Feasibility and Tolerability of Controlled Pulse Parameter Transcrania

Introduction

Controllable pulse parameter Transcranial Magnetic Stimulation (cTMS) allows for the delivery of repetitive monophasic pulses, which appear to impact corticospinal excitability to a greater extent than traditional biphasic pulses in healthy controls.^1,2 Goetz et al¹ note greater inhibition in corticospinal excitability from monophasic pulses compared to biphasic repetitive TMS (rTMS). Further, Arai et al² indicate enhanced magnitude and longevity of monophasic rTMS effects when compared with biphasic rTMS. As monophasic pulses activate a more uniformly distributed population of cortical interneurons, they can produce longer and more pronounced after-effects on the motor cortex, when compared to biphasic pulses.² However, the sensation of cTMS may be a barrier for clinical populations as Peterchev et al³ report that cTMS at 100% and 120% resting motor threshold (RMT) is sharp and uncomfortable in healthy participants. The feasibility of using cTMS in a clinical population remains unknown.

rTMS has been shown to alleviate pain in various chronic pain conditions including neuropathic pain, central pain and fibromyalgia.⁴ However, headache and discomfort due to rTMS stimulation have been reported despite its non-invasiveness⁵ and considering that rTMS protocols are delivered over several days or weeks,⁴ intolerability and refusal to treatment may be a barrier. Chronic pain is associated with hyperalgesia due to central sensitization, which may increase scalp sensation leading to discomfort.⁶ To date, no study has evaluated the feasibility of cTMS in a chronic pain cohort with heightened sensitivity to pain and cTMS has not been performed in a clinical population. As there is no cure for painful diabetic neuropathy (pDN), clinical management primarily relies on pharmacological therapies aimed at alleviating symptoms.⁷ However, they are often limited with suboptimal efficacy and adverse side effects, underscoring the need for alternative therapeutic approaches such as cTMS. The goal of the present study was to determine the feasibility and tolerability of cTMS in two patients with pDN with heightened sensitivity.

Materials and Methods

This is a sub-study report of the full research protocol approved by the Hamilton Integrated Research Ethics Board. Here in, we reported on two individuals before and after the real stimulation component in a larger placebo-controlled, cross-over study. Feasibility was assessed in two male participants (A and B) both aged 65 years suffering from type 2 diabetes and pDN in both feet of >3 years (see Table 1). Patients with pDN suffer from neuropathic pain and present with hyperalgesia and allodynia, suggesting heightened sensitivity to pain.⁷ In our study, participants were directly referred by the physician who diagnosed their pDN which included symptoms of allodynia and hyperalgesia as determined via quantitative sensory testing. Neither participant were engaged in non-pharmacological interventions such as physical therapy or exercise during the study. However, both were maintained on pharmacological treatment regimens that included medications indicated in Table 1. No changes in glycemic control were made during the duration of the study. We used an intensity of 80% RMT,^8,9 which is below the threshold suggested for inducing pain when rTMS is used.¹⁰ In line with Tani et al,¹⁰ the intensity used in repetitive biphasic clinical protocols (80% RMT) is the same as the threshold for pain, which was found to be 79% RMT in healthy individuals. Considering the threshold of 80%, feasibility was tested by assessing for tolerability, effectiveness and safety in patients with pDN.

cTMS protocol consisted of completing five consecutive sessions per week of cTMS for two weeks (10 session total). Both participants were blinded to the type of stimulation (real, placebo) and both received the real stimulation. Ten Hz stimulation was applied to the vertex (Cz) over the presumed leg representation of the primary motor cortex (M1).¹¹ The coil was positioned at a 45° angle with respect to the posterior-to-anterior (PA) axis, and this site was digitally registered using Brainsight Neuronavigation (Rogue Research, Canada). The stimulation was applied at 80% RMT obtained from the right abductor pollicis brevis (APB).¹¹ Each session consisted of 2004 pulses (1.2s trains, 12 pulses per train, 3s interstimulus interval) for 11.5 minutes using a figure-of-eight coil (70mm inner diameter) with an Elevate TMS device (Rogue Research, Canada) and a standard pulse width of 80 µs was used throughout the protocol as used elsewhere.^3,11 RMT was obtained in all 10 sessions. Assessment took place before (T0) and immediately after (T1) the 10-day intervention. The assessment aimed to evaluate feasibility related to adherence to the designed protocol, safety related to the reporting of any adverse events, and tolerability related to participants’ enjoyment and sensation of the stimulation. If participants attended 90% of the sessions, then the protocol was considered feasible. Regarding tolerability, participants were asked to report the sensation and comfort level of the stimulation (comfortable or uncomfortable). We also explored the effectiveness of the stimulation. This included pain intensity numerical rating scale (NRS), as well as a Pain Catastrophizing scale-EN-SF (PCS), Patient-Reported Outcomes Measurement Information System 29-Item Profile (PROMIS-29 v2.0) and the Douleur Neuropathique 4 Questions (DN4).

Results

Both participants completely adhered to the study protocol deeming the study feasible. No adverse events occurred before, during, or up to two months following the intervention. Both participants tolerated cTMS without any discomfort and indicated that the intervention “felt nice” and that they “enjoyed” receiving the intervention. Further, participants noted that no pain was experienced during tapping sensation. Figure 1 shows the changes in PROMIS-29 v2.0, as well as the changes in pain intensity, PCS and DN4.

