Robust modulation of arousal regulation, performance, and frontostriatal activity through central thalamic deep brain stimulation in healthy nonhuman primates.

The central thalamus (CT) is a key component of the brain-wide network underlying arousal regulation and sensory-motor integration during wakefulness in the mammalian brain. Dysfunction of the CT, typically a result of severe brain injury (SBI), leads to long-lasting impairments in arousal regulation and subsequent deficits in cognition. Central thalamic deep brain stimulation (CT-DBS) is proposed as a therapy to reestablish and maintain arousal regulation to improve cognition in select SBI patients. However, a mechanistic understanding of CT-DBS and an optimal method of implementing this promising therapy are unknown. Here we demonstrate in two healthy nonhuman primates (NHPs), Macaca mulatta, that location-specific CT-DBS improves performance in visuomotor tasks and is associated with physiological effects consistent with enhancement of endogenous arousal. Specifically, CT-DBS within the lateral wing of the central lateral nucleus and the surrounding medial dorsal thalamic tegmental tract (DTTm) produces a rapid and robust modulation of performance and arousal, as measured by neuronal activity in the frontal cortex and striatum. Notably, the most robust and reliable behavioral and physiological responses resulted when we implemented a novel method of CT-DBS that orients and shapes the electric field within the DTTm using spatially separated DBS leads. Collectively, our results demonstrate that selective activation within the DTTm of the CT robustly regulates endogenous arousal and enhances cognitive performance in the intact NHP; these findings provide insights into the mechanism of CT-DBS and further support the development of CT-DBS as a therapy for reestablishing arousal regulation to support cognition in SBI patients.

Iterative electrodes increase neural recruitment for deep brain stimulation.

Deep brain stimulators require surgical replacement when primary cell batteries are depleted. We designed novel electrode contact geometries based on the principle of iterative element addition as a method of increasing perimeter. Our hypothesis was that these novel, high-perimeter designs would increase surface current density variation and neuronal activation, thus improving stimulation efficiency by decreasing power requirement. Finite element models of iterative electrodes displayed greater surface current density variations on the electrode surface. Subsequent analysis of their activation efficiency when 100 neurons were randomly positioned either parallel or perpendicular to the electrode yielded higher stimulation efficiencies in response to a monophasic cathodic voltage pulse with a pulse width of 100 µs. Recruitment curves showing the percentage of activated axons as a function of stimulation intensity yielded a ~8% and ~24% reduction in threshold voltage and a ~2% and ~28% reduction in power consumption when nerve fibers were oriented parallel and perpendicular to the electrode, respectively. This heightened efficiency would reduce the frequency of surgical replacements of depleted stimulators, as well as induce fewer side effects associate with high voltage requirement for therapeutic stimulation.

High efficiency electrodes for deep brain stimulation.

Deep brain stimulators are powered with primary cell batteries and require surgical replacement when they are depleted. We sought to decrease power consumption, and thereby increase device lifetime by increasing neuronal stimulating efficiency with novel electrode designs. Our hypothesis was that high-perimeter electrodes that increase the variation of current density on their surface would generate larger activating functions for surrounding neurons, hence increasing stimulation efficiency. We implemented finite element models of cylindrical DBS electrodes with conventional circular perimeters, with serpentine perimeters, and with segmented contacts. The high-perimeter electrodes significantly increased the variation of current density on the electrode surface. We randomly positioned a population of 100 model axons around the electrodes and quantified neural activation with 100 micros cathodic stimuli. Input-output curves of percentage axons activated as a function of stimulation intensity indicated that the novel electrode geometries decreased power consumption by up to approximately 20% for axons parallel to the electrode and up to approximately 35% for axons perpendicular to the electrode. Reduced power consumption achieved with these designs will reduce the costs and risks associated with surgeries to replace depleted stimulators.

Analysis of high-perimeter planar electrodes for efficient neural stimulation.

Planar electrodes are used in epidural spinal cord stimulation and epidural cortical stimulation. Electrode geometry is one approach to increase the efficiency of neural stimulation and reduce the power required to produce the level of activation required for clinical efficacy. Our hypothesis was that electrode geometries that increased the variation of current density on the electrode surface would increase stimulation efficiency. High-perimeter planar disk electrodes were designed with sinuous (serpentine) variation in the perimeter. Prototypes were fabricated that had equal surface areas but perimeters equal to two, three or four times the perimeter of a circular disk electrode. The interface impedance of high-perimeter prototype electrodes measured in vitro did not differ significantly from that of the circular electrode over a wide range of frequencies. Finite element models indicated that the variation of current density was significantly higher on the surface of the high-perimeter electrodes. We quantified activation of 100 model axons randomly positioned around the electrodes. Input-output curves of the percentage of axons activated as a function of stimulation intensity indicated that the stimulation efficiency was dependent on the distance of the axons from the electrode. The high-perimeter planar electrodes were more efficient at activating axons a certain distance away from the electrode surface. These results demonstrate the feasibility of increasing stimulation efficiency through the design of novel electrode geometries.

