Publications by authors named "Warren M Grill"

207 Publications

Voiding behavior in awake unrestrained untethered spontaneously hypertensive and Wistar control rats.

Am J Physiol Renal Physiol 2021 06 21. Epub 2021 Jun 21.

Department of Biomedical Engineering, Duke University, Durham, NC, United States.

The spontaneously hypertensive rat (SHR), a genetic model of high blood pressure, has also been studied as a potential model of overactive bladder (OAB). In vivo studies confirmed the presence of surrogate markers of OAB, including detrusor overactivity (DO), increased urinary frequency, decreased bladder capacity and voided volume, and afferent hypersensitivity to bladder irritation. However, these observations were during awake cystometry (CMG) using implanted bladder catheters tethered to an infusion pump and artificially filled. We conducted studies in awake unrestrained untethered age-matched female SHR and Wistar rats to quantify naïve consumption and voiding behavior and the effect of capsaicin desensitization on consumption and voiding behavior. Food and water consumption, body weight, voiding frequency (VF), and voided volume (VV) were recorded. Rats were placed in metabolism cages for 24 h, up to twice a week, from 17 to 37 weeks of age. In SHRs, body weight, food, and water consumption were decreased compared to Wistars. However, after normalizing for body weight, only water consumption was reduced. Wistars exhibited a diurnal pattern of voiding behavior. Compared to Wistars, SHRs showed smaller VV and lacked a diurnal voiding pattern such that VV was similar during both light cycles. No difference in VF was observed after normalizing for water consumption. We observed no change in SHR voiding behavior following capsaicin desensitization, which was in contrast to a prior awake in vivo cystometry study describing increased VV and micturition interval in SHRs, and suggests that C-fiber activity may not contribute to bladder hypersensitivity in SHRs.
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http://dx.doi.org/10.1152/ajprenal.00564.2020DOI Listing
June 2021

Levodopa-Induced Dyskinesia Is Mediated by Cortical Gamma Oscillations in Experimental Parkinsonism.

Mov Disord 2021 04;36(4):1044-1045

Biomedical Engineering Department, Duke University, Durham, North Carolina, USA.

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http://dx.doi.org/10.1002/mds.28578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173781PMC
April 2021

Non-monotonic kilohertz frequency neural block thresholds arise from amplitude- and frequency-dependent charge imbalance.

Sci Rep 2021 Mar 3;11(1):5077. Epub 2021 Mar 3.

Department of Biomedical Engineering, Duke University, Room 1427, Fitzpatrick CIEMAS, 101 Science Drive, Campus Box 90281, Durham, NC, 27708, USA.

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.
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http://dx.doi.org/10.1038/s41598-021-84503-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930193PMC
March 2021

Control of colonic motility using electrical stimulation to modulate enteric neural activity.

Am J Physiol Gastrointest Liver Physiol 2021 04 24;320(4):G675-G687. Epub 2021 Feb 24.

Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Electrical stimulation of the enteric nervous system (ENS) is an attractive approach to modify gastrointestinal transit. Colonic motor complexes (CMCs) occur with a periodic rhythm, but the ability to elicit a premature CMC depends, at least in part, upon the intrinsic refractory properties of the ENS, which are presently unknown. The objectives of this study were to record myoelectric complexes (MCs, the electrical correlates of CMCs) in the smooth muscle and ) determine the refractory periods of MCs, ) inform and evaluate closed-loop stimulation to repetitively evoke MCs, and ) identify stimulation methods to suppress MC propagation. We dissected the colon from male and female C57BL/6 mice, preserving the integrity of intrinsic circuitry while removing the extrinsic nerves, and measured properties of spontaneous and evoked MCs in vitro. Hexamethonium abolished spontaneous and evoked MCs, confirming the necessary involvement of the ENS for electrically evoked MCs. Electrical stimulation reduced the mean interval between evoked and spontaneous CMCs (24.6 ± 3.5 vs. 70.6 ± 15.7 s, = 0.0002, = 7). The absolute refractory period was 4.3 s (95% confidence interval (CI) = 2.8-5.7 s, = 0.7315, = 8). Electrical stimulation applied during fluid distention-evoked MCs led to an arrest of MC propagation, and following stimulation, MC propagation resumed at an increased velocity ( = 9). The timing parameters of electrical stimulation increased the rate of evoked MCs and the duration of entrainment of MCs, and the refractory period provides insight into timing considerations for designing neuromodulation strategies to treat colonic dysmotility. 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 frequently than spontaneously occurring MCs. Electrical stimulation delivered at the onset of a contraction temporarily suppresses the propagation of MC contractions. Controlled electrical stimulation can either evoke MCs or temporarily delay MCs in the isolated mouse colon, depending on timing relative to ongoing activity.
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http://dx.doi.org/10.1152/ajpgi.00463.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238160PMC
April 2021

State-dependent bioelectronic interface to control bladder function.

Sci Rep 2021 01 11;11(1):314. Epub 2021 Jan 11.

