Showing papers by "Warren M. Grill published in 2021"
TL;DR: The evolution and current status of DBS technology is discussed, future advances are anticipated, and the next major technological advances and hurdles in the field are predicted.
Abstract: Deep brain stimulation (DBS) is a neurosurgical procedure that allows targeted circuit-based neuromodulation. DBS is a standard of care in Parkinson disease, essential tremor and dystonia, and is also under active investigation for other conditions linked to pathological circuitry, including major depressive disorder and Alzheimer disease. Modern DBS systems, borrowed from the cardiac field, consist of an intracranial electrode, an extension wire and a pulse generator, and have evolved slowly over the past two decades. Advances in engineering and imaging along with an improved understanding of brain disorders are poised to reshape how DBS is viewed and delivered to patients. Breakthroughs in electrode and battery designs, stimulation paradigms, closed-loop and on-demand stimulation, and sensing technologies are expected to enhance the efficacy and tolerability of DBS. In this Review, we provide a comprehensive overview of the technical development of DBS, from its origins to its future. Understanding the evolution of DBS technology helps put the currently available systems in perspective and allows us to predict the next major technological advances and hurdles in the field.
259 citations
TL;DR: In this article, the authors focus on several exemplar functions of interoception, including energy regulation (ingestion and excretion), memory, affective and emotional experience, and psychological sense of self.
91 citations
TL;DR: The ASCENT (Automated Simulations to Characterize Electrical Nerve Thresholds) pipeline as discussed by the authors provides a suite of built-in capabilities for user control over the entire workflow, including libraries for parts to assemble electrodes, electrical properties of biological materials, previously published fiber models, and common stimulation waveforms.
Abstract: Electrical stimulation and block of peripheral nerves hold great promise for treatment of a range of disease and disorders, but promising results from preclinical studies often fail to translate to successful clinical therapies. Differences in neural anatomy across species require different electrodes and stimulation parameters to achieve equivalent nerve responses, and accounting for the consequences of these factors is difficult. We describe the implementation, validation, and application of a standardized, modular, and scalable computational modeling pipeline for biophysical simulations of electrical activation and block of nerve fibers within peripheral nerves. The ASCENT (Automated Simulations to Characterize Electrical Nerve Thresholds) pipeline provides a suite of built-in capabilities for user control over the entire workflow, including libraries for parts to assemble electrodes, electrical properties of biological materials, previously published fiber models, and common stimulation waveforms. We validated the accuracy of ASCENT calculations, verified usability in beta release, and provide several compelling examples of ASCENT-implemented models. ASCENT will enable the reproducibility of simulation data, and it will be used as a component of integrated simulations with other models (e.g., organ system models), to interpret experimental results, and to design experimental and clinical interventions for the advancement of peripheral nerve stimulation therapies.
21 citations
TL;DR: In this article, the authors used computational modeling to quantify the spatial effects of ICMS intensity and unify the apparently paradoxical findings of Histed and Stoney by demonstrating that the volume over which action potentials are initiated grows with ICMS amplitude, consistent with Stoney.
16 citations
TL;DR: High-fidelity computational models and in vivo experiments are used to show that non-monotonic threshold-frequency relationships do occur, that they result from amplitude- and frequency-dependent charge imbalances that cause a shift between kilohertz frequency and direct current block regimes, and that these relationships can differ across fiber diameters such that smaller fibers can be blocked at lower thresholds than larger fibers.
Abstract: Reversible block of nerve conduction using kilohertz frequency electrical signals has substantial potential for treatment of disease. However, the ability to block nerve fibers selectively is limited by poor understanding of the relationship between waveform parameters and the nerve fibers that are blocked. Previous in vivo studies reported non-monotonic relationships between block signal frequency and block threshold, suggesting the potential for fiber-selective block. However, the mechanisms of non-monotonic block thresholds were unclear, and these findings were not replicated in a subsequent in vivo study. We used high-fidelity computational models and in vivo experiments in anesthetized rats to show that non-monotonic threshold-frequency relationships do occur, that they result from amplitude- and frequency-dependent charge imbalances that cause a shift between kilohertz frequency and direct current block regimes, and that these relationships can differ across fiber diameters such that smaller fibers can be blocked at lower thresholds than larger fibers. These results reconcile previous contradictory studies, clarify the mechanisms of interaction between kilohertz frequency and direct current block, and demonstrate the potential for selective block of small fiber diameters.
