Marc A. Sommer, PhD - US grants

DESCRIPTION (provided by applicant): The study of neuronal circuits in the brain is essential for determining how the visual system functions and how it becomes impaired in disease states. The long-term goal of this application is to determine how structures in the primate brain cooperate to subserve vision and control eye movements. One prominent visuosaccadic region of cortex is the frontal eye field (FEF), which projects subcortically to contribute to saccade generation. Yet the FEF also receives ascending input from pathways originating in subcortical structures including the superior colliculus (SC), the substantia nigra pars reticulata (SNr), and the dentate nucleus (DN). What are the functions of these ascending pathways? We showed previously that the SC-FEF pathway conveys feedback about saccades (corollary discharge), but relatively little is known about the SNr-FEF and DN-FEF pathways. The SNr is an output node of the basal ganglia, a system necessary for making voluntary movements, while the DN is an output node of the cerebellum, which is more critical for making visually-guided movements. Hence we predict that the SNr-FEF and DN-FEF pathways play differential roles related to making voluntary and visually-guided saccades. The overall goal of this proposal is to determine the functions of the SNr-FEF and DN-FEF pathways. The first specific aim is to record from identified neurons throughout each pathway and determine the signals they encode. We hypothesize that the SNr-FEF and DN-FEF pathways convey activity preferentially correlated with voluntary and visually-guided saccades, respectively. The second aim is to reversibly inactivate each pathway and infer its behavioral function by studying saccadic deficits. We hypothesize that the SNr-FEF pathway contributes to generating or monitoring voluntary saccades while the DN-FEF pathway contributes to generating or monitoring visually-guided saccades. The third aim is to reversibly inactivate each pathway and infer its circuit-level function by studying changes in FEF activity. We hypothesize that the SNr-FEF pathway causes FEF activity accompanying voluntary saccades while the DN-FEF pathway causes FEF activity accompanying visually-guided saccades. The overall result of this study, taken together with our previous work, will be to establish the functions of three parallel pathways ascending to the FEF.

PI: Bohs, Laurence N. and Caves, Kevin
Proposal Number: 0967221

This proposal requests support for the Devices for People with Disabilities program in the Department of Biomedical Engineering at Duke University, in which students design and build custom devices for people with disabilities. The main objectives of this program are to enhance engineering education, improve the quality of life of persons with disabilities, and serve the community. Students will participate in a creative, real-world design experience as they develop one-of-a-kind assistive, recreational, and therapeutic devices. In the process, they will learn formal engineering design methods, gain exposure to ethical issues in engineering, improve communication skills and raise their awareness of disability issues 70 projects will be designed and delivered with support from this grant, involving approximately 250 student designers, a substantial annual increase over the past grant period. The client feedback process initiated during the last three years will be expanded to include quantitative measures based on the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST). New assessment tools will be developed to maximize the impact of student experiences and to improve feedback between students and clients. Students will create professional-quality videos of their projects, which will be incorporated into the course web site to provide a thorough demonstration of project operation and to increase dissemination of their designs.
Intellectual Merit of the Proposed Activity
The PI and course instructors have over 40 combined years of experience in rehabilitation engineering and teaching student design. During the past 13 years, they have supervised over 250 students in completing more than 100 projects for clients with disabilities in the Raleigh-Durham regional area. Strengths of this program include the record of success in delivering the proposed number of projects, and the focus on follow-up support to keep devices in service after delivery. Prototyping facilities at Duke University have improved substantially during the past grant period, with a new student machine shop and full-time machinist dedicated to student projects in the Pratt School of Engineering. These facilities will enhance the students' hands-on experiences, giving them greater ownership of their projects and applied knowledge on methods of fabrication. Outcomes from the proposed projects will be novel devices meeting needs of persons with disabilities not met by commercial products. The overall program will establish and strengthen ties between the university, the local community, and individuals working in the fields of assistive technology and rehabilitation both regionally and nationally.
Broader Impacts of the Proposed Activity
The proposed activity will train undergraduate students in a formal design procedure as applied to real-world, open-ended design problems. Students will incorporate universal design methods wherever possible to maximize the applicability of their designs. Persons with disabilities will be integrated into the activities both by being clients for projects, and also by sharing their experiences with students during in-class discussions. Students will disseminate the results of their work to the larger community through: 1) presentations at the annual RESNA conference; 2) presentations at the regional Assistive Technology Expo conference; and 3) project descriptions in the annual NSF publication on Student Design Projects to Aid Persons with Disabilities. In addition, students building projects for local partner OE Enterprises will enter the design competition for the NISH National Scholar Award for Workplace Innovation and Design. The proposed work will benefit society by providing custom devices for the project clients, creating and disseminating designs applicable to other persons with disabilities, and by inspiring students to serve humanity in their careers. Student projects will be selected from numerous contacts in the Durham/Raleigh/Chapel Hill area, including occupational and physical therapists, special education teachers, medical doctors, and local rehabilitation centers and community organizations. Because projects will be drawn from many sources, the client pool will encompass a broad range of persons with disabilities. A particular focus in this grant period will be to work with therapists in the Durham schools to identify minority students with disabilities who will benefit from custom assistive technology.

