing the efficacy of therapeutic interventions. Furthermore, pain has a significant psychological impact, often resulting in emotional distress. This psychological burden not only influences treatment adherence but also skews perceptions of efficacy. Aside from affecting treatment efficacy, pain and other discomfort can have compound effects on cognitive tasks during TMS sessions. Pain and discomfort have been found to impair cognitive performance [8]. Peripheral sensations caused by TMS significantly influence reaction times. Frontal and inferior scalp regions are particularly affected. Subjective ratings predict reaction time changes better than scalp location. The more complicated ‘flanker’ task is more sensitive to subjective disturbance.

Pain is often accompanied by headaches, and the incidence of headaches for the standard FDA-approved iTBS protocol for treatment-resistant depression has been reported to be 65% [9]. A recent major advance in TMS is the Stanford Neuromodulation Therapy [10], in which headache is reported at 57% in the active treatment group, slightly lower than that reported in the standard intermittent TBS (iTBS). The headache was either self-resolved or resolved after nonprescription pain relief, such as ibuprofen.

Given these discomfort issues associated with traditional TMS techniques, there is a growing need to develop alternative approaches that can effectively mitigate discomfort while maintaining therapeutic efficacy. Recent advancements in TMS technology and technique may offer solutions to address these challenges and improve the overall experience for patients undergoing TMS therapy for pain reduction and other therapeutic purposes. Various strategies have been attempted to reduce pain during TMS [11], and it has been shown that there is a significant reduction in pain by lidocaine injection with or without epinephrine, mild pain reduction by applying foam padding between the coil and the scalp, but neglectable effect when using local anesthetic cream applied to the skin. However, the drawbacks of lidocaine injections include potential discomfort or pain associated with the injection itself, as well as the risk of adverse reactions such as allergic reactions or systemic side effects. In addition, it may require a healthcare professional for administration, adding complexity and cost to the procedure. As for foam padding, it increases the distance between the coil and the scalp, which can result in attenuated stimulus intensity. This attenuation may compromise the effectiveness of neuromodulation or require compensation by increasing the intensity, usually in terms of the percentage of the maximum stimulator output (MSO).

Given the drawbacks of existing methods, we propose a multimodal neuromodulation method to meet the practical need for pain relief measures in TMS. Instead of using TES as a sham control [12], we apply TES at the same site as TMS to reduce pain, as shown in Fig. 1J and S5. We reversed the direction of the TES electrical field compared to the field induced by TMS, thereby partially counteracting the induced electrical field of TMS. Due to the high impedance of the skull, TES field intensity on the scalp is much higher than that in the cerebral cortex, resulting in a significant attenuation of the intensity on the scalp while the attenuation in the cerebral cortex is minimal. We conducted finite element analysis to simulate the induced electrical field (E-field) of a Figure-8 coil with and without the application of electrical stimulation. A computational model was constructed using COMSOL with six layers, simulating the head anatomy (Fig. 1A and E). The model included the scalp (radius = 95 mm, conductivity = 0.465 S/m), skull (radius = 90 mm, conductivity = 0.01 S/m), cerebrospinal fluid (radius = 85 mm, conductivity = 1.654 S/m), gray matter (radius = 80 mm, conductivity = 0.275 S/m), white matter (radius = 75 mm, conductivity = 0.126 S/m), and ventricles (radius = 20 mm, conductivity = 1.654 S/m)[13]. TMS was administered using a Figure-8 coil delivering a sinusoidal current waveform of 2280 × sin (18322 × t[1/s]) [A], with a rate of change of current (di/dt) set at 41.8 × 1e6 A/s. The intensity was set to 40% MSO. TES was administered with a phase difference of 270° and a boundary current source density of 25 × sin (18322 × t[1/s]–pi/2) [A/m²]. The TES electrodes measured 1 cm × 4 cm, were spaced 5 cm apart, and delivered a current of 10 mA. No sensation of pain on the scalp was reported when TES was applied alone. The simulation results demonstrated that the E-field intensity in the scalp and cortical regions at the stimulation site dropped by ~22.4% and 3.8%, respectively (Fig. 1B–D, F–H, S1, S2, Tables S1, S2). We also simulated a human brain model to obtain more realistic simulation results in SimNIBS and again demonstrated that TES significantly reduces the scalp’s E-field intensity while minimally affecting the gray matter’s E-field intensity (Fig. S3).

Fig. 1.

