Brain Metabolic Changes with Longitudinal Transcutaneous Afferent Patterned Stimulation in Essential Tremor Subjects

Abstract

Background: Non-invasive peripheral nerve stimulation, also referred to as transcutaneous afferent patterned stimulation (TAPS), reduces hand tremor in essential tremor (ET) subjects. However, the mechanism of action of TAPS is unknown. Here, we investigated changes in brain metabolism over three months of TAPS use in ET subjects. Methods: This was an interventional, open label, single group study enrolling 5 ET subjects. They received 40 minutes of TAPS treatment twice daily for 90 days. Brain metabolic activity and tremor severity were measured using 18F-fluorodeoxyglucose (FDG) PET/CT, and the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS), respectively, at baseline and after 90 days. Tremor power and frequency was measured before and after all TAPS sessions using an onboard three-axis accelerometer. Results: FDG PET/CT revealed areas of hypermetabolism in ipsilateral cerebellar hemisphere and hypometabolism in contralateral cerebellar hemisphere following 90 days of TAPS treatment, compared to day one (uncorrected p value <0.05). Paired pre-post kinematic measurements over 90 days showed significantly decreased tremor power (p < 0.0001) but no change in tremor frequency. The TETRAS score on day 1 decreased from 6.5 ± 2.5 to 4.1 ± 1.8 following TAPS (p = 0.05). The pre-post TETRAS scores on day 90: 4.9 ± 1.5 and 4.1± 1 were lower than pre-TAPS TETRAS score on day 1 (p = 0.14 and 0.05, respectively). Conclusions: Our results suggest that longitudinal TAPS of the median and radial nerves modulates brain metabolism in areas instrumental to motor coordination and implicated in ET. Clinically, TAPS reduced tremor power, but had no effect on tremor frequency. This study paves the way for comprehensive studies in larger cohorts to further elucidate the mechanism of TAPS. Highlights: Non-invasive peripheral nerve stimulation, also referred to as transcutaneous afferent patterned stimulation (TAPS), reduces hand tremor in essential tremor subjects. Longitudinal TAPS therapy alters cerebellar metabolism, which can be a cause or consequence of tremor reduction. Cerebellar-premotor region connectivity may play a role in the anti-tremor effects of TAPS.

Multiple Comorbidities, Psychiatric Disorders, Healthcare Resource Utilization and Costs Among Adults with Essential Tremor: A Retrospective Observational Study in a Large US Commercially Insured and Medicare Advantage Population

“…24,[43][44][45] Pharmacotherapy is currently the mainstay for ET treatment. 13,14,46 However, it has been reported that the first-line agents are ineffective in 30% to 70% of patients due to lack of response, adverse effects, and poor adherence and persistence. 11,[13][14][15]46 Our data show the wide spectrum of comorbidities among patients with ET, supporting the need for noninvasive, nonpharmacological treatments to minimize risk of adverse events.…”

“…13,14,46 However, it has been reported that the first-line agents are ineffective in 30% to 70% of patients due to lack of response, adverse effects, and poor adherence and persistence. 11,[13][14][15]46 Our data show the wide spectrum of comorbidities among patients with ET, supporting the need for noninvasive, nonpharmacological treatments to minimize risk of adverse events. Novel treatment options can empower healthcare providers and ET care teams to provide safe and effective therapies that can be tailored to the specific healthcare needs of each patient.…”

Non-invasive electrical stimulation of peripheral nerves for the management of tremor

“…TAPS doses consist of forty minutes of noninvasive stimulation that alternates between the median and radial nerves at the wrist at a patient's tremor frequency; motion sensors on a wrist-worn TAPS delivery device measure this tremor frequency during an initial calibration [54]. Randomized sham-controlled single-session clinical trials and subsequent longitudinal at-home clinical trials in ET have shown that TAPS therapy provides at least 50% lasting tremor reduction for the majority of patients, with over 90% of patients receiving at least some tremor reduction [53][54][55][56][57]; that tremor reduction with TAPS persists for over an hour after a TAPS dose for many patients [54,56]; and that repeated daily use of TAPS therapy over three months indicated no habituation or dose tolerance-induced loss of tremor reduction [54]. Efficacy of TAPS for tremor reduction was similar between patients on and off tremor medication [54].…”

“…One hypothesis for this lasting effect is that calibrated afferent PES (TAPS) produces a dephasing effect in the thalamus similar to the coordinated reset by DBS [104,105]. Another hypothesis is that afferent PES has a lasting effect on cerebellar circuits that project into the thalamo-cortical network, as supported by the metabolic increase in the cerebellar region measured via Single Photon Emission Computed Tomography (SPECT) imaging after three months of TAPS therapy in 5 ET patients [57]. Purkinje cell degeneration at the cerebellum is one of the main hypotheses for the cause of ET [106] and the cerebellum is involved in motor control and learning by integrating projections from the thalamo-cortical circuit and primary afferents to adjust the motor response.…”

Real-World Evidence of Transcutaneous Afferent Patterned Stimulation for Essential Tremor

“…TAPS therapy consists of stimulation of the median and radial nerves at the wrist at a frequency individualized to each patient's tremor [17]. TAPS is hypothesized to control ET symptoms by dephasing neural oscillations at the Ventral Intermediate (VIM) nucleus, the thalamic relay where deep brain stimulation (DBS) is implanted for the treatment of ET [18][19][20][21]. In a randomized single-session clinical trial, the magnitude of improvement across tasks in the treatment group corresponded to a 49% reduction in tremor according to patient's self-rated quality of life as measured by Bain and Findley Activities of Daily Living (BF-ADL) and a 42% reduction according to physician-rated Tremor Research Group Essential Tremor Rating Scale (TETRAS) [17].…”