Cardiovascular Response to Intraneural Right Vagus Nerve Stimulation in Adult Minipig.

OBJECTIVE: This study explored intraneural stimulation of the right thoracic vagus nerve (VN) in sexually mature male minipigs to modulate safe heart rate and blood pressure response. MATERIAL AND METHODS: We employed an intraneural electrode designed for the VN of pigs to perform VN stimulation (VNS). This was delivered using different numbers of contacts on the electrode and different stimulation parameters (amplitude, frequency, and pulse width), identifying the most suitable stimulation configuration. All the parameter ranges had been selected from a computational cardiovascular system model. RESULTS: Clinically relevant responses were observed when stimulating with low current intensities and relatively low frequencies delivered with a single contact. Selecting a biphasic, charge-balanced square wave for VNS with a current amplitude of 500 µA, frequency of 10 Hz, and pulse width of 200 µs, we obtained heart rate reduction of 7.67 ± 5.19 beats per minute, systolic pressure reduction of 5.75 ± 2.59 mmHg, and diastolic pressure reduction of 3.39 ± 1.44 mmHg. CONCLUSION: Heart rate modulation was obtained without inducing any observable adverse effects, underlining the high selectivity of the intraneural approach.

Comparison of Paresthesia Mapping With Anatomic Placement in Burst Spinal Cord Stimulation: Long-Term Results of the Prospective, Multicenter, Randomized, Double-Blind, Crossover CRISP Study.

OBJECTIVES: Spinal cord stimulation (SCS) is an effective therapy for chronic intractable pain. Conventional SCS involves electrode placement based on intraoperative paresthesia mapping; however, newer paradigms like burst may allow for anatomic placement of leads. Here, for the first time, we report the one-year safety and efficacy of burst SCS delivered using a lead placed with conventional, paresthesia mapping, or anatomic placement approach in subjects with chronic low back pain (CLBP). MATERIALS AND METHODS: Subjects with CLBP were implanted with two leads. The first lead was placed to cross the T8/T9 disc and active contacts for this lead were chosen through paresthesia mapping. The second lead was placed at the T9/T10 spinal anatomic landmark. Subjects initially underwent a four-week, double-blinded, crossover trial with a two-week testing period with burst SCS delivered through each lead in a random order. At the end of trial period, subjects expressed their preference for one of the two leads. Subsequently, subjects received burst SCS with the preferred lead and were followed up at 3, 6, and 12 months. Pain intensity (visual analog scale), quality-of-life (EuroQol-5D instrument), and disability (Oswestry Disability Index) were evaluated at baseline and follow-up. RESULTS: Forty-three subjects successfully completed the trial. Twenty-one preferred the paresthesia mapping lead and 21 preferred the anatomic placement lead. Anatomic placement lead was activated in one subject who had no preference. The pain scores (for back and leg) significantly improved from baseline for both lead placement groups at all follow-up time points, with no significant between-group differences. CONCLUSIONS: This study demonstrated that equivalent clinical benefits could be achieved with burst SCS using either paresthesia mapping or anatomic landmark-based approaches for lead placement. Nonparesthesia-based approaches, such as anatomic landmark-based lead placement investigated here, have the potential to simplify implantation of SCS and improve current surgical practice.

Multicentre, clinical trial of burst spinal cord stimulation for neck and upper limb pain NU-BURST: a trial protocol.

