Richard Ivry - US grants

DESCRIPTION: The main hypothesis examined in this proposal is that the left hemisphere is specialized for processing high-frequency stimuli in vision and in audition, and that the right hemisphere is specialized for processing low-frequency stimuli in both modalities. Hemispheric specialization for different spatial frequencies in vision was proposed by Sergent, and the investigator and his collaborators have provided evidence that a parallel specialization may exit for sound frequencies. This proposal further examines the nature of asymmetric hemispheric specialization for high-frequency and low-frequency information in audition & in vision by examining auditory asymmetries in normal subjects (Experiments 1 and 2), auditory and visual asymmetries in patients with focal lesions (Experiments 3 and 4), crossmodal comparisons in normal subjects (Experiments 5, 6 and 7), and auditory asymmetries for speech perception in normal and patient groups (Experiments 8-11). In addition, a connectionist model of hemispheric asymmetries in vision and audition is proposed.

9319103 IVRY Theories of object recognition in psychology, physiology, and even computer science have concerned themselves with feature analysis, where features may be line segments, colors, spatial frequencies, etc. According to these theories, recognizing an object involves detecting the features of that object. For example, the features round, shiny, and red might signal an apple. Recently, however, Treisman and her colleagues have pointed out that correct feature registration is not sufficient for veridical object recognition. When many different objects are present, as they are in most natural scenes, observers must not only correctly register the features, but also correctly bind the features into separate objects. Treisman and other have shown that under conditions of a brief exposure, observers will report "illusory conjunctions," or precepts in which they correctly identify the visual features, but combine them incorrectly. For example, an individual briefly presented a red X and a green O would perceive the X as green in some laboratory conditions on up to 30% of the trials. In most circumstances, our visual systems combine features of objects seemingly without error or effort, making the process of feature integration difficult to study. By studying errors in this feature binding process under laboratory conditions (i.e., illusory conjunctions), we can test different theories of feature integration. Unfortunately, the study of feature binding has been hampered for three reasons. First, most theories have been specified in a vague or informal manner. Second, theories have not been formulated in a format that allows a direct test between them. Finally, there has been considerable disagreement on how to measure illusory conjunctions. Many of the widely used methods of measuring feature binding from the occurrence of illusory conjunctions confound feature registration with feature binding. Preliminary research has led to the development of a mathematical model that add resses the above three issues, as well as to the development of a new theory of feature binding, based on probabilistic multidimensional modeling and on the psychophysics of location perception. The 15 experiments to be performed fall into four categories: (1) The formal theory will be tested by varying stimulus values (e.g., color of items) systematically and seeing how they affect parameters of the mathematical model, adjusting the model if necessary. (2) Cognitive variables such as attention will be varied and the effect of these variables on feature integration estimated separately. (3) Different theories of feature binding will be compared directly. (4) The analytic method and formal analysis will be extended to new experimental paradigms, in order to make it as useful as possible to other investigators. ***

A guiding principle of the proposed research is that coordinated behavior is dependent on the integrated operation of specialized neural structures. Initial work in this area focused on the hypothesis that the cerebellum operates as an internal timing system. More recent psychological and neurological evidence has identified other components such as spatia planning (cortical processing) and temporal coupling (unknown subcortical locus). The proposed experiments provide a programmatic examination of the processes involved in timing and temporal coupling. The specific goals are threefold: The first set of studies will further extend our knowledge of human timing using a new method for partitioning variability related to a timing mechanism and variability that is independent of such a mechanism. The second set of studies focus on temporal coupling, exploring a multiple timer model in which the cerebellum is hypothesized to constitute an array of multiple interval-based timing mechanisms, rather thana single internal clock or oscillator. A key idea in this model is that, while timing reflects a ubiquitous property of cerebellar function, the exact circuits within the cerebellum will vary from task to task. A corollary of this hypothesis is that independent circuits may provide the temporal representations required when performing multi-effector movements or judging two perceptual signals. This hypothesis may have important implications for recent neuroimaging work suggesting a cerebellar role in non-motor tasks. It is hypothesized that cerebellar activation in many of these studies may reflect the preparation of (the timing for) multiple responses. The third goal of this proposal is to explore this idea in two neuroimaging studies. As a whole, the proposed studies should provide important insights into the psychological and neural mechanisms of coordinated behavior. This functional analysis is essential for understanding the functional relationship between cortical and subcortical structures of the central nervous system.