Department of Biomedical Engineering, Duke University, Durham, NC, USA.

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.
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http://dx.doi.org/10.1038/s41598-020-79493-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801663PMC
January 2021

Functions of Interoception: From Energy Regulation to Experience of the Self.

Trends Neurosci 2021 01;44(1):29-38

Department of Psychology, Royal Holloway, University of London, London, UK; Department of Behavioural and Cognitive Sciences, Faculty of Humanities, Education and Social Sciences, University of Luxembourg, Luxembourg.

We review recent work on the functions of interoceptive processing, by which the nervous system anticipates, senses, and integrates signals originating from the body. We focus on several exemplar functions of interoception, including energy regulation (ingestion and excretion), memory, affective and emotional experience, and the psychological sense of self. We emphasize two themes across these functions. First, the anatomy of interoceptive afferents makes it difficult to manipulate or directly measure interoceptive signaling in humans. Second, recent evidence shows that multimodal integration occurs across interoceptive modalities and between interoceptive and exteroceptive modalities. Whereas exteroceptive multimodal integration has been studied relatively extensively, fundamental questions remain regarding multimodal integration that involves interoceptive modalities. Future empirical work is required to better understand how and where multimodal interoceptive integration occurs.
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http://dx.doi.org/10.1016/j.tins.2020.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780233PMC
January 2021

Effects of intravesical prostaglandin E on bladder function are preserved in capsaicin-desensitized rats.

Am J Physiol Renal Physiol 2021 02 7;320(2):F212-F223. Epub 2020 Dec 7.

Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Prostaglandin E (PGE) 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 capsaicin desensitization, which causes degeneration of C-fibers, prevented PGE-mediated reductions in bladder capacity, suggesting that PGE acts as an irritant (Maggi CA, Giuliani S, Conte B, Furio M, Santicioli P, Meli P, Gragnani L, Meli A. 145: 105-112, 1988). In the present study, we instilled PGE in female rats after capsaicin desensitization but without the hypogastric nerve transection that was conducted in the Maggi et al. study. One week after capsaicin injection (125 mg/kg sc), rats underwent cystometric and urethral perfusion testing under urethane anesthesia with saline and 100 µM PGE. Similar to naïve rats, capsaicin-desensitized rats exhibited a reduction in bladder capacity from 1.23 ± 0.08 mL to 0.70 ± 0.10 mL ( = 0.002, = 9), a reduction in urethral perfusion pressure from 19.3 ± 2.1 cmHO to 10.9 ± 1.2 cmHO ( = 0.004, = 9), and a reduction in bladder compliance from 0.13 ± 0.020 mL/cmHO to 0.090 ± 0.014 mL/cmHO ( = 0.011, = 9). Thus, changes in bladder function following the instillation of PGE were not dependent on capsaicin-sensitive pathways. Further, these 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.
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http://dx.doi.org/10.1152/ajprenal.00302.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948121PMC
February 2021

Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat.

Front Neurosci 2020 4;14:601479. Epub 2020 Nov 4.

Department of Biomedical Engineering, Duke University, Durham, NC, United States.

It is necessary to understand the morphology of the vagus nerve (VN) to design and deliver effective and selective vagus nerve stimulation (VNS) because nerve morphology influences fiber responses to electrical stimulation. Specifically, nerve diameter (and thus, electrode-fiber distance), fascicle diameter, fascicular organization, and perineurium thickness all significantly affect the responses of nerve fibers to electrical signals delivered through a cuff electrode. We quantified the morphology of cervical and subdiaphragmatic VNs in humans, pigs, and rats: effective nerve diameter, number of fascicles, effective fascicle diameters, proportions of endoneurial, perineurial, and epineurial tissues, and perineurium thickness. The human and pig VNs were comparable sizes (∼2 mm cervically; ∼1.6 mm subdiaphragmatically), while the rat nerves were ten times smaller. The pig nerves had ten times more fascicles-and the fascicles were smaller-than in human nerves (47 vs. 7 fascicles cervically; 38 vs. 5 fascicles subdiaphragmatically). Comparing the cervical to the subdiaphragmatic VNs, the nerves and fascicles were larger at the cervical level for all species and there were more fascicles for pigs. Human morphology generally exhibited greater variability across samples than pigs and rats. A prior study of human somatic nerves indicated that the ratio of perineurium thickness to fascicle diameter was approximately constant across fascicle diameters. However, our data found thicker human and pig VN perineurium than those prior data: the VNs had thicker perineurium for larger fascicles and thicker perineurium normalized by fascicle diameter for smaller fascicles. Understanding these differences in VN morphology between preclinical models and the clinical target, as well as the variability across individuals of a species, is essential for designing suitable cuff electrodes and stimulation parameters and for informing translation of preclinical results to clinical application to advance the therapeutic efficacy of VNS.
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http://dx.doi.org/10.3389/fnins.2020.601479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672126PMC
November 2020

Technology of deep brain stimulation: current status and future directions.