10 citations
TL;DR: The reviewed manuscript has an abstract 100 words over the specified limit and was approved by reviewers in this version in revisions, therefore I was unsure if I should alter the abstract post-approval as mentioned in this paper.
Abstract: Please see the abstract in the uploaded file. The reviewed manuscript has an abstract 100 words over the specified limit and was approved by reviewers in this version in revisions, therefore I was unsure if I should alter the abstract post-approval. Please feel free to reach out with any questions.
9 citations
TL;DR: In this paper, the authors used a multi-electrode array to record transsynaptically-evoked activity as early as 0.7 ms after single pulses of stimulation that was immediately followed by suppressed neural activity lasting 10-150 ms.
Abstract: Objective: Persons with tetraplegia can use brain-machine interfaces to make visually guided reaches with robotic arms. Without somatosensory feedback, these movements will likely be slow and imprecise, like those of persons who retain movement but have lost proprioception. Intracortical microstimulation (ICMS) has promise for providing artificial somatosensory feedback. If ICMS can mimic naturally occurring neural activity, afferent interfaces may be more informative and easier to learn than interfaces that evoke unnaturalistic activity. To develop such biomimetic stimulation patterns, it is important to characterize the responses of neurons to ICMS. Approach: Using a Utah multi-electrode array, we recorded activity evoked by single pulses, and short (~0.2 s) and long (~4 s) trains of ICMS at a wide range of amplitudes and frequencies. As the electrical artifact caused by ICMS typically prevents recording for many milliseconds, we deployed a custom rapid-recovery amplifier with nonlinear gain to limit signal saturation on the stimulated electrode. Across all electrodes after stimulation, we removed the remaining slow return to baseline with acausal high-pass filtering of time-reversed recordings. With these techniques, we could record ~0.7 ms after stimulation offset even on the stimulated electrode. Main results: We recorded likely transsynaptically-evoked activity as early as ~0.7 ms after single pulses of stimulation that was immediately followed by suppressed neural activity lasting 10-150 ms. Instead of this long-lasting inhibition, neurons increased their firing rates for ~100 ms after trains. During long trains, the evoked response on the stimulated electrode decayed rapidly while the response was maintained on non-stimulated channels. Significance: The detailed description of the spatial and temporal response to ICMS can be used to better interpret results from experiments that probe circuit connectivity or function of cortical areas. These results can also contribute to the design of stimulation patterns to improve afferent interfaces for artificial sensory feedback.
7 citations
TL;DR: In this paper, a closed-loop control system that can automatically adjust the stimulation parameters to recover normal activity in model neurons is presented, through simulation in a computational model, and the successful tracking of target beta power in the presence of changes in Parkinsonian state as well as during dynamic changes in the target level of beta power.
Abstract: Clinically deployed deep brain stimulation (DBS) for the treatment of Parkinson's disease operates in an open loop with fixed stimulation parameters, and this may result in high energy consumption and suboptimal therapy. The objective of this manuscript is to establish, through simulation in a computational model, a closed-loop control system that can automatically adjust the stimulation parameters to recover normal activity in model neurons. Exaggerated beta band activity is recognized as a hallmark of Parkinson's disease and beta band activity in model neurons of the globus pallidus internus (GPi) was used as the feedback signal to control DBS of the GPi. Traditional proportional controller and proportional-integral controller were not effective in eliminating the error between the target level of beta power and the beta power under Parkinsonian conditions. To overcome the difficulties in tuning the controller parameters and improve tracking performance in the case of changes in the plant, a supervisory control algorithm was implemented by introducing a Radial Basis Function (RBF) network to build the inverse model of the plant. Simulation results show the successful tracking of target beta power in the presence of changes in Parkinsonian state as well as during dynamic changes in the target level of beta power. Our computational study suggests the feasibility of the RBF network-driven supervisory control algorithm for real-time modulation of DBS parameters for the treatment of Parkinson's disease.
6 citations
TL;DR: In this article, state-dependent stimulation, with different electrical stimulation parameters delivered during filling and emptying, can increase both BC and VE relative to continuous stimulation in rats and cats of both sexes.
