Implantable Direct Current Neural Modulation: Theory, Feasibility, and Efficacy

Implantable neuroprostheses such as cochlear implants, deep brain stimulators, spinal cord stimulators, and retinal implants use charge-balanced alternating current (AC) pulses to recover delivered charge and thus mitigate toxicity from electrochemical reactions occurring at the metal-tissue interface. At low pulse rates, these short duration pulses have the effect of evoking spikes in neural tissue in a phase-locked fashion. When the therapeutic goal is to suppress neural activity, implants typically work indirectly by delivering excitation to populations of neurons that then inhibit the target neurons, or by delivering very high pulse rates that suffer from a number of undesirable side effects. Direct current (DC) neural modulation is an alternative methodology that can directly modulate extracellular membrane potential. This neuromodulation paradigm can excite or inhibit neurons in a graded fashion while maintaining their stochastic firing patterns. DC can also sensitize or desensitize neurons to input. When applied to a population of neurons, DC can modulate synaptic connectivity. Because DC delivered to metal electrodes inherently violates safe charge injection criteria, its use has not been explored for practical applicability of DC-based neural implants. Recently, several new technologies and strategies have been proposed that address this safety criteria and deliver ionic-based direct current (iDC). This, along with the increased understanding of the mechanisms behind the transcutaneous DC-based modulation of neural targets, has caused a resurgence of interest in the interaction between iDC and neural tissue both in the central and the peripheral nervous system. In this review we assess the feasibility of in-vivo iDC delivery as a form of neural modulation. We present the current understanding of DC/neural interaction. We explore the different design methodologies and technologies that attempt to safely deliver iDC to neural tissue and assess the scope of application for direct current modulation as a form of neuroprosthetic treatment in disease. Finally, we examine the safety implications of long duration iDC delivery. We conclude that DC-based neural implants are a promising new modulation technology that could benefit from further chronic safety assessments and a better understanding of the basic biological and biophysical mechanisms that underpin DC-mediated neural modulation

Perceived intensity of somatosensory cortical electrical stimulation

Artificial sensations can be produced by direct brain stimulation of sensory areas through implanted microelectrodes, but the perceptual psychophysics of such artificial sensations are not well understood. Based on prior work in cortical stimulation, we hypothesized that perceived intensity of electrical stimulation may be explained by the population response of the neurons affected by the stimulus train. To explore this hypothesis, we modeled perceived intensity of a stimulation pulse train with a leaky neural integrator. We then conducted a series of two-alternative forced choice behavioral experiments in which we systematically tested the ability of rats to discriminate frequency, amplitude, and duration of electrical pulse trains delivered to the whisker barrel somatosensory cortex. We found that the model was able to predict the performance of the animals, supporting the notion that perceived intensity can be largely accounted for by spatiotemporal integration of the action potentials evoked by the stimulus train

Low Cost, Ease-of-Access Fabrication of Microfluidic Devices Using Wet Paper Molds

Rapid prototyping methods enable the widespread adoption of microfluidic technologies by empowering end-users from non-engineering disciplines to make devices using processes that are rapid, simple and inexpensive. In this work, we developed a liquid molding technique to create silicone/PDMS microfluidic devices by replica molding. To construct a liquid mold, we use inexpensive adhesive-backed paper, an acetate backing sheet, and an off-the-shelf digital cutter to create paper molds, which we then wet with predetermined amounts of water. Due to the immiscibility of water and PDMS, mold patterns can be effectively transferred onto PDMS similarly to solid molds. We demonstrate the feasibility of these wet paper molds for the fabrication of PDMS microfluidic devices and assess the influence of various process parameters on device yield and quality. This method possesses some distinct benefits compared to conventional techniques such as photolithography and 3D printing. First, we demonstrate that the shape of a channel’s cross-section may be altered from rectangular to semicircular by merely modifying the wetting parameters. Second, we illustrate how electrical impedance can be utilized as a marker for inspecting mold quality and identifying defects in a non-invasive manner without using visual tools such as microscopes or cameras. As a proof-of-concept device, we created a microfluidic T-junction droplet generator to produce water droplets in mineral oil ranging in size from 1.2 µL to 75 µL. We feel that this technology is an excellent addition to the microfluidic rapid prototyping toolbox and will find several applications in biological research

