Improving the mechanistic study of neuromuscular diseases through the development of a fully wireless and implantable recording device

Neuromuscular diseases manifest by a handful of known phenotypes affecting the peripheral nerves, skeletal muscle fibers, and neuromuscular junction. Common signs of these diseases include demyelination, myasthenia, atrophy, and aberrant muscle activity—all of which may be tracked over time using one or more electrophysiological markers. Mice, which are the predominant mammalian model for most human diseases, have been used to study congenital neuromuscular diseases for decades. However, our understanding of the mechanisms underlying these pathologies is still incomplete. This is in part due to the lack of instrumentation available to easily collect longitudinal, in vivo electrophysiological activity from mice. There remains a need for a fully wireless, batteryless, and implantable recording system that can be adapted for a variety of electrophysiological measurements and also enable long-term, continuous data collection in very small animals. To meet this need a miniature, chronically implantable device has been developed that is capable of wirelessly coupling energy from electromagnetic fields while implanted within a body. This device can both record and trigger bioelectric events and may be chronically implanted in rodents as small as mice. This grants investigators the ability to continuously observe electrophysiological changes corresponding to disease progression in a single, freely behaving, untethered animal. The fully wireless closed-loop system is an adaptable solution for a range of long-term mechanistic and diagnostic studies in rodent disease models. Its high level of functionality, adjustable parameters, accessible building blocks, reprogrammable firmware, and modular electrode interface offer flexibility that is distinctive among fully implantable recording or stimulating devices. The key significance of this work is that it has generated novel instrumentation in the form of a fully implantable bioelectric recording device having a much higher level of functionality than any other fully wireless system available for mouse work. This has incidentally led to contributions in the areas of wireless power transfer and neural interfaces for upper-limb prosthesis control. Herein the solution space for wireless power transfer is examined including a close inspection of far-field power transfer to implanted bioelectric sensors. Methods of design and characterization for the iterative development of the device are detailed. Furthermore, its performance and utility in remote bioelectric sensing applications is demonstrated with humans, rats, healthy mice, and mouse models for degenerative neuromuscular and motoneuron diseases

Evolution of optogenetic microdevices

Implementation of optogenetic techniques is a recent addition to the neuroscientists\u27 preclinical research arsenal, helping to expose the intricate connectivity of the brain and allowing for on-demand direct modulation of specific neural pathways. Developing an optogenetic system requires thorough investigation of the optogenetic technique and of previously fabricated devices, which this review accommodates. Many experiments utilize bench-top systems that are bulky, expensive, and necessitate tethering to the animal. However, these bench-top systems can make use of power-demanding technologies, such as concurrent electrical recording. Newer portable microdevices and implantable systems carried by freely moving animals are being fabricated that take advantage of wireless energy harvesting to power a system and allow for natural movements that are vital for behavioral testing and analysis. An investigation of the evolution of tethered, portable, and implantable optogenetic microdevices is presented, and an analysis of benefits and detriments of each system, including optical power output, device dimensions, electrode width, and weight is given. Opsins, light sources, and optical fiber coupling are also discussed to optimize device parameters and maximize efficiency from the light source to the fiber, respectively. These attributes are important considerations when designing and developing improved optogenetic microdevices

Biointegrated and wirelessly powered implantable brain devices: a review

Implantable neural interfacing devices have added significantly to neural engineering by introducing the low-frequency oscillations of small populations of neurons known as local field potential as well as high-frequency action potentials of individual neurons. Regardless of the astounding progression as of late, conventional neural modulating system is still incapable to achieve the desired chronic in vivo implantation. The real constraint emerges from mechanical and physical diffierences between implants and brain tissue that initiates an inflammatory reaction and glial scar formation that reduces the recording and stimulation quality. Furthermore, traditional strategies consisting of rigid and tethered neural devices cause substantial tissue damage and impede the natural behaviour of an animal, thus hindering chronic in vivo measurements. Therefore, enabling fully implantable neural devices, requires biocompatibility, wireless power/data capability, biointegration using thin and flexible electronics, and chronic recording properties. This paper reviews biocompatibility and design approaches for developing biointegrated and wirelessly powered implantable neural devices in animals aimed at long-term neural interfacing and outlines current challenges toward developing the next generation of implantable neural devices

Developing Next-generation Brain Sensing Technologies - A Review.

Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients

Coupled resonator based wireless power transfer for bioelectronics

Implantable and wearable bioelectronics provide the ability to monitor and modulate physiological processes. They represent a promising set of technologies that can provide new treatment for patients or new tools for scientific discovery, such as in long-term studies involving small animals. As these technologies advance, two trends are clear, miniaturization and increased sophistication i.e. multiple channels, wireless bi-directional communication, and responsiveness (closed-loop devices). One primary challenge in realizing miniaturized and sophisticated bioelectronics is powering. Integration and development of wireless power transfer (WPT) technology, however, can overcome this challenge. In this dissertation, I propose the use of coupled resonator WPT for bioelectronics and present a new generalized analysis and optimization methodology, derived from complex microwave bandpass filter synthesis, for maximizing and controlling coupled resonator based WPT performance. This newly developed set of analysis and optimization methods enables system miniaturization while simultaneously achieving the necessary performance to safely power sophisticated bioelectronics. As an application example, a novel coil to coil based coupled resonator arrangement to wirelessly operate eight surface electromyography sensing devices wrapped circumferentially around an able-bodied arm is developed and demonstrated. In addition to standard coil to coil based systems, this dissertation also presents a new form of coupled resonator WPT system built of a large hollow metallic cavity resonator. By leveraging the analysis and optimization methods developed here, I present a new cavity resonator WPT system for long-term experiments involving small rodents for the first time. The cavity resonator based WPT arena exhibits a volume of 60.96 x 60.96 x 30.0 cm3. In comparison to prior state of the art, this cavity resonator system enables nearly continuous wireless operation of a miniature sophisticated device implanted in a freely behaving rodent within the largest space. Finally, I present preliminary work, providing the foundation for future studies, to demonstrate the feasibility of treating segments of the human body as a dielectric waveguide resonator. This creates another form of a coupled resonator system. Preliminary experiments demonstrated optimized coupled resonator wireless energy transfer into human tissue. The WPT performance achieved to an ultra-miniature sized receive coil (2 mm diameter) is presented. Indeed, optimized coupled resonator systems, broadened to include cavity resonator structures and human formed dielectric resonators, can enable the effective use of coupled resonator based WPT technology to power miniaturized and sophisticated bioelectronics

Implantable Neural Probes for Brain-Machine Interfaces - Current Developments and Future Prospects

A Brain-Machine interface (BMI) allows for direct communication between the brain and machines. Neural probes for recording neural signals are among the essential components of a BMI system. In this report, we review research regarding implantable neural probes and their applications to BMIs. We first discuss conventional neural probes such as the tetrode, Utah array, Michigan probe, and electroencephalography (ECoG), following which we cover advancements in next-generation neural probes. These next-generation probes are associated with improvements in electrical properties, mechanical durability, biocompatibility, and offer a high degree of freedom in practical settings. Specifically, we focus on three key topics: (1) novel implantable neural probes that decrease the level of invasiveness without sacrificing performance, (2) multi-modal neural probes that measure both electrical and optical signals, (3) and neural probes developed using advanced materials. Because safety and precision are critical for practical applications of BMI systems, future studies should aim to enhance these properties when developing next-generation neural probes

Wireless Simultaneous Stimulation-and-Recording Device (SRD) to Train Cortical Circuits in Rat Somatosensory Cortex

The primary goal of this project is to develop a wireless system for simultaneous recording-and-stimulation (SRD) to deliver low amplitude current pulses to the primary somatosensory cortex (SI) of rats to activate and enhance an interhemispheric cortical pathway. Despite the existence of an interhemispheric connection between similar forelimb representations of SI cortices, forelimb cortical neurons respond only to input from the contralateral (opposite side) forelimb and not to input from the ipsilateral (same side) forelimb. Given the existence of this interhemispheric pathway we have been able to strengthen/enhance the pathway through chronic intracortical microstimulation (ICMS) in previous acute experiments of anesthetized rats. In these acute experiments strengthening the interhemispheric pathway also brings about functional reorganization whereby cortical neurons in forelimb cortex respond to new input from the ipsilateral forelimb. Having the ability to modify cortical circuitry will have important applications in stroke patients and could serve to rescue and/or enhance responsiveness in surviving cells around the stroke region. Also, the ability to induce functional reorganization within the deafferented cortical map, which follows limb amputation, will also provide a vehicle for modulating maladaptive cortical reorganization often associated with phantom limb pain leading to reduced pain. In order to increase our understanding of the observed functional reorganization and enhanced pathway, we need to be able to test these observations in awake and behaving animals and eventually study how these changes persist over a prolonged period of time. To accomplish this a system was needed to allow simultaneous recording and stimulation in awake rats. However, no such commercial or research system exists that meets all requirements for such an experiment. In this project we describe the (1) system design, (2) system testing, (3) system evaluation, and (4) system implementation of a wireless simultaneous stimulation-and-recording device (SRD) to be used to modulate cortical circuits in an awake rodent animal model

