A Diamond-Based Electrode for Detection of Neurochemicals in the Human Brain

Kevin E Bennet, Jonathan R Tomshine, Hoon-Ki Min, Felicia S Manciu, Michael P Marsh, Seungleal B Paek, Megan L Settell, Evan N Nicolai, Charles D Blaha, Abbas Z Kouzani, Su-Youne Chang, Kendall H Lee, Kevin E Bennet, Jonathan R Tomshine, Hoon-Ki Min, Felicia S Manciu, Michael P Marsh, Seungleal B Paek, Megan L Settell, Evan N Nicolai, Charles D Blaha, Abbas Z Kouzani, Su-Youne Chang, Kendall H Lee

Abstract

Deep brain stimulation (DBS), a surgical technique to treat certain neurologic and psychiatric conditions, relies on pre-determined stimulation parameters in an open-loop configuration. The major advancement in DBS devices is a closed-loop system that uses neurophysiologic feedback to dynamically adjust stimulation frequency and amplitude. Stimulation-driven neurochemical release can be measured by fast-scan cyclic voltammetry (FSCV), but existing FSCV electrodes rely on carbon fiber, which degrades quickly during use and is therefore unsuitable for chronic neurochemical recording. To address this issue, we developed durable, synthetic boron-doped diamond-based electrodes capable of measuring neurochemical release in humans. Compared to carbon fiber electrodes, they were more than two orders-of-magnitude more physically-robust and demonstrated longevity in vitro without deterioration. Applied for the first time in humans, diamond electrode recordings from thalamic targets in patients (n = 4) undergoing DBS for tremor produced signals consistent with adenosine release at a sensitivity comparable to carbon fiber electrodes. (Clinical trials # NCT01705301).

Keywords: carbon fiber microelectrode; deep brain stimulation (DBS); diamond-based electrode; dopamine; fast scan cyclic voltammetry (FSCV); neuromodulation.

Figures

Figure 1
Figure 1
Diamond FSCV probe construction. Panel (A) depicts the overall full length electrode suitable for acute large animal and human recordings. The scale bar is 25 mm. Panel (B) shows a detailed optical magnification of the tip and its individual components, scale bar is 500 μm. Panel (C) is an SEM image, showing the transition from the parylene insulation to the diamond sensing tip, scale bar is 100 μm (crystal detail scale bar is 10 μm). Panels (D,E) show Raman spectral maps of the probe depicted in panel (C), scale bar is 10 μm. The three color channels assigned to material constituents are: blue for boron doped diamond, red for diamond, and green for carbon sp2 impurities. Magenta color observed in image (D) is a combination of blue and red. Panel (F) shows the integrated Raman spectrum of Raman images in panels (D,E). The Raman measurements were acquired with a 532 nm excitation source.
Figure 2
Figure 2
Diamond FSCV probe exposed to dopamine at 2.5 μM (A), adenosine at 20 μM (B), and dopamine + adenosine at the same concentrations (C). Note that the signals of the two neurotransmitters occur at different voltages and are effectively additive. That is, the voltammogram of dopamine + adenosine is a linear combination of the voltammograms of the two individual neurotransmitters.
Figure 3
Figure 3
SEM images of diamond electrode (A–C) and carbon fiber electrode (D–F). Panels (A,D) are at t = 0, panels (B,E)t = 72 h, and panels (C,F) are at t = 144 h. Panels (G–I) show diamond and carbon fiber calibration curves for the detection of dopamine at t = 0 h (G), t = 72 h (H), and t = 144 h (I) of continuous use.
Figure 4
Figure 4
Diamond electrode performance in vitro and in vivo. Panel (A) depicts a diamond electrode's response to identical in vitro conditions. Panel (B) depicts the same diamond electrode in the ventral lateral thalamus of an anesthetized pig, where an adenosine-like signature secondary to mechanical stimulation was observed. Panel (C) depicts the same electrode in the subthalamic nucleus of an awake human undergoing DBS lead-placement surgery for essential tremor (prior to the DBS lead placement). In panels (B,C), the signature is consistent with adenosine based on the oxidation peaks near the switching potential at 1.5 V. All “diamond” data was recorded with the same specific electrode (although not in the order shown—the human data were always gathered first).
Figure 5
Figure 5
Comparison of diamond electrode (the same electrode depicted in Figure 4) with a carbon fiber electrode in a flow cell and in vivo in the ventral intermediate (VIM) nucleus of the thalamus in a human patient. In both in vivo cases, neurotransmitter release was evoked by mechanical stimulation (“microthalamotomy” effect) and showed an adenosine-like signal. (A) Carbon fiber electrode in vitro; (B) Diamond electrode in vitro; (C) Carbon fiber electrode in vivo (human); (D) Diamond electrode in vivo (human).
Figure 6
Figure 6
Intraoperative tremor recordings before and after DBS lead placement. This patient underwent DBS lead placement for essential tremor, with the diamond-based electrode placed in the ventral intermediate (VIM) nucleus of the thalamus prior to therapeutic DBS lead placement (top panels A–C). Throughout the surgery, the patient wore a hand-mounted wireless accelerometer to measure tremor. Prior to surgery, the patient displayed a pronounced tremor at 4.2 Hz (left panels, D,F), while after lead placement the mechanical stimulation alone (“microthalamotomy” effect) caused a cessation of this tremor with no applied voltage (right panels, E,G).

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