Nat Rev Neurol 2021 Feb 26;17(2):75-87. Epub 2020 Nov 26.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.

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.
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http://dx.doi.org/10.1038/s41582-020-00426-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116699PMC
February 2021

Excitation properties of computational models of unmyelinated peripheral axons.

J Neurophysiol 2021 01 21;125(1):86-104. Epub 2020 Oct 21.

Department of Biomedical Engineering, Duke University, Durham, North Carolina.

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. 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. 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. 40: 1201-1209, 1993; Sundt D, Gamper N, Jaffe DB. 114: 3140-3153, 2015; Tigerholm J, Petersson ME, Obreja O, Lampert A, Carr R, Schmelz M, Fransén E. 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. 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.
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http://dx.doi.org/10.1152/jn.00315.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087387PMC
January 2021

Evoked potentials reveal neural circuits engaged by human deep brain stimulation.

Brain Stimul 2020 Nov - Dec;13(6):1706-1718. Epub 2020 Oct 6.

Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC, USA; Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. Electronic address:

Background: Deep brain stimulation (DBS) is an effective therapy for reducing the motor symptoms of Parkinson's disease, but the mechanisms of action of DBS and neural correlates of symptoms remain unknown.

Objective: To use the neural response to DBS to reveal connectivity of neural circuits and interactions between groups of neurons as potential mechanisms for DBS.

Methods: We recorded activity evoked by DBS of the subthalamic nucleus (STN) in humans with Parkinson's disease. In follow up experiments we also simultaneously recorded activity in the contralateral STN or the ipsilateral globus pallidus from both internal (GPi) and external (GPe) segments.

Results: DBS local evoked potentials (DLEPs) were stereotyped across subjects, and a biophysical model of reciprocal connections between the STN and the GPe recreated DLEPs. Simultaneous STN and GP recordings during STN DBS demonstrate that DBS evoked potentials were present throughout the basal ganglia and confirmed that DLEPs arose from the reciprocal connections between the STN and GPe. The shape and amplitude of the DLEPs were dependent on the frequency and duration of DBS and were correlated with resting beta band oscillations. In the frequency domain, DLEPs appeared as a 350 Hz high frequency oscillation (HFO) independent of the frequency of DBS.

Conclusions: DBS evoked potentials suggest that the intrinsic dynamics of the STN and GP are highly interlinked and may provide a promising new biomarker for adaptive DBS.
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http://dx.doi.org/10.1016/j.brs.2020.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722102PMC
April 2021

Quantitative comparisons of block thresholds and onset responses for charge-balanced kilohertz frequency waveforms.

J Neural Eng 2020 09 18;17(4):046048. Epub 2020 Sep 18.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, United States of America.

Objective: There is growing interest in delivering kilohertz frequency (KHF) electrical signals to block conduction in peripheral nerves for treatment of various diseases. Previous studies used different KHF waveforms to achieve block, and it remains unclear how waveform affects nerve block parameters.

Approach: We quantified the effects of waveform on KHF block of the rat tibial nerve in vivo and in computational models. We compared block thresholds and onset responses across current-controlled sinusoids and charge-balanced rectangular waveforms with different asymmetries and duty cycles.

Main Results: Sine waves had higher block thresholds than square waves, but used less power at block threshold. Block threshold had an inverse relationship with duty cycle of rectangular waveforms irrespective of waveform asymmetry. Computational model results were consistent with relationships measured in vivo, although the models underestimated the effect of duty cycle on increasing thresholds. The axonal membrane substantially filtered waveforms, the filter transfer function was strikingly similar across waveforms, and filtering resulted in post-filtered rms block thresholds that were approximately constant across waveforms in silico and in vivo. Onset response was not consistently affected by waveform shape, but onset response was smaller at amplitudes well above block threshold. Therefore, waveforms with lower block thresholds (e.g. sine waves or square waves) could be more readily increased to higher amplitudes relative to block threshold to reduce onset response. We also observed a reduction in onset responses across consecutive trials after initial application of supra-block threshold amplitudes.

Significance: Waveform had substantial effects on block thresholds, and the amplitude relative to block threshold had substantial effects on onset response. These data inform choice of waveform in subsequent studies and clinical applications, enhance effective use of block in therapeutic applications, and facilitate the design of parameters that achieve block with minimal onset responses.
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http://dx.doi.org/10.1088/1741-2552/abadb5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7742218PMC
September 2020

A comprehensive model-based framework for optimal design of biomimetic patterns of electrical stimulation for prosthetic sensation.

J Neural Eng 2020 09 18;17(4):046045. Epub 2020 Sep 18.

Department of Biomedical Engineering, Duke University, Durham, NC, United States of America.

