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

The microfluidic components of the freeform stimulator for neural modulation

Electronic devices can be interfaced with tissue via metal electrodes to deliver electrical current to stimulate target neurons for disease treatment. Different from the charge-balanced short pulse that can be safely applied in biology, direct current (DC) has been restricted from being applied for prolonged durations due to the toxicity generated by electrolysis around stimulation electrodes. On the other hand, as revealed by acute studies in animals, DC can be applied to suppress neural activity, a potential beneficial function for vestibular implants and devices intended to block pain signal in peripheral nerves or to treat epilepsy. To enable the use of prolonged DC in a human body, we developed a novel device we named Freeform Stimulator (FS). It is designed to safely deliver DC to neurons for arbitrary long durations without causing electrolysis. FS uses two pairs of electrodes to deliver charge-balanced currents into a microfluidic (µF) channel network. The induced ionic currents in the µF can be rectified into an ionic DC at the output of the device by the cyclical operation of two embedded valves that control the conduction of the channel network. FS could provide a way to safely apply prolonged DC in human body and benefit those applications that use DC to modulate neural activity. This thesis is focused on the development of the µF components that are required in the µF chip of FS which includes a shape memory alloy valve used to control ionic current, an ionic transistor that can be used as a non-mechanical control of ionic current and an ionic current sensor used to measure the ionic DC output. For proof of concept of FS, we tested the obtained µF chip with properly designed control of current and valve and succeeded in rectifying the ionic currents in µF into an ionic DC at the output

Towards Integrating Vestibular Implant Stimulation of the Semicircular Canals and the Otolith End Organs to Drive Posture, Gait, and Eye-Stabilizing Reflexes

Individuals who suffer from bilateral vestibular hypofunction see an increased risk of falling and a decreased quality of life due to symptoms like imbalance, difficulty keeping their eyes on target during head movement, and difficulty walking. The current standard of care to address these symptoms involves rehabilitation exercises to train the central nervous system to rely on visual and proprioceptive signals to compensate for a loss in vestibular signal. However, no sensory substitution can compensate for the extremely fast ocular and spinal reflexes driven by the vestibular nerves. Decades of research led to the development of multichannel vestibular prostheses designed to electrically stimulate the vestibular nerve endings to provide head movement information from a three-axis motion processing unit. The Johns Hopkins Multichannel Vestibular Implant Early Feasibility Study implanted nine study participants with a unilateral vestibular implant targeting the three semicircular canals. The Johns Hopkins Multichannel Vestibular Implant for clinical use does not incorporate circuitry or hardware to stimulate the remaining two sensory organs of the vestibular system, the otolith end organs, responsible for encoding gravitoinertial accelerations that contribute to ocular and spinal reflexes. Stimulation to these end organs were not the priority because they typically elicit much smaller ocular reflexes and encode slower, low-frequency information that can more easily be compensated by the visual and proprioceptive systems. Additionally, their sensory epithelia encode a wider range of information, so mapping a three-axis accelerometer’s signal to stimulation parameters is not straightforward. The research described in this dissertation first assesses the need for otolith-targeted stimulation by measuring otolith-related vestibulo-spinal reflexes via clinical tests of posture and gait in the Multichannel Vestibular Implant Early Feasibility Study with individuals receiving only semicircular canal-targeted stimulation. In the following chapters, the research expands on previous work done in normally functioning chinchillas to explore otolith-targeted stimulation in a rodent model of bilateral vestibular hypofunction and to understand and optimize the stimulation parameters that will be physiologically relevant and useful to restore otolith-specific information to the vestibular nerve endings. The work described in this dissertation is a step toward a more complete vestibular prosthesis to help restore the otolith-driven reflexes to individuals with profound vestibular loss

A MODELING PERSPECTIVE ON DEVELOPING NATURALISTIC NEUROPROSTHETICS USING ELECTRICAL STIMULATION

Direct electrical stimulation of neurons has been an important tool for understanding the brain and neurons, since the field of neuroscience began. Electrical stimulation was used to first understand sensation, the mapping of the brain, and more recently function, and, as our understanding of neurological disorders has advanced, it has become an increasingly important tool for interacting with neurons to design and carry out treatments. The hardware for electrical stimulation has greatly improved during the last century, allowing smaller scale, implantable treatments for a variety of disorders, from loss of sensations (hearing, vision, balance) to Parkinson’s disease and depression. Due to the clinical success of these treatments for a variety of impairments today, there are millions of neural implant users around the globe, and interest in medical implants and implants for human-enhancement are only growing. However, present neural implant treatments restore only limited function compared to natural systems. A limiting factor in the advancement of electrical stimulation-based treatments has been the restriction of using charge-balanced and typically short sub-millisecond pulses in order to safely interact with the brain, due to a reliance on durable, metal electrodes. Material science developments have led to more flexible electrodes that are capable of delivering more charge safely, but a focus has been on density of electrodes implanted over changing the waveform of electrical stimulation delivery. Recently, the Fridman lab at Johns Hopkins University developed the Freeform Stimulation (FS)– an implantable device that uses a microfluidic H-bridge architecture to safely deliver current for prolonged periods of time and that is not restricted to charge-balanced waveforms. In this work, we refer to these non-restricted waveforms as galvanic stimulation, which is used as an umbrella term that encompasses direct current, sinusoidal current, or alternative forms of non-charge-balanced current. The invention of the FS has opened the door to usage of galvanic stimulation in neural implants, begging an exploration of the effects of local galvanic stimulation on neural function. Galvanic stimulation has been used in the field of neuroscience, prior to concerns about safe long-term interaction with neurons. Unlike many systems, it had been historically used in the vestibular system internally and in the form of transcutaneous stimulation to this day. Historic and recent studies confirm that galvanic stimulation of the vestibular system has more naturalistic effects on neural spike timing and on induced behavior (eye velocities) than pulsatile stimulation, the standard in neural implants now. Recent vestibular stimulation studies with pulses also show evidence of suboptimal responses of neurons to pulsatile stimulation in which suprathreshold pulses only induce about half as many action potentials as pulses. This combination of results prompted an investigation of differences between galvanic and pulsatile electrical stimulation in the vestibular system. The research in this dissertation uses detailed biophysical modeling of single vestibular neurons to investigate the differences in the biophysical mechanism of galvanic and pulsatile stimulation. In Chapter 2, a more accurate model of a vestibular afferent is constructed from an existing model, and it is used to provide a theory for how galvanic stimulation produces a number of known effects on vestibular afferents. In Chapter 3, the same model is used to explain why pulsatile stimulation produces fewer action potentials than expected, and the results show that pulse amplitude, pulse rate, and the spontaneous activity of neurons at the axon have a number of interactions that lead to several non-monotonic relationships between pulse parameters and induced firing rate. Equations are created to correct for these non-monotonic relationships and produce intended firing rates. Chapter 4 focuses on how to create a neural implant that induces more naturalistic firing using the scientific understanding from Chapters 2 and 3 and machine learning. The work concludes by describing the implications of these findings for interacting with neurons and population and network scales and how this may make electrical stimulation increasingly more suited for treating complex network-level and psychiatric disorders