Dopamine Measurement during Prolonged Deep Brain Stimulation: A Proof-of-Principle Study of Paired Pulse Voltammetry

Kendall H. Lee,Seungleal Brian Paek,Emily Jane Knight,Su-Youne Chang,J. Luis Lujan,장동표,Kevin E. Bennet 대한의용생체공학회 2013 Biomedical Engineering Letters (BMEL) Vol.3 No.1

Purpose Deep Brain Stimulation (DBS) has been effective in treating various neurological and psychiatric disorders;however, its underlying mechanism hasn’t been completely understood. Fast scan cyclic voltammetry (FSCV) is a valuable tool to elucidate underlying neurotransmitter mechanisms of DBS, due to its sub-second temporal resolution and direct identification of analytes. However, since DBS-like high frequency stimulation evokes neurotransmitter release as well as extracellular pH shift, it is hard to isolate the neurotransmitter signal from the complex environment. Here we demonstrate the efficacy of a modified FSCV technique, Paired Pulse Voltammetry (PPV), in detecting dopamine (DA) release in the caudate nucleus during long-term electrical stimulation of the medial forebrain bundle (MFB) in the rat. Methods Unlike traditional FSCV applying a single triangular waveform, PPV employs a binary waveform with a specific time gap (2.2 ms) in between the comprising pulses. DA measurement was performed with a carbon fiber microelectrode placed in the caudate nucleus and a twisted bipolar stimulating electrode in the MFB. PPV data was collected with the Wireless Instantaneous Neurochemical Concentration Sensing System (WINCS). Results Using PPV, the detection of DA was evident throughout the long-term stimulation (5 minutes); however, without PPV,in vivo environmental changes including pH shift eventually obscured the characteristic oxidation current of DA at 0.6V. Conclusions These results indicate that PPV can be a valuable tool to accurately determine DA dynamics in a complex in vivo environment during long-term electrical stimulation.

Fast Scan Cyclic Voltammetry Recordings in Humans during Neurosurgery: Challenges and Opportunities

Kendall H. Lee 대한의용생체공학회 2011 Biomedical Engineering Letters (BMEL) Vol.1 No.3

It is with great pleasure to congratulate the launch of the premier journal of “Biomedical Engineering Letters”, which is an official journal of the Korean Society of Medical and Biological Engineering. Biomedical engineering technology is one of the most crucial components in the interdisciplinary and translational research area. I believe this era will be the golden age of biomedical technology, applying the most advanced applications to scientific research. The launch of Biomedical Engineering Letters reflects this vision, and with its strong editorial board it will play a leading role opening up the biomedical engineering’s last frontier. Here, I briefly introduce the novel biomedical method of deep brain stimulation (DBS). DBS has been demonstrated to be an effective neurosurgical treatment for many neurological and psychiatric disorders including Parkinson’s disease, tremor,epilepsy, depression, and chronic pain. We have developed a novel intraoperative neurochemical monitoring device called wireless instantaneous neurotransmitter concentration sensor (WINCS) system, which combines digital telemetry with amperometry and fast-scan cyclic voltammetry (FSCV) for real-time neuro-chemical measurements at an implanted microelectrode. WINCS could detect neurotransmitters such as dopamine, adenosine, serotonin, glutamate, and histamine with micro second temporal resolution and high sensitivity. We have now utilized the system in rats, pigs, and in human Parkinson’s Disease (PD) and Essential Tremor (ET) patients during DBS neurosurgery. WINCS hardware is a micro-processor controlled, MRIcompatible,battery-powered instrument that combines Bluetooth® digital telemetry with FSCV and constant potential amperometry. The WINCS base-station software (WINCSware) controls the wireless patient module and processes the received data stream, and displays the results in nearly real time. The WINCS Electrode (WINCStrode) is based on an approved human extracellular tungsten electrophysiology electrode that was modified by the addition of a short section of carbon-fiber to enable FSCV recordings. To date, the WINCS hardware, WINCSware, and WINCStrode were used in rats, pigs, and in 15 human PD or ET Patients during clinical DBS neurosurgery. Leksell Model G Stereotactic headframe, MRI guided neuronavigation system was used for surgical targeting. Our protocol was approved by the Mayo Clinic IRB for human studies. Successful real-time analysis of wireless FSCV recordings from WINCS using the WINCStrode were performed both in a flow cell in vitro, rats, pigs, and in human PD and ET patients undergoing DBS neurosurgery. For FSCV,neurochemical data were transmitted by the WINCS hardware to the computer base station for presentation of a continuous three-dimensional color plot of sequential backgroundsubtracted voltammograms. Analysis of the voltammograms revealed signals consistent with measurements of dopamine efflux when the WINCStrode was placed in the caudate and adenosine efflux when placed in the VIM thalamus. Following WINCS recordings, the patients had good clinical response from the bilateral STN or VIM DBS electrodes, without complication. Our studies represent the successful feasibility and safety study using WINCS in animals and in humans. We believe the combination of these sophisticated in vivo techniques will provide important new insights into the neurobiological mechanisms of DBS action. Further, our results suggest that next generation DBS systems that couples digital telemetry with FSCV may be useful as the sensing component of a “smart” DBS device providing enhanced utility to human patients.

