Directed stimulation of the dentato-rubro-thalamic tract for deep brain stimulation in essential tremor: a blinded clinical trial.

OBJECTIVE: Observational studies utilising diffusion tractography have suggested a common mechanism for tremor alleviation in deep brain stimulation for essential tremor: the decussating portion of the dentato-rubro-thalamic tract. We hypothesised that directional stimulation of the dentato-rubro-thalamic tract would result in greater tremor improvement compared to sham programming, as well as comparable improvement as more tedious standard-of-care programming. METHODS: A prospective, blinded crossover trial was performed to assess the feasibility, safety and outcomes of programming based solely on dentato-rubro-thalamic tract anatomy. Using magnetic resonance imaging diffusion-tractography, the dentato-rubro-thalamic tract was identified and a connectivity-based treatment setting was derived by modelling a volume of tissue activated using directional current steering oriented towards the dentato-rubro-thalamic tract centre. A sham setting was created at approximately 180° opposite the connectivity-based treatment. Standard-of-care programming at 3 months was compared to connectivity-based treatment and sham settings that were blinded to the programmer. The primary outcome measure was percentage improvement in the Fahn-Tolosa-Marín tremor rating score compared to the preoperative baseline. RESULTS: Among the six patients, tremor rating scores differed significantly among the three experimental conditions (P=0.030). The mean tremor rating score improvement was greater with the connectivity-based treatment settings (64.6% ± 14.3%) than with sham (44.8% ± 18.6%; P=0.031) and standard-of-care programming (50.7% ± 19.2%; P=0.062). The distance between the centre of the dentato-rubro-thalamic tract and the volume of tissue activated inversely correlated with the percentage improvement in the tremor rating score (R2=0.24; P=0.04). No significant adverse events were encountered. CONCLUSIONS: Using a blinded, crossover trial design, we have shown the technical feasibility, safety and potential efficacy of connectivity-based stimulation settings in deep brain stimulation for treatment of essential tremor.

Connectivity correlates to predict essential tremor deep brain stimulation outcome: Evidence for a common treatment pathway.

BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) is the most common surgical treatment for essential tremor (ET), yet there is variation in outcome and stimulation targets. This study seeks to consolidate proposed stimulation "sweet spots," as well as assess the value of structural connectivity in predicting treatment outcomes. MATERIALS AND METHODS: Ninety-seven ET individuals with unilateral thalamic DBS were retrospectively included. Using normative brain connectomes, structural connectivity measures were correlated with the percentage improvement in contralateral tremor, based on the Fahn-Tolosa-Marin tremor rating scale (TRS), after parameter optimization (range 3.1-12.9 months) using a leave-one-out cross-validation in 83 individuals. The predictive feature map was used for cross-validation in a separate cohort of 14 ET individuals treated at another center. Lastly, estimated volumes of tissue activated (VTA) were used to assess a treatment "sweet spot," which was compared to seven previously reported stimulation sweet spots and their relationship to the tract identified by the predictive feature map. RESULTS: In the training cohort, structural connectivity between the VTA and dentato-rubro-thalamic tract (DRTT) correlated with contralateral tremor improvement (R = 0.41; p < 0.0001). The same connectivity profile predicted outcomes in a separate validation cohort (R = 0.59; p = 0.028). The predictive feature map represented the anatomical course of the DRTT, and all seven analyzed sweet spots overlapped the predictive tract (DRTT). CONCLUSIONS: Our results strongly support the possibility that structural connectivity is a predictor of contralateral tremor improvement in ET DBS. The results suggest the future potential for a patient-specific functionally based surgical target. Finally, the results showed convergence in "sweet spots" suggesting the importance of the DRTT to the outcome.

Edge-enhancing gradient echo with multi-image co-registration and averaging (EDGE-MICRA) for targeting thalamic centromedian and parafascicular nuclei.

BACKGROUND AND PURPOSE: Deep brain stimulation of the thalamus is an effective treatment for multiple neurological disorders. The centromedian and parafascicular nuclei are recently emerging targets for multiple conditions, such as epilepsy and Tourette syndrome; however, their limited visibility on conventional magnetic resonance imaging sequences has been a major obstacle. The goal of this study was to demonstrate the feasibility of a high-resolution and high-contrast targeting sequence for centromedian-parafascicular deep brain stimulation using a recently described magnetic resonance imaging sequence, three-dimensional edge-enhancing gradient echo. METHODS: The three-dimensional edge-enhancing gradient echo sequence was performed on a normal volunteer for a total of six acquisitions. Multi-image co-registration and averaging was performed by first co-registering each of the six scans and then averaging to produce an edge-enhancing gradient echo-multi-image co-registration and averaging scan. The averaging was also performed for two, three, four and five scans to assess the change in the signal-to-noise ratio and identify the ideal balance of image quality and scan time. RESULTS: The edge-enhancing gradient echo-multi-image co-registration and averaging scan allowed clear boundary delineation of the centromedian and parafascicular nuclei. The signal-to-noise ratio increased as a function of increasing scan number, but the added gain was small beyond four scans for the imaging parameters used in this study. CONCLUSIONS: The recently described three-dimensional edge-enhancing gradient echo sequence provides an easily implementable approach, using widely available magnetic resonance imaging technology without complex post-processing techniques, to delineate centromedian and parafascicular nuclei for deep brain stimulation targeting.