BACKGROUND: Spinal cord stimulation (SCS) is an established therapy for chronic neuropathic pain and most frequently utilised for Failed Back Surgery Syndrome (FBSS). BurstDR™ also known as DeRidder Burst-SCS, a novel waveform, has demonstrated superiority to conventional tonic stimulation of the thoracic spine in FBSS. There are case reports of an improvement in multidimensional pain outcomes using DeRidder Burst-SCS in the cervical spine for chronic neck and cervical radicular pain. The safety and efficacy of cervical DeRidder Burst-SCS stimulation still however remain undetermined. METHODS/DESIGN: This is a prospective, multicentre feasibility trial evaluating the safety and therapeutic efficacy of DeRidder Burst-SCS stimulation for the treatment of chronic intractable neck pain with or without radiation to the arm, shoulder, and upper back. After baseline evaluation, subjects will undergo an SCS trial using the Abbott Invisible Trial system according to standard clinical procedures. During the trial phase, SCS leads will be implanted in the cervical epidural space. At the end of the SCS trial, subjects experiencing at least 50% pain relief will be considered for permanent implant. Pain intensity, medication usage, and other multidimensional pain outcomes will be collected. The timing of these will be at baseline, end of the SCS trial and at 3-, 6-, and 12-month visits. Incidence of adverse events will be collected throughout the study duration. DISCUSSION: The results of this feasibility study will validate the efficacy and safety of DeRidder Burst-SCS stimulation in the cervical spine. The results obtained in this study will potentially be used to generate a level 1 evidence-based study with formal statistical hypotheses testing. TRIAL REGISTRATION: www.clinicaltrials.gov Identifier: NCT03159169.

Novel Intermittent Dosing Burst Paradigm in Spinal Cord Stimulation.

INTRODUCTION: Intermittent dosing (ID), in which periods of stimulation-on are alternated with periods of stimulation-off, is generally employed using 30 sec ON and 90 sec OFF intervals with burst spinal cord stimulation (SCS). The goal of this study was to evaluate the feasibility of using extended stimulation-off periods in patients with chronic intractable pain. MATERIALS AND METHODS: This prospective, multicenter, feasibility trial evaluated the clinical efficacy of the following ID stimulation-off times: 90, 120, 150, and 360 sec with burst waveform parameters. After a successful trial (≥50% pain relief) using ID stimulation, subjects were titrated with OFF times beginning with 360 sec. Pain, quality of life, disability, and pain catastrophizing were evaluated at one, three, and six months after permanent implant. RESULTS: Fifty subjects completed an SCS trial using ID stimulation settings of 30 sec ON and 90 sec OFF, with 38 (76%) receiving ≥50% pain relief. Pain scores were significantly reduced from baseline at all time points (p < 0.001). Improvements in quality of life, disability, and pain catastrophizing were aligned with pain relief outcomes; 45.8% of the subjects that completed the six-month follow-up visit used an OFF period of 360 seconds. CONCLUSIONS: ID burst SCS effectively relieved pain for six months. The largest group of subjects used IDB settings of 30 sec ON and 360 sec OFF. These findings present intriguing implications for the optimal "dose" of electricity in SCS and may offer many advantages such as optimizing the therapeutic window, extending battery life, reducing recharge burden and, potentially, mitigating therapy habituation or tolerance.

Frequency-dependent spike-pattern changes in motor cortex during thalamic deep brain stimulation.

The cerebellar-receiving area of the motor thalamus is the primary anatomical target for treating essential tremor with deep brain stimulation (DBS). Although neuroimaging studies have shown that higher stimulation frequencies in this target correlate with increased cortical metabolic activity, less is known about the cellular-level functional changes that occur in the primary motor cortex (M1) with thalamic stimulation and how these changes depend on the frequency of DBS. In this study, we used a preclinical animal model of DBS to collect single-unit spike recordings in M1 before, during, and after DBS targeting the cerebellar-receiving area of the motor thalamus (VPLo, nucleus ventralis posterior lateralis pars oralis). The effects of VPLo-DBS on M1 spike rates, interspike interval entropy, and peristimulus phase-locking were compared across stimulus pulse train frequencies ranging from 10 to 130 Hz. Although VPLo-DBS modulated the spike rates of 20-50% of individual M1 cells in a frequency-dependent manner, the population-level average spike rate only weakly depended on stimulation frequency. In contrast, the population-level entropy measure showed a pronounced decrease with high-frequency stimulation, caused by a subpopulation of cells that exhibited strong phase-locking and general spike-pattern regularization. Contrarily, low-frequency stimulation induced an entropy increase (spike-pattern disordering) in a relatively large portion of the recorded population, which diminished with higher stimulation frequencies. These results also suggest that changes in phase-locking and spike-pattern entropy are not necessarily equivalent pattern phenomena, but rather that they should both be weighed when quantifying stimulation-induced spike-pattern changes.NEW & NOTEWORTHY The network mechanisms of thalamic deep brain stimulation (DBS) are not well understood at the cellular level. This study investigated the neuronal firing rate and pattern changes in the motor cortex resulting from stimulation of the cerebellar-receiving area of the motor thalamus. We showed that there is a nonintuitive relationship between general entropy-based spike-pattern measures and phase-locked regularization to DBS.