Objective: Touch and proprioception are essential to motor function as shown by the movement deficits that result from the loss of these senses, e.g. due to neuropathy of sensory nerves. To achieve a high-performance brain-controlled prosthetic arm/hand thus requires the restoration of somatosensation, perhaps through intracortical microstimulation (ICMS) of somatosensory cortex (S1). The challenge is to generate patterns of neuronal activation that evoke interpretable percepts. We present a framework to design optimal spatiotemporal patterns of ICMS (STIM) that evoke naturalistic patterns of neuronal activity and demonstrate performance superior to four previous approaches.

Approach: We recorded multiunit activity from S1 during a center-out reach task (from proprioceptive neurons in Brodmann's area 2) and during application of skin indentations (from cutaneous neurons in Brodmann's area 1). We implemented a computational model of a cortical hypercolumn and used a genetic algorithm to design STIM that evoked patterns of model neuron activity that mimicked their experimentally-measured counterparts. Finally, from the ICMS patterns, the evoked neuronal activity, and the stimulus parameters that gave rise to it, we trained a recurrent neural network (RNN) to learn the mapping function between the physical stimulus and the biomimetic stimulation pattern, i.e. the sensory encoder to be integrated into a neuroprosthetic device.

Main Results: We identified ICMS patterns that evoked simulated responses that closely approximated the measured responses for neurons within 50 µm of the electrode tip. The RNN-based sensory encoder generalized well to untrained limb movements or skin indentations. STIM designed using the model-based optimization approach outperformed STIM designed using existing linear and nonlinear mappings.

Significance: The proposed framework produces an encoder that converts limb state or patterns of pressure exerted onto the prosthetic hand into STIM that evoke naturalistic patterns of neuronal activation.
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http://dx.doi.org/10.1088/1741-2552/abacd8DOI Listing
September 2020

Spinal cord stimulation for the restoration of bladder function after spinal cord injury.

Healthc Technol Lett 2020 Jun 25;7(3):87-92. Epub 2020 Jun 25.

Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.

Spinal cord injury (SCI) results in the inability to empty the bladder voluntarily, and neurogenic detrusor overactivity (NDO) and detrusor sphincter dyssynergia (DSD) negatively impact both the health and quality of life of persons with SCI. Current approaches to treat bladder dysfunction in persons with SCI, including self-catheterisation and anticholinergic medications, are inadequate, and novel approaches are required to restore continence with increased bladder capacity, as well as to provide predictable and efficient on-demand voiding. Improvements in bladder function following SCI have been documented using a number of different modalities of spinal cord stimulation (SCS) in both persons with SCI and animal models, including SCS alone or SCS with concomitant activity-based training. Improvements include increased volitional voiding, voided volumes, bladder capacity, and quality of life, as well as decreases in NDO and DSD. Further, SCS is a well-developed therapy for chronic pain, and existing Food And Drug Administration (FDA)-approved devices provide a clear pathway to sustainable commercial availability and impact. However, the effective stimulation parameters and the appropriate timing and location of stimulation for SCS-mediated restoration of bladder function require further study, and studies are needed to determine underlying mechanisms of action.
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http://dx.doi.org/10.1049/htl.2020.0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353924PMC
June 2020

Sources of off-target effects of vagus nerve stimulation using the helical clinical lead in domestic pigs.

J Neural Eng 2020 07 24;17(4):046017. Epub 2020 Jul 24.

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States of America. Mayo Clinic, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, United States of America. Wisconsin Institute of Neuroengineering (WITNe), University of Wisconsin-Madison, WI, United States of America.

Objective: Clinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig—an animal model with vagus anatomy similar to human—using the bipolar helical lead deployed clinically.

Approach: Intrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses.

Main Results: Contraction of the cricoarytenoid muscle occurred at low amplitudes (~0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (~1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting Aδ-, B-, and C-fibers.

Significance: Our data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 μA). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with Aδ- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.
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http://dx.doi.org/10.1088/1741-2552/ab9db8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717671PMC
July 2020

Kilohertz waveforms optimized to produce closed-state Na+ channel inactivation eliminate onset response in nerve conduction block.

PLoS Comput Biol 2020 06 15;16(6):e1007766. Epub 2020 Jun 15.

Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, United States of America.

The delivery of kilohertz frequency alternating current (KHFAC) generates rapid, controlled, and reversible conduction block in motor, sensory, and autonomic nerves, but causes transient activation of action potentials at the onset of the blocking current. We implemented a novel engineering optimization approach to design blocking waveforms that eliminated the onset response by moving voltage-gated Na+ channels (VGSCs) to closed-state inactivation (CSI) without first opening. We used computational models and particle swarm optimization (PSO) to design a charge-balanced 10 kHz biphasic current waveform that produced conduction block without onset firing in peripheral axons at specific locations and with specific diameters. The results indicate that it is possible to achieve onset-free KHFAC nerve block by causing CSI of VGSCs. Our novel approach for designing blocking waveforms and the resulting waveform may have utility in clinical applications of conduction block of peripheral nerve hyperactivity, for example in pain and spasticity.
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http://dx.doi.org/10.1371/journal.pcbi.1007766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316353PMC
June 2020

Frequency-Specific Optogenetic Deep Brain Stimulation of Subthalamic Nucleus Improves Parkinsonian Motor Behaviors.

