Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Henchcliffe reports she is a consultant for Amneal Pharmaceuticals, Prevail Therapeutics, and US WorldMeds, and receives grant/research support from Biogen.

SYNOPSIS: Using MRI BOLD and seed-based functional connectivity, during a grip-force task, network-level connectivity was shown to be highly distinct between two otherwise phenotypically overlapping tremor types — dystonic tremor and essential tremor.

SOURCE: DeSimone JC, Archer DB, Vaillancourt DE, Wagle Shukla A. Network-level connectivity is a critical feature distinguishing dystonic tremor and essential tremor. Brain 2019;142:1644-1659.

DeSimone et al examined 20 subjects with dystonic tremor (DT), 18 with essential tremor (ET), and 18 control subjects without tremor, using clinical diagnosis as the gold standard. Of the 20 with DT, 19 had cervical dystonia with a head tremor; of these, 13 also had tremor in the arms/hands. One had spasmodic dysphonia and unilateral upper limb tremor. Groups were well-matched for age, although disease duration was very different between those with ET (23.0 ± 21.0 years) and DT (6.5 ± 6.3 years). Medications were withdrawn overnight prior to MRI to minimize their effects on the studies. Previously, visual feedback was known to augment force tremor in ET. In this study, the investigators demonstrated that this also is the case for DT, allowing them to use different visual feedback conditions to manipulate tremor during neuroimaging procedures. MRI-based measures in this study were made during a grip-force task performed under high and low visual feedback conditions and comprised blood oxygen level-dependent (BOLD) signal amplitude and seed-based determination of functional connectivity.

Reduction in BOLD amplitude occurred in both ET and DT patients compared with controls in the cerebellum and cortex, but in distinct patterns. Reduction was greater in ET than DT in sensorimotor, visual, and mesial premotor cortex and in the inferior parietal lobule, whereas reduction was greater in DT than ET in the middle frontal gyrus. Functional connectivity was markedly abnormal in DT and ET compared with controls, based on seeding from the dentate nucleus, ventral intermediate thalamic nucleus, globus pallidus pars interna, and sensorimotor cortex. However, abnormalities were much more widespread in DT than ET, involving higher level cortical regions, basal ganglia, and cerebellum irrespective of seed location. By combining specific measures, this approach achieved 83% sensitivity and 65% specificity in distinguishing ET and DT, with area under the curve (AUC) of 0.77 in the ROC analysis. By including all regions of interest measured under high and low visual feedback conditions, this improved to 78% sensitivity and 100% specificity, with AUC = 0.89.

COMMENTARY

ET is a common cause of tremor that affects an estimated 7 million individuals in the United States. Although its presentation is variable, it is important to make an accurate diagnosis given the potential for not only pharmacologic but also surgical therapies, the latter including the highly effective deep brain stimulation and, more recently, MRI-guided focused ultrasound. However, DT, occurring in a part of the body affected by dystonia or in a part of the body not affected by dystonia, may mimic ET. It is less common, less well-recognized, and is important to distinguish from ET both for practical considerations when advising patients on standard of care, as well as from a clinical research perspective.

DT and its underlying mechanisms are not well understood. Current diagnosis depends on clinical acumen and there is no diagnostic test. Therefore, clinicians must pay close attention to tremor characteristics and “company kept,” meaning examining for signs of dystonia that may in many cases be variable and/or subtle. There are several key findings from this innovative study. First, as in ET, visual feedback worsens DT tremor in the force task used, and this seems likely related to impaired functional connectivity of a number of structures with the visual cortex. Second, specific abnormalities in BOLD changes during activation were noted in DT, that overlap with previous data on specific isolated dystonias and are distinct from ET. Third, changes in functional connectivity also distinguish DT and ET, with more widespread deficits in DT. These novel findings not only serve as a first step to better understand the underlying mechanisms of DT but also may boost efforts to diagnose and eventually provide better treatment.