Comparison of Paresthesia Mapping to Anatomical Placement in Burst Spinal Cord Stimulation: Initial Trial Results of the Prospective, Multicenter, Randomized, Double-Blinded, Crossover, CRISP Study.

INTRODUCTION: In this prospective, multicenter, double-blinded, randomized, crossover study, we compared the therapeutic efficacy of burst SCS delivered using a lead implanted with the paresthesia mapping approach to a lead implanted with an anatomic placement approach. MATERIALS AND METHODS: Subjects with chronic low back pain were implanted with two leads, one using paresthesia-mapping approach (PM) and the second using anatomical placement procedure (AP). Stimulation contacts were chosen using the standard intraoperative paresthesia-testing procedure for the paresthesia-mapped lead or an activated bipole overlapping the T9-T10 junction for the anatomical lead. Amplitude for either lead was selected such that no sensory percepts were generated. Subjects were assessed at baseline and after a trial period during which they tested each lead for two weeks in random order. Eligible subjects had the option to receive permanent implants using their preferred AP or PM approach at end-of-trial. RESULTS: Of the 53 subjects who completed both trial periods, 43 (81.1%) experienced at least 50% back pain relief with at least one lead. Nearly half of these (20; 46.5%) were profound responders who experienced at least 80% back pain relief with either leads. Primary and secondary outcomes, at the end of trial, showed significant improvements for both AP and PM leads from baseline yet were not significantly different from each other. DISCUSSION: The trial results of this study suggest that similar clinical outcomes can be achieved in burst SCS when performing lead placement either using paresthesia mapping or anatomical placement with imaging references.

Comparison of Paresthesia Coverage of Patient's Pain: Dorsal Root Ganglion vs. Spinal Cord Stimulation. An ACCURATE Study Sub-Analysis.

OBJECTIVES: This was a sub-analysis of the ACCURATE clinical trial that evaluated the accuracy and necessity of targeting paresthesia coverage of painful areas with dorsal root ganglion (DRG) stimulation vs. tonic spinal cord stimulation (SCS). MATERIALS AND METHODS: On diagrams of the torso and lower limbs, subjects marked where they felt pain at baseline and paresthesias at three months postimplant. Seventy-five subjects (41 DRG and 34 SCS) with diagrams of sufficient quality were scanned, digitized, and included in this analysis. Subject completed diagrams were digitized and superimposed with a grid of 1398 squares. Quantification of the percentage of bodily areas affected by pain and stimulation induced paresthesias was performed. RESULTS: The percent of painful areas covered by paresthesia was significantly lower for DRG subjects than for SCS subjects (13% vs. 28% of the painful regions, p < 0.05), possibly because significantly more DRG subjects felt no paresthesia during stimulation when compared to SCS subjects (13/41 DRG vs. 3/34 SCS) (p < 0.05). The amount of paresthesia produced outside the painful areas (unrequired paresthesia) was significantly lower in DRG subjects than that of SCS subjects. On average, the percent of unrequired paresthesia was only 20% of the subjects' total painful body surface area in the DRG group compared to 210% in the SCS group (p < 0.01). CONCLUSIONS: The results of this ACCURATE study sub-analysis show that DRG stimulation produces paresthesias, on average, that are less frequent, less intense, with a smaller footprint on the body and less dependent on positional changes.

Nonawake vs Awake Placement of Spinal Cord Stimulators: A Prospective, Multicenter Study Comparing Safety and Efficacy.

