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

Abstract

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.

Keywords: Essential tremor; deep brain stimulation; dentato-rubro-thalamic tract.

Figure 1.

Example stimulation settings. Coronal view of the decussating dentato-rubro-thalamic tract (dDRTT; yellow) is shown relative to final electrode position and volumes of tissue activated (VTAs). (a) The standard-of-care VTA (blue) is shown for reference. (b) Connectivity-based treatment (CBT) VTA (green) is directionally oriented towards the dDRTT. (c) The sham VTA (red) is directionally oriented near 180 degrees from the CBT setting away from the dDRTT. The standard-of-care VTA was similarly oriented in direction as the CBT setting, but further in proximity from the tract.

Figure 2.

(a) Sagittal image showing the location of all electrodes relative to the ventral intermediate nucleus (Vim) (yellow), as defined in the deep brain stimulation intrinsic atlas (DISTAL). (b) Group volumes of tissue activated (VTAs) relative to Vim (yellow) for the standard-of-care programming settings (b; blue), connectivity-based treatment (CBT) setting (c; green) and sham settings (d; red).

Figure 3.

(a) Improvement in Fahn–Tolosa–Marín tremor rating score (TRS) for each patient with standard-of-care (SOC) programming, connectivity-based treatment (CBT) and sham setting. (b) Linear regression and 95% confidence interval of the distance from volume of tissue activated (VTA) to the central, maximal probability voxel of the decussating dentato-rubro-thalamic tract (dDRTT) and percentage improvement in TRS (R² = 0.24; y = −0.08x + 7.1; P = 0.04).

Figure 4.

Sagittal images with green crosshairs showing the peak centre-of-gravity (COG) of volumes of tissue activated (VTAs) relative to the group average decussating dentato-rubro-thalamic tract (dDRTT; red-orange heat map) for the (a) standard-of-care (SOC) setting, (b) connectivity-based treatment (CBT) setting and (c) sham setting. The CBT setting COG lies within the central portion of the dDRTT, while the SOC and sham settings are generally more anterior and superior.