Mesut Sahin - US grants

DESCRIPTION (provided by applicant): Electrical activation of the peripheral and central nervous system has been investigated for treatment of neural disorders for many decades and a number of devices have already moved into the clinical phase with success. Cochlear prostheses, sacral root stimulation for bladder and bowel control in spinal cord injury, and vagus nerve stimulation in epilepsy are some of the well-known examples of such devices that are being implanted in thousands of patients every year. A major obstacle that has been preventing or otherwise impeding the implementation of many other neural prosthetic devices is the mechanical mismatch of the stimulation electrodes with the neural tissue and the tethering of the wire connections that result in tissue trauma. Electrical stimulators that are remotely controllable with no interconnects and sufficiently small so that a good spatial selectivity is achieved with minimal replacement of the neural tissue are greatly needed. We propose to develop very small (approximately 200 um) photovoltaic elements that can be implanted into the spinal cord or the brain cortex and activated from outside the dura mater through the neural tissue using near infrared laser beams. The geometry and the interface properties of these floating light activated micro electrical stimulators (FLAMES) will be optimized for maximum transfer of energy into the tissue while minimizing the device size. Devices with various sizes will be designed to meet the requirements of different neural stimulation applications. The stimulation properties of the optimized FLAMES will be tested in medium (agar/saline) and in vivo (rat). Future designs will include advanced versions of the FLAMES that are tuned for different wavelengths of light for selective activation. The silicon technology of optical communication has already been developed and studied extensively and can be modified for neural stimulation with reasonable amount of research. Some of the immediate applications include but not limited to visual and auditory cortex stimulation for substitution of these senses, and micro-stimulation of the lumbo-sacral cord for bladder control and locomotion in spinal cord injury.

[unreadable] DESCRIPTION (provided by applicant): Following spinal cord damage from trauma or disease, skeletal muscles distal to the point of damage become paralyzed due to disrupted neural conduction. In high-level spinal cord injury (quadriplegia), there is a great need for a method that can substitute the voluntary control for self-mobility, computer access, or environmental control. [unreadable] Current Solution: The 'brain-computer interfaces' have been developed to extract this volitional control information from the motor cortex. The cortical signals are recorded with microelectrode/microwire arrays implanted and interpreted with advanced signal processing algorithms? Short Comings: [unreadable] However, there remain two main problems to be solved that are inherent to the cortical approach. First, with the cortical implantation of the electrodes the population of neurons recorded from changes day to day, thus requiring a training session for the signal processor every day. Second, the number of good electrodes that actually record activity in each array (yield) is very low and all the signals are lost after sometime. Our Proposal: The alternative method proposed here is to extract the volitional motor signals from the proximal spinal cord that is still intact above the site of injury. The distal portions of the severed axons go through Wallerian degeneration. However, the proximal part of the axon continues to function years after the injury since its connection to the cell body in the cortex is still intact. A Spinal Cord- [unreadable] Computer Interface (SCCI) can have information flow rates that are much higher than that of brain-computer interfaces since a majority of the recording electrodes will be functional (see background and significance). The stability of the recordings will also be improved due to the neuroanatomy of the spinal cord. These improvements are crucially needed before such neural interfaces can move into the clinical phase to help individuals with high level spinal cord injury. Significance: Each year about 15,000 spinal cord injuries occur in the US. Majority of these cases survive and need help for their basic needs. The average life expectance of this population is 40 years. Any tool or instrument that can provide them with self-mobility, environmental control, and computer access is priceless. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Electrical activation of central and peripheral nervous system has been investigated for treatment of neural disorders for many decades and a number of devices have already moved into clinical phase with success. As we learn more about the neural circuitry in the spinal cord and the brain, new applications are targeting more specific circuits in the central nervous system and thus requiring much more localized means of electrical stimulation. Some example neural prosthetic applications are microstimulation of the spinal cord to restore locomotion or micturition in spinal cord injury, microstimulation of the cochlear nucleus, midbrain, or auditory cortex to restore hearing, and stimulation of the visual cortex in the blind subjects. In order to satisfy the demand in these applications, microelectrode arrays have been developed over the past decade. However, the current implantable microelectrode arrays use wired interconnects for applying the electric stimulations. These fine wires are a major source of device failure since they are the first to break in chronic implants. Moreover, the brain and the spinal cord experience significant amounts of translation inside the skull and the spinal column. Movement of the tissue around these rigid microelectrodes causes significant shear forces due to the mechanical mismatch between the electrode material and the neural tissue. These shear forces, exacerbated by the tethering forces of the wired interconnects, result in a thick encapsulation tissue layer that forms around the electrode. The mechanical mismatch and tethering forces not only cause cellular damage but also the loss of specificity of the stimulations because of this barrier that forms between the electrode and the targeted neurons. We propose a floating micro-electrical device as an alternative technology to micro-electrode arrays. The proposed micro-stimulators will be energized with an infrared light beam through an optical fiber located just outside the dura mater. The floating microstimulators will be free from any interconnects and tethering forces. Because the overall device size is much smaller, the insult to the neural tissue will also be much reduced. The main objective of this proposal is to develop and characterize these floating light activated micro-electrical stimulators (FLAMES). This technology can be instrumental in translation of many neural prosthetic approaches into the clinic, particularly those that involve microstimulation of the spinal cord. PUBLIC HEALTH RELEVANCE: The main objective of this proposal is to develop and test wireless microstimulators (<300 micron) for electrical activation of the central nervous system in neural prosthetic applications, such as those developed for individuals with spinal cord injury to regain some vital functions. We believe that these wireless micro-stimulators will eliminate the problems encountered with current microelectrode technology and thus enable the transfer of many neural prosthetic projects into the clinic.

