Electrical rejuvenation of chronically implanted macroelectrodes in nonhuman primates.

Objective.Electrodes chronically implanted in the brain undergo complex changes over time that can lower the signal to noise ratio (SNR) of recorded signals and reduce the amount of energy delivered to the tissue during therapeutic stimulation, both of which are relevant for the development of robust, closed-loop control systems. Several factors have been identified that link changes in the electrode-tissue interface (ETI) to increased impedance and degraded performance in micro- and macro-electrodes. Previous studies have demonstrated that brief pulses applied every few days can restore SNR to near baseline levels during microelectrode recordings in rodents, a process referred to as electrical rejuvenation. However, electrical rejuvenation has not been tested in clinically relevant macroelectrode designs in large animal models, which could serve as preliminary data for translation of this technique. Here, several variations of this approach were tested to characterize parameters for optimization.Approach. Alternating-current (AC) and direct-current (DC) electrical rejuvenation methods were explored in three electrode types, chronically implanted in two adult male nonhuman primates (NHP) (Macaca mulatta), which included epidural electrocorticography (ECoG) electrodes and penetrating deep-brain stimulation (DBS) electrodes. Electrochemical impedance spectroscopy (EIS) was performed before and after each rejuvenation paradigm as a gold standard measure of impedance, as well as at subsequent intervals to longitudinally track the evolution of the ETI. Stochastic error modeling was performed to assess the standard deviation of the impedance data, and consistency with the Kramers-Kronig relations was assessed to evaluate the stationarity of EIS measurement.Main results. AC and DC rejuvenation were found to quickly reduce impedance and minimize the tissue component of the ETI on all three electrode types, with DC and low-frequency AC producing the largest impedance drops and reduction of the tissue component in Nyquist plots. The effects of a single rejuvenation session were found to last from several days to over 1 week, and all rejuvenation pulses induced no observable changes to the animals' behavior.Significance. These results demonstrate the effectiveness of electrical rejuvenation for diminishing the impact of chronic ETI changes in NHP with clinically relevant macroelectrode designs.

Selective activation of central thalamic fiber pathway facilitates behavioral performance in healthy non-human primates.

Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. However, the mechanisms of CT-DBS that promote restoration of cognitive functions are unknown, and the heterogeneous etiology and recovery profiles of SBI patients contribute to variable outcomes when using conventional DBS strategies,which may result in off-target effects due to activation of multiple pathways. To disambiguate the effects of stimulation of two adjacent thalamic pathways, we modeled and experimentally compared conventional and novel 'field-shaping' methods of CT-DBS within the central thalamus of healthy non-human primates (NHP) as they performed visuomotor tasks. We show that selective activation of the medial dorsal thalamic tegmental tract (DTTm), but not of the adjacent centromedian-parafascicularis (CM-Pf) pathway, results in robust behavioral facilitation. Our predictive modeling approach in healthy NHPs directly informs ongoing and future clinical investigations of conventional and novel methods of CT-DBS for treating cognitive dysfunctions in SBI patients, for whom no therapy currently exists.

Interactive computation and visualization of deep brain stimulation effects using Duality.

Deep brain stimulation (DBS) is an established treatment for movement disorders such as Parkinson's disease or essential tremor. Currently, the selection of optimal stimulation settings is performed by iteratively adjusting the stimulation parameters and is a time consuming procedure that requires multiple clinic visits of several hours. Recently, computational models to predict and visualize the effect of DBS have been developed with the goal to simplify and accelerate this procedure by providing visual guidance and such models have been made available also on mobile devices. However, currently available visualization software still either lacks mobility, i.e., it is running on desktop computers and not easily available in clinical praxis, or flexibility, as the simulations that are visualized on mobile devices have to be precomputed. The goal of the pipeline presented in this paper is to close this gap: Using Duality, a newly developed software for the interactive visualization of simulation results, we implemented a pipeline that allows to compute DBS simulations in near-real time and instantaneously visualize the result on a tablet computer. Therefore, a client-server setup is used, so that the visualization and user interaction occur on the tablet computer, while the computations are carried out on a remote server. We present two examples for the use of Duality, one for postoperative programming and one for the planning of DBS surgery in a pre- or intraoperative setting. We carry out a performance analysis and present the results of a case study in which the pipeline for postoperative programming was applied.

Deep brain stimulation activation volumes and their association with neurophysiological mapping and therapeutic outcomes.