J Neurosci 2020 05 20;40(22):4323-4334. Epub 2020 Apr 20.

Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapy for the motor symptoms of Parkinson's disease (PD). However, the neural elements mediating symptom relief are unclear. A previous study concluded that direct optogenetic activation of STN neurons was neither necessary nor sufficient for relief of parkinsonian symptoms. However, the kinetics of the channelrhodopsin-2 (ChR2) used for cell-specific activation are too slow to follow the high rates required for effective DBS, and thus the contribution of activation of STN neurons to the therapeutic effects of DBS remains unclear. We quantified the behavioral and neuronal effects of optogenetic STN DBS in female rats following unilateral 6-hydroxydopamine (6-OHDA) lesion using an ultrafast opsin (Chronos). Optogenetic STN DBS at 130 pulses per second (pps) reduced pathologic circling and ameliorated deficits in forelimb stepping similarly to electrical DBS, while optogenetic STN DBS with ChR2 did not produce behavioral effects. As with electrical DBS, optogenetic STN DBS exhibited a strong dependence on stimulation rate; high rates produced symptom relief while low rates were ineffective. High-rate optogenetic DBS generated both increases and decreases in firing rates of single neurons in STN, globus pallidus externa (GPe), and substantia nigra pars reticular (SNr), and disrupted β band oscillatory activity in STN and SNr. High-rate optogenetic STN DBS can indeed ameliorate parkinsonian motor symptoms through reduction of abnormal oscillatory activity in the STN-associated neural circuit, and these results highlight that the kinetic properties of opsins have a strong influence on the effects of optogenetic stimulation. Whether STN local cells contribute to the therapeutic effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) remains unclear. We re-examined the role of STN local cells in mediating the symptom-relieving effects of STN DBS using cell type-specific optogenetic stimulation with a much faster opsin, Chronos. Direct optogenetic stimulation of STN neurons was effective in treating the symptoms of parkinsonism in the 6-hydroxydopamine (6-OHDA) lesion rat. These results highlight that the kinetic properties of opsins can have a strong influence on the effects of optogenetic activation/inhibition and must be considered when employing optogenetic to study high-rate neural stimulation.
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http://dx.doi.org/10.1523/JNEUROSCI.3071-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252487PMC
May 2020

Stimulation of the pelvic nerve increases bladder capacity in the PGE cat model of overactive bladder.

Am J Physiol Renal Physiol 2020 06 20;318(6):F1357-F1368. Epub 2020 Apr 20.

Department of Biomedical Engineering, Duke University, Durham, North Carolina.

Selective electrical stimulation of the pudendal nerve exhibits promise as a potential therapy for treating overactive bladder (OAB) across species (rats, cats, and humans). More recently, pelvic nerve (PelN) stimulation was demonstrated to improve cystometric bladder capacity in a PGE rat model of OAB. However, PelN stimulation in humans or in an animal model that is more closely related to humans has not been explored. Therefore, our objective was to quantify the effects of PGE and PelN stimulation in the cat. Acute cystometry experiments were conducted in 14 α-chloralose-anesthetized adult, neurologically intact female cats. Intravesical PGE decreased bladder capacity, residual volume, threshold contraction pressure, and mean contraction pressure. PelN stimulation reversed the PGE-induced decrease in bladder capacity and increased evoked external urethral sphincter electromyographic activity without influencing voiding efficiency. The increases in bladder capacity generated by PelN stimulation were similar in the rat and cat, but the stimulation parameters to achieve this effect differed (threshold amplitude at 10 Hz in the rat vs. twice threshold amplitude at 1 Hz in the cat). These results highlight the potential of PGE as a model of OAB and provide further evidence that PelN stimulation is a promising approach for the treatment of OAB symptoms.
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http://dx.doi.org/10.1152/ajprenal.00068.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717121PMC
June 2020

Proceedings of the Seventh Annual Deep Brain Stimulation Think Tank: Advances in Neurophysiology, Adaptive DBS, Virtual Reality, Neuroethics and Technology.

Front Hum Neurosci 2020 27;14:54. Epub 2020 Mar 27.

Laboratory for Neural Dynamics and Cognition, Rockefeller University, New York, NY, United States.

The Seventh Annual Deep Brain Stimulation (DBS) Think Tank held on September 8th of 2019 addressed the most current: (1) use and utility of complex neurophysiological signals for development of adaptive neurostimulation to improve clinical outcomes; (2) Advancements in recent neuromodulation techniques to treat neuropsychiatric disorders; (3) New developments in optogenetics and DBS; (4) The use of augmented Virtual reality (VR) and neuromodulation; (5) commercially available technologies; and (6) ethical issues arising in and from research and use of DBS. These advances serve as both "markers of progress" and challenges and opportunities for ongoing address, engagement, and deliberation as we move to improve the functional capabilities and translational value of DBS. It is in this light that these proceedings are presented to inform the field and initiate ongoing discourse. As consistent with the intent, and spirit of this, and prior DBS Think Tanks, the overarching goal is to continue to develop multidisciplinary collaborations to rapidly advance the field and ultimately improve patient outcomes.
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http://dx.doi.org/10.3389/fnhum.2020.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7134196PMC
March 2020

Functional vagotopy in the cervical vagus nerve of the domestic pig: implications for the study of vagus nerve stimulation.