BACKGROUND: Spinal cord stimulation (SCS) is a common intervention for managing intractable pain. Generally, leads are implanted in a minimally invasive procedure with verbal feedback regarding the location and nature of generated paresthesias by active stimulation; in this way their optimal location can be confirmed. However, lead placement under general anesthesia can have additional benefits. OBJECTIVE: To investigate the outcomes of awake vs asleep lead placement procedures. METHODS: In this prospective multicenter open label trial, subjects were assigned to undergo asleep (n = 19) or awake (n = 11) SCS implantations in a nonrandomized fashion. Subjects received paddle leads following laminotomy. The process for intraoperative programming differed between the groups: awake subjects participated by verbally reporting on pain-paresthesia overlap, while for asleep subjects, paresthesia location was inferred based on electromyographic monitoring. RESULTS: Operative time was shorter for the asleep group compared to the awake group (88.9 ± 51.2 min vs 125.2 ± 37.9, respectively; P = .018), as well as 27% less total time spent in the operating room (95.4 ± 48.6 min vs 130.6 ± 39.9; P = .014). At 6 wk postimplant, subjects in the asleep group had better pain-paresthesia overlap than the awake group (83.5% ± 19.8 coverage vs 46.6% ± 44.5, respectively; P = .05) and fewer extraneous paresthesia (16.7% ± 23.1 vs 71.2% ± 30.3; P < .001). Both groups had equivalent levels of pain relief (more than 50%) after 6 and 24 wk of treatment. There were 2 adverse events in the asleep group compared to 6 in the awake group. CONCLUSION: Electrophysiological monitoring during asleep SCS implantation is a robust tool becoming more frequently used. This comparative prospective series demonstrates that asleep placement allows for shorter procedure and operating room times with superior paresthesia coverage profiles, while maintaining lower adverse events and equal clinical outcomes for pain relief.

Burst SCS Microdosing Is as Efficacious as Standard Burst SCS in Treating Chronic Back and Leg Pain: Results From a Randomized Controlled Trial.

INTRODUCTION: The burst waveform, a recent innovation in spinal cord stimulation (SCS), can achieve better outcomes than conventional tonic SCS, both for de novo implants and as a salvage therapy. Burst stimulation delivers more energy per second than tonic stimulation, which is a consideration for battery consumption. The clinical effectiveness of an energy-conserving strategy was investigated. METHODS: Subjects were experienced users of BurstDR SCS for back and leg pain. Three 2-week stimulation paradigms were presented in blinded random order: standard (continuously delivered) BurstDR, microdosing A: 5 sec of BurstDR alternating with 5 sec of no stimulation, and microdosing B: 5 sec of BurstDR alternating with 10 sec of no stimulation. The primary outcome for each paradigm was change in pain ratings, and secondary outcomes included changes in scores for quality of life, satisfaction, and preference. RESULTS: Twenty-five subjects assessed all three stimulation paradigms. There were no significant differences in pain (visual analog scale) or quality of life (EQ-5D) when comparing standard burst outcomes with those of microdosing A and, separately, microdosing B. Microdosing paradigms were graded with slightly higher level of satisfaction and were generally preferred above standard burst stimulation. DISCUSSION: These results suggest that the use of energy-efficient burst microdosing stimulation paradigms with alternating stimulation-on and stimulation-off periods can provide clinically equivalent results to standard burst stimulation. This is important for extending SCS battery life. Further research is needed to comprehensively characterize the clinical utility of this approach and the neurophysiological mechanisms for the maintenance of pain relief during stimulation-off periods.

Deep brain stimulation induces sparse distributions of locally modulated neuronal activity.

Deep brain stimulation (DBS) therapy is a potent tool for treating a range of brain disorders. High frequency stimulation (HFS) patterns used in DBS therapy are known to modulate neuronal spike rates and patterns in the stimulated nucleus; however, the spatial distribution of these modulated responses are not well understood. Computational models suggest that HFS modulates a volume of tissue spatially concentrated around the active electrode. Here, we tested this theory by investigating modulation of spike rates and patterns in non-human primate motor thalamus while stimulating the cerebellar-receiving area of motor thalamus, the primary DBS target for treating Essential Tremor. HFS inhibited spike activity in the majority of recorded cells, but increasing stimulation amplitude also shifted the response to a greater degree of spike pattern modulation. Modulated responses in both categories exhibited a sparse and long-range spatial distribution within motor thalamus, suggesting that stimulation preferentially affects afferent and efferent axonal processes traversing near the active electrode and that the resulting modulated volume strongly depends on the local connectome of these axonal processes. Such findings have important implications for current clinical efforts building predictive computational models of DBS therapy, developing directional DBS lead technology, and formulating closed-loop DBS strategies.

