# Strategies to Mitigate Scalp Discomfort during Repetitive Transcranial Magnetic Stimulation

Jennifer I Lissemore, Derrick M Buchanan, Jean-Marie Batail, Irakli Kaloiani, Clive Veerapal, Gregory L Sahlem, Nolan R Williams

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## To cite this version:

Jennifer I Lissemore, Derrick M Buchanan, Jean-Marie Batail, Irakli Kaloiani, Clive Veerapal, et al. Strategies to Mitigate Scalp Discomfort during Repetitive Transcranial Magnetic Stimulation. Brain Stimulation, 2024, 17 (5), pp.1131-1133. 10.1016/j.brs.2024.09.004. hal-04714735

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# Strategies to mitigate scalp discomfort during repetitive transcranial magnetic stimulation

Dear Editor,

While repetitive transcranial magnetic stimulation (rTMS) is a safe and well-tolerated treatment for various psychiatric conditions, up to 40 % of patients experience scalp discomfort or pain during stimulation [1, 2]. Discomfort at the site of stimulation can make it difficult for some patients to reach their target dose, and has been associated with non-response to treatment [3,4]. Effective, feasible solutions to alleviate pain at the stimulation site could enhance tolerability and treatment outcomes, yet there is a shortage of empirical data on methods to mitigate discomfort during stimulation. Borckardt et al. found preliminary evidence of reduced pain during rTMS after local injections of lidocaine (n = 2) and lidocaine with epinephrine (n = 3) [5]. Scalp injections are relatively invasive, and require a medical professional, which may limit their adoption in clinical practice. Alternatively, topical lidocaine, scalp cooling with ice, and administration of ibuprofen/acetaminophen are non-invasive strategies that have been reported upon as strategies to enhance rTMS tolerability [2,6–8]. However, the effects of these non-invasive methods on discomfort during stimulation have not yet been quantitatively evaluated. Additionally, the efficacy of other known analgesics, such as topical menthol, have not yet been explored.

We conducted a pragmatic pilot study on the efficacy of four non-invasive strategies for reducing discomfort during a single session of dorsomedial prefrontal cortex (DMPFC) intermittent theta burst stimulation (iTBS) (Fig. 1A). Ten healthy volunteers (5 males, mean ± SD age = 28 ± 5.2 years) underwent five iTBS conditions across several days in pseudo-randomized order: 1) iTBS without intervention, 2) topical lidocaine hydrochloride 4 % application before iTBS (Maximum Strength Lidocaine Plus cream), 3) acetaminophen (1000mg) and ibuprofen (600mg) taken orally before iTBS, 4) scalp cooling with ice before iTBS (flexible gel ice pack), and 5) topical menthol application before iTBS (Biofreeze Pain Relief Spray; 10.5 % menthol). For analgesic medication, lidocaine, and menthol interventions, subsequent conditions were tested on a different day to avoid carryover effects.

Foot resting motor threshold (MT) was first established using a Magventure D-B80 coil. Midline DMPFC was targeted using scalp-based measurements [9], with the coil positioned tangentially to the head and the coil handle pointing posteriorly. All iTBS sessions were delivered using a MagVenture X100 with the Cool D-B80 coil. For each condition, a single 10-min accelerated iTBS session with 1800 pulses was administered, consisting of 60 cycles of 10 bursts delivered in 2-s trains (5 Hz), with an 8-s intertrain interval, where each burst consisted of 3 pulses at 50Hz. In each session, stimulation was gradually increased based on individual tolerance levels from 15 to 20 % of maximum stimulator output (MSO) until the target dose was reached, maximum tolerability was reached, or the iTBS session finished. Immediately after each iTBS session, participants rated their maximal level of discomfort during stimulation using a verbal analogue scale ranging from 1 (no pain) to 10

(intolerable pain) [4]. This study was approved by the Stanford Institutional Review Board. All participants provided written, informed consent.

The primary outcome was change in pain ratings as compared to the no-intervention condition. A linear mixed effects model was performed to compare pain ratings across conditions, with condition as a fixed effect and participant as a random effect. Model residuals were checked using histograms and quantile-quantile plots. To correct for multiple comparisons, Dunnett's method was used to compare pain ratings between each intervention and the no-intervention condition. Two participants were missing data from some conditions for logistical reasons (Fig. 1A).

We observed considerable variability across individuals in the baseline tolerability of iTBS, with some experiencing stimulation as painful, and others as minorily uncomfortable (Fig. 1C and D). Without any intervention, 6 of 10 participants were able to tolerate iTBS at full dose. MTs ranged from 35 to 56 % MSO (mean ± SD = 45 ± 6.2 %). As expected, those with the highest MTs (56, 52, 51 % MSO) experienced the greatest difficulty in reaching their target dose (percentage of MT tolerated without intervention: 66, 78, 80 %, respectively).