Carbon Nanofiber Multiplexed Array and Wireless Instantaneous Neurotransmitter Concentration Sensor for Simultaneous Detection of Dissolved Oxygen and Dopamine

Michael P. Marsh,Kendall H. Lee,Kevin E. Bennet,Jessica E. Koehne,Russell J. Andrews,M. Meyyappan 대한의용생체공학회 2012 Biomedical Engineering Letters (BMEL) Vol.2 No.4

Purpose While the mechanism of Deep Brain Stimulation (DBS) remains poorly understood, previous studies have shown that it evokes release of neurochemicals and induces activation of functional magnetic resonance imaging (fMRI)blood oxygen level-dependent signal in distinct areas of the brain. Therefore, the main purpose of this paper is to demonstrate the capabilities of the Wireless Instantaneous Neurotransmitter Concentration Sensor system (WINCS) in conjunction with a carbon nanofiber (CNF) multiplexed array electrode as a powerful tool for elucidating the mechanism of DBS through the simultaneous detection of multiple bioactivemolecules. Methods Patterned CNF nanoelectrode arrays were prepared on a 4-inch silicon wafer where each device consists of 3 ×3 electrode pads, 200 μm square, that contain CNFs spaced at 1 μm intervals. The multiplexed carbon nanofiber CNF electrodes were integrated with WINCS to detect mixtures of dopamine (DA) and oxygen (O2) using fast scan cyclic voltammetry (FSCV) in vitro. Results First, simultaneous detection of O2 at two spatially different locations, 200 um apart, was demonstrated. Second,simultaneous detection of both O2 and DA at two spatially different locations, using two different decoupled waveforms was demonstrated. Third, controlled studies demonstrated that the waveform must be interleaved to avoid electrode crosstalk artifacts in the acquired data. Conclusions Multiplexed CNF nanoelectrode arrays for electrochemical detection of neurotransmitters show promise for the detection of multiple analytes with the application of time independent decoupled waveforms. Electrochemistry on CNF electrodes may be helpful in elucidating the mechanism of DBS, and may also provide the precision and sensitivity required for future applications in feedback modulated DBS neural control systems.

Combat-Related Intradural Gunshot Wound to the Thoracic Spine: Significant Improvement and Neurologic Recovery Following Bullet Removal

Thijs M Louwes,William H Ward,Kendall H. Lee,Brett A Freedman 대한척추외과학회 2015 Asian Spine Journal Vol.9 No.1

The vast majority of combat-related penetrating spinal injuries from gunshot wounds result in severe or complete neurological deficit. Treatment is based on neurological status, the presence of cerebrospinal fluid (CSF) fistulas, and local effects of any retained fragment(s). We present a case of a 46-year-old male who sustained a spinal gunshot injury from a 7.62‑mm AK-47 round that became lodged within the subarachnoid space at T9–T10. He immediately suffered complete motor and sensory loss. By 24–48 hours postinjury, he had recovered lower extremity motor function fully but continued to have severe sensory loss (posterior cord syndrome). On post-injury day 2, he was evacuated from the combat theater and underwent a T9 laminectomy, extraction of the bullet, and dural laceration repair. At surgery, the traumatic durotomy was widened and the bullet, which was laying on the dorsal surface of the spinal cord, was removed. The dura was closed in a water-tight fashion and fibrin glue was applied. Postoperatively, the patient made a significant but incomplete neurological recovery. His stocking-pattern numbness and sub-umbilical searing dysthesia improved. The spinal canal was clear of the foreign body and he had no persistent CSF leak. Postoperative magnetic resonance imaging of the spine revealed contusion of the spinal cord at the T9 level. Early removal of an intra-canicular bullet in the setting of an incomplete spinal cord injury can lead to significant neurological recovery following even high-velocity and/or high-caliber gunshot wounds. However, this case does not speak to, and prior experience does not demonstrate, significant neurological benefit in the setting of a complete injury.