Abstract: Electrical stimulation therapies to promote bladder filling and prevent incontinence deliver continuous inhibitory stimulation, even during bladder emptying. However, continuous inhibitory stimulation that increases bladder capacity (BC) can reduce the efficiency of subsequent voiding (VE). Here we demonstrate that state-dependent stimulation, with different electrical stimulation parameters delivered during filling and emptying can increase both BC and VE relative to continuous stimulation in rats and cats of both sexes. We show that continuous 10 Hz pudendal nerve stimulation increased BC (120-180% of control) but decreased VE (12-71%, relative to control). In addition to increasing BC, state-dependent stimulation in both rats and cats increased VE (280-759% relative to continuous stimulation); motor bursting in cats increased VE beyond the control (no stimulation) condition (males: 323%; females: 161%). These results suggest that a bioelectronic bladder pacemaker can treat complex voiding disorders, including both incontinence and retention, which paradoxically are often present in the same individual.
6 citations
TL;DR: This work implemented a single-compartment model of vagal afferents from Schild et al. 1994 and extended the model into a multi-compartments axon, presenting the first cable model of a C-fiber vagal Afferent, and compared the responses of these novel models to published models of unmyelinated axons.
Abstract: Biophysically based computational models of nerve fibers are important tools for designing electrical stimulation therapies, investigating drugs that affect ion channels, and studying diseases that affect neurons. Although peripheral nerves are primarily composed of unmyelinated axons (i.e., C-fibers), most modeling efforts focused on myelinated axons. We implemented the single-compartment model of vagal afferents from Schild et al. (1994) (Schild JH, Clark JW, Hay M, Mendelowitz D, Andresen MC, Kunze DL. J Neurophysiol 71: 2338-2358, 1994) and extended the model into a multicompartment axon, presenting the first cable model of a C-fiber vagal afferent. We also implemented the updated parameters from the Schild and Kunze (1997) model (Schild JH, Kunze DL. J Neurophysiol 78: 3198-3209, 1997). We compared the responses of these novel models with those of three published models of unmyelinated axons (Rattay F, Aberham M. IEEE Trans Biomed Eng 40: 1201-1209, 1993; Sundt D, Gamper N, Jaffe DB. J Neurophysiol 114: 3140-3153, 2015; Tigerholm J, Petersson ME, Obreja O, Lampert A, Carr R, Schmelz M, Fransen E. J Neurophysiol 111: 1721-1735, 2014) and with experimental data from single-fiber recordings. Comparing the two models by Schild et al. (1994, 1997) revealed that differences in rest potential and action potential shape were driven by changes in maximum conductances rather than changes in sodium channel dynamics. Comparing the five model axons, the conduction speeds and strength-duration responses were largely within expected ranges, but none of the models captured the experimental threshold recovery cycle-including a complete absence of late subnormality in the models-and their action potential shapes varied dramatically. The Tigerholm et al. (2014) model best reproduced the experimental data, but these modeling efforts make clear that additional data are needed to parameterize and validate future models of autonomic C-fibers.NEW & NOTEWORTHY Peripheral nerves are primarily composed of unmyelinated axons, and there is growing interest in electrical stimulation of the autonomic nervous system to treat various diseases. We present the first cable model of an unmyelinated vagal nerve fiber and compare its ion channel isoforms and conduction responses with other published models of unmyelinated axons, establishing important tools for advancing modeling of autonomic nerves.
5 citations
TL;DR: In this article, the spatial effects of single pulse ICMS, including the radial distance to activated neurons and the density of activated neurons as a function of stimulation intensity, were quantified.
Abstract: Background Intracortical microstimulation (ICMS) is used to map neural circuits and restore lost sensory modalities such as vision, hearing, and somatosensation. The spatial effects of ICMS remain controversial: Stoney and colleagues proposed that the volume of somatic activation increased with stimulation intensity, while Histed et al. suggested activation density, but not somatic activation volume, increases with stimulation intensity. Objective We used computational modeling to quantify the spatial effects of ICMS intensity and unify the apparently paradoxical findings of Histed and Stoney. Methods We implemented a biophysically-based computational model of a cortical column comprising neurons with realistic morphology and representative synapses. We quantified the spatial effects of single pulse ICMS, including the radial distance to activated neurons and the density of activated neurons as a function of stimulation intensity. Results At all amplitudes, the dominant mode of somatic activation was by antidromic propagation to the soma following axonal activation, rather than via trans-synaptic activation. There were no occurrences of direct activation of somata or dendrites. The volume over which antidromic action potentials were initiated grew with stimulation amplitude, while the volume of somatic activations did not. However, the density of somatic activation within the activated volume increased with stimulation amplitude. Conclusions The results resolve the apparent paradox between Stoney and Histed’s results by demonstrating that the volume over which action potentials are initiated grows with ICMS amplitude, consistent with Stoney. However, the volume occupied by the activated somata remains approximately constant, while the density of activated neurons within that volume increase, consistent with Histed. HIGHLIGHTS Implemented a biophysically-based computational model of cortical column comprising cortical neurons with realistic morphology and representative synapses. Quantified the spatial patterns of neural activation by intracortical microstimulation to resolve the paradoxical findings of Stoney et al., 1968 and Histed et al., 2009. The dominant mode of neural activation near the electrode was direct (i.e., via antidromic propagation from direct activation of the axon) and not trans-synaptic. The dominant effect of increased ICMS intensity was to increase the density of activated neurons but not the volume of activation.
