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*These authors contributed equally to this work.Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

Significance We studied deep brain stimulation effects in two types of dystonia and conclude that different specific connections between the pallidum and thalamus are responsible for optimal treatment effects. Since alternative treatment options for dystonia beyond deep brain stimulation are scarce, our results will be crucial to maximize treatment outcome in this population of patients.

Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus is one of the main advanced neurosurgical treatments for drug-resistant tremor. However, not every patient may be eligible for this procedure. Nowadays, various other functional neurosurgical procedures are available. In particular cases, radiofrequency thalamotomy, focused ultrasound and radiosurgery are proven alternatives to DBS. Besides, other DBS targets, such as the posterior subthalamic area (PSA) or the dentato-rubro-thalamic tract (DRT), may be appraised as well. In this review, the clinical characteristics and pathophysiology of tremor syndromes, as well as long-term outcomes of DBS in different targets, will be summarized. The effectiveness and safety of lesioning procedures will be discussed, and an evidence-based clinical treatment approach for patients with drug-resistant tremor will be presented. Lastly, the future directions in the treatment of severe tremor syndromes will be elaborated.

Deep brain stimulation (DBS) is an effective treatment for Parkinson’s disease but can be complicated by side-effects such as cognitive decline. There is often a delay before this side-effect is apparent and the mechanism is unknown, making it difficult to identify patients at risk or select appropriate DBS settings. Here, we test whether connectivity between the stimulation site and other brain regions is associated with cognitive decline following DBS. First, we studied a unique patient cohort with cognitive decline following subthalamic DBS for Parkinson’s disease (n = 10) where re-programming relieved the side-effect without loss of motor benefit. Using resting state functional connectivity data from a large normative cohort (n = 1000), we computed connectivity between each stimulation site and the subiculum, an a priori brain region functionally connected to brain lesions causing memory impairment. Connectivity between DBS sites and this same subiculum region was significantly associated with DBS induced cognitive decline (P < 0.02). We next performed a data-driven analysis to identify connnections most associated with DBS induced cognitive decline. DBS sites causing cognitive decline (versus those that did not) were more connected to the anterior cingulate, caudate nucleus, hippocampus, and cognitive regions of the cerebellum (Pfwe< 0.05). The spatial topography of this DBS-based circuit for cognitive decline aligned with an a priori lesion-based circuit for memory impairment (P = 0.017). To begin translating these results into a clinical tool that might be used for DBS programming, we generated a “heatmap” in which the intensity of each voxel reflects the connectivity to our cognitive decline circuit. We then validated this heatmap using an independent dataset of PD patients in which cognitive performance was measured following subthalamic DBS (n = 33). Intersection of DBS sites with our heatmap was correlated with changes in the Mattis dementia rating scale one year after lead implantation (r = 0.39; p = 0.028). Finally, to illustrate how this heatmap might be used in clinical practice, we present a case that was flagged as “high risk” for cognitive decline based on intersection of the patient’s DBS site with our heatmap. This patient had indeed experienced cognitive decline and our heatmap was used to select alternative DBS parameters. At 14 days follow-up the patient’s cognition improved without loss of motor benefit. These results lend insight into the mechanism of DBS induced cognitive decline and suggest that connectivity-based heatmaps may help identify patients at risk and who might benefit from DBS reprogramming.