OBJECTIVE: Despite the clinical success of deep brain stimulation (DBS) for the treatment of Parkinson's disease (PD), little is known about the electrical spread of the stimulation. The primary goal of this study was to integrate neuroimaging, neurophysiology and neurostimulation data sets from 10 patients with PD, unilaterally implanted with subthalamic nucleus (STN) DBS electrodes, to identify the theoretical volume of tissue activated (VTA) by clinically defined therapeutic stimulation parameters. METHODS: Each patient specific model was created with a series of five steps: (1) definition of the neurosurgical stereotactic coordinate system within the context of preoperative imaging data; (2) entry of intraoperative microelectrode recording locations from neurophysiologically defined thalamic, subthalamic and substantia nigra neurons into the context of the imaging data; (3) fitting a three dimensional brain atlas to the neuroanatomy and neurophysiology of the patient; (4) positioning the DBS electrode in the documented stereotactic location, verified by postoperative imaging data; and (5) calculation of the VTA using a diffusion tensor based finite element neurostimulation model. RESULTS: The patient specific models show that therapeutic benefit was achieved with direct stimulation of a wide range of anatomical structures in the subthalamic region. Interestingly, of the five patients exhibiting a greater than 40% improvement in their Unified PD Rating Scale (UPDRS), all but one had the majority of their VTA outside the atlas defined borders of the STN. Furthermore, of the five patients with less than 40% UPDRS improvement, all but one had the majority of their VTA inside the STN. CONCLUSIONS: Our results are consistent with previous studies suggesting that therapeutic benefit is associated with electrode contacts near the dorsal border of the STN, and provide quantitative estimates of the electrical spread of the stimulation in a clinically relevant context.

Cicerone: stereotactic neurophysiological recording and deep brain stimulation electrode placement software system.

Stereotactic neurosurgery and neurophysiological microelectrode recordings in both humans and monkeys are typically done with conventional 2D atlases and paper records of the stereotactic coordinates. This approach is prone to error because the brain size, shape, and location of subcortical structures can vary between subjects. Furthermore, paper record keeping is inefficient and limits opportunities for data visualization. To address these limitations, we developed a software tool (Cicerone) that enables interactive 3D visualization of co-registered magnetic resonance images (MRI), computed tomography (CT) scans, 3D brain atlases, neurophysiological microelectrode recording (MER) data, and deep brain stimulation (DBS) electrode(s) with the volume of tissue activated (VTA) as a function of the stimulation parameters. The software can be used in pre-operative planning to help select the optimal position on the skull for burr hole (in humans) or chamber (in monkeys) placement to maximize the likelihood of complete microelectrode and DBS coverage of the intended anatomical target. Intra-operatively, Cicerone allows entry of the stereotactic microdrive coordinates and MER data, enabling real-time interactive visualization of the electrode location in 3D relative to the surrounding neuroanatomy and neurophysiology. In addition, the software enables prediction of the VTA generated by DBS for a range of electrode trajectories and tip locations. In turn, the neurosurgeon can use the combination of anatomical (MRI/CT/3D brain atlas), neurophysiological (MER), and electrical (DBS VTA) data to optimize the placement of the DBS electrode prior to permanent implantation.

StimExplorer: deep brain stimulation parameter selection software system.

StimExplorer is a Windows-based software package intended to aid the clinical implementation of deep brain stimulation (DBS) technology. StimExplorer uses detailed computer models to provide a quantitative description of the 3D volume of tissue activated (VTA) by DBS as a function of the stimulation parameters and electrode location within the brain. The stimulation models are tailored to the individual patient by importing their magnetic resonance imaging (MRI) data and interactively scaling 3D anatomical nuclei to fit the patient anatomy. The user also inputs the DBS electrode orientation, location, and impedance data. The software then provides theoretically optimal stimulation parameter suggestions, intended to represent the start point for clinical programming of the DBS device. The software system is packaged into a clinician-friendly graphical user interface that allows for simultaneous interactive 3D visualization of the MRI, anatomical nuclei, DBS electrode, and VTAs for a wide range of stimulation parameter settings (contact, impedance, voltage, pulse width, and frequency). The goals of the StimExplorer system are to educate clinicians on the impact of stimulation parameter manipulation, and improve therapeutic outcomes by providing quantitative anatomical and electrical information useful for customizing DBS to individual patients.

Post-light potentiation at type B to A photoreceptor connections in Hermissenda.

We investigated whether the long (approximately 30-s) or short (approximately 3-s) light stimuli that have been used during behavioral training would induce post-light potentiation (PLP) at the type B to A photoreceptor connections of the isolated nervous system of Hermissenda. We found that a single approximately 30-s light step induced PLP at these connections relative to both pre-light baseline and seawater control preparations, as did a series of nine short (approximately 3-s) light steps. In addition, a 30-s step of depolarization-elicited type B cell activity induced potentiation comparable to that induced by a approximately 30-s light step, indicating that light-elicited type B cell activity contributes to the induction of PLP. By contrast, even though a series of short (3-s) light steps induced potentiation, short steps of depolarization-evoked type B cell activity did not. Hence, light-evoked processes other than type B cell depolarization or activity (e.g., perhaps intracellular Ca2+ release) also contribute to the induction of PLP. Further results suggest that these other light-evoked processes interact nonadditively with type B cell activity to generate PLP. Some but not all instances of synaptic potentiation were accompanied by various changes in parameters of type B cell action potentials and afterhyperpolarizing potentials, suggesting diverse underlying mechanisms, including increases in neurotransmitter release. Given that the type A cells have been proposed to polysynaptically excite the motor neurons that drive phototaxis, a light-evoked potentiation of synaptic strength at the inhibitory type B to A photoreceptor connections may play a mechanistic role in light-elicited nonassociative learning.