Using neural biomarkers to personalize dosing of vagus nerve stimulation.

BACKGROUND: Vagus nerve stimulation (VNS) is an established therapy for treating a variety of chronic diseases, such as epilepsy, depression, obesity, and for stroke rehabilitation. However, lack of precision and side-effects have hindered its efficacy and extension to new conditions. Achieving a better understanding of the relationship between VNS parameters and neural and physiological responses is therefore necessary to enable the design of personalized dosing procedures and improve precision and efficacy of VNS therapies. METHODS: We used biomarkers from recorded evoked fiber activity and short-term physiological responses (throat muscle, cardiac and respiratory activity) to understand the response to a wide range of VNS parameters in anaesthetised pigs. Using signal processing, Gaussian processes (GP) and parametric regression models we analyse the relationship between VNS parameters and neural and physiological responses. RESULTS: Firstly, we illustrate how considering multiple stimulation parameters in VNS dosing can improve the efficacy and precision of VNS therapies. Secondly, we describe the relationship between different VNS parameters and the evoked fiber activity and show how spatially selective electrodes can be used to improve fiber recruitment. Thirdly, we provide a detailed exploration of the relationship between the activations of neural fiber types and different physiological effects. Finally, based on these results, we discuss how recordings of evoked fiber activity can help design VNS dosing procedures that optimize short-term physiological effects safely and efficiently. CONCLUSION: Understanding of evoked fiber activity during VNS provide powerful biomarkers that could improve the precision, safety and efficacy of VNS therapies.

Online Bayesian optimization of vagus nerve stimulation.

Objective.In bioelectronic medicine, neuromodulation therapies induce neural signals to the brain or organs, modifying their function. Stimulation devices capable of triggering exogenous neural signals using electrical waveforms require a complex and multi-dimensional parameter space to control such waveforms. Determining the best combination of parameters (waveform optimization or dosing) for treating a particular patient's illness is therefore challenging. Comprehensive parameter searching for an optimal stimulation effect is often infeasible in a clinical setting due to the size of the parameter space. Restricting this space, however, may lead to suboptimal therapeutic results, reduced responder rates, and adverse effects.Approach. As an alternative to a full parameter search, we present a flexible machine learning, data acquisition, and processing framework for optimizing neural stimulation parameters, requiring as few steps as possible using Bayesian optimization. This optimization builds a model of the neural and physiological responses to stimulations, enabling it to optimize stimulation parameters and provide estimates of the accuracy of the response model. The vagus nerve (VN) innervates, among other thoracic and visceral organs, the heart, thus controlling heart rate (HR), making it an ideal candidate for demonstrating the effectiveness of our approach.Main results.The efficacy of our optimization approach was first evaluated on simulated neural responses, then applied to VN stimulation intraoperatively in porcine subjects. Optimization converged quickly on parameters achieving target HRs and optimizing neural B-fiber activations despite high intersubject variability.Significance.An optimized stimulation waveform was achieved in real time with far fewer stimulations than required by alternative optimization strategies, thus minimizing exposure to side effects. Uncertainty estimates helped avoiding stimulations outside a safe range. Our approach shows that a complex set of neural stimulation parameters can be optimized in real-time for a patient to achieve a personalized precision dosing.

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.