DESCRIPTION (provided by applicant): Transcranial magnetic stimulation (TMS) is a non-invasive method for stimulating the human brain. It has contributed greatly to our understanding of normal brain function and shows promise in therapies for psychiatric and neurological disorders. Exactly what TMS does to neuronal activity, however, remains unknown. We will apply single pulses of TMS while recording from single neurons in behaving non-human primates. Our TMS methods will correspond to those used in humans and will be easily adoptable by any primate neurophysiology laboratory. A team of researchers will design custom TMS coils to direct the focus of stimulation to precise locations of cerebral cortex, innovative electronics to permit neuronal recordings within 1 ms after TMS pulses, and controlled visual- oculomotor tasks to allow systematic variation of behavioral and thus neuronal state. We will record from single neurons and field potentials at both the site of stimulation and at distant but monosynaptically connected sites. The end result of our work will be to discover how TMS influences the brain at the level of single neurons and simple circuits. Implications will include improved, physiologically-guided TMS protocols for human basic research studies and therapeutic applications. PUBLIC HEALTH RELEVANCE: Non-invasive stimulation of the human brain using magnetic pulses near the head (transcranial magnetic stimulation or TMS) is a valuable tool for studying vision, cognition, and movement, but exactly how TMS affects brain activity is an open question. The proposed work will answer this question by recording from single neurons in the brains of behaving primates during TMS. The project is a technical challenge but its feasibility has been confirmed, its inherent risks will be managed by a team of wide-ranging experts, and its end result will be transformative: data on the physiological mechanisms of TMS will improve basic research on the human brain and help clinicians fulfill the promise of TMS as an effective therapeutic intervention.

DESCRIPTION (provided by applicant): The cerebellum is a crucial brain structure for the control of movement. Recent data from lesion studies, neuroimaging, and neuroanatomy also implicate its lateral portion in non-motor functions, including cognitive processes. The lateral cerebellum may participate in such functions through its closed-loop connections with prefrontal and parietal cerebral cortex. A critical segment of these loops involves circuitry within the laterl cerebellum itself, extending through its cortical mantle to the dentate nucleus. Essentially nothing is known about non-motor signals in these intracerebellar circuits. We will record the signals directly in macaque monkeys that perform tasks involving cognitive demands such as self-timing of behavior. The studies are challenging because the cerebellar cortex, even just its lateral portion, is vast. Moreover it is highly foliated and deep in the brain, making it difficultto survey neurophysiologically. Efficient and systematic neurophysiology can now be achieved, however, based on recently available neuroanatomical maps that detail the motor and non- motor domains of cerebellar cortex. Our first aim is to record from neurons in two restricted zones of lateral cerebellar cortex known to be functionally connected with prefrontal and parietal cerebral cortex. The recording zones will be targeted using structural MRIs of each monkey's cerebellum referenced to published connectivity maps. During recordings, we will use physiological criteria to identify signals conveyed at three functional levels: cerebellar cortical output (Purkinje cells), input (mossy and climbing fibers), and local processing (Golgi cells). Our second aim provides for a definitive follow-up by comparing our recording sites with histologically documented cerebellar circuits in the same animals. This anatomical conclusion is crucial for interpreting the results of the first aim and for informing the strategies of future studies. The end result of this project will be a systematic description of both the non-motor and motor information conveyed within physiologically identified, and anatomically confirmed, circuits of the lateral cerebellum. The broader outcomes will be to improve our understanding of how the cerebellum helps to mediate cognition and to provide a novel functional perspective on the relation between cerebellar dysfunction and neuropsychiatric disorders. PUBLIC HEALTH RELEVANCE: It is textbook knowledge that the cerebellum contributes to motor learning and coordination, but recent evidence from imaging, anatomy, and lesion studies implicate it, as well, in non-motor functions such as cognition. Our work will analyze the information conveyed within microcircuits of the cerebellum in monkeys that perform both motor and non-motor tasks. The results will provide a circuit-level description of cerebellar participatin in non-motor functions and new insights into the association between cerebellar dysfunction and neuropsychiatric disorders.

