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Kendall H. Lee, Su-Youne Chang, David W. Roberts and Uhnoh Kim

Object. High-frequency stimulation (HFS) delivered through implanted electrodes in the subthalamic nucleus (STN) has become an established treatment for Parkinson disease (PD). The precise mechanism of action of deep brain stimulation (DBS) in the STN is unknown, however. In the present study, the authors tested the hypothesis that HFS within the STN changes neuronal action potential firing rates during the stimulation period by modifying neurotransmitter release.

Methods. Intracellular electrophysiological recordings were obtained using sharp electrodes in rat STN neurons in an in vitro slice preparation. A concentric bipolar stimulating electrode was placed in the STN slice, and electrical stimulation (pulse width 50–100 µsec, duration 100–2000 µsec, amplitude 10–500 µA, and frequency 10–200 Hz) was delivered while simultaneously obtaining intracellular recordings from an STN neuron.

High-frequency stimulation of the STN either generated excitatory postsynaptic potentials (EPSPs) and increased the action potential frequency or it generated inhibitory postsynaptic potentials and decreased the action potential frequency of neurons within the STN. These effects were blocked after antagonists to glutamate and γ-aminobutyric acid were applied to the tissue slice, indicating that HFS resulted in the release of neurotransmitters. Intracellular recordings from substantia nigra pars compacta (SNc) dopaminergic neurons during HFS of the STN revealed increased generation of EPSPs and increased frequency of action potentials in SNc neurons.

Conclusions. During HFS of STN neurons the mechanism of DBS may involve the release of neurotransmitters rather than the primary electrogenic inhibition of neurons.

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Kendall H. Lee, Frederick L. Hitti, Mark H. Shalinsky, Uhnoh Kim, James C. Leiter and David W. Roberts

Object

The mechanism of action whereby high-frequency stimulation (HFS) in the thalamus ameliorates tremor and epilepsy is unknown. The authors studied the effects of HFS on thalamocortical relay neurons in a ferret in vitro slice preparation to test the hypothesis that HFS abolishes synchronized oscillations by neurotransmitter release.

Methods

Intracellular and extracellular electrophysiological recordings were made in thalamic slices. The neurons in the thalamic slice spontaneously generated spindle oscillations, and treatment with picrotoxin, a γ-aminobutyric acid A receptor antagonist, resulted in 3- to 4-Hz absence seizurelike activity. High-frequency stimulation (stimulation parameters: 10–1000-µA amplitude; 100-µsec pulse width; 100-Hz frequency; 1–60 seconds) was applied using a concentric bipolar stimulating electrode placed adjacent to the recording electrodes.

High-frequency stimulation within the thalamus generated inhibitory and excitatory postsynaptic potentials, membrane depolarization, an increase in action potential firing during the stimulation period, and abolished the spindle oscillations in the thalamocortical relay neurons. High-frequency stimulation applied to 20-µM picrotoxin-treated slices eliminated the 3- to 4-Hz absence seizurelike activity.

Conclusions

High-frequency stimulation eliminates spontaneous spindle oscillations and picrotoxin-induced absence seizurelike activity in thalamic slices by synaptic neurotransmitter release; thus, HFS may abolish synchronous oscillatory activities such as those that generate tremor and seizures. Paradoxically, HFS, which is excitatory, and surgical lesions of the ventrointermedius thalamus, which are presumably inhibitory, both suppress tremors. This paradox is resolved by recognizing that HFS-mediated neurotransmitter release and thalamic surgery both disrupt the circuit generating tremor or seizure, albeit by different mechanisms.

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Jamie J. Van Gompel, Fredric B. Meyer, W. Richard Marsh, Kendall H. Lee and Gregory A. Worrell

Object

Intracranial monitoring for temporal lobe seizure localization to differentiate neocortical from mesial temporal onset seizures requires both neocortical subdural grids and hippocampal depth electrode implantation. There are 2 basic techniques for hippocampal depth electrode implantation. This first technique uses a stereotactically guided 8-contact depth electrode directed along the long axis of the hippocampus to the amygdala via an occipital bur hole. The second technique involves direct placement of 2 or 3 4-contact depth electrodes perpendicular to the temporal lobe through the middle temporal gyrus and overlying subdural grid. The purpose of this study was to determine whether one technique was superior to the other by examining monitoring success and complications.

Methods

Between 1997 and 2005, 41 patients underwent invasive seizure monitoring with both temporal subdural grids and depth electrodes placed in 2 ways. Patients in Group A underwent the first technique, and patients in Group B underwent the second technique.

Results

Group A consisted of 26 patients and Group B 15 patients. There were no statistically significant differences between Groups A and B regarding demographics, monitoring duration, seizure localization, or outcome (Engel classification). There was a statistically significant difference at the point in time at which these techniques were used: Group A represented more patients earlier in the series than Group B (p < 0.05). The complication rate attributable to the grids and depth electrodes was 0% in each group. It was more likely that the depth electrodes were placed through the grid if there was a prior resection and the patient was undergoing a new evaluation (p < 0.05). Furthermore, Group A procedures took significantly longer than Group B procedures.

