Practical Closed-Loop Strategies for Deep Brain Stimulation: Lessons From Chronic Pain

Deep brain stimulation (DBS) is a plausible therapy for various neuropsychiatric disorders, though continuous tonic stimulation without regard to underlying physiology (open-loop) has had variable success. Recently available DBS devices can sense neural signals which, in turn, can be used to control stimulation in a closed-loop mode. Closed-loop DBS strategies may mitigate many drawbacks of open-loop stimulation and provide more personalized therapy. These devices contain many adjustable parameters that control how the closed-loop system operates, which need to be optimized using a combination of empirically and clinically informed decision making. We offer a practical guide for the implementation of a closed-loop DBS system, using examples from patients with chronic pain. Focusing on two research devices from Medtronic, the Activa PC+S and Summit RC+S, we provide pragmatic details on implementing closed- loop programming from a clinician’s perspective. Specifically, by combining our understanding of chronic pain with data-driven heuristics, we describe how to tune key parameters to handle feature selection, state thresholding, and stimulation artifacts. Finally, we discuss logistical and practical considerations that clinicians must be aware of when programming closed-loop devices.

Wireless, battery-free, and fully implantable electrical neurostimulation in freely moving rodents

Implantable deep brain stimulation (DBS) systems are utilized for clinical treatment of diseases such as Parkinson’s disease and chronic pain. However, long-term efficacy of DBS is limited, and chronic neuroplastic changes and associated therapeutic mechanisms are not well understood. Fundamental and mechanistic investigation, typically accomplished in small animal models, is difficult because of the need for chronic stimulators that currently require either frequent handling of test subjects to charge battery-powered systems or specialized setups to manage tethers that restrict experimental paradigms and compromise insight. To overcome these challenges, we demonstrate a fully implantable, wireless, battery-free platform that allows for chronic DBS in rodents with the capability to control stimulation parameters digitally in real time. The devices are able to provide stimulation over a wide range of frequencies with biphasic pulses and constant voltage control via low-impedance, surface-engineered platinum electrodes. The devices utilize off-the-shelf components and feature the ability to customize electrodes to enable broad utility and rapid dissemination. Efficacy of the system is demonstrated with a readout of stimulation-evoked neural activity in vivo and chronic stimulation of the medial forebrain bundle in freely moving rats to evoke characteristic head motion for over 36 days.

Low‐Level Tragus Stimulation Modulates Atrial Alternans and Fibrillation Burden in Patients With Paroxysmal Atrial Fibrillation

Background Low‐level tragus stimulation (LLTS) has been shown to significantly reduce atrial fibrillation (AF) burden in patients with paroxysmal AF. P‐wave alternans (PWA) is believed to be generated by the same substrate responsible for AF. Hence, PWA may serve as a marker in guiding LLTS therapy. We investigated the utility of PWA in guiding LLTS therapy in patients with AF. Methods and Results Twenty‐eight patients with AF were randomized to either active LLTS or sham (earlobe stimulation). LLTS was delivered through a transcutaneous electrical nerve stimulation device (pulse width 200 μs, frequency 20 Hz, amplitude 10–50 mA), for 1 hour daily over a 6‐month period. AF burden over 2‐week periods was assessed by noninvasive continuous ECG monitoring at baseline, 3 months, and 6 months. A 5‐minute control ECG for PWA analysis was recorded during all 3 follow‐up visits. Following the control ECG, an additional 5‐minute ECG was recorded during active LLTS in all patients. At baseline, acute LLTS led to a significant rise in PWA burden. However, active patients receiving chronic LLTS demonstrated a significant reduction in both PWA and AF burden after 6 months ( P <0.05). Active patients who demonstrated an increase in PWA burden with acute LLTS showed a significant drop in AF burden after 6 months of chronic LLTS. Conclusions Chronic, intermittent LLTS resulted in lower PWA and AF burden than did sham control stimulation. Our results support the use of PWA as a potential marker for guiding LLTS treatment of paroxysmal AF.