DESCRIPTION (provided by applicant): Transcranial magnetic stimulation (TMS) is a non-invasive method for probing and modulating human brain function. It is approved for the treatment of depression and pre-surgical cortical mapping; it also shows promise in other neurological and psychiatric disorders. Exactly what TMS does to neuronal activity, however, remains unknown. This gap in our knowledge precludes us from biologically-based, rational design of TMS protocols. To fill this gap, we need a better mechanistic understanding of the effect of TMS on cerebral neurons and a database of dose-response curves that describe how the selection of TMS parameters (the dose) relates to changes of neuronal activity (the response). Our project aims to contribute such mechanistic insight and empirical data. Our interdisciplinary team has developed a novel repertoire of tools and techniques that permit us to manipulate the TMS stimulus parameters, model the resulting electromagnetic fields and neuronal responses, and record from cerebral neurons while TMS is applied. In our first set of experiments (Aim 1), we will vary the temporal parameters of TMS. Using a custom TMS pulse generator, we will systematically change what the individual pulses look like (the pulse waveform) and how they are applied sequentially (the pulse train). Concomitant recordings in the zone of stimulation will determine how the various parameters modulate the firing rates of axons, excitatory neurons, and inhibitory neurons. Second (Aim 2), we will vary the spatial parameters of TMS using various coil locations and types of stimulation coils, including macaque-scaled approximations to conventional figure-8 coils as well as less focal coils recently approved for depression treatment (H coils). With simultaneous targeted recordings in the brain we will map the neural response in various cortical regions. In parallel to these empirical studies, we will construct individual, realistic, MRI-based head models coupled with neural response models to simulate, respectively, the electric field spatial distribution and the resultin response of various neuron types. The simulations will both guide and be informed by the empirical neural recordings, enhancing our understating of the mechanisms of TMS and providing a novel simulation tool that could inform TMS dosage. The end result of this project will be to discover how TMS influences the brain at the level of single neurons and simple circuits. The outcome should be transformative in helping researchers and clinicians to navigate the vast parametric space of TMS so that it may be used more effectively as a probe in neuroscience, and as a clinical treatment.

Award Title:
The Role of Frontal Cortex in Primate Metacognition

Award Abstract:
Rarely do we stop thinking. The mental experience of humans is one of continuity, with thoughts leading to other thoughts. When we reflect on our past decisions and ponder how we may act in the future, we are manipulating our own thought processes, a process termed metacognition. Most research on thought processes at both the psychological and neural levels has focused on single events such as how we remember a picture or decide our next move in a game of chess. Little is understood about serial cognitive events, such as the chain of decisions required to plan several moves ahead in chess. Understanding how individual thought processes influence each other -- venturing beyond cognition to metacognition -- is a challenging but important next step for brain research. Dr. Marc Sommer at Duke University studies metacognition using novel approaches that combine psychological experiments with direct recordings of neurons in the brain. With his Duke colleague, computational neuroscientist Dr. Jeff Beck, he examines not only how decisions are made, but also how they are remembered and controlled. Psychological testing of humans and non-human primates reveal how well they adjust their decision-making when circumstances change, and computer-aided modeling of the data allows for precise comparisons of metacognitive abilities between subjects and species. Neural recordings from the frontal cortex of non-human primates while they control their own decisions sheds light on how the brain is able to link thoughts across time. Specific implications of this work include a better understanding of human cognition and behavior in fast-paced and unpredictable situations that require constant evaluation and planning of decisions. The project will offer hands-on laboratory training opportunities for undergraduates and high school students and will be highlighted in STEM outreach to K12 schools, community lectures, and lay articles on cognitive neuroscience. The research aligns with the public's emerging interest in metacognition as an important factor in education, mental health, and the management of oneself and others.