Fidelity of frequency and phase entrainment of circuit-level spike activity during DBS.

High-frequency stimulation is known to entrain spike activity downstream and upstream of several clinical deep brain stimulation (DBS) targets, including the cerebellar-receiving area of thalamus (VPLo), subthalamic nucleus (STN), and globus pallidus (GP). Less understood are the fidelity of entrainment to each stimulus pulse, whether entrainment patterns are stationary over time, and how responses differ among DBS targets. In this study, three rhesus macaques were implanted with a single DBS lead in VPLo, STN, or GP. Single-unit spike activity was recorded in the resting state in motor cortex during VPLo DBS, in GP during STN DBS, and in STN and pallidal-receiving area of motor thalamus (VLo) during GP DBS. VPLo DBS induced time-locked spike activity in 25% (n = 15/61) of motor cortex cells, with entrained cells following 7.5 ± 7.4% of delivered pulses. STN DBS entrained spike activity in 26% (n = 8/27) of GP cells, which yielded time-locked spike activity for 8.7 ± 8.4% of stimulus pulses. GP DBS entrained 67% (n = 14/21) of STN cells and 32% (n = 19/59) of VLo cells, which showed a higher fraction of pulses effectively inhibiting spike activity (82.0 ± 9.6% and 86.1 ± 16.6%, respectively). Latency of phase-locked spike activity increased over time in motor cortex (58%, VPLo DBS) and to a lesser extent in GP (25%, STN DBS). In contrast, the initial inhibitory phase observed in VLo and STN during GP DBS remained stable following stimulation onset. Together, these data suggest that circuit-level entrainment is low-pass filtered during high-frequency stimulation, most notably for glutamatergic pathways. Moreover, phase entrainment is not stationary or consistent at the circuit level for all DBS targets.

Deep brain stimulation: how does it work?

Chronic deep brain stimulation (DBS) has become a widely accepted surgical treatment for medication-refractory movement disorders and is under evaluation for a variety of neurological disorders. In order to create opportunities to improve treatment efficacy, streamline parameter selection, and foster new potential applications, it is important to have a clear and comprehensive understanding of how DBS works. Although early hypothesis proposed that high-frequency electrical stimulation inhibited neuronal activity proximal to the active electrode, recent studies have suggested that the output of the stimulated nuclei is paradoxically activated by DBS. Such regular, time-locked output is thought to override the transmission of pathological bursting and oscillatory activity through the stimulated nuclei, as well as inducing synaptic plasticity and network reorganization. This chapter reviews electrophysiological experiments, biochemical analyses, computer modeling and imaging studies positing that, although general principles exist, the therapeutic mechanism(s) of action depend both on the site of stimulation and on the disorder being treated.

Deep brain stimulation imposes complex informational lesions.

Deep brain stimulation (DBS) therapy has become an essential tool for treating a range of brain disorders. In the resting state, DBS is known to regularize spike activity in and downstream of the stimulated brain target, which in turn has been hypothesized to create informational lesions. Here, we specifically test this hypothesis using repetitive joint articulations in two non-human Primates while recording single-unit activity in the sensorimotor globus pallidus and motor thalamus before, during, and after DBS in the globus pallidus (GP) GP-DBS resulted in: (1) stimulus-entrained firing patterns in globus pallidus, (2) a monophasic stimulus-entrained firing pattern in motor thalamus, and (3) a complete or partial loss of responsiveness to joint position, velocity, or acceleration in globus pallidus (75%, 12/16 cells) and in the pallidal receiving area of motor thalamus (ventralis lateralis pars oralis, VLo) (38%, 21/55 cells). Despite loss of kinematic tuning, cells in the globus pallidus (63%, 10/16 cells) and VLo (84%, 46/55 cells) still responded to one or more aspects of joint movement during GP-DBS. Further, modulated kinematic tuning did not always necessitate modulation in firing patterns (2/12 cells in globus pallidus; 13/23 cells in VLo), and regularized firing patterns did not always correspond to altered responses to joint articulation (3/4 cells in globus pallidus, 11/33 cells in VLo). In this context, DBS therapy appears to function as an amalgam of network modulating and network lesioning therapies.

