Development of the Mayo Investigational Neuromodulation Control System: toward a closed-loop electrochemical feedback system for deep brain stimulation

Laboratory investigation

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Object

Conventional deep brain stimulation (DBS) devices continue to rely on an open-loop system in which stimulation is independent of functional neural feedback. The authors previously proposed that as the foundation of a DBS “smart” device, a closed-loop system based on neurochemical feedback, may have the potential to improve therapeutic outcomes. Alterations in neurochemical release are thought to be linked to the clinical benefit of DBS, and fast-scan cyclic voltammetry (FSCV) has been shown to be effective for recording these evoked neurochemical changes. However, the combination of FSCV with conventional DBS devices interferes with the recording and identification of the evoked analytes. To integrate neurochemical recording with neurostimulation, the authors developed the Mayo Investigational Neuromodulation Control System (MINCS), a novel, wirelessly controlled stimulation device designed to interface with FSCV performed by their previously described Wireless Instantaneous Neurochemical Concentration Sensing System (WINCS).

Methods

To test the functionality of these integrated devices, various frequencies of electrical stimulation were applied by MINCS to the medial forebrain bundle of the anesthetized rat, and striatal dopamine release was recorded by WINCS. The parameters for FSCV in the present study consisted of a pyramidal voltage waveform applied to the carbon-fiber microelectrode every 100 msec, ramping between −0.4 V and +1.5 V with respect to an Ag/AgCl reference electrode at a scan rate of either 400 V/sec or 1000 V/sec. The carbon-fiber microelectrode was held at the baseline potential of −0.4 V between scans.

Results

By using MINCS in conjunction with WINCS coordinated through an optic fiber, the authors interleaved intervals of electrical stimulation with FSCV scans and thus obtained artifact-free wireless FSCV recordings. Electrical stimulation of the medial forebrain bundle in the anesthetized rat by MINCS elicited striatal dopamine release that was time-locked to stimulation and increased progressively with stimulation frequency.

Conclusions

Here, the authors report a series of proof-of-principle tests in the rat brain demonstrating MINCS to be a reliable and flexible stimulation device that, when used in conjunction with WINCS, performs wirelessly controlled stimulation concurrent with artifact-free neurochemical recording. These findings suggest that the integration of neurochemical recording with neurostimulation may be a useful first step toward the development of a closed-loop DBS system for human application.

Abbreviations used in this paper:ADC = analog-to-digital converter; CFM = carbon-fiber microelectrode; DAC = digital-to-analog converter; DBS = deep brain stimulation; FSCV = fast-scan cyclic voltammetry; MFB = medial forebrain bundle; MINCS = Mayo Investigational Neuromodulation Control System; WINCS = Wireless Instantaneous Neurochemical Concentration Sensing System.

Article Information

Dr. Chang and Mr. Kimble contributed equally to this work.

Address correspondence to: Kendall H. Lee, M.D., Ph.D., Departments of Neurologic Surgery and Physiology and Biomedical Engineering, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. email: lee.kendall@mayo.edu.

Please include this information when citing this paper: published online October 11, 2013; DOI: 10.3171/2013.8.JNS122142.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    MINCS-WINCS hardware. A: Schematic representation of the computer base station, WINCS, and MINCS. The neurochemical recording device, WINCS, and the synchronized stimulator, MINCS, are linked via an optical connection. Both units connect wirelessly via Bluetooth technology to a base station, which commands both systems via WincsWare software. Leads from each device provide connections to the recording and reference electrodes (red and green circles) and 4 stimulating electrodes (red, black, yellow, and white circles). B: Photograph of the MINCS-WINCS hardware showing relative size, optical connection, and recording and stimulating electrode leads. ADC = analog-to-digital converter; DAC = digital-to-analog converter; LPF = low-pass filter; MC = microcontroller; TIA = transimpedance amplifier; V/I Sense = voltage/current sense. Numbers 1 and 4 indicate the microcontrollers; 2 and 3 are the Bluetooth modules.

  • View in gallery

    An example of the WincsWare user interface for defining stimulation parameters and synchronizing stimulation with FSCV. The user interface includes 1) the “Stimulus Sequence Definition Method” panel for selecting the characteristics of the stimulus pulses (for example, polarity, frequency, pulse duration, and amplitude); 2) the “Stimulus Sequence Parameters” panel for selecting the stimulus mode and presentation characteristics of the stimulus pulses (for example, initial delay, pulse pattern settings, and electrode contact); 3) the “Pulse Pattern” display in which a single pulse pattern can be user-adjusted via computer mouse; and 4) the “Stimulus Sequence” chart, depicting an overview of the user-selected stimulus pulse train in relation to the sync pulse from WINCS. The sync pulse indicates the end of an FSCV scan. The software facilitates interleaving stimulus pulses with FSCV scans.

