Pedram Mohseni - US grants

[unreadable] DESCRIPTION (provided by applicant): In this Cutting-Edge Basic Research Award (CEBRA) proposal, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate to develop an ultra-small, implantable device for wireless neural monitoring and stimulation in awake animals. This device will advance the investigation of biologic mechanisms of drug addiction by extending recent innovations in fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM). By virtue of chemically selective recording with sub-second temporal resolution at a micron-sized probe, FSCV at a CFM is recognized as state-of-the-art for neurotransmitter monitoring. In the last decade, great strides have been made applying FSCV at a CFM to ambulatory rats for studying the role of phasic dopaminergic transmission in goal-directed behaviors, particularly with regard to cocaine reinforcement, and combining chemical and electrical measurements at the same probe for quantifying postsynaptic effects of brain dopamine dynamics. By extending the already attractive analytical attributes of FSCV at a CFM on several fronts, we firmly believe that the device proposed here meets criteria for the CEBRA program. Proposed developments include: (1) replacing the hardwired connection with a digital telemetry link; (2) replacing the external stimulus generator with an on-chip component; (3) significantly reducing overall dimensions, weight, and power consumption; (4) supporting multiple, independently configurable channels for FSCV, electrophysiology, and combined measurements. Collectively, these advances address concerns related to the current use of "large" head-mounted devices as well as tethering animals to equipment, which may alter behavior, act as a noise source, and preclude measurements in smaller, but valuable animal models such as transgenic mice. Moreover, multiple data channels afford the enticing prospect of marrying two powerful technologies for neural monitoring, FSCV at a CFM and multielectrode array single-unit recording, to assess complex circuit-level control of drug-related behavior on an integrative level. The three specific aims are to: (1) using very-large-scale-integration techniques in standard complementary-metal-oxide-semiconductor technology, develop a 16-channel device supporting voltammetry, electrophysiology, and combined measurements, as well as electrical stimulation; (2) test and characterize the device on several levels, including benchtop engineering assessment, in vitro calibration with flow injection analysis, and anesthetized and awake rats; (3) showcase device features in two pilot applications, FSCV dopamine measurements in the awake rat during high-dose administration of the psychostimulant amphetamine and single-unit recording with microwire bundles chronically implanted in a transgenic mouse model. By developing the first wireless integrated circuit supporting chemical and electrical sensing and electrical stimulation, this CEBRA proposal will address key limitations of existing instrumentation for FSCV at a CFM and advance this already powerful neural monitoring technique. PUBLIC HEALTH RELEVANCE: This project will develop a miniaturized wireless device supporting chemical and electrical recording as well as electrical stimulation in the brain of small laboratory animals. This device will advance basic science research investigating neural mechanisms of drug addiction. [unreadable] [unreadable] [unreadable]

This award supports a collaborative effort between PIs at Case Western Research University and Illinois State University to develop new instrumentation in support of neurobiology research. Monitoring neural activity in awake laboratory animals has proven to be a powerful tool for investigating how the brain ultimately controls behavior. Driving this approach are recent advances in microsensors for probing brain function very quickly and on microscopic scales as the behavior occurs. However, neuromonitoring at implanted microsensors remains particularly challenging, as the majority of available measurement systems are hampered by large size, high power requirements, and wired connections between animal and recording equipment. These technological limitations will be overcome by developing the next generation of ultra-small, low-power wireless devices for neurochemical and neuroelectrical monitoring and for neuromodulation using electrical stimulation in freely behaving animals.

State-of-the-art engineering methods called very-large-scale-integration (VLSI) and complementary-metal-oxide-semiconductor (CMOS) technologies will be employed to manufacture the proposed devices. This fabrication process will result in multichannel, multifunctional, wireless devices whose size and weight are suitable for implantation, freeing the animal from exposed, bulky instruments and cables that alter behavior, generate noise artifacts during movement, and limit experimental design. Power consumption will be dramatically reduced as well by the fabrication strategy, enabling the use of miniature batteries as a power source during operation. Once constructed, assembled and packaged into a chronically implantable form, and tested, these devices will be used in animal experiments to investigate the role of dopamine in motivated behavior. This important brain neurotransmitter has been implicated in responding to rewards or the cues that predict rewards, and in altering the long-term functioning of brain circuits involved in motivation.

