Connectomic Basis for Tremor Control in Stereotactic Radiosurgical Thalamotomy

Abstract

Background and purpose: Given the increased use of stereotactic radiosurgical thalamotomy and other ablative therapies for tremor, new biomarkers are needed to improve outcomes. Using resting-state fMRI and MR tractography, we hypothesized that a "connectome fingerprint" can predict tremor outcomes and potentially serve as a targeting biomarker for stereotactic radiosurgical thalamotomy.

Materials and methods: We evaluated 27 patients who underwent unilateral stereotactic radiosurgical thalamotomy for essential tremor or tremor-predominant Parkinson disease. Percentage postoperative improvement in the contralateral limb Fahn-Tolosa-Marin Clinical Tremor Rating Scale (TRS) was the primary end point. Connectome-style resting-state fMRI and MR tractography were performed before stereotactic radiosurgery. Using the final lesion volume as a seed, "connectivity fingerprints" representing ideal connectivity maps were generated as whole-brain R-maps using a voxelwise nonparametric Spearman correlation. A leave-one-out cross-validation was performed using the generated R-maps.

Results: The mean improvement in the contralateral tremor score was 55.1% (SD, 38.9%) at a mean follow-up of 10.0 (SD, 5.0) months. Structural connectivity correlated with contralateral TRS improvement (r = 0.52; P = .006) and explained 27.0% of the variance in outcome. Functional connectivity correlated with contralateral TRS improvement (r = 0.50; P = .008) and explained 25.0% of the variance in outcome. Nodes most correlated with tremor improvement corresponded to areas of known network dysfunction in tremor, including the cerebello-thalamo-cortical pathway and the primary and extrastriate visual cortices.

Conclusions: Stereotactic radiosurgical targets with a distinct connectivity profile predict improvement in tremor after treatment. Such connectomic fingerprints show promise for developing patient-specific biomarkers to guide therapy with stereotactic radiosurgical thalamotomy.

Trial registration: ClinicalTrials.gov NCT03305588.

FIG 1.

Pipeline for generation of a single-subject lesion connectivity map and lesion tract map (A and B). The lesion is segmented from the posttreatment MR imaging (C). The mean BOLD time-series for the lesion is extracted and correlated to all other brain voxels. D, The resulting t-score map is a patient-specific lesion connectivity map. E, The lesion is used as a seed region to generate a patient-specific lesion tract map representing the probability of all streamlines connected to the lesion.

FIG 2.

Tract fingerprint representing the ideal tract connectivity pattern for tremor improvement. Commonly implicated areas of abnormality in tremor are identified, including the cerebello-thalamo-cortical motor network, as well as striate and extrastriate cortical regions.

FIG 3.

Group tract R-map of pathways most correlated with tremor improvement.

FIG 4.

A, Leave-one-out cross-validation of the tract fingerprint shows greater similarity of the individual’s lesion tract map to the fingerprint map predicted measured improvement in tremor (r = 0.52; P  = .006). B, Leave-one-out cross-validation of the functional fingerprint also shows that greater similarity of the individual’s lesion functional map to the fingerprint map predicted measured improvement in tremor (r = 0.50; P  = .008).

FIG 5.

Functional fingerprint representing the ideal tract connectivity pattern for tremor improvement. Similar to the tract fingerprint, commonly implicated areas of abnormality in tremor are identified, including the cerebello-thalamo-cortical motor network as well as the striate and extrastriate cortical regions.