  • View in gallery

    An example of the WincsWare user interface displaying acquired data in nearly real time. The displayed elements include 1) a color plot depicting data acquired throughout a recording session; 2) a panel displaying user-entered annotations; 3) raw (not background-subtracted) voltammograms, plotting electrode current as a function of applied potential for an FSCV scan. The blue line shows dopamine (DA) oxidation and ortho-quinone (O-Q) reduction peak currents superimposed on the white line of the background current; 4) a current-versus-time strip chart of electrode currents measured at 1 or more selected applied potentials (typically the oxidation and reduction potentials for the analyte of interest; in this case, oxidation of DA and reduction of O-Q); 5) a background-subtracted voltammogram, here showing peaks for DA oxidation (at +0.56 V) and O-Q reduction (at −0.16 V); 6) the color plot of electrode current (represented by horizontal color traces) as a function of applied potential (vertical axis) for a sequence of FSCV scans over time (horizontal axis), here showing DA oxidation (green trail at +0.56 V) and O-Q reduction back to DA (yellow and black trail at −0.15 V); 7) stimulation status information, including pattern and sequence count, elapsed time of stimulation, stimulating electrode impedance (calculated on the basis of measured stimulus current and voltage); and 8) a strip chart displaying intervals of stimulation. In panels 3 and 5, <1 indicates a forward direction (−0.4 V → +1.5 V) and <2 indicates a backward direction (+1.5 V → −0.4 V). The units on the x axes in panels 2, 4, 6, and 8 are seconds, and in panels 3 and 5 they are volts. The units on the y axis in panels 3–5 are nA and in panel 6 they are volts.

  • View in gallery

    Elimination of stimulus pulse artifacts using MINCS-WINCS synchronization. A and B: Diagrams comparing the stimulus pulse sequences provided by a conventional stimulator (left) and MINCS (right) in relation to FSCV scans (pyramidal waveforms). Optically synced with WINCS, MINCS eliminates stimulus pulse interference with FSCV measurements by imposing a delay after every scan. C and D: Comparison of color plots of striatal dopamine release acquired in vivo from MFB stimulation (30-second stimulation at 60-Hz, 200-μA, 2-msec biphasic pulse duration) in the anesthetized rat with (right) and without (left) stimulus pulse synchronization. Stimulus pulse artifacts are readily apparent as repeating diagonal bands in the color plot (left). E and F: Cyclic voltammograms recorded at the peak of stimulation-evoked dopamine release (right; dashed red arrow in D) and coincident to stimulus pulse interference (left; dashed black arrow in C). Note the marked distortion of the voltammogram recorded during the occurrence of a stimulus pulse. G and H: Time courses of stimulation-evoked changes in dopamine oxidation current extracted from each respective color plot record at the applied voltage of +0.6 V (right, solid red line in D; left, solid black line in C). Stimulus pulse artifacts (negative-going spikes in current) were readily apparent using a conventional stimulator, while entirely absent using MINCS.

  • View in gallery

    In vivo functionality tests of the integrated MINCS-WINCS devices showing frequency-dependent striatal dopamine release evoked by MFB electrical stimulation in anesthetized rats. A: Color plots obtained in response to electrical stimulation delivered at 30 Hz (left), 60 Hz (center), and 120 Hz (right). The number of pulses (120), stimulation intensity (200 μA), and pulse duration (2 msec) for the biphasic stimulation train were the same for each test frequency. The FSCV triangle waveform was applied from −0.4 V to +1.5 V with dopamine oxidation peak currents readily apparent at +0.6 V. B: Time course of changes in dopamine oxidation current in response to 30-, 60-, and 120-Hz electrical stimulation. These changes in dopamine oxidation currents were detected at the applied voltage (+0.6 V) shown in each color plot (line a). C: Voltammograms of dopamine oxidation and reduction after subtraction of prestimulation background current. These voltammograms were extracted at the time corresponding to maximal increases in dopamine oxidation current (line b). D: Stimulation frequency–dependent striatal dopamine release showing an exponential increase in mean ± SEM peak dopamine oxidation current as a function of increasing stimulation frequency. Note that the data shown in panels A–C are from a representative animal and data are the mean ± SEM of 3 stimulations/frequency in the same animal.

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