Distinct generation of subjective vividness and confidence during naturalistic memory retrieval in the angular gyrus

Subjective experience of remembering is a hallmark of episodic memory, which is deemed crucial for effective behavior. A fundamental and enduring puzzle is the origin of confidence in memory; for example, does the confidence during episodic retrieval depend upon the subjective sensed vividness? The angular gyrus (AnG) exhibits a sensitivity to the subjective experience of remembering, but its direct contribution to the monitoring of subjective mnemonic experience has hitherto been lacking. Here, using a naturalistic video-watching paradigm combined with repetitive transcranial magnetic stimulation (rTMS) and resting-state functional magnetic resonance imaging, we found that pre-retrieval rTMS targeting the left AnG selectively alters the vividness efficiency compared to control stimulation while keeping metacognitive efficiency and objective memory accuracy unaffected. Using trial-wise data, we showed that AnG stimulation altered the mediating role of vividness in confidence in the accuracy of memory judgment. Furthermore, resting-state functional connectivity of hippocampus and AnG was specifically associated with vividness efficiency, while the connectivity of hippocampus and medial prefrontal cortex was associated with metacognitive efficiency across individuals. These findings identify the causal involvement of AnG in gauging the vividness, but not the confidence, of memory, thereby providing evidence for a differentiation account of conscious assessment of memory retrieval.

Distinct generation of subjective vividness and confidence during naturalistic memory retrieval in angular gyrus

Subjective experience of remembering is a hallmark of episodic memory, which enables us to monitor experiences, identify mistakes, and adjust our decisions accordingly. A fundamental and enduring puzzle is the origin of confidence in memory; for example, does the confidence during episodic retrieval depend upon the subjective sensed vividness, or does confidence and vividness reflect dissociable introspective processes? The angular gyrus (AnG) exhibits a sensitivity to subjective experience of remembering, but its direct contribution to the monitoring of internal subjective mnemonic experience has hitherto been lacking. Here we combined a novel naturalistic video-watching paradigm with repetitive transcranial magnetic stimulation (rTMS) and resting-state functional magnetic resonance imaging (fMRI) to test the idea that vividness and confidence are generated differently during retrieval. We found that pre-retrieval rTMS targeting the left AnG selectively alters the vividness efficiency compared to control stimulation while keeping metacognitive efficiency and objective memory accuracy unaffected. Using trial-wise data, we showed that vividness mediates the association between confidence and objective memory accuracy and such mediation was eradicated by AnG stimulation. Furthermore, resting-state functional connectivity of hippocampus and AnG was specifically associated with vividness efficiency, while the connectivity of hippocampus and medial prefrontal cortex was associated with metacognitive efficiency across individuals. These findings identify a role for the AnG in gauging the vividness, but not the confidence, of memory, thereby providing evidence for a differentiation account of conscious assessment of memory by functionally and anatomically dissociating the monitoring of vividness from confidence.

Stimulating the hippocampal posterior-medial network enhances task-dependent connectivity and memory

Successful episodic memory involves dynamic increases in activity across distributed hippocampal networks, including the posterior-medial (PMN) and the anterior-temporal (ATN) networks. We tested whether this up-regulation of functional connectivity during memory processing can be enhanced within hippocampal networks by noninvasive stimulation, and whether such task-dependent connectivity enhancement predicts memory improvement. Participants received stimulation targeting the PMN or an out-of-network control location. We compared the effects of stimulation on fMRI connectivity during an autobiographical retrieval task versus during rest within the PMN and the ATN. PMN-targeted stimulation significantly increased connectivity during autobiographical retrieval versus rest within the PMN. This effect was not observed in the ATN, or in either network following control stimulation. Task-dependent increases in connectivity within the medial temporal lobe predicted improved performance of a separate episodic memory test. It is therefore possible to enhance the task-dependent regulation of hippocampal network connectivity that supports memory processing using noninvasive stimulation.

Structural plasticity of dendritic secretory compartments during LTP-induced synaptogenesis

Long-term potentiation (LTP), an increase in synaptic efficacy following high-frequency stimulation, is widely considered a mechanism of learning. LTP involves local remodeling of dendritic spines and synapses. Smooth endoplasmic reticulum (SER) and endosomal compartments could provide local stores of membrane and proteins, bypassing the distant Golgi apparatus. To test this hypothesis, effects of LTP were compared to control stimulation in rat hippocampal area CA1 at postnatal day 15 (P15). By two hours, small spines lacking SER increased after LTP, whereas large spines did not change in frequency, size, or SER content. Total SER volume decreased after LTP consistent with transfer of membrane to the added spines. Shaft SER remained more abundant in spiny than aspiny dendritic regions, apparently supporting the added spines. Recycling endosomes were elevated specifically in small spines after LTP. These findings suggest local secretory trafficking contributes to LTP-induced synaptogenesis and primes the new spines for future plasticity.