Lateral cerebellothalamic tract activation underlies DBS therapy for Essential Tremor

Abstract

Background: While deep brain stimulation (DBS) therapy can be effective at suppressing tremor in individuals with medication-refractory Essential Tremor, patient outcome variability remains a significant challenge across centers. Proximity of active electrodes to the cerebellothalamic tract (CTT) is likely important in suppressing tremor, but how tremor control and side effects relate to targeting parcellations within the CTT and other pathways in and around the ventral intermediate (VIM) nucleus of thalamus remain unclear.

Methods: Using ultra-high field (7T) MRI, we developed high-dimensional, subject-specific pathway activation models for 23 directional DBS leads. Modeled pathway activations were compared with post-hoc analysis of clinician-optimized DBS settings, paresthesia thresholds, and dysarthria thresholds. Mixed-effect models were utilized to determine how the six parcellated regions of the CTT and how six other pathways in and around the VIM contributed to tremor suppression and induction of side effects.

Results: The lateral portion of the CTT had the highest activation at clinical settings (p < 0.05) and a significant effect on tremor suppression (p < 0.001). Activation of the medial lemniscus and posterior-medial CTT was significantly associated with severity of paresthesias (p < 0.001). Activation of the anterior-medial CTT had a significant association with dysarthria (p < 0.05).

Conclusions: This study provides a detailed understanding of the fiber pathways responsible for therapy and side effects of DBS for Essential Tremor, and suggests a model-based programming approach will enable more selective activation of lateral fibers within the CTT.

Keywords: Cerebellothalamic tract; Deep brain stimulation; Essential Tremor; Pathway activation models.

Fig. 1.. Subject-specific pathway activation models of DBS for Essential Tremor.

(A) High resolution brain imaging was performed on each subject to define anatomy, tissue conductivity, and lead localization. (B) Predicting pathway activation involved coupling finite element models, pathway morphologies, and biophysical representations of individual axons.

Fig. 2.. Pathways modeled for each DBS lead implant.

Examples are shown for lead implants with electrodes primarily in (A) VIM and (B) PSA, with visualization in the sagittal (left) and coronal (right) perspectives. A subsample of axonal fibers are shown for the cerebellothalamic tract with axons terminating in VIMi (blue) and VIMe (yellow); medial lemniscus (green); and corticothalamocortical pathways: S1-VC (green), M1-VIM (yellow, blue), pMC-VOA/P (violet). The arrow represents the row with the electrode(s) used in the clinician-optimized DBS setting. Pathways not pictured include axons terminating in Rt, and the thalamic and lenticular fascicularis pathways.

Fig. 3.. Subject-specific pathway activation for clinician-optimized DBS settings.

Activation percentages are shown (A) together for all 23 leads, and (B) for each subject.

Fig. 4.. Pathway activation associations with DBS therapy.

(A) Activation across all pathways (*p < 0.05, **p < 0.005), with the white/black dot representing the median and the horizontal line representing the mean activation for each pathway. A black median dot represents significant pathway activation compared to zero (p < 0.001). Inset shows the mixed effects model results for the ZI, CTT, and ML pathways (*p < 0.0001). Odds ratio estimates with 95% confidence intervals not overlapping the dotted grey line were considered to have a significant effect on therapy outcome. (B) The CTT was subdivided into 6 pathways with fibers entering the posterior (P) and anterior (A) Rt, VIMe and VIMi regions of thalamus. Significantly different pathway activations are demarcated by *p < 0.001. (C) Mixed effects model results are shown for subsections of CTT that had greater than 20% activation at clinician-optimized stimulation settings (*p < 0.001).

Fig. 5.. Pathway activation at persistent paresthesia thresholds.

(A) Activation of pathways at stimulation thresholds for persistent paresthesia was high for ML (*p < 0.001) along with CTT and ZI. A black median dot represents significant pathway activation compared to zero (p < 0.001). (B) A mixed effects model for paresthesia outcome showed that ML and CTT were similarly associated with paresthesia presence and severity (*p < 0.001). (C) Mixed effects model results for paresthesia outcome including the 6 subsections of CTT fibers showed posterior VIMi as the CTT fibers most associated with paresthesias (*p < 0.05, **p < 0.001).

Fig. 6.. Pathway activation at thresholds for stimulation-induced dysarthria.

(A) Pathway activation at thresholds for stimulation-induced dysarthria were elevated for both ZI and pathways within the CTT. (B) Mixed effects model results for dysarthria showed CTT as the only pathway significantly associated with dysarthria. (C) A mixed effects model for dysarthria including directional subsections of CTT fibers showed the anterior VIMi fibers of the CTT as the only subsection significantly associated with dysarthria.

Fig. 7.. Pathway activation across therapeutic and side effect-inducing DBS settings.

(A) Representative example (Subject 12-L) of modeled pathways, including M1 to VIMe (yellow), M1 to VIMi (blue), pMC to VOA/P (lavender), S1 to VC (green), ML (green), CTT to VIMe (yellow) and CTT to VIMi (blue). (B) Pathway activation using ring mode (contact 3ABC) as the cathode (0.5 mA) resulted in complete arrest of tremor without inducing side effects. Activated axons appear in their corresponding pathway color. Non-activated axons are transparent grey. (C) Persistent paresthesias were induced using contact 1 as the cathode (2.5 mA), and (D) dysarthria was generated using contact 4 as the cathode (4 mA). In both cases, full tremor control was also achieved.