Local glutamate release in the rat ventral lateral thalamus evoked by high-frequency stimulation.

Thalamic deep brain stimulation (DBS) is proven therapy for essential tremor, Parkinson's disease and Tourette's syndrome. We tested the hypothesis that high-frequency electrical stimulation results in local thalamic glutamate release. Enzyme-linked glutamate amperometric biosensors were implanted in anesthetized rat thalamus adjacent to the stimulating electrode. Electrical stimulation was delivered to investigate the effect of frequency, pulse width, voltage-controlled or current-controlled stimulation, and charge balancing. Monophasic electrical stimulation-induced glutamate release was linearly dependent on stimulation frequency, intensity and pulse width. Prolonged stimulation evoked glutamate release to a plateau that subsequently decayed back to baseline after stimulation. Glutamate release was less pronounced with voltage-controlled stimulation and not present with charge balanced current-controlled stimulation. Using fixed potential amperometry in combination with a glutamate bioprobe and adjacent microstimulating electrode, the present study has shown that monophasic current-controlled stimulation of the thalamus in the anesthetized rat evoked linear increases in local extracellular glutamate concentrations that were dependent on stimulation duration, frequency, intensity and pulse width. However, the efficacy of monophasic voltage-controlled stimulation, in terms of evoking glutamate release in the thalamus, was substantially lower compared to monophasic current-controlled stimulation and entirely absent with biphasic (charge balanced) current-controlled stimulation. It remains to be determined whether similar glutamate release occurs with human DBS electrodes and similar charge balanced stimulation. As such, the present results indicate the importance of evaluating local neurotransmitter dynamics in studying the mechanism of action of DBS.

Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) for intraoperative neurochemical monitoring.

The Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) measures extracellular neurotransmitter concentration in vivo and displays the data graphically in nearly real time. WINCS implements two electroanalytical methods, fast-scan cyclic voltammetry (FSCV) and fixed-potential amperometry (FPA), to measure neurotransmitter concentrations at an electrochemical sensor, typically a carbon-fiber microelectrode. WINCS comprises a battery-powered patient module and a custom software application (WINCSware) running on a nearby personal computer. The patient module impresses upon the electrochemical sensor either a constant potential (for FPA) or a time-varying waveform (for FSCV). A transimpedance amplifier converts the resulting current to a signal that is digitized and transmitted to the base station via a Bluetooth radio link. WINCSware controls the operational parameters for FPA or FSCV, and records the transmitted data stream. Filtered data is displayed in various formats, including a background-subtracted plot of sequential FSCV scans - a representation that enables users to distinguish the signatures of various analytes with considerable specificity. Dopamine, glutamate, adenosine and serotonin were selected as analytes for test trials. Proof-of-principle tests included in vitro flow-injection measurements and in vivo measurements in rat and pig. Further testing demonstrated basic functionality in a 3-Tesla MRI unit. WINCS was designed in compliance with consensus standards for medical electrical device safety, and it is anticipated that its capability for real-time intraoperative monitoring of neurotransmitter release at an implanted sensor will prove useful for advancing functional neurosurgery.

Microthalamotomy effect during deep brain stimulation: potential involvement of adenosine and glutamate efflux.

Deep brain stimulation (DBS) of the thalamus is widely used in humans to treat essential tremor and tremor dominant Parkinson's disease. After DBS lead implantation, tremor is often reduced even without electrical stimulation. Often called "microthalamotomy" effect, the exact mechanism is unknown, although it is presumed to be due to micro lesioning. Here, we tested whether microthalamotomy effect may, in fact, be mediated via release of neurotransmitters adenosine and glutamate, using fast scan cyclic voltammetry (FSCV) and amperometry, respectively. Implantation of microelectrodes into the ventrolateral (VL) thalamus of the rat resulted in transient rise in adenosine and glutamate level from mechanical stimulation. Similarly, high frequency stimulation (100 - 130 Hz) of the VL thalamus also resulted in adenosine and glutamate release. These results suggest that glutamate and adenosine release may be an important and unappreciated mechanism whereby mechanical stimulation via electrode implantation procedure may achieve the microthalamotomy effect.

