# Medical Devices for Tremor Suppression: Current Status and Future Directions
## 3 Electrical Stimulation Systems  
### Median and Radial Nerve Excitation  
High frequency transcutaneous electrical nerve stimulation (TENS) has been widely studied and used in the treatment of nociceptive and neuropathic pain [50; 51; 52; 53]. The use of TENS in the treatment of movement disorders, including mycolonic dystonia and ET, was first explored by [PERSON] and [PERSON] in 1985 [54]. While the exact mechanism of TENS remains unclear, putative mechanisms focus on its ability to modulate the afferent transmission of sensory information from the periphery to the central nervous system (CNS) [50]. Conventional TENS intends to selectively stimulate the large, myelinated peripheral proprioceptive A-beta (A\(\beta\)) sensory fibers [50]. The excitation of the A\(\beta\) fibers reduces the transmission of the sensory signals elicited by noxious stimulus, thereby reducing the pain perception [55; 56; 57; 58]. These A\(\beta\) fibers carry proprioceptive sensory information into the thalamic circuits that are hypothesized to be involved in tremor generation [59]. Most [54; 60; 61; 62; 63], but not all [64], studies suggest that treatment with TENS in patients who have tremors was associated with improved muscle strength and tremor reduction. However, sham-controlled randomized trials are needed to confirm these findings due to potential confounding effects associated with the reason for use. In 2018, Cala ONE was the first wearable transcutaneous electrical nerve stimulator to be approved by the FDA [40]. The newer version of this device, Cala Trio (Cala Health, USA; previously known as Cala TWO), is currently FDA-registered. The PROSpective study for SymPtomatic relief of Essential tremor with Cala Therapy (PROSPECT) pivotal trial for Cala Trio was completed in 2019 [65], but it is still waiting for approval by the FDA. Clinically, Cala Trio is designed to replace Cala ONE for use in the transient, symptomatic relief of hand tremors in adults with ET. This device can be worn for therapy on the left or right wrist. Cala Trio involves two working electrodes positioned over the median and radial nerves on the anterior surface of the wrist and a counter electrode placed on the posterior surface of the wrist. An accelerometer within this device measures the frequency of the patient's tremor, allowing individualized calibration of the stimulation intensity. The two working electrodes deliver electrical signals that intermittently excite the median and radial nerves in the upper limbs. Peripheral sensory nerves, including the median and radial nerves, also project to the VIM and the neural circuits that are implicated in ET. Similar to DBS, electrical stimulation of the VIM peripherally via the median [66; 67] and radial [68] nerves elicits very fast oscillations, which induce thalamic neuronal oscillations and disrupt the pathological oscillations of tremors (Figure 1). A study involving five patients with tremors due to ET or PD demonstrated that electrical stimulation of the median and radial nerves leads to a 57% tremor suppression (\(p<0.01\)) [69]. Over time, this stimulation with Cala Trio aims to normalize the neural firing in the pathological tremor network in the CNS to reduce tremors. The pivotal trial for Cala ONE, a sham-controlled randomized trial of a single 40-min TENS session among 77 patients with ET, found no significant improvements in the Archimedes spiral task, as measured using the Tremor Research Group Essential Tremor Rating Assessment Scale (TETRAS) (\(p=0.26\)) [70]. However, the Cala ONE stimulation did show significantly improved upper limb TETRAS tremor scores (\(p=0.017\)) and subject-rated Bain and Findley ADL scores (\(p=0.001\)), corresponding to a 42% (versus 28% with sham) and a 49% (versus 27% with sham) reduction in tremor amplitude, respectively [70]. The PROSPECT pivotal trial for Cala Trio, an open-label study of TENS treatment in adults with ET, compared twice-daily home therapy TENS sessions over a three-month period among 263 patients [71].