DESCRIPTION (provided by applicant): Following spinal cord damage from trauma or disease, skeletal muscles distal to the point of damage become paralyzed due to disrupted neural conduction. In high-level spinal cord injury/damage, there is a great need for a method that can substitute for the voluntary control in order to regain self-mobility, environmental control, and computer access. Each year about 15,000 spinal cord injuries occur in the US. Majority of these cases survive and depend on others for their basic needs. The average life expectancy of this population is 40 years. Current Solution: 'Brain-Computer Interfaces' have been developed to extract the volitional control information from various brain cortices. Activity of single neurons is recorded with micro electrode/wire arrays implanted and interpreted with advanced signal processing algorithms. Shortcomings: There remain two major problems after many years of research that are inherent to single spike recording method from the cerebral cortex. First, the population of neurons recorded from changes day to day, thus requiring a training session for the signal processing algorithm before each use. The number of good electrodes that record neural activity in an array (yield) is low and the single spike signals are lost completely after sometime due to glial cell growth around the electrode. Second, the information provided by each neuron is very noisy. A very large number of neurons need to be sampled to achieve stable and finely tunable command signals. This requires many electrode arrays implanted in multiple brain areas. Our Proposal: The alternative method proposed here is to extract the volitional motor signals from the proximal spinal cord that is still intact above the site of injury and use the population activity of the axons in the motor tracts rather than single spikes. The distal portions of the severed motor axons go through Wallerian degeneration. However, the proximal part of the axon continues to function years after injury since its connection to the cell body in the brain remains intact. Spinal cord approach has at least two important advantages. First, the recorded neural signals will be strongly coupled to the motor function due to closeness of the spinal cord to the motor apparatus in the signal path. Second, the neural recordings will be much more stable because the method relies on the population activity rather than single spikes.

Project Summary: Decoding the electrical and chemical signals in neural circuits is essential to understand the communication between different brain regions and how these neural networks give rise to a particular function at the level of the whole organism. Therefore, recording or modulating neural activity with high spatiotemporal resolution is necessary. Ideally it is desired to achieve this noninvasively for long-term translation of these technologies to behaving animals and eventually to humans. The general tradeoff in neural stimulation and recording technologies is between spatial resolution and the size of the region covered by the recording/stimulation sites. Noninvasive technologies offer stimulation and recording capability in a large brain area, but suffer from low spatial and temporal resolution and limited depth. Invasive technologies provide improved spatial and temporal resolution to interrogate the activity of a single neuron, but fail to scale beyond tens or hundreds of neurons. In this project, we aim to develop a tool that is capable of ultrasonic neural stimulation in a 3D volume by dynamic beamforming and real-time recording of hemodynamic activity in response to stimulation by volumetric photoacoustic imaging. The described technology will equip the neuroscience community with a research tool to further explore the emerging field of ultrasonic neural stimulation and to monitor metabolic/hemodynamic responses in awake/behaving animals with real-time photoacoustic imaging. Using high-frequency ultrasound enables micrometer-millisecond spatiotemporal resolution for stimulation. Using a fast-repeating laser source, the same can be achieved for monitoring the activity. Use of a 2D transducer array enables combination of ultrasound neuromodulation and photoacoustic imaging in the same device because a target site in a 3D volume can be stimulated and hemodynamic response can be monitored by photoacoustic imaging at all other points in the overall 3D volume. 2D transducer arrays that are commonly available can stimulate a point on a plane and reconstruct the image of the same plane only, which is very restricting. The specific objective of this exploratory study is to develop a 10-MHz, 16x16-element, 2D CMUT array with integrated electronics and optics that is capable of ultrasonic neural stimulation in a 20x20x20-mm3 volume by dynamic transmit beamforming and real-time recording of hemodynamic activity in response to stimulation by volumetric photoacoustic imaging. To fulfill this objective, we have identified the following specific aims: Specific Aim 1: Design and implement a 10-MHz, 16x16-element 2D wideband (>100% fractional band- width, i.e. from 5 MHz to 15 MHz) CMUT array with through-wafer interconnects. Specific Aim 2: Design and implement a pixel-pitch-matched integrated circuit with 16x16 channels capable of phased array transmission for ultrasound neural stimulation and receiving from all elements in a time-multiplexed fashion for photoacoustic imaging. Specific Aim 3: Validate the prototype in-vivo in anesthetized and behaving animals.