The experimental approach is to use an integrated set of psychophysical and neurophysiological studies in which all data are analyzed and interpreted with computational modeling. The rationale for the project is that humans are adept at metacognitive operations, for example thinking about how to make a later decision, but little is known about the underlying neural mechanisms. Dr. Sommer previously recorded from neurons in the monkey frontal lobe and discovered signals in one area, the supplementary eye field (SEF), that maintained a trace of past decisions. The overall hypothesis of this proposal is that the SEF contributes, as well, to the metacognitive control of future decisions. The first objective is to quantify metacognitive behavior in monkeys as compared with humans. Both species will be tested on a novel rule selection task. Within a trial, subjects select a rule for making a visual decision (metacognitive control), but across trials, subjects bias their rule selection based on past outcomes (metacognitive monitoring). The second objective is to determine whether SEF activity is related to metacognitive control and monitoring. The approach will be to record from neurons in monkey SEF during the rule selection task. The third objective is to test whether the SEF is necessary for metacognitive control and monitoring. The approach will be to reversibly inactivate the monkey SEF during the rule selection task. Dr. Beck will assist with modeling and analysis of the data to ensure all results are statistically sound and clearly interpretable.

Non-invasive methods for stimulating the human brain show great promise for safe, effective treatments of psychiatric and motor disorders, and are in widespread use for basic research on human behavior and cognition. One such method, transcranial magnetic stimulation (TMS), is the application of time-varying magnetic fields above the scalp that induce transient electrical fields in the brain. TMS clearly stimulates the brain and affects behavior, but we do not know why it works; its effects on neural activity within brain regions and networks are not understood at a biological level. This project seeks to determine the neural basis of effects caused by TMS as applied in sequences of pulses, known as repetitive TMS (rTMS), a technique approved by the FDA for depression. Leveraging our expertise in application of TMS methodology during concurrent single neuron recording techniques in non-human primates and imaging and scalp potential techniques in humans (fMRI and EEG), we aim to resolve three interlocking problems in the design and application of rTMS: timing, spatial targeting, and interactions with brain state. In all studies, neuronal responses to rTMS will be quantified in human and non-human primates as they perform a visual motion task that allows systematic manipulation of brain activity and cognitive state. In both species, we will focus on a specific motion-selective brain area, MT, and the circuits that connect with it. First, we will determine the effects of timing on the pulse sequences delivered during rTMS. We will systematically trade off frequency with number of pulses delivered as human and non-human primates perform the task and brain activity and behavioral performance are monitored. Definitive dose-response relationships for rTMS temporal parameters will be established for both species. Second, we will assess simple but principled methods for spatial targeting of distributed networks. Based on imaging of white-matter connectivity and computational models of rTMS-induced neural activation, we will examine how location and orientation of the TMS coil differentially recruits two major pathways that emanate from it, the dorsal and ventral streams of the visual system. Third, we will tackle the fundamental question of how rTMS interacts with endogenous activity in the brain. By manipulating task demands, we will systematically control brain state and quantify how this alters the influence of rTMS on neural activity and cognitive performance. Taken together, this project will yield a multi-scale data set that links results from non- human primates to humans through experiments that should generalize well to the study of other cerebral cortical circuits. The results will help to advance rTMS from a method that relies on trial-and-error testing toward one that is founded on clear biological principles.

