LAUSR

Severe action and intention tremor is one of the most common and disabling movement disorders. Often with unknown cause in essential tremor, tremor can also be a disabling symptom of Parkinson’s disease, multiple sclerosis, and many other disorders. Medication is often insufficient, motivating invasive treatments. Lesion-based therapies for tremor date back to the mid-1900s, evolving into stereotactic radio-frequency lesioning in the 1950s and permanently implanted deep brain stimulation (DBS) electrodes in 1989. Following a head-to-head study of DBS versus radio-frequency lesioning, DBS became the treatment of choice for most tremor patients over the past two decades. However, lesion-based therapies for tremor have persisted and evolved, including incisionless technologies such as magnetic resonance imaging guided focused ultrasound (MRgFUS). In total, more than 200,000 patients have been treated with DBS and it is estimated that approximately 30% of these patients are treated primarily because of their tremor. The optimal neuroanatomical target for tremor is still debated despite this long-standing history and widespread clinical use. One of the first targets for tremor was the vascular territory of the anterior choroidal artery, where accidental ligation led to a thalamic / basal ganglia stroke and tremor improvement. The ventro-lateral thalamus was then identified by T. Riechert and I.S. Cooper as a more specific target for tremor. Multiple thalamic nuclei were subsequently targeted for tremor, with the field eventually converging on a target at the ventral border of the ventral intermediate (VIM) nucleus (Fig). This “classic” VIM target is generally identified using stereotactic coordinates and then modified intra-operatively as needed based on test stimulation. The VIM remains the most common target in clinical practice, both for DBS and lesion-based treatments such as MRgFUS. However, there is debate as to whether the ideal target for tremor is the VIM nucleus itself, or a complex region inferior and posterior to the VIM, termed the posterior subthalamic area (PSA). The PSA includes the zona incerta, pallidothalamic tracts (thalamic fasciculus and lenticular fasciculus), and the prelemniscal radiation (RaPrl). The RaPrl is thought to include multiple different white matter tracts, including fibers connecting the cerebellum and the thalamus referred to as the cerebellothalamic tract (CTT) or dentato-rubro-thalamic tract (DRT). Uncertainty regarding the ideal tremor target has been confounded by a lack of clear neuroanatomical landmarks on clinical neuroimaging. Neither the VIM nucleus nor any of the above PSA structures are visible on conventional MRI scans, making it difficult to retrospectively determine what was targeted or to prospectively target a specific structure. The need to identify and refine our tremor target has never been greater. Increased popularity of DBS interventions under anesthesia mean that tremor improvement cannot be confirmed intra-operatively, increasing the importance of image-guidance. Similarly, MRgFUS is motivating some to return to lesion-based treatments, in which the accuracy of the target becomes essential given the irreversibility of the procedure and the inability to compensate for off-target placement as one can with DBS programming. It is possible that refining the DBS tremor target could help inform lesion therapies, however given different mechanisms the optimal tremor targets may also differ. Three papers in this issue of the ANNALS of NEUROLOGY add to our knowledge regarding the optimal DBS target for tremor. These papers each take a different approach, including a large retrospective analysis of DBS tremor outcomes by Nowacki and colleagues, a neuroimaging marker that may identify the preferred tremor target in individual patients by Neudorfer and colleagues, and a prospective randomized trial comparing the two tremor targets by Kvernmo and colleagues. Remarkably, these three papers all agree that the optimal target for tremor is not the classic target in the VIM nucleus of the thalamus, but in the PSA, aligning with the location of white matter fibers connecting the cerebellum with the thalamus (Fig). The first of these studies performed the largest analysis of DBS electrode locations for tremor to date, including 119 patients from five European centers. Some centers targeted the VIM while others targeted the PSA, resulting in variability in lead location and tremor