TL;DR: In this article, the isolated mouse colon induces rhythmic cyclic myoelectric complexes (MCs) evoked repeatedly by closed-loop electrical stimulation entrain MCs more fre...
Abstract: Maintained physiological distension of the isolated mouse colon induces rhythmic cyclic myoelectric complexes (MCs). MCs evoked repeatedly by closed-loop electrical stimulation entrain MCs more fre...
TL;DR: In this article, the authors used microCT to quantify the structure and neuroanatomy of human cervical vagus nerve and found that the high degree of splitting and merging of fascicles in humans may explain the clinical heterogeneity in patient responses.
Abstract: Vagus nerve stimulation (VNS) is FDA approved for stroke rehabilitation, epilepsy and depression; however, the underlying vagus functional anatomy underlying the implant is poorly understood. We used microCT to quantify fascicular structure and neuroanatomy within human cervical vagus nerves. Fascicles split or merged every ~560 μm (17.8 ± 6.1 events/cm). The high degree of splitting and merging of fascicles in humans may explain the clinical heterogeneity in patient responses.
01 Jan 2021
TL;DR: This paper characterized the long-term voiding, defecation, and consumption behavior of age-matched spontaneously hypertensive and Wistar rats without the influence of anesthesia or catheters.
Abstract: We characterized the long-term (20 wk) voiding, defecation, and consumption behavior of age-matched spontaneously hypertensive and Wistar rats without the influence of anesthesia or catheters. Spon...
TL;DR: In this paper, female obese prone (OP) and obese resistant (OR) rats were fed a 60kcal% fat diet at 8 weeks old, and a subset of OP rats underwent uroflowmetry biweekly for 18 weeks in metabolic cages.
Abstract: AIMS Detrusor underactivity (DU) is an understudied health concern with inadequate clinical management. The pathophysiology of DU is unclear, and current therapies fail to improve symptoms. The current studies characterized voiding function and contractility of bladder and urethral tissues in a novel rat model of DU. METHODS Female obese prone (OP) and obese resistant (OR) rats were fed a 60 kcal% fat diet at 8 weeks old. A subset of rats (n = 4/strain) underwent uroflowmetry biweekly for 18 weeks in metabolic cages. At 40-56 weeks old, rats (n = 9-10/strain) underwent instrumented cystometry under urethane anesthesia. Following cystometry, bladder and urethral tissues (n = 8-9/strain) were harvested for in vitro assessments of contractility in response to carbachol, electric field stimulation, atropine, alpha, beta-methylene ATP, and caffeine. RESULTS OP rats exhibited increased urinary frequency (p = 0.0031), decreased voided volume (p = 0.0093), and urine flow rate (p = 0.0064) compared to OR rats during uroflowmetry. Bethanechol (10 mg/kg) did not alter uroflowmetry parameters. During cystometry, OP rats exhibited decreased bladder emptying efficiency (p < 0.0001), decreased pressure to generate a void (p < 0.0001), and increased EUS activity during filling (p = 0.0011). Bladder contractility was decreased in OP rats when exposed to carbachol (p < 0.0003) and ATP (p = 0.0004), whereas middle urethral contractility was increased when exposed to carbachol (p = 0.0014), EFS (p = 0.0289), and caffeine (p = 0.0031). CONCLUSION Impaired cholinergic and purinergic signaling in the bladder may contribute to poor voiding function in OP rats. In addition, increased urethral activity may engage a guarding reflex to augment continence and exacerbate incomplete emptying.
TL;DR: Results suggest that urethral relaxation/weakness and/or increased detrusor pressure as a result of decreased compliance may contribute to urinary urgency and highlight potential targets for new therapies for overactive bladder.
Abstract: Prostaglandin E2 (PGE2) instilled into the bladder generates symptoms of urinary urgency in healthy women and reduces bladder capacity and urethral pressure in both humans and female rats. Systemic...