Impedance characteristics of deep brain stimulation electrodes in vitro and in vivo.

The objective of this study was to quantify the electrode-tissue interface impedance of electrodes used for deep brain stimulation (DBS). We measured the impedance of DBS electrodes using electrochemical impedance spectroscopy in vitro in a carbonate- and phosphate-buffered saline solution and in vivo following acute implantation in the brain. The components of the impedance, including the series resistance (R(s)), the Faradaic resistance (R(f)) and the double layer capacitance (C(dl)), were estimated using an equivalent electrical circuit. Both R(f) and C(dl) decreased as the sinusoidal frequency was increased, but the ratio of the capacitive charge transfer to the Faradaic charge transfer was relatively insensitive to the change of frequency. R(f) decreased and C(dl) increased as the current density was increased, and above a critical current density the interface impedance became nonlinear. Thus, the magnitude of the interface impedance was strongly dependent on the intensity (pulse amplitude and duration) of stimulation. The temporal dependence and spatial non-uniformity of R(f) and C(dl) suggested that a distributed network, with each element of the network having dynamics tailored to a specific stimulus waveform, is required to describe adequately the impedance of the DBS electrode-tissue interface. Voltage transients to biphasic square current pulses were measured and suggested that the electrode-tissue interface did not operate in a linear range at clinically relevant current amplitudes, and that the assumption of the DBS electrode being ideally polarizable was not valid under clinical stimulating conditions.

Fabrication and evaluation of conductive elastomer electrodes for neural stimulation.

This study explored the feasibility of applying nanocomposites derived from conducting organic polymers and silicone elastomers to fabricate electrodes for neural stimulation. A novel combination of nanoparticulate polypyrrole polymerized within a processable elastomeric silicone host polymer was evaluated in vitro and in vivo. The electrical properties of the elastomeric conductors were strongly dependent on their composition, and mixtures were identified that provided high and stable conductivity. Methods were developed for incorporating conductive polymer-siloxane co-polymer nanocomposite and silicone insulating polymers into thin-layered structures for simple single-poled electrode fabrication. In vitro testing revealed that the materials were stable under continuous pulsing for at least 10 days. Single contact prototype nerve cuff electrodes were fabricated and device functionality was demonstrated in vivo following acute implantation. The results of this study demonstrate the feasibility of conductive elastomers for peripheral nerve stimulating electrodes. Matching the mechanical properties of cuff electrode to those of the underlying neural tissue is expected to improve the long-term tissue response to the presence of the electrode.

Current density distributions, field distributions and impedance analysis of segmented deep brain stimulation electrodes.

Deep brain stimulation (DBS) electrodes are designed to stimulate specific areas of the brain. The most widely used DBS electrode has a linear array of 4 cylindrical contacts that can be selectively turned on depending on the placement of the electrode and the specific area of the brain to be stimulated. The efficacy of DBS therapy can be improved by localizing the current delivery into specific populations of neurons and by increasing the power efficiency through a suitable choice of electrode geometrical characteristics. We investigated segmented electrode designs created by sectioning each cylindrical contact into multiple rings. Prototypes of these designs, made with different materials and larger dimensions than those of clinical DBS electrodes, were evaluated in vitro and in simulation. A finite element model was developed to study the effects of varying the electrode characteristics on the current density and field distributions in an idealized electrolytic medium and in vitro experiments were conducted to measure the electrode impedance. The current density over the electrode surface increased towards the edges of the electrode, and multiple edges increased the non-uniformity of the current density profile. The edge effects were more pronounced over the end segments than over the central segments. Segmented electrodes generated larger magnitudes of the second spatial difference of the extracellular potentials, and thus required lower stimulation intensities to achieve the same level of neuronal activation as solid electrodes. For a fixed electrode conductive area, increasing the number of segments (edges) decreased the impedance compared to a single solid electrode, because the average current density over the segments increased. Edge effects played a critical role in determining the current density distributions, neuronal excitation patterns, and impedance of cylindrical electrodes, and segmented electrodes provide a means to increase the efficiency of DBS.