Outan: An On-Head System for Driving micro-LED Arrays Implanted in Freely Moving Mice

In the intact brain, neural activity can be recorded using sensing electrodes and manipulated using light stimulation. Silicon probes with integrated electrodes and micro-LEDs enable the detection and control of neural activity using a single implanted device. Miniaturized solutions for recordings from small freely moving animals are commercially available, but stimulation is driven by large, stationary current sources. We designed and fabricated a current source chip and integrated it into a headstage PCB that weighs 1.37 g. The proposed system provides 10-bit resolution current control for 32 channels, driving micro-LEDs with up to 4.6 V and sourcing up to 0.9 mA at a refresh rate of 5 kHz per channel. When calibrated against a micro-LED probe, the system allows linear control of light output power, up to 10 micro-W per micro-LED. To demonstrate the capabilities of the system, synthetic sequences of neural spiking activity were produced by driving multiple micro-LEDs implanted in the hippocampal CA1 area of a freely moving mouse. The high spatial, temporal, and amplitude resolution of the system provides a rich variety of stimulation patterns. Combined with commercially available sampling headstages, the system provides an easy to use back-end, fully utilizing the bi-directional potential of integrated opto-electronic arrays.Comment: 11 pages, 9 figure

Improving Neural Recording Technology at the Nanoscale

University of Minnesota Ph.D. dissertation. august 2011. Major: Biomedical Engineering. Advisor: A Redish. 1 computer file (PDF); xviii, 119 pages.Neural recording electrodes are widely used to study normal brain function (e.g., learning, memory, and sensation) and abnormal brain function (e.g., epilepsy, addiction, and depression) and to interface with the nervous system for neuroprosthetics. With a deep understanding of the electrode interface at the nanoscale and the use of novel nanofabrication processes, neural recording electrodes can be designed that surpass previous limits and enable new applications. In this thesis, I will discuss three projects. In the first project, we created an ultralow-impedance electrode coating by controlling the nanoscale texture of electrode surfaces. In the second project, we developed a novel nanowire electrode for long-term intracellular recordings. In the third project, we created a means of wirelessly communicating with ultra-miniature, implantable neural recording devices. The techniques developed for these projects offer significant improvements in the quality of neural recordings. They can also open the door to new types of experiments and medical devices, which can lead to a better understanding of the brain and can enable novel and improved tools for clinical applications

Wireless tools for neuromodulation

Epilepsy is a spectrum of diseases characterized by recurrent seizures. It is estimated that 50 million individuals worldwide are affected and 30% of cases are medically refractory or drug resistant. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) are the only FDA approved device based therapies. Neither therapy offers complete seizure freedom in a majority of users. Novel methodologies are needed to better understand mechanisms and chronic nature of epilepsy. Most tools for neuromodulation in rodents are tethered. The few wireless devices use batteries or are inductively powered. The tether restricts movement, limits behavioral tests, and increases the risk of infection. Batteries are large and heavy with a limited lifetime. Inductive powering suffers from rapid efficiency drops due to alignment mismatches and increased distances. Miniature wireless tools that offer behavioral freedom, data acquisition, and stimulation are needed. This dissertation presents a platform of electrical, optical and radiofrequency (RF) technologies for device based neuromodulation. The platform can be configured with features including: two channels differential recording, one channel electrical stimulation, and one channel optical stimulation. Typical device operation consumes less than 4 mW. The analog front end has a bandwidth of 0.7 Hz - 1 kHz and a gain of 60 dB, and the constant current driver provides biphasic electrical stimulation. For use with optogenetics, the deep brain optical stimulation module provides 27 mW/mm2 of blue light (473 nm) with 21.01 mA. Pairing of stimulating and recording technologies allows closed-loop operation. A wireless powering cage is designed using the resonantly coupled filter energy transfer (RCFET) methodology. RF energy is coupled through magnetic resonance. The cage has a PTE ranging from 1.8-6.28% for a volume of 11 x 11 x 11 in3. This is sufficient to chronically house subjects. The technologies are validated through various in vivo preparations. The tools are designed to study epilepsy, SUDEP, and urinary incontinence but can be configured for other studies. The broad application of these technologies can enable the scientific community to better study chronic diseases and closed-loop therapies