Figure 1 Changes in PROMISE-29 v2.0 (social participation (a) and physical function (b)), pain intensity (c), PCS (d), and DN4 (e). “A” represents Participant A and “B” represents Participant B.

Discussion

Our results indicated that cTMS delivered over 10 sessions was feasible and tolerated by two participants with pDN. Long durations of therapy and the associated time commitment (i.e., over 6 weeks) are often barriers for participants completing clinical rTMS studies.¹² However, both participants attended all sessions of cTMS at a rate of 5 sessions per week, within the time frame of two weeks. Additionally, tolerance of rTMS studies may be low in pain populations for reasons such as headache, migraine, scalp sensitivity, and discomfort.⁶ In our study, both participants tolerated the protocol and neither reported discomfort such as sharpness or headache associated with cTMS. Despite the participants’ hypersensitivity to pain, no adverse events were reported.

Importantly, we delivered cTMS at 80% RMT. Peterchev et al³ reported discomfort and sharpness with cTMS at approximately 100% RMT and 120% RMT in their healthy control group. Using a stimulation intensity of 80% RMT aligns with established safety guidelines for TMS, minimizing the risk of seizures, excessive cortical activation, or other adverse events.¹³ This subthreshold intensity is frequently used in clinical protocols to optimize the balance between safety and therapeutic efficacy. RMT at 80% has been shown to recruit excitatory cortical neurons while remaining below the threshold for activating peripheral pain fibers, thereby enhancing tolerability and reducing discomfort.^4,11,14 This intensity is beneficial for use in pain populations where minimizing adverse effects is essential for maintaining compliance and retention.

Our study employed a standard pulse width of 80 µs, which may contribute to greater tolerability, as shorter pulse widths (i.e., 30 µs) used in cTMS have been associated with sharper pain and discomfort compared to wider pulses.³ Shorter durations (<80 µs) generate more focal stimulation by limiting the duration of current delivery, which reduces the likelihood of activating deeper structures. However, this also decreases the total energy delivered, potentially leading to insufficient neuronal recruitment unless the stimulation intensity is increased. In contrast, longer pulse widths (>120 µs) can expand the spread of activation to non-target areas, increasing the risk of discomfort and off-target effects.^3,15 A pulse width of 80 µs is therefore considered a practical balance that provides adequate cortical activation while minimizing the stimulation of scalp nociceptors and reducing the likelihood of discomfort. These findings underscore the importance of parameter selection in the application of cTMS to manage chronic pain, given its tolerability and effectiveness in this patient group.

Relating to effectiveness, cTMS resulted in an improvement in the ability to participate in social roles and physical function as both participants reached normal levels and/or stayed within the normal level. Participant A showed no change in pain intensity, whereas participant B, who exhibited more severe pain at the baseline, noted a 10% reduction. While a 10–20% reduction on the NRS is generally considered the minimal clinically important difference,¹⁶ it may still represent a meaningful improvement in quality of life, particularly in the context of refractory symptoms and limited treatment options. Both participants A and B indicated improvement in pain catastrophizing by 6 points and 2 points, respectively. However, these changes are below the 8 point difference in the pain catastrophizing scale required for a clinically meaningful change.¹⁷ These findings align with studies using rTMS to decrease pain in diabetic neuropathy where participants received traditional rTMS stimulations for 5 days.^18,19 The DN4 data revealed no change in participant B and a 33% improvement for participant A. Importantly, it is our view that even modest symptom relief may indicate the potential effectiveness of cTMS and support its further investigation in painful diabetic neuropathy. Collectively, the data suggest variability in the responses across the various measures with some indication of improvement and other data suggesting little to no change. Importantly, no participant experienced worsening of symptoms. These preliminary findings support the acceptability of the intervention and provide valuable insights to guide outcome measure selection and study design for the larger ongoing trial.

Contextual and motivational factors may have contributed to the adherence and tolerability observed in this study. Participants were aware that they would receive both real and placebo interventions, this might have contributed to study retention and positive attitudes towards the study as a whole. Further, the physician who diagnosed and manages their pDN referred the participants to the study, which may have encouraged retention in the study. Efforts were made to ensure that the lab was accessible to participants such as close proximity to parking spaces, flexible time of testing, the use of pillows and other comfort aids during testing, all of which may contribute to the tolerability of the intervention. Last, the two participants expressed that they were refractory to other pain treatments, which may have increased motivation to adhere to the study protocol.

A limitation of this study is the absence of a placebo as this is a sub-study of the full research protocol. The full research protocol is a placebo-controlled, cross-over study where all participants will receive either a ‘real’ or ‘placebo’ cTMS condition and then receive the opposite condition after a 2-month washout period. Of note, the efficacy results of this case series study are preliminary and based on a sample size of two participants. The importance of placebo control in TMS trials for chronic pain lies in its ability to rigorously isolate true neuromodulatory effects from non-specific factors such as participant expectations and the treatment context, which are particularly pronounced in pain populations.²⁰ This is especially critical given that the placebo response can itself produce analgesia, approaching or exceeding the effects of real stimulation.

Conclusion

This study is the first to use cTMS in a chronic pain condition, specifically in pDN, and it suggests that cTMS is tolerable and feasible when delivered at 80% RMT for 10 sessions over a two-week intervention in this population. These case findings provide preliminary evidence supporting the feasibility and potential therapeutic effects of cTMS in pDN. However, as this report is based on a subset of participants from an ongoing placebo-controlled, cross-over trial, definitive conclusions regarding efficacy must await completion of the full study.