Comparative connectivity correlates of dystonic and essential tremor deep brain stimulation.

The pathophysiology of dystonic tremor and essential tremor remains partially understood. In patients with medication-refractory dystonic tremor or essential tremor, deep brain stimulation (DBS) targeting the thalamus or posterior subthalamic area has evolved into a promising treatment option. However, the optimal DBS targets for these disorders remains unknown. This retrospective study explored the optimal targets for DBS in essential tremor and dystonic tremor using a combination of volumes of tissue activated estimation and functional and structural connectivity analyses. We included 20 patients with dystonic tremor who underwent unilateral thalamic DBS, along with a matched cohort of 20 patients with essential tremor DBS. Tremor severity was assessed preoperatively and approximately 6 months after DBS implantation using the Fahn-Tolosa-Marin Tremor Rating Scale. The tremor-suppressing effects of DBS were estimated using the percentage improvement in the unilateral tremor-rating scale score contralateral to the side of implantation. The optimal stimulation region, based on the cluster centre of gravity for peak contralateral motor score improvement, for essential tremor was located in the ventral intermediate nucleus region and for dystonic tremor in the ventralis oralis posterior nucleus region along the ventral intermediate nucleus/ventralis oralis posterior nucleus border (4 mm anterior and 3 mm superior to that for essential tremor). Both disorders showed similar functional connectivity patterns: a positive correlation between tremor improvement and involvement of the primary sensorimotor, secondary motor and associative prefrontal regions. Tremor improvement, however, was tightly correlated with the primary sensorimotor regions in essential tremor, whereas in dystonic tremor, the correlation was tighter with the premotor and prefrontal regions. The dentato-rubro-thalamic tract, comprising the decussating and non-decussating fibres, significantly correlated with tremor improvement in both dystonic and essential tremor. In contrast, the pallidothalamic tracts, which primarily project to the ventralis oralis posterior nucleus region, significantly correlated with tremor improvement only in dystonic tremor. Our findings support the hypothesis that the pathophysiology underpinning dystonic tremor involves both the cerebello-thalamo-cortical network and the basal ganglia-thalamo-cortical network. Further our data suggest that the pathophysiology of essential tremor is primarily attributable to the abnormalities within the cerebello-thalamo-cortical network. We conclude that the ventral intermediate nucleus/ventralis oralis posterior nucleus border and ventral intermediate nucleus region may be a reasonable DBS target for patients with medication-refractory dystonic tremor and essential tremor, respectively. Uncovering the pathophysiology of these disorders may in the future aid in further improving DBS outcomes.

Variability Between Direct and Indirect Targeting of the Anterior Nucleus of the Thalamus.

BACKGROUND: Preoperative thalamic targeting methods have historically relied on indirect targeting techniques that do not fully account for variances in anatomy or for thalamic atrophy in epilepsy. We aimed to address variability noted between traditional indirect targeting and direct targeting methods for the anterior nucleus of the thalamus (ANT). METHODS: Fifteen consecutive patients undergoing ANT deep brain stimulator placement were evaluated (30 thalamic nuclei). Direct ANT targeting was performed using a fast gray matter acquisition T1 inversion recovery sequence and compared with standard stereotactic coordinates. Thalamic volumes were calculated for each patient, and degree of thalamic volume loss was assessed compared with matched control subjects. Vertex analysis was performed to assess shape changes in the thalamus compared with age- and sex-matched subjects. RESULTS: There was significant variation between direct and indirect targets in the y-axis and z-axis on both sides. On the left, the direct target was located at y = 2 ± 1.3 mm and z = 9.3 ± 1.8 mm (both P = 0.02). On the right, the direct target was located at y = 2.9 ± 1.8 mm and z = 9.2 ± 2 mm (both P ≤ 0.0003). There was no significant difference in the x-coordinate on either side (P > 0.5). Additionally, there was a correlation between thalamic volume and difference between direct and indirect targets in the y-axis and the z-axis. CONCLUSIONS: We showed a significant difference in direct and indirect targeting in the y-axis and z-axis when targeting the ANT for deep brain stimulation for epilepsy. This difference is correlated to thalamic volume, with a larger difference noted in patients with thalamic atrophy.