Thursday, November 21, 2013

New Deep Brain Stimulation System Measures Neurotransmitter Release

Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) Patient Module printed circuit board & sterilizable case. (Fig. 1, Kimble et al. 2009).

Last month, the New York Times reported that the Defense Advanced Research Projects Agency (DARPA) will spend $70 million to further the development of technologies that use deep brain stimulation (DBS), which has been highly successful in treating Parkinson's Disease (PD). The SUBNETS program (Systems-Based Neurotechnology for Emerging Therapies) is part of the BRAIN Initiative that aims to "revolutionize our understanding of the human mind."

DARPA issued their call for proposals on October 25. My original take was that the goals were overly ambitious and nearly impossible to achieve within the specified time frame:
To elaborate, over a 5 year period, the successful applicants must conduct clinical trials in human patients with 7 specified psychiatric and neurological disorders (not including PD), some of which have never been treated with DBS. The successful teams will use devices that both stimulate and record neural activity, and provide real-time data that can be decoded as reflecting a particular behavioral state... basically, a futuristic implant that can adjust its own stimulation parameters based on how the patient is doing. At least, that's how I interpret it. 

How close are we to seeing a DBS implant that not only stimulates neural tissue, but also records electrical or chemical signals and then uses this information to adjust the stimulation parameters? Closer than I originally suspected. A recent Nature News article reported on the Mayo Clinic's efforts to develop a DARPAesque, state-of-the-art implant that aims to track brain signals in real time:
Researchers hope that the device will identify the electrical and chemical signals in the brain that correlate in real time with the presence and severity of symptoms, including the tremors experienced by people with Parkinson’s disease. This information could help to uncover where and how DBS exerts its therapeutic effects on the brain, and why it sometimes fails, says Kendall Lee, a neurosurgeon at the Mayo Clinic in Rochester, Minnesota, who is leading the project.
. . .

...Using a method called fast-scan cyclic voltammetry, the device applies a localized voltage change in the brain. This transiently pulls electrons off certain neurotransmitters — the brain chemicals that activate or inhibit neurons — giving rise to electrical currents that can be measured. Each neurotransmitter molecule produces a different electrochemical signature, which can be used to identify it and estimate its concentration every 10 milliseconds.

Studies in awake behaving rats have used fast-scan cyclic voltammetry to measure phasic dopamine release associated with burst firing (Robinson et al., 2003).

Fig, 3 (Robinson et al., 2003). Heterogeneity of electrically evoked dopamine release in the nucleus accumbens of a freely moving rat.

Further information about the device is provided in this article from the Mayo Clinic, which indicates that the WINCS has already been tested in 15 human patients with Parkinson's disease or essential tremor. The study registered in is described as an Efficacy Study whose primary purpose is basic science:
Neurotransmitter Measurements Using Wireless Instantaneous Neurotransmitter Concentration System (WINCS) During Deep Brain Stimulation Neurosurgery

In this study, the investigators will monitor extracellular neurotransmitter levels using a probe that is able to perform real time electrochemical detection during deep brain stimulation surgery. The overall question this study is designed to answer is: Are there neurotransmitters released during deep brain stimulation?

Interestingly, the primary outcome measure is adenosine1 release recorded by WINCS, and the secondary outcome measure is dopamine release (pre-, during, and post-DBS, over a time frame of 30 min). Adenosine A2A antagonists may extend the duration of action of L-dopa, a primary treatment for PD. Preliminary studies in rats were able to detect subsecond dopamine and adenosine release at an implanted sensor in the striatum during high-frequency stimulation of ascending fibers (Kimble et al., 2009). It seems the early results in patients were also successful in measuring neurotransmitter release.

The WINCS will be integrated with another device, the MINCS (Mayo Investigational Neuromodulation Control System), which is optically linked to WINCS. The entire system is being tested in animal models to deliver brain stimulation wirelessly.

Fig 1B (Chang et al., 2013). 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.

These developments in DBS devices for Parkinson's disease are very impressive indeed, but DARPA wants to go 7 steps further by developing similar closed-loop systems for use in Post-Traumatic Stress Disorder (PTSD), Major Depression, Borderline Personality Disorder (BPD), General Anxiety Disorder (GAD), Traumatic Brain Injury (TBI), Substance Abuse/Addiction, and Fibromyalgia/Chronic Pain. As I said previously:
To the best of my knowledge, there is no published literature on DBS for PTSD, BPD, GAD [as opposed to OCD], or TBI [except for minimally conscious state]. At, a Pilot Study of DBS of the Amygdala for Treatment-Refractory Combat PTSD was withdrawn prior to enrollment. There's one DBS trial for TBI that aims to enroll 5 patients over a 4 year period. I couldn't find anything for BPD or GAD (although these disorders might possibly be comorbid in some patients treated for depression or OCD).

Although there is a tremendous amount yet to learn about Parkinson's, much more is known about the pathophysiology of PD than of any of the disorders listed above. But given the list of speakers at a recent Society for Neuroscience symposium on the Mechanisms of Deep Brain Stimulation Efficacy in Neuropsychiatric Disorders, scientists and clinicians at Mayo, Emory, Butler/Brown, and Case Western are certainly working on these problems. $70 million from DARPA would sure come in handy, even if the ambitious endpoints are unattainable within 5 years.


1 Caffeine is an adenosine antagonist, but the drugs used as adjunct therapies in PD are istradefylline and preladenant.


Chang SY, Kimble CJ, Kim I, Paek SB, Kressin KR, Boesche JB, Whitlock SV, Eaker DR, Kasasbeh A, Horne AE, Blaha CD, Bennet KE, & Lee KH (2013). Development of the Mayo Investigational Neuromodulation Control System: toward a closed-loop electrochemical feedback system for deep brain stimulation. Journal of Neurosurgery. PMID: 24116724

Kimble CJ, Johnson DM, Winter BA, Whitlock SV, Kressin KR, Horne AE, Robinson JC, Bledsoe JM, Tye SJ, Chang SY, Agnesi F, Griessenauer CJ, Covey D, Shon YM, Bennet KE, Garris PA, & Lee KH (2009). Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) for intraoperative neurochemical monitoring. Conference proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2009, 4856-9. PMID: 19963865

Robinson DL, Venton BJ, Heien ML, Wightman RM. (2003). Detecting subsecond dopamine release with fast-scan cyclic voltammetry in vivo. Clin Chem. 49:1763-73.

Nature News link via @GholsonLyon

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At November 21, 2013 2:43 PM, Anonymous Anonymous said...

"the goals were overly ambitious and nearly impossible to achieve within the specified time frame"

That is DARPA's definition.

At November 21, 2013 11:40 PM, Blogger The Neurocritic said...

I'd be curious to read the proposals submitted to DARPA for the SUBNETS program. Will the Mayo Clinic researchers (etc.) provide a timeline for how they'll actually reach the milestones for Phase One within two years?

Generate models for two DSM diagnosis categories chosen from: (A) Major Depression, (B) PTSD, (C) General Anxiety Disorder, (D) Borderline Personality Disorder.

Generate models for one disrupted neurologic of physiologic system chosen from: (A) Fibromyalgia/Chronic Pain, (B) TBI, (C) Substance Abuse/Addiction.

Demonstrate ability to intraoperatively relieve symptom severity with computer in the loop (measured through neural signature of disease as well as phenotypic presentation).

Evaluate the effects of intraoperative stimulation on symptomology at four hours, 24 hours, and 72 hours through neural recordings and behavioral experiments.


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