We found a significant effect of iTBS condition on pain ratings (F<sub>4,32</sub> = 2.92, *p* = 0.036). Specifically, pre-treatment with Biofreeze (*p* = 0.029, Cohen's *d* = 0.88) or acetaminophen/ibuprofen (*p* = 0.014, Cohen's *d* = 1.0) significantly reduced discomfort during iTBS, as compared to no intervention (Fig. 1B). There was considerable inter-individual variability in the efficacy of each intervention for reducing discomfort (Fig. 1C). Small, non-significant reductions in pain were also observed after ice pack (*p* = 0.66, Cohen's *d* = 0.44) or topical lidocaine interventions (*p* = 0.68, Cohen's *d* = 0.43), reflecting reduced discomfort in some individuals (5/9 and 4/10 participants, respectively) but not others. Importantly, after scalp cooling with ice, some participants reported re-warming of the scalp during coil setup. Therefore, optimization of this pain mitigation strategy is merited in future work; for example by leveraging neuronavigation to reduce the latency between ice removal and stimulation. Preliminary evidence also indicates scalp cooling with ice can decrease corticomotor excitability [10]. Therefore, whether scalp cooling necessitates a change in rTMS dose at frontal cortical targets requires further investigation.

Beyond tolerability concerns, pain associated with rTMS also poses methodological concerns when blinding sham conditions in randomized controlled trials. Given the preliminary evidence that these non-invasive strategies may reduce rTMS-related pain, future work investigating whether these strategies enhance the success of blinding in sham-controlled trials is needed.

Future studies should also assess whether combinations of these strategies, such as analgesic medications combined with topical menthol, can further optimize tolerability. Similarly, other approaches
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Effects of non-invasive pain mitigation strategies on DMPFC iTBS scalp pain and tolerability. **A.** In a within-subjects design, iTBS was performed without intervention, or after pre-treatment with topical lidocaine (n = 10), analgesic medication (n = 9), an ice pack (n = 9), or topical menthol (n = 8). **B.** Estimated marginal means of pain ratings across pain mitigation strategies. Error bars reflect standard error of the mean. The mean percentage reduction in pain ratings compared to no intervention is displayed in boxes for each intervention. **C.** Individual changes in pain ratings across pain mitigation strategies. **D.** Individual changes in the percentage of motor threshold tolerated across pain mitigation strategies. The target dose was 100 % of motor threshold.</figcaption></figure>

for managing pain during rTMS might be used in parallel, such as adjusting stimulation intensity or providing reassurance and education on the transient nature of pain at the stimulation site8. Of note, the modest sample size of this pilot study should be considered when interpreting the findings, and future studies should replicate these findings in clinical populations. Additionally, placebo effects may be present in the current findings, and future work should include a placebo control. Individual intervention preferences should also be considered in clinical practice and in future work. Lastly, in line with standard clinical practice, iTBS was dosed based on MT, however future work might explore the efficacy of these interventions at different stimulation intensities, independently of MT.

In conclusion, these preliminary results suggest that several non-invasive strategies can be used to improve the tolerability of iTBS for some individuals, including over-the-counter analgesic medications and topical menthol. Given the accessible and low-cost nature of these strategies, rTMS providers might consider employing these non-invasive interventions for patients experiencing difficulty in tolerating their intended dose.

### CRediT authorship contribution statement

**Jennifer I. Lissemore:** Writing – review & editing, Writing – original draft, Visualization, Project administration, Methodology, Investigation, Formal analysis, Conceptualization.
**Derrick M. Buchanan:** Writing – review & editing, Writing – original draft.
**Jean-Marie Batail:** Writing – review & editing, Project administration, Methodology, Investigation,

Conceptualization. **Irakli Kaloiani:** Writing – review & editing, Project administration, Methodology, Investigation.
**Clive Veerapal:** Writing – review & editing, Investigation.
**Gregory L. Sahlem:** Writing – review & editing, Supervision, Project administration, Methodology, Conceptualization.
**Nolan R. Williams:** Writing – review & editing, Supervision, Resources, Funding acquisition, Conceptualization.

### Declaration of competing interest

C.V. has equity in Magnus Medical. G.L.S. has collaborated with MagVenture and MECTA as part of investigator-initiated trials, consults for and has equity in the company Trial Catalyst, and has provided consultation to Indivior. N.R.W. is a named inventor on Stanford-owned intellectual property relating to accelerated TMS pulse pattern sequences and neuroimaging-based TMS targeting; he has served on scientific advisory boards for Otsuka, NeuraWell, Magnus Medical, and Nooma as a paid advisor; and he has equity/stock options in Magnus Medical, NeuraWell, and Nooma. All other investigators declare no competing interests.

### Acknowledgements

Supported by Canadian Institutes of Health Research Fellowships (176536 and 181910 to J.I.L. and D.M.B., respectively); Steve and Genevieve Jurvetson, and the Pritzker Neuropsychiatric Disorders Research Consortium.
References

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Jennifer I. Lissemore, Derrick M. Buchanan
Department of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, Palo Alto, CA, USA

Jean-Marie Batail
Department of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, Palo Alto, CA, USA
Centre Hospitalier Guillaume Régnier, Rennes, France
Centre d'Investigation Clinique de Rennes - CIC 1414 Inserm,
"Neuropsychiatrie du comportement et du développement", CHU Rennes,
France
Université de Rennes, Rennes, France

Irakli Kaloiani, Clive Veerapal, Gregory L. Sahlem, Nolan R. Williams*
Department of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, Palo Alto, CA, USA

* Corresponding author. Brain Stimulation Lab Associate Professor, Department of Psychiatry and Behavioral Sciences, Stanford University 401 Quarry Rd. Stanford, CA 94304, USA.
E-mail address: nolanw@stanford.edu (N.R. Williams).