By overcoming technical limitations of existing instrumentation, these new miniature wireless devices for will advance neurobiological investigations in the primary animal models used for the study of brain-behavior relationships and will extend this line of research to smaller animals whose size has previously limited inquiry. Such devices will ultimately be commercially viable driven by the needs of the larger neuroscience community. Through dissemination of these sensors and collaboration with users the sensor platform can evolve to meet emerging research needs. Additionally, this project will not only train undergraduate and graduate students in both science and engineering in the respective laboratories of the investigators, but it will also foster interdisciplinary training as the two laboratories will extensively and closely work together to develop and apply the new instrumentation. In a broader vein, the award will lead to establishing new working relationship between neurobiologists and engineers in support of both research and education.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).
Understanding the inner workings of the brain remains one of the last frontiers in all of
neurobiology. Large gaps in our knowledge exist, because of the inherent difficulty in studying brain function. Indeed, this organ, which contains trillions of neurons, intricately interconnected, is decidedly complex. The brain also fundamentally works by a combination of fast information- carrying electrical signals called action potentials, and chemical neurotransmitters acting on fast time scales in microscopic conjunctions between neurons called synapses. It is thus not surprising that the development of new techniques for monitoring brain activity is critical to the continued success in advancing the field of neurobiology. This CAREER project focuses on new instrumentation supporting microsensor measurements for the study of the brain . Great strides have been made over the last few years in developing multisite microsensors for monitoring both the chemical and electrical signals in the brain. In sharp contrast, development of instruments supporting these powerful new microsensors has lagged behind considerably. The two main technical limitations of existing devices are large size and high power needs.
Specifically in this CAREER project, a miniaturized low-power device will be developed to support neurobiological experiments in small laboratory animals. This new instrument will simultaneously record from multiple microsensors measuring neurotransmitters and action potentials in real time, i.e., as these signals happen, during behavior. A state-of-the-art engineering method called very-large-scale-integration (VLSI) will be used to fabricate the device, roughly the size of a common cold capsule. Because of its small size and low power consumption, miniature batteries can serve as the power supply. To permit natural behavior by the animal during experiments, this device will be safely implanted under the skin and will transmit recorded brain signals wirelessly using an ultra wideband (UWB) telemetry link. The new device will be further tested in animal experiments investigating the role of dopamine in goal-directed behavior. This important neurotransmitter is critically involved in the brain functions of motivation and learning, yet its precise role has eluded definition despite decades of extensive study.
In the short-term, project information such as system architecture, design schematics,
performance assessment results, and neurobiological findings will be disseminated through publications/presentations in journals/conferences that target engineering and neuroscience communities. In the long-term, the PI will seek to make the device available to qualified researchers in the scientific community through commercialization. Such devices should ultimately be commercially viable, due to the interest they will receive from a broad base of investigators working in the neuroscience fields, but also because they can evolve to accommodate additional sensor technologies that emerge in the future.
As part of the educational plan of this CAREER project, undergraduate and graduate
students will be trained to conduct interdisciplinary research in engineering and science.
Moreover, this CAREER project recognizes the importance of an integrated approach to value creation, spanning the continuum of innovative ideas to start-up enterprise creation. Therefore, a centerpiece of its educational effort is to provide engineering students with a mechanism to learn the fundamentals of technology opportunity assessment. This will provide an invaluable opportunity for the students to thoroughly assess their research ideas from both the technological feasibility and commercialization viability standpoints. They are expected to learn that there are not many 'absolute truths', but numerous best practices and benchmarks that can help the entrepreneurial engineer.