A Hydrogel-Based Microfluidic Nerve Cuff for Neuromodulation of Peripheral Nerves

Implantable neuromodulation devices typically have metal in contact with soft, ion-conducting nerves. These neural interfaces excite neurons using short-duration electrical pulses. While this approach has been extremely successful for multiple clinical applications, it is limited in delivering long-duration pulses or direct current (DC), even for acute term studies. When the charge injection capacity of electrodes is exceeded, irreversible electrochemical processes occur, and toxic byproducts are discharged directly onto the nerve, causing biological damage. Hydrogel coatings on electrodes improve the overall charge injection limit and provide a mechanically pliable interface. To further extend this idea, we developed a silicone-based nerve cuff lead with a hydrogel microfluidic conduit. It serves as a thin, soft and flexible interconnection and provides a greater spatial separation between metal electrodes and the target nerve. In an in vivo rat model, we used this cuff to stimulate and record from sciatic nerves, with performance comparable to that of metal electrodes. Further, we delivered DC through the lead in an acute manner to induce nerve block that is reversible. In contrast to most metallic cuff electrodes, which need microfabrication equipment, we built this cuff using a consumer-grade digital cutter and a simplified molding process. Overall, the device will be beneficial to neuromodulation researchers as a general-purpose nerve cuff electrode for peripheral neuromodulation experiments

Perceived intensity of somatosensory cortical electrical stimulation

Artificial sensations can be produced by direct brain stimulation of sensory areas through implanted microelectrodes, but the perceptual psychophysics of such artificial sensations are not well understood. Based on prior work in cortical stimulation, we hypothesized that perceived intensity of electrical stimulation may be explained by the population response of the neurons affected by the stimulus train. To explore this hypothesis, we modeled perceived intensity of a stimulation pulse train with a leaky neural integrator. We then conducted a series of two-alternative forced choice behavioral experiments in which we systematically tested the ability of rats to discriminate frequency, amplitude, and duration of electrical pulse trains delivered to the whisker barrel somatosensory cortex. We found that the model was able to predict the performance of the animals, supporting the notion that perceived intensity can be largely accounted for by spatiotemporal integration of the action potentials evoked by the stimulus train

Usefulness of a noninvasive device to identify elevated left ventricular filling pressure using finger photoplethysmography during a Valsalva maneuver.

The high rate of re-hospitalization for heart failure might be reduced by improving noninvasive techniques for identifying elevated left ventricular (LV) filling pressure. We previously showed that changes in a finger photoplethysmography (PPG) waveform during the Valsalva maneuver (VM) reflect invasively measured LV end-diastolic pressure (LVEDP). We have since developed a hand-held device that analyzes PPG while guiding the expiratory effort of a VM. Here we assessed the sensitivity and specificity of this device for identifying elevated LVEDP in patients. We tested 82 participants (28 women), aged 40 to 85 years, before a clinically indicated left heart catheterization. Each performed a VM between 18 and 25 mm Hg for 10 seconds into a pressure transducer. PPG was recorded continuously before and during the VM. LVEDP was measured during the catheterization. An equation for calculating LVEDP was derived using (1) ratio of signal amplitudes: minimum during VM to average at baseline, (2) ratio of peak-to-peak time intervals: minimum during VM to average at baseline, and (3) mean blood pressure. Calculated and measured LVEDP were compared. The range of measured LVEDP was 4 to 35 mm Hg. Calculated LVEDP correlated with measured LVEDP (p20 mm Hg had a 70% sensitivity and 86% specificity for identifying measured LVEDP \u3e20 mm Hg (area under receiver-operating characteristic curve 0.83). In conclusion, a hand-held device for assessing LV filling pressure had high specificity and good sensitivity for identifying LVEDP \u3e20 mm Hg, a clinically meaningful threshold in heart failure