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

Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA.
Journal of Neurosurgery (Impact Factor: 3.74). 06/2009; 111(4):701-11. DOI: 10.3171/2009.3.JNS0990
Source: PubMed


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.
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.
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.
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.

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    • "This could be explained by the surgical procedure of this model that involves the direct manipulation of the brain. In fact, it has been previously reported that brain stimulation increases EAA levels, both in humans and animal models [43]. On the other hand, Glu levels were similar between stroke patients and controls, as well as between rats with brain ischemia and their corresponding shams, indicating that Glu levels are not specific to brain tissue lesions, which is similar to inflammatory cytokines. "
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    ABSTRACT: Backgroundour objective was to examine the plasma levels of three biological markers involved in cerebral ischemia (IL-6, glutamate and TNF-alpha) in stroke patients and compare them with two different rat models of focal ischemia (embolic stroke model- ES and permanent middle cerebral artery occlusion ligation model-pMCAO) to evaluate which model is most similar to humans. Secondary objectives: 1) to analyze the relationship of these biological markers with the severity, volume and outcome of the brain infarction in humans and the two stroke models; and 2) to study whether the three biomarkers are also increased in response to damage in organs other than the central nervous system, both in humans and in rats.Methods Multi-center, prospective, case-control study including acute stroke patients (n¿=¿58) and controls (n¿=¿19) with acute non-neurological diseases Main variables: plasma biomarker levels on admission and at 72 h; stroke severity (NIHSS scale) and clinical severity (APACHE II scale); stroke volume; functional status at 3 months (modified Rankin Scale [mRS] and Barthel index [BI]). Experimental groups: ES (n¿=¿10), pMCAO (n¿=¿6) and controls (tissue stress by leg compression) (n¿=¿6). Main variables: plasma biomarker levels at 3 and 72 h; volume of ischemic lesion (H&E) and cell death (TUNEL).Resultsin stroke patients, IL-6 correlated significantly with clinical severity (APACHE II scale), stroke severity (NIHSS scale), infarct volume (cm3) and clinical outcome (mRS) (r¿=¿0.326, 0.497, 0.290 and 0.444 respectively; P¿<¿0.05). Glutamate correlated with stroke severity, but not with outcome, and TNF-alpha levels with infarct volume. In animals, The ES model showed larger infarct volumes (median 58.6% vs. 29%, P¿<¿0.001) and higher inflammatory biomarkers levels than pMCAO, except for serum glutamate levels which were higher in pMCAO. The ES showed correlations between the biomarkers and cell death (r¿=¿0.928 for IL-6; P¿<¿0.001; r¿=¿0.765 for TNF-alpha, P¿<¿0.1; r¿=¿0.783 for Glutamate, P¿<¿0.1) and infarct volume (r¿=¿0.943 for IL-6, P¿<¿0.0001) more similar to humans than pMCAO. IL-6, glutamate and TNF-¿ levels were not higher in cerebral ischemia than in controls.Conclusions Both models, ES and pMCAO, show differences that should be considered when conducting translational studies. IL-6, Glutamate and TNF-¿ are not specific for cerebral ischemia either in humans or in rats.
    Journal of Translational Medicine 08/2014; 12(1):220. DOI:10.1186/s12967-014-0220-3 · 3.93 Impact Factor
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    • "Alternatively, neurochemical analysis techniques such as microdialysis, amperometry, and voltammetry, can detect local changes in neurotransmitter concentration evoked by internal and external mechanical, electrical, and chemical stimuli (Dale et al., 2005; Wightman, 2006). Neurochemical recordings have been used to monitor in vivo release of analytes such as oxygen, dopamine, adenosine, serotonin, and glutamate in small and large animal models of DBS (Agnesi et al., 2009; Bledsoe et al., 2009; Chang et al., 2009; Kimble et al., 2009; Griessenauer et al., 2010; Shon et al., 2010a,b). "
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    ABSTRACT: Current strategies for optimizing deep brain stimulation (DBS) therapy involve multiple postoperative visits. During each visit, stimulation parameters are adjusted until desired therapeutic effects are achieved and adverse effects are minimized. However, the efficacy of these therapeutic parameters may decline with time due at least in part to disease progression, interactions between the host environment and the electrode, and lead migration. As such, development of closed-loop control systems that can respond to changing neurochemical environments, tailoring DBS therapy to individual patients, is paramount for improving the therapeutic efficacy of DBS. Evidence obtained using electrophysiology and imaging techniques in both animals and humans suggests that DBS works by modulating neural network activity. Recently, animal studies have shown that stimulation-evoked changes in neurotransmitter release that mirror normal physiology are associated with the therapeutic benefits of DBS. Therefore, to fully understand the neurophysiology of DBS and optimize its efficacy, it may be necessary to look beyond conventional electrophysiological analyses and characterize the neurochemical effects of therapeutic and non-therapeutic stimulation. By combining electrochemical monitoring and mathematical modeling techniques, we can potentially replace the trial-and-error process used in clinical programming with deterministic approaches that help attain optimal and stable neurochemical profiles. In this manuscript, we summarize the current understanding of electrophysiological and electrochemical processing for control of neuromodulation therapies. Additionally, we describe a proof-of-principle closed-loop controller that characterizes DBS-evoked dopamine changes to adjust stimulation parameters in a rodent model of DBS. The work described herein represents the initial steps toward achieving a "smart" neuroprosthetic system for treatment of neurologic and psychiatric disorders.
    Frontiers in Neuroscience 06/2014; 8(8):169. DOI:10.3389/fnins.2014.00169 · 3.66 Impact Factor
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    • "The system has been extensively tested using WINCSbased neurochemical recordings in a large animal model (pig) of DBS as a prelude to the studies in humans. It can measure in vivo dopamine and adenosine release with CFMs and glutamate release with an enzyme-linked biosensor during DBS (Agnesi et al. 2009; Bledsoe et al. 2009; Shon et al. 2010a,b). "
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    ABSTRACT: The brain operates through complex interactions in the flow of information and signal processing within neural networks. The "wiring" of such networks, being neuronal or glial, can physically and/or functionally go rogue in various pathological states. Neuromodulation, as a multidisciplinary venture, attempts to correct such faulty nets. In this review, selected approaches and challenges in neuromoduation are discussed. The use of water-dispersible carbon nanotubes have proven effective in modulation of neurite outgrowth in culture as well as in aiding regeneration after spinal cord injury in vivo. Studying neural circuits using computational biology and analytical engineering approaches brings to light geometrical mapping of dynamics within neural networks, much needed information for stimulation interventions in medical practice. Indeed, sophisticated desynchronization approaches used for brain stimulation have been successful in coaxing "misfiring" neuronal circuits to resume productive firing patterns in various human disorders. Devices have been developed for the real time measurement of various neurotransmitters as well as electrical activity in the human brain during electrical deep brain stimulation. Such devices can establish the dynamics of electrochemical changes in the brain during stimulation. With increasing application of nanomaterials in devices for electrical and chemical recording and stimulating in the brain, the era of cellular, and even intracellular, precision neuromodulation will soon be upon us. © 2012 International Society for Neurochemistry, J. Neurochem. (2012) 10.1111/jnc.12105.
    Journal of Neurochemistry 11/2012; 124(4). DOI:10.1111/jnc.12105 · 4.28 Impact Factor
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