Objective: To investigate the mechanism of transcutaneous afferent pattern stimulation (TAPS) using PET imaging to assess brain metabolic changes associated with tremor reduction in individuals with essential tremor (ET).

Background: ET is a common movement disorder affecting 0.4% to 6% of the population.[1] While pharmaceutical and surgical treatments like deep brain stimulation (DBS) exist, they carry side effects and risks.[2-4] TAPS provides tremor relief non-invasively, delivering alternating electrical pulses to the median and radial nerves, calibrated to each patient’s tremor frequency.[5-8] Other non-invasive stimulation techniques and modalities (e.g., vibration) have not shown significant tremor relief.[9-10] A pilot study (N=5) suggested TAPS may alter cerebellar metabolism after 90 days.[11] This study used PET imaging to analyze brain metabolic changes in a larger patient cohort.

Method: This study enrolled 16 patients. Eligibility required patients to be at least 21 years old and approved for DBS surgery for ET by the Mayo Clinic DBS Committee. Exclusion criteria included moderate to severe ethanol dependence and implanted devices (e.g., pacemakers, defibrillators, DBS stimulators). Patients underwent pre- and post-stimulation assessments, including the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) and 18-fluorodeoxyglucose (FDG) PET/CT scans. Data were analyzed to compare baseline and follow-up measurements of tremor severity and brain metabolic activity at days 1 and 90.

Results: In the 11 patients who completed the study, the TETRAS score on day 1 decreased from 5.4 ± 2 to 3.5 ± 1.5 following TAPS (p<0.0001). At day 90, the pre- and post-stimulation TETRAS scores were 2.9 ± 2.4 and 2.3 ± 2.0, respectively. These were lower than the day 1 pre-stimulation score (p=0.0086 and 0.0012, respectively). Analysis of normalized FDG uptake in the cerebellum, pons and other brain locations showed changes in brain metabolic activity between day 1 and day 90.

Conclusion: This study showed that TAPS of median and radial nerves with waveforms calibrated to tremor frequency modulates metabolic activity in areas instrumental to tremor circuitry (e.g. cerebellum). Behavioral assessments indicate a decrease in tremor symptoms following TAPS out to 90 days. These findings support the use of TAPS as a non-invasive treatment option for essential tremor.

Figure 1

References: [1] Louis ED, McCreary M. How Common is Essential Tremor? Update on the Worldwide Prevalence of Essential Tremor. Tremor Other Hyperkinet Mov (N Y). 2021 Jul 9; 11:28. doi: 10.5334/tohm.632. PMID: 34277141; PMCID: PMC8269764.

[2] Hopfner F, Deuschl G. Managing Essential Tremor. Neurotherapeutics. 2020 Oct;17(4):1603-1621. doi: 10.1007/s13311-020-00899-2. Erratum in: Neurotherapeutics. 2021 Jul;18(3):2132. doi: 10.1007/s13311-021-01131-5. PMID: 32915385; PMCID: PMC7851235.

[3] Koller WC, Vetere-Overfield B. Acute and chronic effects of propranolol and primidone in essential tremor. Neurology. 1989;39(12):1587-1588. doi:10.1212/wnl.39.12.1587.

[4] Wong JK, Hess CW, Almeida L, Middlebrooks EH, Christou EA, Patrick EE, Shukla AW, Foote KD, Okun MS. Deep brain stimulation in essential tremor: targets, technology, and a comprehensive review of clinical outcomes. Expert Rev Neurother. 2020 Apr;20(4):319-331. doi: 10.1080/14737175.2020.1737017. Epub 2020 Mar 2. Erratum in: Expert Rev Neurother. 2020 Apr;20(4):i. doi: 10.1080/14737175.2020.1741260. PMID: 32116065; PMCID: PMC7174089.

[5] Pahwa R, Dhall R, Ostrem J, et al. An Acute Randomized Controlled Trial of Noninvasive Peripheral Nerve Stimulation in Essential Tremor. Neuromodulation : Journal of the International Neuromodulation Society. 2019 Jul;22(5):537-545. DOI: 10.1111/ner.12930. PMID: 30701655; PMCID: PMC6766922.

[6] Isaacson SH, Peckham E, Tse W, et al. Prospective Home-use Study on Non-invasive Neuromodulation Therapy for Essential Tremor. Tremor and Other Hyperkinetic Movements (New York, N.Y.). 2020 Aug;10:29. DOI: 10.5334/tohm.59. PMID: 32864188; PMCID: PMC7427656.

[7] Lu C, Khosla D, Kent A, Bronte-Stewart HM, Rosenbluth KH. Transcutaneous Afferent Patterned Stimulation for Essential Tremor: Real-World Evidence with Long Term Follow-Up. Tremor and Other Hyperkinetic Movements (New York, N.Y.). 2023 ;13:29. DOI: 10.5334/tohm.775. PMID: 37663529; PMCID: PMC10473165.

[8] Dai D, Fernandes J, Kim H, Coetzer H. Comparative Effectiveness of Transcutaneous Afferent Patterned Stimulation Therapy for Essential Tremor: A Randomized Pragmatic Clinical Trial. Tremor and Other Hyperkinetic Movements (New York, N.Y.). 2023 ;13:38. DOI: 10.5334/tohm.798. PMID: 37869579; PMCID: PMC10588491.

[9] Lora-Millán JS, López-Blanco R, Gallego JÁ, Méndez-Guerrero A, González De La Aleja J, Rocon E. Mechanical vibration does not systematically reduce the tremor in essential tremor patients. Sci Rep. 2019;9(1):16476. doi:10.1038/s41598-019-52988-8

[10] Metzner C, Stringham A, Hislop B, et al. Brief Submotor-Threshold Electrical Stimulation Applied Synchronously Over Wrist Flexor and Extensor Muscles does Not Suppress Essential Tremor, Independent of Stimulation Frequency. Tremor and Other Hyperkinetic Movements. 2023;13(1):30. doi:10.5334/tohm.740

[11] Barath AS, Rusheen AE, Min HK, et al. Brain Metabolic Changes with Longitudinal Transcutaneous Afferent Patterned Stimulation in Essential Tremor Subjects. Tremor and Other Hyperkinetic Movements. 2020;10(0):52. doi:10.5334/tohm.565

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