Analyzing the visual world requires the meticulous coordination of both eyes, achieved by six muscles that surround each eye. Controlled by motoneurons in the brainstem, these muscles move the eyes rapidly to acquire targets (using saccades) or track them (smooth pursuit). The muscles also make slower adjustments to maintain proper binocular alignment in depth (vergence) and keep the eyes still for target inspection (fixation). Common visuomotor disorders such as strabismus result from abnormalities in this neuromuscular system. Current treatments mitigate symptoms, but do not fix the underlying problems. To progress toward cures for the disorders, we need to learn more about the details of the neuromuscular circuits. A longstanding curiosity about extraocular muscle fibers has been that they come in two major types: multiply-innervated fibers (MIFs) that receive numerous neuromuscular junctions along their entire length, and singly-innervated fibers (SIFs) that receive a single band of neuromuscular junctions in their middle region. It was discovered recently in primates that these two types of muscle fibers are supplied by distinct groups of motoneurons, revealing that the MIF vs. SIF distinction extends to full motor units. Anatomical characteristics of MIFs and their motoneurons suggest they control slow, binocular alignment (vergence and fixation) whereas SIFs and their motoneurons control faster, targeting movements (saccades and smooth pursuit). The overall goal is to test this hypothesis of dual- motor control of the eyes. This will be accomplished using linear array recordings and optogenetics to study MIF and SIF motoneurons in behaving macaques. Pilot work showed that macaque extraocular motoneurons can be virally transduced to express exogenous genes, setting the stage for the optogenetic approach. The first aim is to achieve reliable, robust viral transduction and opsin expression in macaque motoneurons. Three viral vectors will be injected into orbital muscles at varying volumes and titers. Consequent transgene expression in motoneurons, along with any evidence of neurotoxicity, will be analyzed histologically up to 1 year post-injection to determine optimal parameters. The second aim is to distinguish the functional roles of MIF and SIF motoneurons. Exploiting the separate, colinear locations of MIF and SIF motoneurons in the primate oculomotor nucleus, we will angle linear array electrodes to sample both populations simultaneously. Motoneuron activity will be analyzed in relation to vergence, saccade, and smooth pursuit movements made by the macaques. MIF motoneurons will be identified with in vivo optogenetic phototagging and histological analyses. The outcome of the study will be to resolve whether MIF and SIF motor units constitute a dual-motor system for controlling the eyes. If the MIF subsystem is specialized for binocular alignment, as predicted, it would be implicated as a locus of disruption in strabismus, providing a specific target for treatment. More generally, the work will provide new viral and neurophysiological techniques for studying primate motoneurons, establish a novel testbed for primate optogenetics, and inform the safety and efficacy of gene therapy for neuromuscular disorders.

The use of transcranial magnetic stimulation (TMS) as a therapeutic intervention is FDA-cleared for treating depression, obsessive-compulsive disorder, and migraine, and shows promise for a host of other brain disorders. The appeal of TMS is its safety, non-invasiveness, and well-established capacity for modulating the activity of brain regions. In human subjects, that modulation is assessed only at the gross scale of behavioral, cognitive, or aggregate physiological effects (e.g. EMG, EEG, fMRI). The fine-scale responses and mechanisms of TMS, at the level of biophysical and biological effects on neurons and circuits, remain poorly understood. This knowledge gap hinders rational design of TMS protocols and leaves researchers and clinicians dependent on trial-and-error approaches and inferences from macroscopic data to improve the methodology. The lack of reductionistic insight is particularly detrimental when targeting non-motor areas such as prefrontal cortex where a readout of the immediate neural response is unavailable, for example due to the stimulus artifact in EEG. Our overall goal is to fill in this knowledge gap by studying the neural circuit mechanisms of TMS in the non-human primate brain. The approach integrates neurophysiological experiments featuring direct single-unit and local field potential recordings and multiscale computational simulations of neural circuits in both primary motor cortex and prefrontal cortex. Aim 1 is to establish the circuit mechanisms of acute responses to single and paired TMS pulses. Determining the pulse response of single neural elements and recurrent cortical circuits permits a detailed examination of the biophysics and biology of neural recruitment at a short time scale. A main goal of TMS therapy is to achieve controlled, lasting neuromodulation, however, so in Aim 2 we will extend the same neurophysiological and modeling approaches to the study of responses to repetitive TMS (rTMS). Here the goal of the neurophysiology will be to quantify the effects of rTMS pulse trains on long-lasting changes in neural activity and, accordingly, the neural simulations will incorporate synaptic plasticity. Critically, in both Aims we will conduct the experiments and modeling both in primary motor cortex, where spinal potential recordings and electromyography can supplement direct readout of neural effects in cortex, and prefrontal cortex, where only cortical-level recordings are suited to characterize neuromodulatory effects. The overall product will be an experiment- and model-driven mechanistic understanding of the effect of TMS on cortical circuits, enabling a transformational advance in the interpretation of the effects of TMS. Taken together, the results will promote a more biologically-grounded, rational approach to designing TMS protocols for neuromodulation.