Conclusions

In this patient series, there was no difference in efficacy of monitoring, complications, or outcome between hippocampal depth electrodes placed laterally through temporal grids or using an occipital bur hole stereotactic approach. Placement of the depth electrodes perpendicularly through the grids and middle temporal gyrus is technically more practical because multiple head positions and redraping are unnecessary, resulting in shorter operative times with comparable results.

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Jeffrey P. Mullin, Jamie J. Van Gompel, Kendall H. Lee, Fredric B. Meyer and Matt Stead

Heterotopic gray matter has been implicated in epilepsy; however, not much is known regarding heterotopia beyond epilepsy. Here, the authors describe 2 pediatric patients with deep heterotopias contiguous with basal ganglia structures. These heterotopias appear to have manifested as movement disorders. One patient presented with a left-sided myoclonus and choreiform movements associated with a right caudate heterotopia; she experienced vast improvement after resection of periventricular heterotopia. The other patient presented with progressive dystonia and a ballistic movement disorder. Initial bilateral globus pallidus internus stimulation resulted in successful treatment of the dystonia; however, her movement disorder worsened. After an extensive workup, including STATISCOM (statistical ictal SPECT coregistered to MR imaging), the patient underwent cortical stimulation with improvement in her movement disorder. To the best of our knowledge, these cases are the first reported instances of heterotopic gray matter associated with movement disorders. Both patients experienced significant improvements following resection of their heterotopias.

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Tejas Sankar and Andres M. Lozano

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Jamie J. Van Gompel, Bryan T. Klassen, Gregory A. Worrell, Kendall H. Lee, Cheolsu Shin, Cong Zhi Zhao, Desmond A. Brown, Steven J. Goerss, Bruce A. Kall and Matt Stead

OBJECT

Anterior nuclear (AN) stimulation has been reported to reduce the frequency of seizures, in some cases dramatically; however, it has not been approved by the US Food and Drug Administration. The anterior nucleus is difficult to target because of its sequestered location, partially surrounded by the ventricle. It has traditionally been targeted by using transventricular or lateral transcortical routes. Here, the authors report a novel approach to targeting the anterior nucleus and neurophysiologically confirming effective stimulation of the target, namely evoked potentials in the hippocampus.

METHODS

Bilateral AN 3389 electrodes were placed in a novel trajectory followed by bilateral hippocampal 3391 electrodes from a posterior trajectory. Each patient was implanted bilaterally with a Medtronic Activa PC+S device under an investigational device exemption approval. Placement was confirmed with CT. AN stimulation-induced hippocampal evoked potentials were measured to functionally confirm placement in the anterior nucleus.

RESULTS

Two patients had implantations by way of a novel AN trajectory with concomitant hippocampal electrodes. There were no lead misplacements. Postoperative stimulation of the anterior nucleus with a PC+S device elicited evoked potentials in the hippocampus. Thus far, both patients have reported a > 50% improvement in seizure frequency.

CONCLUSIONS

Placing AN electrodes posteriorly may provide a safer trajectory than that used for traditionally placed AN electrodes. In addition, with a novel battery that is capable of electroencephalographic recording, evoked potentials can be used to functionally assess the Papez circuit. This treatment paradigm may offer increased AN stimulation efficacy for medically intractable epilepsy by assessing functional placement more effectively and thus far has proven safe.

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Young-Min Shon, Su-Youne Chang, Susannah J. Tye, Christopher J. Kimble, Kevin E. Bennet, Charles D. Blaha and Kendall H. Lee

Object

The authors of previous studies have demonstrated that local adenosine efflux may contribute to the therapeutic mechanism of action of thalamic deep brain stimulation (DBS) for essential tremor. Real-time monitoring of the neurochemical output of DBS-targeted regions may thus advance functional neurosurgical procedures by identifying candidate neurotransmitters and neuromodulators involved in the physiological effects of DBS. This would in turn permit the development of a method of chemically guided placement of DBS electrodes in vivo. Designed in compliance with FDA-recognized standards for medical electrical device safety, the authors report on the utility of the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for real-time comonitoring of electrical stimulation–evoked adenosine and dopamine efflux in vivo, utilizing fast-scan cyclic voltammetry (FSCV) at a polyacrylonitrile-based (T-650) carbon fiber microelectrode (CFM).