J Neural Eng 2020 04 9;17(2):026022. Epub 2020 Apr 9.

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States of America. Mayo Clinic, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, United States of America.

Objective: Given current clinical interest in vagus nerve stimulation (VNS), there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the pig, whose vagus nerve organization and size approximates the human vagus nerve.

Approach: Here we combined microdissection, histology, and immunohistochemistry to provide data on key features across the cervical vagus nerve in a swine model, and compare our results to other animal models (mouse, rat, dog, non-human primate) and humans.

Main Results: In a swine model we quantified the nerve diameter, number and diameter of fascicles, and distance of fascicles from the epineural surface where stimulating electrodes are placed. We also characterized the relative locations of the superior and recurrent laryngeal branches of the vagus nerve that have been implicated in therapy limiting side effects with common electrode placement. We identified key variants across the cohort that may be important for VNS with respect to changing sympathetic/parasympathetic tone, such as cross-connections to the sympathetic trunk. We discovered that cell bodies of pseudo-unipolar cells aggregate together to form a very distinct grouping within the nodose ganglion. This distinct grouping gives rise to a larger number of smaller fascicles as one moves caudally down the vagus nerve. This often leads to a distinct bimodal organization, or 'vagotopy'. This vagotopy was supported by immunohistochemistry where approximately half of the fascicles were immunoreactive for choline acetyltransferase, and reactive fascicles were generally grouped in one half of the nerve.

Significance: The vagotopy observed via histology may be advantageous to exploit in design of electrodes/stimulation paradigms. We also placed our data in context of historic and recent histology spanning multiple models, thus providing a comprehensive resource to understand similarities and differences across species.
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http://dx.doi.org/10.1088/1741-2552/ab7ad4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306215PMC
April 2020

Effects of ramped-frequency thalamic deep brain stimulation on tremor and activity of modeled neurons.

Clin Neurophysiol 2020 03 26;131(3):625-634. Epub 2019 Dec 26.

Department of Biomedical Engineering, Duke University, Durham, NC, USA; Department of Neurobiology, Duke University Medical Center, Durham, NC, USA; Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA; Department of Electrical and Computer Engineering, Duke University, Durham, NC, USA. Electronic address:

Objective: We conducted intraoperative measurements of tremor to quantify the effects of temporally patterned ramped-frequency DBS trains on tremor.

Methods: Seven patterns of stimulation were tested in nine subjects with thalamic DBS for essential tremor: stimulation 'off', three ramped-frequency stimulation (RFS) trains from 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz, and three constant frequency stimulation (CFS) trains at 72, 82, and 130 Hz. The same patterns were applied to a computational model of the thalamic neural network.

Results: Temporally patterned 130 → 60 Hz ramped-frequency trains suppressed tremor relative to stimulation 'off,' but 130 → 50 Hz, 130 → 60 Hz, and 235 → 90 Hz ramped-frequency trains were no more effective than constant frequency stimulation with the same mean interpulse interval (IPI). Computational modeling revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but long IPIs, concurrent with pauses in afferent cerebellar and cortical firing, allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions.

Conclusion: Frequency-ramped DBS produced equivalent tremor suppression as constant frequency thalamic DBS. Tremor-related thalamic burst activity may result from burst-driver input, rather than by an intrinsic rebound mechanism.

Significance: Ramping stimulation frequency may exacerbate thalamic burst firing by introducing consecutive pauses of increasing duration to the stimulation pattern.
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http://dx.doi.org/10.1016/j.clinph.2019.11.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023987PMC
March 2020

Continuous deep brain stimulation of the subthalamic nucleus may not modulate beta bursts in patients with Parkinson's disease.

Brain Stimul 2020 Mar - Apr;13(2):433-443. Epub 2019 Dec 17.

Biomedical Engineering Department, Duke University, Durham, NC, USA; Neurobiology and Neurosurgery Departments, Duke University Medical Center, Durham, NC, USA; Electrical and Computer Engineering Department, Duke University, Durham, NC, USA. Electronic address:

Background: Neural oscillations represent synchronous neuronal activation and are ubiquitous throughout the brain. Oscillatory activity often includes brief high-amplitude bursts in addition to background oscillations, and burst activity may predict performance on working memory, motor, and comprehension tasks.

Objective: We evaluated beta burst activity as a possible biomarker for motor symptoms in Parkinson's disease (PD). The relationship between beta amplitude dynamics and motor symptoms is critical for adaptive DBS for treatment of PD.

