Advances in Neuromodulation for Essential Tremor

Essential tremor (ET) is the most common movement disorder in adults with an overall prevalence of ~1.3%, and 4.8% among those older than 65 years.¹ ET commonly manifests as a postural or kinetic tremor of the upper extremities, but it can also affect the lower extremities, head, torso, or voice. Chronically progressive tremor may impair physical and social function, and treatment of ET is associated with an improvement in quality of life.² First-line pharmacologic therapies include propranolol and primidone, which may reduce tremor amplitude by 50% to 60%; however, pharmacologic treatment is insufficient for up to 50% of treated individuals. Pharmacologic therapies have a high rate (7.5% to 42%) of adverse effects (AEs), including hypotension, somnolence, and subjective cognitive impairment.³ Given these limitations, there is increasing interest in neuromodulatory treatments for medication-refractory ET.

Early surgical treatments for ET included radiofrequency thalamotomy and gamma knife stereotactic radiosurgery targeting the ventral intermediate nucleus of the thalamus (VIM). Deep brain stimulation (DBS), which was approved by the Food and Drug Administration (FDA) for treatment of ET in 1997, has largely supplanted radiofrequency thalamotomy and stereotactic radiosurgery, owing to its equivalent efficacy in tremor suppression and a lower rate of persistent AEs compared with surgical interventions.⁴ In 2016, magnetic resonance–guided focused ultrasound (MRgFUS) was approved by the FDA for treatment of ET. The first transcutaneous afferent patterned stimulation (TAPS) device for treatment of ET was approved by the FDA in 2018. Table 1 includes an overview of procedural therapies for medication-refractory ET.

Deep Brain Stimulation

DBS uses surgically implanted electrodes with multiple contacts to deliver electrical current to specific brain targets. In most cases, the VIM is the selected brain target for the treatment of ET, although alternative areas are targeted rarely. In addition to standard stereotactic guidance, microelectrode recording and intraoperative physical examination testing can be used to confirm optimal electrode placement.

A systematic review has demonstrated reduction in tremor by 40% to 75% after unilateral VIM DBS.⁵ Factors influencing the degree of tremor improvement include severity of tremor, proximity of the DBS electrode to the target structure, stimulation parameters, and compliance with follow-up.

The pathophysiology of ET is thought to involve abnormal neuronal oscillatory activity involving the dentato-rubro-thalamic tract (DRTT). The DRTT is composed of decussating and nondecussating fibers. Unilateral VIM DBS can suppress tremor bilaterally by stimulating the decussating and nondecussating DRTT fibers, but bilateral DBS has the most optimal outcomes.⁶ Bilateral DBS may also be more effective for axial or voice tremor but is associated with greater stimulation-induced AEs, including paresthesias, gait difficulty, and dysarthria.⁵

DBS of the VIM has demonstrated sustained benefit for ET symptoms over >10 years of follow-up. However, a phenomenon of gradual reduction in DBS efficacy over time has also been observed. This habituation is likely due to both ET progression and a local or circuit-level breakthrough in pathologic oscillations.^7-9 Strategies to mitigate habituation include alternating stimulation patterns, turning DBS off overnight, and DBS deactivation for days to weeks.

The most common alternative to VIM DBS is targeting the caudal zona incerta or posterior subthalamic area. The use of this target was suggested by findings that within the VIM, ventral contacts (adjacent to the subthalamic area) were more effective than dorsal contacts. A randomized, blinded, single-center, prospective trial of posterior subthalamic area DBS compared with VIM DBS suggested that this intervention had similar efficacy as VIM DBS with lower stimulation amplitude.¹⁰ However, this may come at the expense of higher AE rates.¹¹ Retrospective studies of caudal zona incerta DBS have had inconsistent results: in shorter-term follow-up, improved tremor suppression with lower rates of acute stimulation-induced AEs was noted,¹² but benefit after 3 years was reduced, and the risk of stimulation-induced dysarthria was higher.¹³

DBS is generally a well-tolerated procedure with a favorable side effect profile. The most common surgical AEs are infection (~3%), intracranial hemorrhage (~2%), and wound dehiscence (~3%). Stimulation-related AEs have an incidence of ~25%, although most are mild and either transient or resolvable with adjustment of stimulation parameters. Among stimulation-related AEs, dysarthria, paresthesias, and ataxic gait disturbance are most frequent.¹⁴ Microlesional effects from the electrode may also contribute to gait ataxia more commonly in individuals who had a previous gait deficit, which may accompany longstanding severe ET.^15,16

Various DBS hardware and software technology advances have optimized DBS therapy. For example, the therapeutic window (the range of stimulation amplitudes between efficacy and side effect thresholds) has been improved through the development of DBS electrodes with directional steering. Using this technology, radially segmented contacts direct current toward the intended target and away from structures that may cause side effects, even within the same dorsoventral contract position.¹⁷ Some DBS electrodes are also capable of recording neuronal local field potentials through the electrode contacts. This information is being used in designing and studying adaptive or closed-loop DBS systems in which stimulation can be automatically triggered or adjusted based on oscillatory signals that correspond with behaviors such as limb movement or symptoms such as tremor.¹⁸

Magnetic Resonance–Guided Focused Ultrasound

MRgFUS uses an array of high-intensity ultrasound waves to create a targeted thermal tissue ablation. MRI is used to map the target and monitor real-time tissue temperature increases during repeated sonications. MRgFUS requires the patient’s head to be shaved and pinned to a stereotactic head frame, which is then positioned in a water-filled bladder surrounded by the ultrasound array. Awake individuals are assessed clinically after each round of sonication, including tests of tremor such as finger-to-nose and spiral drawing, speech, sensation, and strength.¹⁹ The sonication temperature is increased gradually until tremor is adequately treated or until AEs (most commonly paresthesias) appear, which are usually transient.

