Eric R Cole’s research while affiliated with Georgia Institute of Technology and other places

Objectives: To determine if motor evoked potentials (mEP) – stimulation-induced muscle activation measured using electromyography – can serve as a biomarker of corticobulbar (CBT) and corticospinal (CST) tract activation for deep brain stimulation (DBS) programming. Methods: In 12 patients with Parkinson′s disease and subthalamic or pallidal DBS, contact mapping determined clinical motor side effect thresholds. For equivalent stimulation parameters, EMG was recorded from cranial and arm muscles to determine the presence, peak amplitudes and latencies of mEP. Clinical and mEP thresholds were compared and accuracy metrics calculated to assess similarity between mEP and reported side effects. Results: The mEP amplitudes increased with stimulation intensity. Latencies were shorter for cranial muscles, which were more likely to generate an mEP. Clinical and mEP thresholds were significantly correlated (R2 = 0.31; p=0.0006), although most mEP thresholds were lower than clinical side effect thresholds. The mEP accuracy in predicting side effects was 0.72, with a sensitivity of 0.68 and a specificity of 0.73. Conclusions: EMG-recorded mEP correlated well with clinical side effects, and mEP often indicated subclinical CBT and CST activations. Significance: This study characterizes motor potentials evoked by DBS and demonstrates their utility as an objective biomarker for motor side effect threshold detection during DBS programming.

Deep brain stimulation (DBS) is an effective treatment for Parkinson’s disease (PD); however, there is limited understanding of which subthalamic pathways are recruited in response to stimulation. Here, by focusing on the polarity of the stimulus waveform (cathodic vs. anodic), our goal was to elucidate biophysical mechanisms that underlie electrical stimulation in the human brain. In clinical studies, cathodic stimulation more easily triggers behavioral responses, but anodic DBS broadens the therapeutic window. This suggests that neural pathways involved respond preferentially depending on stimulus polarity. To experimentally compare the activation of therapeutically relevant pathways during cathodic and anodic subthalamic nucleus (STN) DBS, pathway activation was quantified by measuring evoked potentials resulting from antidromic or orthodromic activation in 15 PD patients undergoing DBS implantation. Cortical evoked potentials (cEP) were recorded using subdural electrocorticography, DBS local evoked potentials (DLEP) were recorded from non-stimulating contacts and EMG activity was recorded from arm and face muscles. We measured: 1) the amplitude of short-latency cEP, previously demonstrated to reflect activation of the cortico-STN hyperdirect pathway, 2) DLEP amplitude thought to reflect activation of STN-globus pallidus (GP) pathway, and 3) amplitudes of very short-latency cEP and motor evoked potentials (mEP) for activation of cortico-spinal/bulbar tract (CSBT). We constructed recruitment and strength-duration curves for each EP/pathway to compare the excitability for different stimulation polarities. We compared experimental data with the most advanced DBS computational models. Our results provide experimental evidence that subcortical cathodic and anodic stimulation activate the same pathways in the STN region, and that cathodic stimulation is in general more efficient. However, relative efficiency varies for different pathways so that anodic stimulation is the least efficient in activating CSBT, more efficient in activating the HDP and as efficient as cathodic in activating STN-GP pathway. Our experiments confirm biophysical model predictions regarding neural activations in the central nervous system and provide evidence that stimulus polarity has differential effects on passing axons, terminal synapses, and local neurons. Comparison of experimental results with clinical DBS studies provides further evidence that the hyperdirect pathway may be involved in the therapeutic mechanisms of DBS.

Deep brain stimulation (DBS) requires individualized programming of stimulation parameters, a time-consuming process performed manually by clinicians with specialized training. This process limits DBS accessibility, delays treatment, and constrains the potential for next-generation technology to improve patient outcomes. This review describes technological advancements that could automate DBS programming, focusing on Parkinson’s disease biomarkers that can provide objective outcome measurement and algorithms that can quickly and automatically identify optimal DBS settings. We first define key performance criteria for an automated programming system, including effectiveness, efficiency, and ease of use, and then describe and evaluate each component with respect to these criteria. We conclude that the state of current research provides a strong foundation for developing automated DBS programming. The primary remaining obstacle lies in identifying and deploying the best combination of available techniques that will overcome the high entry barrier needed for wide-scale clinical deployment and adoption.

A bstract During cortical spreading depolarization (CSD), neurons exhibit a dramatic increase in cytosolic calcium, which may be integral to CSD-mediated seizure termination. This calcium increase greatly exceeds that during seizures, suggesting the calcium source may not be solely extracellular. Thus, we sought to determine if the endoplasmic reticulum (ER), the largest intracellular calcium store, is involved. We developed a two-photon calcium imaging paradigm to simultaneously record the cytosol and ER during seizures in awake mice. Paired with direct current recording, we reveal that CSD can manifest as a slow post-ictal cytosolic calcium wave with a concomitant depletion of ER calcium that is spatiotemporally consistent with a calcium-induced calcium release. Importantly, we observed both naturally occurring and electrically induced CSD suppressed post-ictal epileptiform activity. Collectively, this work links ER dynamics to CSD, which serves as an innate process for seizure suppression and a potential mechanism underlying therapeutic electrical stimulation for epilepsy.

Objective. To treat neurological and psychiatric diseases with deep brain stimulation (DBS), a trained clinician must select parameters for each patient by monitoring their symptoms and side-effects in a months-long trial-and-error process, delaying optimal clinical outcomes. Bayesian optimization has been proposed as an efficient method to quickly and automatically search for optimal parameters. However, conventional Bayesian optimization does not account for patient safety and could trigger unwanted or dangerous side-effects. Approach. In this study we develop SAFE-OPT, a Bayesian optimization algorithm designed to learn subject-specific safety constraints to avoid potentially harmful stimulation settings during optimization. We prototype and validate SAFE-OPT using a rodent multielectrode stimulation paradigm which causes subject-specific performance deficits in a spatial memory task. We first use data from an initial cohort of subjects to build a simulation where we design the best SAFE-OPT configuration for safe and accurate searching in silico. Main results. We then deploy both SAFE-OPT and conventional Bayesian optimization without safety constraints in new subjects in vivo, showing that SAFE-OPT can find an optimally high stimulation amplitude that does not harm task performance with comparable sample efficiency to Bayesian optimization and without selecting amplitude values that exceed the subject’s safety threshold. Significance. The incorporation of safety constraints will provide a key step for adopting Bayesian optimization in real-world applications of DBS.

Brain stimulation holds promise for treating brain disorders, but personalizing therapy remains challenging. Effective treatment requires establishing a functional link between stimulation parameters and brain response, yet traditional methods like random sampling (RS) are inefficient and costly. To overcome this, we developed an active learning (AL) framework that identifies optimal relationships between stimulation parameters and brain response with fewer experiments. We validated this framework through three experiments: (1) in silico modeling with synthetic data from a Parkinson’s disease model, (2) in silico modeling with real data from a non-human primate, and (3) in vivo modeling with a real-time rat optogenetic stimulation experiment. In each experiment, we compared AL models to RS models, using various query strategies and stimulation parameters (amplitude, frequency, pulse width). AL models consistently outperformed RS models, achieving lower error on unseen test data in silico (p<0.0056, N=1000) and in vivo (p=0.0036, N=20). This approach represents a significant advancement in brain stimulation, potentially improving both research and clinical applications by making them more efficient and effective. Our findings suggest that AL can substantially reduce the cost and time required for developing personalized brain stimulation therapies, paving the way for more effective and accessible treatments for brain disorders.