Methods

The WINCS was used for FSCV, which consisted of a triangle wave scanned between −0.4 and +1.5 V at a rate of 400 V/second and applied at 10 Hz. All voltages applied to the CFM were with respect to an Ag/AgCl reference electrode. The CFM was constructed by aspirating a single T-650 carbon fiber (r = 2.5 μm) into a glass capillary and pulling to a microscopic tip using a pipette puller. The exposed carbon fiber (the sensing region) extended beyond the glass insulation by ~ 50 μm. Proof of principle tests included in vitro measurements of adenosine and dopamine, as well as in vivo measurements in urethane-anesthetized rats by monitoring adenosine and dopamine efflux in the dorsomedial caudate putamen evoked by high-frequency electrical stimulation of the ventral tegmental area and substantia nigra.

Results

The WINCS provided reliable, high-fidelity measurements of adenosine efflux. Peak oxidative currents appeared at +1.5 V and at +1.0 V for adenosine, separate from the peak oxidative current at +0.6 V for dopamine. The WINCS detected subsecond adenosine and dopamine efflux in the caudate putamen at an implanted CFM during high-frequency stimulation of the ventral tegmental area and substantia nigra. Both in vitro and in vivo testing demonstrated that WINCS can detect adenosine in the presence of other easily oxidizable neurochemicals such as dopamine comparable to the detection abilities of a conventional hardwired electrochemical system for FSCV.

Conclusions

Altogether, these results demonstrate that WINCS is well suited for wireless monitoring of high-frequency stimulation-evoked changes in brain extracellular concentrations of adenosine. Clinical applications of selective adenosine measurements may prove important to the future development of DBS technology.

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Jamie J. Van Gompel, Su-Youne Chang, Stephan J. Goerss, In Yong Kim, Christopher Kimble, Kevin E. Bennet and Kendall H. Lee

Deep brain stimulation (DBS) is effective when there appears to be a distortion in the complex neurochemical circuitry of the brain. Currently, the mechanism of DBS is incompletely understood; however, it has been hypothesized that DBS evokes release of neurochemicals. Well-established chemical detection systems such as microdialysis and mass spectrometry are impractical if one is assessing changes that are happening on a second-to-second time scale or for chronically used implanted recordings, as would be required for DBS feedback. Electrochemical detection techniques such as fast-scan cyclic voltammetry (FSCV) and amperometry have until recently remained in the realm of basic science; however, it is enticing to apply these powerful recording technologies to clinical and translational applications. The Wireless Instantaneous Neurochemical Concentration Sensor (WINCS) currently is a research device designed for human use capable of in vivo FSCV and amperometry, sampling at subsecond time resolution. In this paper, the authors review recent advances in this electrochemical application to DBS technologies. The WINCS can detect dopamine, adenosine, and serotonin by FSCV. For example, FSCV is capable of detecting dopamine in the caudate evoked by stimulation of the subthalamic nucleus/substantia nigra in pig and rat models of DBS. It is further capable of detecting dopamine by amperometry and, when used with enzyme linked sensors, both glutamate and adenosine. In conclusion, WINCS is a highly versatile instrument that allows near real-time (millisecond) detection of neurochemicals important to DBS research. In the future, the neurochemical changes detected using WINCS may be important as surrogate markers for proper DBS placement as well as the sensor component for a “smart” DBS system with electrochemical feedback that allows automatic modulation of stimulation parameters. Current work is under way to establish WINCS use in humans.

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Christoph J. Griessenauer, Su-Youne Chang, Susannah J. Tye, Christopher J. Kimble, Kevin E. Bennet, Paul A. Garris and Kendall H. Lee

Object

The authors previously reported the development of the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for measuring dopamine and suggested that this technology may be useful for evaluating deep brain stimulation–related neuromodulatory effects on neurotransmitter systems. The WINCS supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially resolved neurotransmitter measurements. The FSCV parameters used to establish WINCS dopamine measurements are not suitable for serotonin, a neurotransmitter implicated in depression, because they lead to CFM fouling and a loss of sensitivity. Here, the authors incorporate into WINCS a previously described N-shaped waveform applied at a high scan rate to establish wireless serotonin monitoring.

Methods

Optimized for the detection of serotonin, FSCV consisted of an N-shaped waveform scanned linearly from a resting potential of +0.2 to +1.0 V, then to −0.1 V and back to +0.2 V, at a rate of 1000 V/second. Proof-of-principle tests included flow injection analysis and electrically evoked serotonin release in the dorsal raphe nucleus of rat brain slices.

Results

Flow cell injection analysis demonstrated that the N waveform, applied at a scan rate of 1000 V/second, significantly reduced serotonin fouling of the CFM, relative to that observed with FSCV parameters for dopamine. In brain slices, WINCS reliably detected subsecond serotonin release in the dorsal raphe nucleus evoked by local high-frequency stimulation.

Conclusions

The authors found that WINCS supported high-fidelity wireless serotonin monitoring by FSCV at a CFM. In the future such measurements of serotonin in large animal models and in humans may help to establish the mechanism of deep brain stimulation for psychiatric disease.