Methods: We applied threshold-based and support vector machine (SVM) analyses of burst parameters to a defined on/off oscillator and to intraoperative recordings of local field potentials from the subthalamic nucleus of 16 awake patients with PD.

Results: Filtering and time-frequency analysis techniques critically influenced the accuracy of identifying burst activity. Threshold-based analysis lead to biased results in the presence of changes in long-term beta amplitude and accurate quantification of bursts with thresholds required unknowable a priori knowledge of the time in bursts. We therefore implemented an SVM analysis, and we did not observe changes in burst fraction, rate, or duration with the application of cDBS in the participant data, even though SVM analysis was able to correctly identify bursts of the defined on/off oscillator.

Conclusion: Our results suggest that cDBS of the STN may not change beta burst activity. Additionally, threshold-based analysis can bias the fraction of time spent in bursts. Improved analysis strategies for continuous and adaptive DBS may achieve improved symptom control and reduce side-effects.
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http://dx.doi.org/10.1016/j.brs.2019.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961347PMC
August 2020

Simulation of transcranial magnetic stimulation in head model with morphologically-realistic cortical neurons.

Brain Stimul 2020 Jan - Feb;13(1):175-189. Epub 2019 Oct 7.

Department of Biomedical Engineering, Duke University, Durham, NC, 27708, USA; Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, 27710, USA; Department of Electrical and Computer Engineering, Duke University, Durham, NC, 27708, USA; Department of Neurosurgery, School of Medicine, Duke University, Durham, NC, 27710, USA. Electronic address:

Background: Transcranial magnetic stimulation (TMS) enables non-invasive modulation of brain activity with both clinical and research applications, but fundamental questions remain about the neural types and elements TMS activates and how stimulation parameters affect the neural response.

Objective: To develop a multi-scale computational model to quantify the effect of TMS parameters on the direct response of individual neurons.

Methods: We integrated morphologically-realistic neuronal models with TMS-induced electric fields computed in a finite element model of a human head to quantify the cortical response to TMS with several combinations of pulse waveforms and current directions.

Results: TMS activated with lowest intensity intracortical axonal terminations in the superficial gyral crown and lip regions. Layer 5 pyramidal cells had the lowest thresholds, but layer 2/3 pyramidal cells and inhibitory basket cells were also activated at most intensities. Direct activation of layers 1 and 6 was unlikely. Neural activation was largely driven by the field magnitude, rather than the field component normal to the cortical surface. Varying the induced current direction caused a waveform-dependent shift in the activation site and provided a potential mechanism for experimentally observed differences in thresholds and latencies of muscle responses.

Conclusions: This biophysically-based simulation provides a novel method to elucidate mechanisms and inform parameter selection of TMS and other cortical stimulation modalities. It also serves as a foundation for more detailed network models of the response to TMS, which may include endogenous activity, synaptic connectivity, inputs from intrinsic and extrinsic axonal projections, and corticofugal axons in white matter.
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http://dx.doi.org/10.1016/j.brs.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889021PMC
June 2020

Model-Based Evaluation of Closed-Loop Deep Brain Stimulation Controller to Adapt to Dynamic Changes in Reference Signal.

Front Neurosci 2019 10;13:956. Epub 2019 Sep 10.

Department of Biomedical Engineering, Duke University, Durham, NC, United States.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing the motor symptoms of Parkinson's disease (PD). Current clinically-deployed DBS technology operates in an open-loop fashion, i.e., fixed parameter high-frequency stimulation is delivered continuously, invariant to the needs or status of the patient. This poses two major challenges: (1) depletion of the stimulator battery due to the energy demands of continuous high-frequency stimulation, (2) high-frequency stimulation-induced side-effects. Closed-loop deep brain stimulation (CL DBS) may be effective in suppressing parkinsonian symptoms with stimulation parameters that require less energy and evoke fewer side effects than open loop DBS. However, the design of CL DBS comes with several challenges including the selection of an appropriate biomarker reflecting the symptoms of PD, setting a suitable reference signal, and implementing a controller to adapt to dynamic changes in the reference signal. Dynamic changes in beta oscillatory activity occur during the course of voluntary movement, and thus there may be a performance advantage to tracking such dynamic activity. We addressed these challenges by studying the performance of a closed-loop controller using a biophysically-based network model of the basal ganglia. The model-based evaluation consisted of two parts: (1) we implemented a Proportional-Integral (PI) controller to compute optimal DBS frequencies based on the magnitude of a dynamic reference signal, the oscillatory power in the beta band (13-35 Hz) recorded from model globus pallidus internus (GPi) neurons. (2) We coupled a linear auto-regressive model based mapping function with the Routh-Hurwitz stability analysis method to compute the parameters of the PI controller to track dynamic changes in the reference signal. The simulation results demonstrated successful tracking of both constant and dynamic beta oscillatory activity by the PI controller, and the PI controller followed dynamic changes in the reference signal, something that cannot be accomplished by constant open-loop DBS.
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http://dx.doi.org/10.3389/fnins.2019.00956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746932PMC
September 2019

Beta Frequency Oscillations in the Subthalamic Nucleus Are Not Sufficient for the Development of Symptoms of Parkinsonian Bradykinesia/Akinesia in Rats.

eNeuro 2019 Sep/Oct;6(5). Epub 2019 Oct 22.