Unilateral MRgFUS targeting VIM was FDA-approved for ET in 2016 after a randomized parallel-arm, sham-controlled trial of 81 individuals with medication-refractory upper-extremity tremor reported tremor improvement of 47% at 3 months with associated improvement in quality of life and disability measures in the treatment group.^3,20 AEs included gait disturbance (36%) and paresthesias or sensory disturbance (38%), which improved to 9% and 14%, respectively, at 12 months. Bilateral MRgFUS was FDA-approved in 2022, provided the procedure is staged with at least a 9-month interval. Three-year follow-up data suggested a sustained 50% reduction in tremor and improved quality of life.²¹ Acute AEs were more common after bilateral MRgFUS (70% of individuals experienced gait impairment, dysarthria, dysphagia, or dysgeusia or dysesthesia²²), but meta-analyses suggested a similar rate of persistent AEs (4% for gait disturbance, 8% for sensory changes), most of which were mild to moderate.^23,24

The ability to perform MRgFUS is limited by the permeability of the skull to ultrasound waves. MRgFUS requires a skull density ratio (SDR; the cancellous:cortical bone ratio in Hounsfield units) of >0.45 ± 0.5.²⁵ A higher SDR is favorable for performing MRgFUS due to reduced impedance of the ultrasound waves. Lower SDR values correlate with higher energy requirements, but successful lesioning and clinical improvement may still be possible in individuals with an SDR <0.4.²⁶ Focal areas of increased bone density may also complicate successful lesioning even in individuals with an optimal SDR. Thus, although SDR is a useful benchmark, it should be considered alongside other factors for ultimate determination of candidacy for MRgFUS.

There is a potential for tremor recurrence in individuals who undergo MRgFUS. An early pilot study showed worsening of tremor by about 23% after the first year.¹⁹ This may be attributable to inaccurate targeting, inadequate lesioning after resolution of perioperative edema, or disease progression. Repeat MRgFUS can be performed in these cases.

There have been no direct head-to-head studies comparing MRgFUS and DBS for treatment of ET; however, comparative evaluations suggest a similar improvement in tremor control.^27-30 DBS may have more benefit for axial tremor compared with MRgFUS.²⁷ Available data suggest a higher rate of gait- and sensory-related AEs after MRgFUS but a higher rate of speech-related side effects after DBS.²⁸ MRgFUS does not require craniotomy; therefore, risk of infection or periprocedural hemorrhage is low. Because MRgFUS ablation is irreversible, the rate of persistent side effects is higher. Table 2 includes a detailed comparison of DBS and MRgFUS for ET.

Transcranial Stimulation

Transcranial stimulation—including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS)—is being explored as a noninvasive treatment option for ET. Both rTMS and tDCS can target the cerebellar cortex, given its potential role in ET pathogenesis.⁶ Evidence for either strategy is scant and of low quality. One open-label study found that 1-Hz cerebellar rTMS daily for 5 sessions reduced tremor over 30 days³⁰; however, a subsequent blinded sham-controlled study failed to confirm these findings.³¹ One double-blind placebo-controlled study of cerebellar tDCS showed no significant improvement in tremor or disability scores.³²

Transcutaneous Afferent Patterned Stimulation

Electric stimulation of the median nerve at the wrist can evoke thalamic very-high-frequency oscillations, which may interfere with the thalamic relay of pathologic tremor osscilations.³³ The Cala Trio device (Cala Health, San Mateo, CA) can deliver TAPS to the median and radial nerves; the amplitude and frequency are tailored to each individual’s tremor during an initial calibration procedure. One randomized, sham-controlled trial evaluated the effect of 150-Hz TAPS of the median and radial nerves in ET. This study did not meet the primary end point (difference in tremor by the Essential Tremor Rating Assessment Scale Archimedes spiral) but did meet secondary outcomes of improvement in activities of daily living (49% vs 27%, treatment vs sham) and upper-limb tremor scores (42% vs 28%, treatment vs sham).³⁴ A subsequent open-label study (Prospective Study for Symptomatic Relief of ET With Cala Therapy [PROSPECT], NCT03597100) recruited 265 individuals to use the Cala-Trio device for 40 minutes twice daily for 3 months. A total of 62% of individuals experienced an improvement in tremor severity from moderate/severe to mild based on Essential Tremor Rating Assessment Scale score. AEs, such as wrist discomfort or skin irritation, were reported in ~20% of individuals.³⁵ The Cala Trio device received FDA clearance for treatment of ET in 2018. After a single TAPS session (~40 minutes), the duration of tremor suppression is ~60 minutes.³⁶ Given this short duration of benefit, TAPS is generally offered to individuals with medication-refractory ET who decline or are not candidates for DBS or MRgFUS.

Conclusion

Neuromodulatory therapies are appropriate for individuals with medication-refractory ET. Each modality has advantages and limitations. DBS has a favorable long-term safety and efficacy profile, and offers the benefit of adjustability and reversibility, allowing for fine-tuning of stimulation parameters to optimize control of progressive tremor. However, DBS is invasive and requires surgical implantation of electrodes and periodic battery replacements, with the potential for infection and hardware malfunction. MRgFUS provides a less-invasive alternative by using focused ultrasound to create a thalamic thermal ablation. This method is effective in reducing tremor but lacks the flexibility and reversibility of DBS. The choice between DBS and MRgFUS should be guided by a comprehensive evaluation that includes assessment of tremor severity and distribution, presence of gait disturbance or other preexisting ataxic symptoms, surgical candidacy, and shared decision-making between patients and clinicians. TAPS can be offered to individuals in place of DBS or MRgFUS, but only offers transient benefit.