5-Hydroxytryptamine Measurement using Paired Pulse Voltammetry

장동표,김수영,오윤배,신호진,김인영,Kevin Bennet,Kendall H. Lee,김도형 대한의용생체공학회 2013 Biomedical Engineering Letters (BMEL) Vol.3 No.2

Purpose Although paired-pulse voltammetry (PPV) has significantly reduced the effects of confounding factors such as pH changes, its appliance has been limited to triangular waveforms. Here, we extend PPV to N-waveform, known to be effective in differentiating serotonin (5-HT) from other analytes. Methods Unlike previous PPV that employs a triangular binary waveform with a specified time gap between the comprising pulses, this study experiments PPV with Nwaveform. N-waveform, the most conventional waveform for detecting 5-HT, sweeps from 0.2 V to 1.0 V to -1.0 V and back to 0.2 V at a sweep rate of 1000 V/s, while the electrode is held at a holding potential of +0.2 V between the voltammetric pulses. After experimenting with various gap times (2 ms, 10 ms, 30 ms, and 45 ms), N-shape PPV was optimized to the parameter of 100 ms repetition time (2 Hz)and 2 ms gap time that displayed the highest sensitivity. 5-HT measurement was performed with a carbon fiber microelectrode placed in the flow cell. PPV data was collected with the Wireless Instantaneous Neurochemical Concentration Sensing System. Results At the optimized parameter, the oxidation peak in secondary pulse of N-waveform PPV recorded about 68% of the peak of the primary pulse. In addition, the fitting of peak currents in primary, secondary, and primary-secondary in Nshape PPV in relation to the concentration level between 0.25 μM to 2 μM displayed high reliability (R-squared values = 0.9823, 0.9895, 0.9914, respectively). When 5-HT 3 μM and 0.1 ΔpH is mixed, the 10 nA artifact created by 0.1ΔpH in P-S voltammogram was almost completely removed while the oxidative peak by 5-HT was detected. Conclusions These results demonstrate that N-shape PPV will enable more accurate measures of real-time serotonin changes, especially in complex environment.

Early Experience of Pre- and Post-Contrast 7.0T MRI in Brain Tumors

백승릴,정영섭,백선하,황재하,손철호,최승홍,손영돈,김영보,김동규,Kendall H. Lee,조장희 대한의학회 2013 Journal of Korean medical science Vol.28 No.9

We investigated the safety and clinical applicability of 7.0 Tesla (T) brain magnetic resonance imaging (MRI) in patients with brain tumors. Twenty-four patients with intraaxial or extraaxial brain tumors were enrolled in this study. 7.0T MRIs of T2*-weighted axial and T1-weighted coronal or sagittal images were obtained and compared with 1.5T brain MRIs. The T2*-weighted images from 7.0T brain MRI revealed detailed microvasculature and the internal contents of supratentorial brain tumors better than that of 1.5T brain MRI. For brain tumors located in parasellar areas or areas adjacent to major cerebral vessels, flow-related artifacts were exaggerated in the 7.0T brain MRIs. For brain tumors adjacent to the skull base, susceptibility artifacts in the interfacing areas of the paranasal sinus and skull base hampered the aquisition of detailed images and information on brain tumors in the 7.0T brain MRIs. This study shows that 7.0T brain MRI can provide detailed information on the intratumoral components and margins in supratentorial brain tumors. Further studies are needed to develop refined MRI protocols for better images of brain tumors located in the skull base, parasellar, and adjacent major cerebrovascular structures.

Deep Brain Stimulation: Technology at the Cutting Edge

Rahul S. Shah,Su-Youne Chang,민훈기,조장희,Charles D. Blaha,Kendall H. Lee 대한신경과학회 2010 Journal of Clinical Neurology Vol.6 No.4

Deep brain stimulation (DBS) surgery has been performed in over 75,000 people worldwide, and has been shown to be an effective treatment for Parkinson’s disease, tremor, dystonia, epilepsy,depression, Tourette’s syndrome, and obsessive compulsive disorder. We review current and emerging evidence for the role of DBS in the management of a range of neurological and psychiatric conditions, and discuss the technical and practical aspects of performing DBS surgery. In the future, evolution of DBS technology may depend on several key areas, including better scientific understanding of its underlying mechanism of action, advances in high-spatial resolution imaging and development of novel electrophysiological and neurotransmitter microsensor systems. Such developments could form the basis of an intelligent closed-loop DBS system with feedback-guided neuromodulation to optimize both electrode placement and therapeutic efficacy.

Multi-waveform fast-scan cyclic voltammetry mapping of adsorption/desorption kinetics of biogenic amines and their metabolites

Kim, Do Hyoung,Oh, Yoonbae,Shin, Hojin,Park, Cheonho,Blaha, Charles D.,Bennet, Kevin E.,Kim, In Young,Lee, Kendall H.,Jang, Dong Pyo The Royal Society of Chemistry 2018 Analytical methods Vol.10 No.24

