Structural connectivity predicts clinical outcomes of deep brain stimulation for Tourette syndrome

Abstract

Deep brain stimulation may be an effective therapy for select cases of severe, treatment-refractory Tourette syndrome; however, patient responses are variable, and there are no reliable methods to predict clinical outcomes. The objectives of this retrospective study were to identify the stimulation-dependent structural networks associated with improvements in tics and comorbid obsessive-compulsive behaviour, compare the networks across surgical targets, and determine if connectivity could be used to predict clinical outcomes. Volumes of tissue activated for a large multisite cohort of patients (n = 66) implanted bilaterally in globus pallidus internus (n = 34) or centromedial thalamus (n = 32) were used to generate probabilistic tractography to form a normative structural connectome. The tractography maps were used to identify networks that were correlated with improvement in tics or comorbid obsessive-compulsive behaviour and to predict clinical outcomes across the cohort. The correlated networks were then used to generate ‘reverse’ tractography to parcellate the total volume of stimulation across all patients to identify local regions to target or avoid. The results showed that for globus pallidus internus, connectivity to limbic networks, associative networks, caudate, thalamus, and cerebellum was positively correlated with improvement in tics; the model predicted clinical improvement scores (P = 0.003) and was robust to cross-validation. Regions near the anteromedial pallidum exhibited higher connectivity to the positively correlated networks than posteroventral pallidum, and volume of tissue activated overlap with this map was significantly correlated with tic improvement (P < 0.017). For centromedial thalamus, connectivity to sensorimotor networks, parietal-temporal-occipital networks, putamen, and cerebellum was positively correlated with tic improvement; the model predicted clinical improvement scores (P = 0.012) and was robust to cross-validation. Regions in the anterior/lateral centromedial thalamus exhibited higher connectivity to the positively correlated networks, but volume of tissue activated overlap with this map did not predict improvement (P > 0.23). For obsessive-compulsive behaviour, both targets showed that connectivity to the prefrontal cortex, orbitofrontal cortex, and cingulate cortex was positively correlated with improvement; however, only the centromedial thalamus maps predicted clinical outcomes across the cohort (P = 0.034), but the model was not robust to cross-validation. Collectively, the results demonstrate that the structural connectivity of the site of stimulation are likely important for mediating symptom improvement, and the networks involved in tic improvement may differ across surgical targets. These networks provide important insight on potential mechanisms and could be used to guide lead placement and stimulation parameter selection, as well as refine targets for neuromodulation therapies for Tourette syndrome.

Normative vs. patient-specific brain connectivity in Deep Brain Stimulation

“…Similarly, some DBS cohorts are rare to unique world-wide and individualized connectivity data was not acquired for them. Examples include patients suffering from Alzheimer’s Disease stimulated with fornical DBS within the ADvance trials (Laxton et al, 2010), DBS cohorts suffering from rare diseases such as Tourette’s Syndrome (Johnson et al, 2019) or STN-DBS datasets for treatment of cervical dystonia (Ostrem et al, 2011).…”

“…This concept has since then been applied to explore connectivity associated with clinical or behavioral changes in multiple diseases (Al-Fatly et al, 2019; J. C. Baldermann et al, 2019; Johnson et al, 2019; J. Baldermann et al, 2019; de Almeida Marcelino et al, 2019; Irmen et al, 2019; Li et al, 2019; Neumann et al, 2018).…”

Opportunities of connectomic neuromodulation

“…In OCD, connectivity with the DBS site was able to explain about 30% of variance in clinical improvement in a split-half design ( Baldermann et al, 2019b ). A similar connectome-based approachhas been used to study clinical response to DBS in chronic pain ( Fernandes et al, 2015 ), dystonia ( Corp et al, 2019 ), depression ( Choi et al, 2015 ; Riva-Posse et al,2014 ), treatment-refractory epilepsy ( Middlebrooks et al, 2018a ) and Tourette’s Syndrome ( Johnson et al, 2020 ). These studies established a direct–if correlational – link between clinical improvements and brain connectivity with the DBS site.…”

Connectivity Patterns of Deep Brain Stimulation Targets in Patients with Gilles de la Tourette Syndrome

“…Our analysis showed significant differences within the pallidal and also within the thalamic targets ( Figure 5 ). In previous tractography studies, the CM-Pf and the CM/Voi were merged into one target, and in some cases the two pallidal targets were also regarded as one [ 19 , 22 ]. Based on our findings, all targets must be analyzed separately to provide a recommendation for lead placement or targeted stimulation.…”

“…Recent studies have reported a correlation between the connectivity patterns of different DBS targets and a reduction in the symptoms of GTS patients [ 20 , 21 , 22 ]. However, most studies have focused on a single DBS target, with only one study comparing pallidal and thalamic stimulation [ 22 ]. The analyses were based either on normative structural connectome atlases or on patient-specific diffusion-weighted MRI, which complicates the comparison of the findings.…”