DESCRIPTION (provided by applicant): Neurochemical Pattern Generation with Smart Electrical Stimulation Pedram Mohseni1 and Paul A. Garris2 1 Case Western Reserve University 2 Illinois State University In this Small Research Grant (Parent R03) proposal, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate to develop the next generation of wireless neurochemical sensing integrated circuits (ICs) by incorporating the additional functionality of chemical pattern generation with electrical stimulation. Real-time chemical microsensors hold great promise for investigating brain function and pathology. Their defining analytical characteristic is the capability to interrogate the activity of a single neuron type, by virtue of identifying the released neurotransmitter. Perhaps the most monumental achievement to date with this measurement modality is dopamine monitoring with subsecond temporal resolution at a brain-implanted, micron-sized probe during goal-directed behavior using fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM). Great strides have also been made in wireless ICs supporting this ground-breaking technology. Adding neurochemical pattern generation to extant sensing- only ICs substantively expands the utility of chemical sensing ICs, ultimately laying foundational work for future closed-loop devices. We submit that extending passive chemical measurements to the realm of high-precision, dynamic chemical control is consistent with the R03 scope of development of new research technology. The two specific aims of this proposal are to: (1) develop a neurochemical sensing IC supporting FSCV at a CFM with integrated electrical stimulation capability for neurochemical pattern generation; (2) test and characterize the IC. The engineering innovation is that IC architecture will precisely synchronize the timing of voltammetry and stimulus current generation to avoid temporal overlap and minimize the possibility of stimulus artifacts interfering with FSCV recordings, whenever the stimulator is activated via an external trigger. In addition to benchtop engineering assessment, functionality will be tested in vitro with flow injection analysis and in vivo with anesthetized rats, using diverse neurochemical patterns as templates. The conceptual innovation is transfer function-driven neurochemical pattern generation and subsequent verification of the fidelity of the generated profile by the stimulating-sensing IC. Selection of dopamine as the test analyte in this work is very judicious. Involved in important brain functions and debilitating neuropathologies, dopamine is amenable to FSCV detection, is the most studied neurotransmitter using microsensors, and has well-established transfer functions suitable for time- and amplitude-based pattern generation. Transferable to other neurotransmitters, microsensor strategies, and applications, we emphasize the general versatility of the proposed IC as a more wide-ranging device beyond these development tests with dopamine. Thus, in the long term, the proposed IC will provide an innovative and powerful addition to the neurobiology toolkit for investigating the neural underpinnings of behavior and disease symptoms, and could have additional clinical bearing by providing the framework for ultimately developing new neuromodulation devices for many human neuropathologies. PUBLIC HEALTH RELEVANCE: Neurochemical Pattern Generation with Smart Electrical Stimulation Pedram Mohseni1 and Paul A. Garris2 1 Case Western Reserve University 2 Illinois State University Relevance to Public Health: This project will develop an advanced integrated circuit for measuring and controlling neurotransmitter levels in the brain of laboratory animals. This technology will advance basic biomedical research and the development of neuroprostheses for treating human neuropathologies.

DESCRIPTION (provided by applicant): A Closed-Loop Microsystem for Neuromodulation of Reward Circuitry Pedram Mohseni1 and Paul A. Garris2 1 Case Western Reserve University 2 Illinois State University While great strides have been made in our understanding of the basic neurobiology of addiction, many outstanding questions still remain. There is also a grave necessity to develop new treatments, as current options exhibit high recidivism. For good reason, particular attention has focused on the role of dopamine neurons in compulsory drug taking and addictive behavior. One emergent hypothesis is that abused substances usurp reward-processing circuits by hyperactivating phasic dopamine signaling, which leads to altered synaptic plasticity and the overvaluation of cues predicting drug availability. Driving the pursuit of this potentially unifying hypothesis are recent technical advances in microsensors, transgenic animals, and optogenetics. Collectively, these powerful approaches permit high-fidelity dopamine monitoring and ultra-fine molecular control over dopamine neurons and their targets. However, there is a dearth in the current state of technology for dynamic, state-dependent control. Such technology would actively link neuromonitoring and neurostimulation in closed-loop manner to permit extant neural activity and a priori criteria determine the desired outcome. The long-term objective of this research is thus to realize closed-loop devices supporting research in drug abuse and clinical therapies for treating addiction. To this end, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate on the present Cutting-Edge Basic Research Awards (CEBRA) proposal to develop a computation and control integrated circuit (IC) for such linking of neuromonitoring and neurostimulation. This IC will incorporate fast- scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM), a state-of-the-art neuromonitoring technique with exquisite temporal, spatial, and chemical resolution, and principal component regression (PCR), a chemometrics approach for resolving single analytes from complex neurochemical profiles. The three specific aims are to: (1) develop a sensing, computation, and control IC supporting FSCV at a CFM; (2) test and characterize the IC; (3) pilot dopamine-sensing-based feedback control with the IC for neutralizing activated phasic dopamine signaling. We submit that developing this IC is a transformative step for addiction research, by laying the foundation for novel implantable microsystems supporting applications in biomedical research and ultimately for smart therapeutic neuroprostheses in the clinical realm. Feedback control based on the ability of FSCV and PCR to interrogate the neurochemical activity of a single neuron-type also represents a significant technical advance toward the development of closed-loop devices. This research is additionally innovative, because an IC for neurochemical feedback control has not been realized, and the proposed IC will be capable of modulating both static and dynamic neurochemical activity and accommodating a broad repertoire of analytes important in addiction. This project will also train one doctoral student each in the fields of electrical engineering-computer science and neurobiology-analytical chemistry during its two-year duration.