<P>Fast-scan cyclic voltammetry (FSCV) is an effective method for investigating electro-active neurochemical species. In recent years, FSCV has been used to measure electro-active neurotransmitters in a variety of neuroscience studies. We previously reported on the use of paired-pulse voltammetry (PPV) that enables FSCV to differentiate various analytes and minimize confounding factors by taking advantage of the adsorption characteristics of the analyte on carbon fiber microelectrodes. In spite of a number of studies regarding adsorption/desorption characteristics of neurotransmitters, the difference in adsorption/desorption properties among neurotransmitters has yet to be fully explored. To calculate adsorption/desorption constants for neurotransmitters, we propose the use of multi-waveform FSCV (M-FSCV), which consists of ten triangular waveforms in a single scan. Within the multiple waveforms, the voltammetric response of dopamine decayed exponentially because of the decreased adsorption time period. The decay pattern was mathematically described using adsorption/desorption characteristics and two additional initial points: an exponential decay constant (<I>K</I>) and an initial quantity (<I>A</I>), which were extracted from the decay equation. Using this method, we were able to quantify the decay constant (<I>K</I>-map) and an initial quantity (<I>A</I>-map) color plot in addition to a conventional pseudo color plot. M-FSCV was evaluated with two biogenic amine groups (catecholamines and indolamines) to characterize their inherent adsorption/desorption constants. As a result, the <I>A</I>-map showed a high correlation with concentration and the <I>K</I>-map for each group to be significantly differentiated. These results demonstrate that M-FSCV has the potential to be a useful technique for acquiring additional adsorption/desorption information regarding neurotransmitters.</P>

Fast Cyclic Square-Wave Voltammetry To Enhance Neurotransmitter Selectivity and Sensitivity

Park, Cheonho,Oh, Yoonbae,Shin, Hojin,Kim, Jaekyung,Kang, Yumin,Sim, Jeongeun,Cho, Hyun U.,Lee, Han Kyu,Jung, Sung Jun,Blaha, Charles D.,Bennet, Kevin E.,Heien, Michael L.,Lee, Kendall H.,Kim, In Youn American Chemical Society 2018 ANALYTICAL CHEMISTRY - Vol.90 No.22

<P>Although fast-scan cyclic voltammetry (FSCV) has been widely used for in vivo neurochemical detection, the sensitivity and selectivity of the technique can be further improved. In this study, we develop fast cyclic square-wave voltammetry (FCSWV) as a novel voltammetric technique that combines large-amplitude cyclic square-wave voltammetry (CSWV) with background subtraction. A large-amplitude, square-shaped potential was applied to induce cycling through multiple redox reactions within a square pulse to increase sensitivity and selectivity when combined with a two-dimensional voltammogram. As a result, FCSWV was significantly more sensitive than FSCV (<I>n</I> = 5 electrodes, two-way ANOVA, <I>p</I> = 0.0002). In addition, FCSWV could differentiate dopamine from other catecholamines (e.g., epinephrine and norepinephrine) and serotonin better than conventional FSCV. With the confirmation that FCSWV did not influence local neuronal activity, despite the large amplitude of the square waveform, it could monitor electrically induced phasic changes in dopamine release in rat striatum before and after injecting nomifensine, a dopamine reuptake inhibitor.</P> [FIG OMISSION]</BR>

Dopamine Measurement during Prolonged Deep Brain Stimulation: A Proof-of-Principle Study of Paired Pulse Voltammetry

Seungleal Brian Paek,Emily Jane Knight,Su-Youne Chang,J. Luis Lujan,장동표,Kevin E. Bennet,Kendall H. Lee 대한의용생체공학회 2014 Biomedical Engineering Letters (BMEL) Vol.4 No.2

Purpose Deep Brain Stimulation (DBS) has been effective in treating various neurological and psychiatric disorders; however, its underlying mechanism hasn’t been completely understood. Fast scan cyclic voltammetry (FSCV) is a valuable tool to elucidate underlying neurotransmitter mechanisms of DBS, due to its sub-second temporal resolution and direct identification of analytes. However, since DBS-like high frequency stimulation evokes neurotransmitter release as well as extracellular pH shift, it is hard to isolate the neurotransmitter signal from the complex environment. Here we demonstrate the efficacy of a modified FSCV technique, Paired Pulse Voltammetry (PPV), in detecting dopamine (DA) release in the caudate nucleus during long-term electrical stimulation of the medial forebrain bundle (MFB) in the rat. Methods Unlike traditional FSCV applying a single triangular waveform, PPV employs a binary waveform with a specific time gap (2.2 ms) in between the comprising pulses. DA measurement was performed with a carbon fiber microelectrode placed in the caudate nucleus and a twisted bipolar stimulating electrode in the MFB. PPV data was collected with the Wireless Instantaneous Neurochemical Concentration Sensing System (WINCS). Results Using PPV, the detection of DA was evident throughout the long-term stimulation (5 minutes); however, without PPV, in vivo environmental changes including pH shift eventually obscured the characteristic oxidation current of DA at 0.6V. Conclusions These results indicate that PPV can be a valuable tool to accurately determine DA dynamics in a complex in vivo environment during long-term electrical stimulation.