Deep Brain Stimulation: From Sweet Spots to Sweet Networks?

Member Authors
Hollunder B, Ganos C, Horn A.
Biol Psychiatry Cogn Neurosci Neuroimaging.


Tourette syndrome (TS) constitutes a childhood-onset brain disorder with the defining presence of tic behaviors. Tics are repetitive movements or sounds that resemble voluntary actions but appear without embedment to discernable context (1). Effective therapy is complicated by phenotypical hetero-geneity, which arises not only from a wide variability of presenting tic behaviors among individuals, but also from commonly co-occurring neuropsychiatric comorbidities-such as obsessive-compulsive behaviors (OCBs), attention-deficit/ hyperactivity disorder, anxiety, or depression (1-5). For select, severe cases of TS that are refractory to psychophar-macological or behavioral first-line interventions, deep brain stimulation (DBS) represents a valuable alternative treatment option (1-5) that can reduce tic severity by at least 50% in more than half of patients across proposed targets (2). While pioneered by Vandewalle et al. (6) in 1999 with stimulation to the nucleus ventro-oralis internus and the centromedial-parafascicular thalamic complex, further exploration of this modality as a potential therapy for TS has moved slowly. In particular, owing to variable effectiveness and proportions of nonresponders across several case series, mostly comprising small samples, along with only limited numbers of randomized controlled trials conducted to date, the treatment could not be fully established, nor could a single optimal target be determined among multiple proposed stimulation sites within the cortico-basal ganglia-thalamo-cortical circuit (2,4). Moreover, ambiguities regarding the optimal subterritory within some of these anatomical sites remain [e.g., the posterolateral vs. ante-romedial globus pallidus internus (GPi) (2,4)]. In the current issue of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, Johnson et al. (3) zoom into the GPi target zone and apply a sophisticated methodological framework to study localized DBS network effects associated with clinical improvements along the TS symptom spectrum. Based on retrospective, longitudinal multisite data of 35 patients receiving bilateral GPi DBS, the authors first integrated individual electrode locations and stimulation parameters into both single-and bihemispheric activation models for specific normative basal ganglia and internal capsule pathways (7). Comparably higher percentages of stimulation settings activated the associative pallido-subthalamic pathway, ansa lenticularis, and anterior lenticular fasciculus, as well as the premotor and prefrontal internal capsule pathways. Although lateralized stimulation parameters were uncommon among patients, several bundles (most prominently the ansa lenticularis and internal capsule pathways) exhibited asymmetry, possibly owing to hemispheric differences in lead localization. Second, the resulting bilateral models of estimated pathway activation were related to tic (operationalized via the Yale Global Tic Severity Scale) and comorbid OCB improvements (assessed via the Yale-Brown Obsessive Compulsive Behavior Scale) across patients and stimulation settings. Tic improvement significantly correlated with the relative bilateral degree of activation of the associative pallido-subthalamic tract and ansa len-ticularis, as well as the prefrontal internal capsule pathway. OCB improvement, on the other hand, was associated with activation of associative and sensorimotor pallido-subthalamic pathways, along with all three internal capsule pathway partitions. Finally, recombinations of pathway activation models with multiple patient-wise stimulation parameter settings and clinical variables (months since surgery, baseline severity, and pathway activation) were compared and cross-validated regarding their predictive utility for postoperative tic or comorbid OCB improvements over multiple follow-up time points. The best-fit model for tic outcomes comprised baseline severity combined with bihemispheric associative pallido-subthalamic pathway activation, while the winning model for OCB improvements included baseline severity and bilateral sensorimotor pallido-subthalamic pathway activation. Both models were predictive for symptom-specific outcome across individuals, underscoring their generalizability to novel patients. In this study, Johnson et al. (3) unite numerous strengths that allow for significant conclusions, most notably through an innovative combination of state-of-the-art resources. As one particular highlight, the study’s comparably big sample goes against the odds of only handfuls of operations performed on patients with TS at individual centers annually. Doing so was largely enabled by the International TS DBS Registry and Database (4) (https://tourettedeepbrainstimulationregistry.ese. initiated by Michael Okun in a combined effort across multiple international DBS sites. This platform is exceptional in its kind, and with aggregation of currently 320 TS DBS cases, it sets an important prototype for data sharing and DBS registries with the potential for efficacious and sufficiently statistically powered research into the effects of DBS for rare, and presently investigational, indications. The article by Johnson et al. (3) is a prime example of how much can be achieved if DBS centers collaborate on a global scale. Apart from that, Johnson et al. (3) pave an avenue toward in vivo simulation of white matter pathway activations at particularly granular levels that-if augmented and replicated by future studies-may hold promise for precise planning of stereotactic targeting and postoperative stimulation parameter tuning at the single-subject level. Such fine-grained scale of the anatomical model definition was only possible.
Published: Oct 2021