Title: Underlying Mechanisms of Cerebellar tDCS Abstract Common symptoms reported with schizophrenia and autism spectrum disorders include poor motor coordination, a deficiency also manifested in cerebellar injuries. Conversely, cerebellar injury patients often suffer from cognitive deficits, including impaired timing, attention, memory and language. Interestingly, changes in cerebellar anatomy are among the most reliable indicators of autism. Therefore, interventions targeting the cerebellum are emerging as an alternative strategy to treat cognitive disorders. Transcranial direct current stimulation (tDCS) of the cerebellum, an easy-to-apply, noninvasive, and safe intervention, has seen a surge of clinical reports in recent years suggesting that it improves motor learning, cognitive and emotional processes. However, few animal studies have investigated the electrophysiological mechanisms underlying the beneficial effects of tDCS on the cerebellar function. The primary objective of the current proposal is to generate the animal experimental data essential to identify the synaptic, cellular, and network level mechanisms by which tDCS impacts the cerebellar function. Classical trace conditioning of the eyeblink response will be used as a model cognitive task that requires coordination of the cerebellum and the prefrontal cortex. The neural mechanisms of how cerebellar tDCS modulates the trace eyeblink conditioning will be investigated in behaving animals. The fundamental knowledge gained through this investigation can be extrapolated to other cognitive and psychiatric disorders that involve the cerebellum and their treatment with tDCS.

Electrical and Ultrasonic Modulation of Lateral Cerebellar Nucleus Abstract The cerebellum has been overlooked for its potential for neuromodulation for decades. Traditionally thought of as critical for motor coordination, anatomical, clinical and imaging evidence now indicate that the cerebellum also has central roles in cognition and emotion, and that cerebellar dysfunction impacts these functions. Consistent with these findings of cerebellar involvement in motor and non-motor functions, projections from the cerebellar nuclei (CN) target, via the thalamus, both motor and non-motor areas of the cortex and the basal ganglia. Thus, modulation of cerebellar outputs should be able to affect areas throughout the forebrain, and therefore has the potential to treat numerous disorders. Gap in Prior Research: Stimulation of the cerebellar cortex produced mixed results in clinical trials, almost fifty years ago, and discouraged further attempts. Whereas stimulation of the CN, where the efferent axons from the cerebellar cortex converge, has recently been shown to have clinical benefits in patients and animal models. However, direct stimulation of the CN requires surgical implantation of deep brain stimulation leads into the cerebellum. Novel Solution by Current Technology: Focused Ultrasound (FUS) Stimulation and Transcranial Electrical Stimulation (tES) are two non-invasive brain stimulation methods that have great potentials for clinical applications and provide ideal tools for cerebellar stimulation. FUS has the potential to stimulate the CN directly with its superior focusing and steering capabilities. tES would be the preferred method for stimulation of the cerebellar cortex due to its ease of application and the inexpensive equipment involved. Cerebellar stimulation with ultrasound has not been reported by any other group to date and tES for the cerebellum is severely lacking animal data for understanding of underlying mechanisms. Advances in the past two decades on functional imaging and anatomical mapping provide an improved understanding of the circuitry of the cerebellar cortex and its connections to the cerebellar nuclei. Thus, we have novel tools and the knowledge base to develop protocols for effective modulation of the cerebellar outputs. Current Proposal: The overarching goal of this proposal is to develop a non-invasive and effective modulation paradigm for one of the cerebellar nuclei, the lateral cerebellar nucleus (LCN). Optimal stimulation parameters will be investigated for selective stimulation of neuronal subtypes in the LCN. Novel mechanisms of neuromodulation will be investigated that can emerge from combined application of the electrical and ultrasonic methods. The modulation paradigms developed in this project should generalize to numerous motor and non- motor brain functions in which the cerebellum is involved.