Pain reduction during TMS using electrical stimulation. A, E The 6-layer spherical model used for finite element analysis-based electric field simulation of a Figure-8 coil and TES. B The E-field distribution in the scalp under TMS only. C The E-field distribution in the scalp under both TMS and TES. D The E-field distribution in the scalp is reduced by 22.4%. F The E-field distribution in the gray matter under TMS only. G The E-field distribution in the gray matter under both TMS and TES. H The E-field in the gray matter is reduced by only 3.8%. I Stimulation sites over the scalp, determined by the 5-cm rule (blue), functional connectivity (red), and structural connectivity (green), together with the trigeminal nerve. J The experimental settings of this study. K, L Pain reduction occurs when electrical stimulation is applied.

To verify whether the decrease in E-field intensity has an effect on pain relief during TMS, we recruited ten healthy male participants, aged 25 to 45 years, and asked them to rate their pain feelings using a pain scale during TMS with and without TES. The stimulation target was between F3 and AF3 on the left forehead, ensuring ease of electrode placement on hairless skin. A custom-designed pulsed TES device was utilized (Fig. S4A), delivering a stimulus current of 10 mA. Two gel electrodes were positioned above the left eyebrow and below the hairline, spaced ~5 cm apart (Fig. S5A). TMS was administered using a Super Rapid² with a D70 Alpha Flat Coil (Magstim, West Wales, UK). TMS was trigged by TES for synchronization (Fig. S4B, C). The coil was mounted on a UR5e robotic arm (Universal Robots, Odense, Denmark), oriented vertically upwards (Fig. 1J and S5B), to ensure precise positioning and stability during the experimental procedure. Participants were seated on a chair with a headrest and familiarized with the FPS-R pain rating scale [14]. Electrodes were then affixed to the left forehead, snugly against the TMS coil, with participants instructed to maintain head position throughout. In our experiment, a TMS-alone trial consists of operating in 50 Hz iTBS mode, with TMS delivering three pulses at 20-ms intervals, followed by a 1-s interval, repeated three times. Each participant underwent a single experimental session, during which the TMS trial (TMS alone in iTBS mode) and the TMS+TES trial (combined TES and TMS stimulation) were sequentially applied and repeated twice. An interval of 30 s separated the four trials. Participants were not informed of this sequence before rating the pain scales. They were asked to rate the pain scale for the third and fourth trials after the session. As shown in Fig. 1K and L and Table S3, 9 out of 10 participants reported lower pain ratings and the average score decreased from 5.9 (± 1.3) to 4.6 (± 1.0), which is statistically significant (paired t-test, P = 0.0092). More importantly, a score of 4 was regarded as tolerable by the majority of the participants, which means 6 out of 9 participants (67%) who were intolerant became tolerant to TMS when TES was applied.

In summary, we have discovered the pain relief effect of TES when applied to the TMS site. During TMS sessions, some subjects may report scalp pain sensations, often characterized as prickling, needling, or tingling. These sensations typically manifest in the scalp region proximal to where TMS pulses are targeted towards the brain. In the majority of cases, such tingling sensations are mild and transient, posing no significant hindrance to the course or efficacy of treatment. However, these sensations may occasionally lead to discomfort, particularly when the target site within the dorsolateral prefrontal cortex is situated adjacent to the AF3 position defined in the 10-20 system. This arises due to the innervation of AF3 by branches of the trigeminal nerve, one of the largest cranial nerves. Comprising multiple branches primarily distributed across the head and face, stimulation or damage to the trigeminal nerve may induce diffuse sensations of pain. Addressing the pain caused by TMS targeting around this site is essential to ensure the feasibility of the treatment.

The present study provides, for the first time, biological evidence that electrical stimulation has the effect of pain relief during TMS sessions if applied properly to the stimulation site. It is relatively low-cost and can be made convenient to use because it is feasible to integrate the TES electrodes into the coil design and the TES stimulator with the TMS stimulator, making the operation of TES-assisted pain relief naturally workable with TMS. This facilitates the opening up of new clinical trials, which could not be conducted before, such as those involving large dosages and specific regions restricted from stimulation due to intolerance caused by pain sensations. Future work on fine-tuning the TES parameters based on individual pain thresholds and experiments on a larger cohort may help us to further optimize this multimodal approach for reducing discomfort and intolerance during TMS sessions, potentially enhancing the overall efficacy and tolerability of TMS procedures.

Supplementary Information

Below is the link to the electronic supplementary material.

Data availability

All relevant data and computation codes are available from the corresponding authors upon request.

Conflict of interest

The authors claim that there are no conflicts of interest.

Ethical approval

The study was approved by the Ethics Committee of the Institute of Automation Chinese Academy of Sciences, approved number IA21-2302-02. All participants were informed of the detailed contents of the experiment and the potential discomfort it may cause before the experiment, and they signed an informed consent form.