Department of Biomedical Engineering, Duke University, Durham, NC 27708

Substantial correlative evidence links the synchronized, oscillatory patterns of neural activity that emerge in Parkinson's disease (PD) in the beta (β) frequency range (13-30 Hz) with bradykinesia in PD. However, conflicting evidence exists, and whether these changes in neural activity are causal of motor symptoms in PD remains unclear. We tested the hypothesis that the synchronized β oscillations that emerge in PD are causal of symptoms of bradykinesia/akinesia. We designed patterns of stimulation that mimicked the temporal characteristics of single unit β bursting activity seen in PD animals and humans. We applied these β-patterned stimulation patterns along with continuous low-frequency and high-frequency controls to the subthalamic nucleus (STN) of intact and 6-OHDA-lesioned female Long-Evans and Sprague-Dawley rats. β-Patterned paradigms were superior to low-frequency controls at induction of β power in downstream substantia nigra reticulata (SNr) neurons and in ipsilateral motor cortex. However, we did not detect deleterious effects on motor performance across a wide battery of validated behavioral tasks. Our results suggest that β frequency oscillations (BFOs) may not be sufficient for the generation of bradykinesia/akinesia in PD.
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http://dx.doi.org/10.1523/ENEURO.0089-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817717PMC
May 2020

Randomized Controlled Trial to Assess the Impact of High Concentration Intraurethral Lidocaine on Urodynamic Voiding Parameters.

Urology 2019 Nov 26;133:72-77. Epub 2019 Aug 26.

Department of Biomedical Engineering, Duke University, Durham, NC. Electronic address:

Objective: To assess whether intraurethral anesthesia decreased voiding efficiency (VE), reduced catheterization pain, and impacted urodynamic parameters in healthy adult females.

Methods: In a randomized, double-blind, placebo-controlled trial, participants received two 5 mL doses of either intraurethral aqueous gel or 4% lidocaine gel. The primary outcome was VE during randomized condition uroflow, defined as voided volume/(voided volume + residual volume). The secondary outcomes were pain during catheterization and to confirm previously reported pressure-flow changes. A sample size of 10 per group was planned to detect a clinically significant decrease in VE with a power (1-β) of 0.99.

Results: From October to December 2018, 23 women were screened and 18 were randomized to receive placebo (n = 10) or lidocaine (n = 8). Baseline uroflow VE was similar between the placebo and lidocaine groups (88 ± 6.6% vs 91 ± 5.8%, P = .33). After study drug administration, the changes in VE (post-pre) were similar between placebo and lidocaine groups (-5.4 ± 14% vs 1.7 ± 6.4%, P = .21). Visual analog scores were similar following catheterizations (26.7 ± 12.8 mm vs 36.9 ± 26.8 mm, P = .34). The lidocaine group exhibited lower average flow rates per voided volume (0.04 ± 0.02 s vs 0.02 ± 0.01 s, P = .04).

Conclusion: Intraurethral administration of 4% lidocaine did not decrease VE compared to placebo and did not change pain scores following catheterization. In the lidocaine group, the average flow rate per voided volume was lower. The decrease in flow rate after local anesthesia to the urethra may indicate that urethral sensory feedback contributes to voiding in human micturition.
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http://dx.doi.org/10.1016/j.urology.2019.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842692PMC
November 2019

Accuracy of robotic coil positioning during transcranial magnetic stimulation.

J Neural Eng 2019 09 17;16(5):054003. Epub 2019 Sep 17.

Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC 27710, United States of America. Department of Neurosurgery, Duke University, Durham, NC 27710, United States of America. Department of Electrical and Computer Engineering, Duke University, Durham, NC 27708, United States of America.

Objective: Robotic positioning systems for transcranial magnetic stimulation (TMS) promise improved accuracy and stability of coil placement, but there is limited data on their performance. Investigate the usability, accuracy, and limitations of robotic coil placement with a commercial system, ANT Neuro, in a TMS study.

Approach: 21 subjects underwent a total of 79 TMS sessions corresponding to 160 hours under robotic coil control. Coil position and orientation were monitored concurrently through an additional neuronavigation system.

Main Results: Robot setup took on average 14.5 min. The robot achieved low position and orientation error with median 3.54 mm (overall, 1.34 mm without coil-head spacing) and 3.48°. The error increased over time at a rate of 0.4%/minute for both position and orientation.

Significance: Robotic TMS systems can provide accurate and stable coil position and orientation in long TMS sessions. Lack of pressure feedback and of manual adjustment of all coil degrees of freedom were limitations of this robotic system.
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http://dx.doi.org/10.1088/1741-2552/ab2953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297297PMC
September 2019