Development of the Wireless Instantaneous Neurotransmitter Concentration System for intraoperative neurochemical monitoring using fast-scan cyclic voltammetry.

OBJECT: Emerging evidence supports the hypothesis that modulation of specific central neuronal systems contributes to the clinical efficacy of deep brain stimulation (DBS) and motor cortex stimulation (MCS). Real-time monitoring of the neurochemical output of targeted regions may therefore advance functional neurosurgery by, among other goals, providing a strategy for investigation of mechanisms, identification of new candidate neurotransmitters, and chemically guided placement of the stimulating electrode. The authors report the development of a device called the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for intraoperative neurochemical monitoring during functional neurosurgery. This device supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially and chemically resolved neurotransmitter measurements in the brain. METHODS: The FSCV study consisted of a triangle wave scanned between -0.4 and 1 V at a rate of 300 V/second and applied at 10 Hz. All voltages were compared with an Ag/AgCl reference electrode. The CFM was constructed by aspirating a single carbon fiber (r = 2.5 mum) into a glass capillary and pulling the capillary to a microscopic tip by using a pipette puller. The exposed carbon fiber (that is, the sensing region) extended beyond the glass insulation by approximately 100 microm. The neurotransmitter dopamine was selected as the analyte for most trials. Proof-of-principle tests included in vitro flow injection and noise analysis, and in vivo measurements in urethane-anesthetized rats by monitoring dopamine release in the striatum following high-frequency electrical stimulation of the medial forebrain bundle. Direct comparisons were made to a conventional hardwired system. RESULTS: The WINCS, designed in compliance with FDA-recognized consensus standards for medical electrical device safety, consisted of 4 modules: 1) front-end analog circuit for FSCV (that is, current-to-voltage transducer); 2) Bluetooth transceiver; 3) microprocessor; and 4) direct-current battery. A Windows-XP laptop computer running custom software and equipped with a Universal Serial Bus-connected Bluetooth transceiver served as the base station. Computer software directed wireless data acquisition at 100 kilosamples/second and remote control of FSCV operation and adjustable waveform parameters. The WINCS provided reliable, high-fidelity measurements of dopamine and other neurochemicals such as serotonin, norepinephrine, and ascorbic acid by using FSCV at CFM and by flow injection analysis. In rats, the WINCS detected subsecond striatal dopamine release at the implanted sensor during high-frequency stimulation of ascending dopaminergic fibers. Overall, in vitro and in vivo testing demonstrated comparable signals to a conventional hardwired electrochemical system for FSCV. Importantly, the WINCS reduced susceptibility to electromagnetic noise typically found in an operating room setting. CONCLUSIONS: Taken together, these results demonstrate that the WINCS is well suited for intraoperative neurochemical monitoring. It is anticipated that neurotransmitter measurements at an implanted chemical sensor will prove useful for advancing functional neurosurgery.

Wireless Instantaneous Neurotransmitter Concentration System-based amperometric detection of dopamine, adenosine, and glutamate for intraoperative neurochemical monitoring.

