Mechanism of Action Concept: Tremor Suppression with Peripheral Nerve Stimulation

ET is one of the most common movement disorders, and though the mechanisms are not fully understood, it is known that activity changes in the cerebello-thalamo-cortical loop (central tremor network) underly the disorder(Figure 1).1, 2 The most effective treatment option to date is deep brain stimulation (DBS) of the ventral inter-mediate nucleus of the thalamus (VIM), which is a key relay point within this circuit. DBS in the VIM (Figure 2) is thought to decrease tremor by functioning in effect as a thalamic filter, interrupting thalamic neuronal oscillations within the circuit with electrical stimulation and reducing hand tremor.3

Figure 1 Presumed Pathways Involved in the Pathophysiology of Essential Tremor. The cortico ponto–cerebello thalamo cortical loop (central tremor network) and the Guillain–Mollaret triangle, dentate nucleus to red nucleus to inferior olivary nucleus to dentate nucleus (via the cerebellar cortex). The main target for surgical treatment is the ventral intermediate (VIM) nucleus of the thalamus. The zona incerta is the ventral continuation of the reticular nucleus of the thalamus and gets input from the prelemniscal radiation and the thalamic fasciculus (which is composed of the ansa lenticularis fibers and the lenticular fasciculus fibers).

Black Pathways: The cortico ponto–cerebello thalamo cortical loop (central tremor network) Light Blue: Cerebellar cortex

Green: Ansa lenticularis fiber and lenticular fasciculus fibers

This same central tremor network is accessible via peripheral nerves that project to the VIM, including the median and radial nerves in the wrist (Figure 2). Electrical stimulation of these nerves is able to change activity in the VIMin a manner that is a representation of the bursting paradigm at the median and radial nerves in the wrist.4 Ithas been demonstrated that median nerve stimulation-induced changes in sensory and motor excitability are contingent upon activity in the VIM and cerebellum, suggesting that the relay through the VIM is key in thisnetwork.5 Additionally, median and radial nerve stimulation at specific stimulation frequencies has been shownto evoke very fast oscillations in the VIM, which is known to induce thalamicneuronal inhibition and interruptpathological tremor oscillations, as related to DBS.6, 7

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Figure 2 Schematic of Deep Brain Stimulation implanted pulse generator and stimulation lead (left) and Cala bioelectronic circuit therapy via ventral intermediate nucleus of the thalamus (VIM).

Previous studies have demonstrated the effective use of electrical stimulation of the median and radial nerves for the control of hand tremor.8 Based on the above described physiology, it is thought that this effect is causedby engagement and activation of sensory nerves that project through the median and radial nerves (Figure 2). Based on these observations, the wrist-worn Cala Therapy is designed to stimulate the median and radialnerve system that non-invasively targets the central tremor network and interrupting the tremulous signal viathe VIM. This device has demonstrated that frequency-dependent stimulation of the median and radial nervescan temporarily yet significantly reduce symptomatic hand tremor in patients with ET.9, 10

materials to look inconsistent

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VIM Nucleus of Thalamus

Wire Under Skin

Median Nerve

Radial Nerve

WearableStimulator & Battery

Cortex

Cerebellum & Brainstem

Spinal Cord

ImplantedStimulator & Battery

References

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1. Haubenberger D, Hallett M. Essential Tremor. N Engl J Med 2018;378:1802-1810.2. Deuschl G, Raethjen J, Hellriegel H, Elble R. Treatment of patients with essential tremor. Lancet Neurol 2011;10:148-161.3. Milosevic L, Kalia SK, Hodaie M, Lozano AM, Popovic MR, Hutchison WD. Physiological mechanisms of thalamic ventral intermediate nucleus stimulation for tremor suppression. Brain 2018;141:2142-2155.4. Grisolia JS, Wiederholt WC. Short latency somatosensory evoked potentials from radial, median and ulnar nerve stimulation in man. Electroencephalogr Clin Neurophysiol 1980;50:375-381.5. Klostermann F, Wahl M, Schomann J, Kupsch A, Curio G, Marzinzik F. Thalamo-cortical processing of near-threshold somatosensory stimuli in humans. Eur J Neurosci 2009;30:1815-1822.6. Hanajima R, Chen R, Ashby P, et al. Very fast oscillations evoked by median nerve stimulation in the human thalamus and subthalamic nucleus. J Neurophysiol 2004;92:3171-3182.7. Hanajima R, Dostrovsky JO, Lozano AM, et al. Somatosensory evoked potentials (SEPs) recorded from deep brain stimulation (DBS) electrodes in the thalamus and subthalamic nucleus (STN). Clin Neurophysiol 2004;115:424-434.8. Dosen S, Muceli S, Dideriksen JL, et al. Online tremor suppression using electromyography and low-level electrical stimulation. IEEE Trans Neural Syst Rehabil Eng 2015;23:385-395.9. Lin PT, Ross EK, Chidester P, et al. Noninvasive neuromodulation in essential tremor demonstrates relief in a sham-controlled pilot trial. Mov Disord 2018.

10. Pahwa R, Dhall R, Ostrem J, et al. An Acute Randomized Controlled Trial of Noninvasive Peripheral Nerve Stimulation in Essential Tremor. Neuromodulation 2019.