Sign-specific stimulation 'hot' and 'cold' spots in Parkinson's disease validated with machine learning

Deep brain stimulation of the subthalamic nucleus has become a standard therapy for Parkinson's disease. Despite extensive experience, however, the precise target of optimal stimulation and the relationship between site of stimulation and alleviation of individual signs remains unclear. We examined whether machine learning could predict the benefits in specific Parkinsonian signs when informed by precise locations of stimulation. We studied 275 Parkinson's disease patients who underwent subthalamic nucleus deep brain stimulation between 2003 and 2018. We selected pre-deep brain stimulation and best available post-deep brain stimulation scores from motor items of the Unified Parkinson's Disease Rating Scale (UPDRS-III) to discern sign-specific changes attributable to deep brain stimulation. Volumes of tissue activated were computed and weighted by (i) tremor, (ii) rigidity, (iii) bradykinesia and (iv) axial signs changes. Then, sign-specific sites of optimal ('hot spots') and suboptimal efficacy ('cold spots') were defined. These areas were subsequently validated using machine learning prediction of sign-specific outcomes with in-sample and out-of-sample data (n = 51 subthalamic nucleus deep brain stimulation patients from another institution). Tremor and rigidity hot spots were largely located outside and dorsolateral to the subthalamic nucleus whereas hot spots for bradykinesia and axial signs had larger overlap with the subthalamic nucleus. Using volume of tissue activated overlap with sign-specific hot and cold spots, support vector machine classified patients into quartiles of efficacy with ≥92% accuracy. The accuracy remained high (68-98%) when only considering volume of tissue activated overlap with hot spots but was markedly lower (41-72%) when only using cold spots. The model also performed poorly (44-48%) when using only stimulation voltage, irrespective of stimulation location. Out-of-sample validation accuracy was ≥96% when using volume of tissue activated overlap with the sign-specific hot and cold spots. In two independent datasets, distinct brain areas could predict sign-specific clinical changes in Parkinson's disease patients with subthalamic nucleus deep brain stimulation. With future prospective validation, these findings could individualize stimulation delivery to optimize quality of life improvement.