OBJECT: In a companion study, the authors describe the development of a new instrument named the Wireless Instantaneous Neurotransmitter Concentration System (WINCS), which couples digital telemetry with fast-scan cyclic voltammetry (FSCV) to measure extracellular concentrations of dopamine. In the present study, the authors describe the extended capability of the WINCS to use fixed potential amperometry (FPA) to measure extracellular concentrations of dopamine, as well as glutamate and adenosine. Compared with other electrochemical techniques such as FSCV or high-speed chronoamperometry, FPA offers superior temporal resolution and, in combination with enzyme-linked biosensors, the potential to monitor nonelectroactive analytes in real time. METHODS: The WINCS design incorporated a transimpedance amplifier with associated analog circuitry for FPA; a microprocessor; a Bluetooth transceiver; and a single, battery-powered, multilayer, printed circuit board. The WINCS was tested with 3 distinct recording electrodes: 1) a carbon-fiber microelectrode (CFM) to measure dopamine; 2) a glutamate oxidase enzyme-linked electrode to measure glutamate; and 3) a multiple enzyme-linked electrode (adenosine deaminase, nucleoside phosphorylase, and xanthine oxidase) to measure adenosine. Proof-of-principle analyses included noise assessments and in vitro and in vivo measurements that were compared with similar analyses by using a commercial hardwired electrochemical system (EA161 Picostat, eDAQ; Pty Ltd). In urethane-anesthetized rats, dopamine release was monitored in the striatum following deep brain stimulation (DBS) of ascending dopaminergic fibers in the medial forebrain bundle (MFB). In separate rat experiments, DBS-evoked adenosine release was monitored in the ventrolateral thalamus. To test the WINCS in an operating room setting resembling human neurosurgery, cortical glutamate release in response to motor cortex stimulation (MCS) was monitored using a large-mammal animal model, the pig. RESULTS: The WINCS, which is designed in compliance with FDA-recognized consensus standards for medical electrical device safety, successfully measured dopamine, glutamate, and adenosine, both in vitro and in vivo. The WINCS detected striatal dopamine release at the implanted CFM during DBS of the MFB. The DBS-evoked adenosine release in the rat thalamus and MCS-evoked glutamate release in the pig cortex were also successfully measured. Overall, in vitro and in vivo testing demonstrated signals comparable to a commercial hardwired electrochemical system for FPA. CONCLUSIONS: By incorporating FPA, the chemical repertoire of WINCS-measurable neurotransmitters is expanded to include glutamate and other nonelectroactive species for which the evolving field of enzyme-linked biosensors exists. Because many neurotransmitters are not electrochemically active, FPA in combination with enzyme-linked microelectrodes represents a powerful intraoperative tool for rapid and selective neurochemical sampling in important anatomical targets during functional neurosurgery.

Evolution of Deep Brain Stimulation: Human Electrometer and Smart Devices Supporting the Next Generation of Therapy.

Deep Brain Stimulation (DBS) provides therapeutic benefit for several neuropathologies including Parkinson's disease (PD), epilepsy, chronic pain, and depression. Despite well established clinical efficacy, the mechanism(s) of DBS remains poorly understood. In this review we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies, e.g., human electrometer and closed-loop smart devices, for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.

Comparison of cartilage thickness with radiologic grade of knee osteoarthritis.

OBJECTIVE: To compare joint space width (JSW) measurements obtained from magnetic resonance imaging (MRI) with a semi-automated computer algorithm to the Kellgren and Lawrence grading of osteoarthritis (OA). MATERIALS AND METHODS: Three hundred and six patients (234 female, 72 male) with a mean age of 56.7 years (range 31-81 years) underwent MRI of their knees with a fast oblique spiral spoiled gradient (SPGR) sequence. A board-certified musculoskeletal radiologist graded the OA of all the patients in accordance with the Kellgren and Lawrence OA scale. A previously validated computer algorithm was used to determine the minimum JSW for both the tibiofemoral joint and the patellofemoral joint. An analysis of variance (ANOVA) with the Student-Newman-Kuels post-hoc test was used to determine if there were differences in JSW as a function of OA grade. RESULTS: The radiologic grade of OA was inversely associated with the JSW. In the medial compartment the JSW did not change significantly between grade 1 and grade 2, but there was a significant decrease in JSW between grade 0 (normal) and grade 1 and for each OA grade above grade 2. In the lateral compartment no statistical differences were found till grade 2, while grade 3 was found to be statistically different from the previous one. The number of patients with a grade 4 patellofemoral OA was too low for the statistical significance to be assessed. In the patellofemoral joint the JSW did not change significantly until grade 2, while a statistically significant reduction was found for both grade 3 and grade 4. CONCLUSION: This study showed that an inverse non-linear relationship exists between radiologic grade and JSW. The relationship differs for the tibiofemoral and the patellofemoral joint.