9873474
Russell
This project will develop a unified theory of how natural and artificial systems can learn to solve complex motor tasks, such as running, diving, throwing, and flying, that entail significant sensory input and the coordination., sequencing, and fine-tuning of many low-level activities. Such a project is possible because of significant experimental advances in our understanding of motor control systems in humans and other animals, and because of increased sophistication in our mathematical models of control learning. These models will be used not only to analyze and predict natural phenomena in motor control, but also to derive effective adaptive controllers for artificial systems carrying out complex tasks.
To generate complex behaviors, natural and artificial systems must be organized hierarchically with multiple layers of abstraction. The first research task will therefore be to identify appropriate levels of representation at which the physical system can be modclled and at which control actions can be defined. For example, in describing an insect flying from A to B, possible levels might be 1) nerve signals and mechanical properties controlling the detailed shaping of each wingbcat 2) basic wingbeat cycle 3) 11 steering" the cycle to direct flight 4) takeoff, navigation, landing. Detailed motion, force, and/or airflow measurements will be made under a variety of experimental circumstances and tasks to establish the correspondence between formal models and physical systems. These experiments will be carried out for a variety of organisms, possibly including flying in insects, running in cockroaches, and for running, diving, and throwing in humans. These studies (and, in the case of insects, neurophysiological studies) will also establish the sensory inputs that are available at each level of the control system.
Given the general structure of the control system and the appropriate sensory inputs, the next step is to design learning algorithms capable of learning to perform the given task successfully. The learning method to be used is reinforcement learning, a technique designed to adjust the control algorithm to optimize an objective function-that is, the long-term accumulated value of a specified reward signal. The reward is supplied to the learning algorithm as part of the sensory input. New reinforcement learning algorithms will be developed that operate using both local and global reward signals within a hierarchical control structure; furthermore, these algorithms will be proved to converge even using nonlinear representations of the overall objective function. This research should shed light on the central question of whether this form of learning in animals and humans can be viewed as driven by optimization or by some other principle, such as the preservation of fixed interface characteristics among the various levels of the system. Discovery of consistent reward functions in animals, especially humans, would have significant consequences for general theories of learning.

DESCRIPTION (provided by applicant): The focus of this proposal centers on the psychological processes and neural mechanisms underlying the representation of temporal information. The cerebellum has been found to be essential in tasks requiring the representation of short temporal intervals. The cerebellar timing hypothesis provides a parsimonious account of a number of disparate cerebellar functions, including its role in motor control, certain perceptual tasks, and sensorimotor learning. Such tasks involve event timing, situations in which explicit representations of the temporal events are required. In contrast, timing may be an emergent property in many actions, reflecting temporal consistencies that arise through the control of other movement parameters. Preliminary work suggests that the importance of the cerebellum is diminished under such conditions. The specific goals are fourfold: First, the proposed distinction between event timing and emergent timing will be examined in a series of movement tasks involving neurologically impaired and neurologically healthy individuals. Second, functional magnetic resonance imaging will be used to test the hypothesis that the cerebellum is critical for movements involving event timing. These experiments will evaluate whether the cerebellar involvement is related to the representation of a temporally defined goal, the control of transition events related to the initiation and termination of the actions, or a combination of these factors. Third, the performance of patients with cerebellar, basal ganglia, or frontal pathology will be compared on motor and perceptual temporal processing tasks. The experiments in this section are designed to isolate processes involved in temporal representation from those associated with the working memory and/or attentional demands required in such tasks. Fourth, functional neuroimaging will be used to directly examine neural regions recruited during motor and perceptual timing tasks, and to examine the relationship of event timing to the more general cognitive function of generating predictions about future events. The proposed studies will contribute to our understanding of how temporal information is processed in the brain, and provide important new insights into the contribution of the cerebellum to movement and cognition.

Coordinated, skillful movements are remarkable achievements of the human nervous system. While we have succeeded in building computer systems that can beat the best human chess player, it has been extremely difficult to develop an artificial system that can pick up and move the chess pieces about the board with anything resembling the grace and ease of the novice chess player. How the brain produces coordinated movements remains an important challenge for cognitive neuroscience. Part of the answer will come from an understanding of cerebellar function, a prominent component of the motor pathways. With support from the National Science Foundation, Dr. Richard Ivry of the University of California, Berkeley and Dr. Jörn Diedrichsen of the University of Wales, Bangor, will pursue a multi-faceted research program to further our understanding of the role of the cerebellum in coordination. Building on new theoretical insights from the field of robotics, the research program will center on evaluating two hypotheses: Is cerebellar function best understood as part of the control circuitry that shapes the motor commands to the muscles based on sensory and motor signals from other limbs? Or is this structure essential for generating predictions concerning the sensory consequences of our actions, a process known as state estimation? While it has long been recognized that cerebellar dysfunction leads to a loss of skilled movement, the symptoms of ataxia may be due to poor control, poor prediction, or both. To distinguish among these hypotheses, participants will be trained to perform novel bimanual movements in which the movement of one hand will depend on an accurate prediction of the state of the other hand. Functional magnetic resonance imaging will be used to determine if cerebellar activation is related to state estimation or control. The imaging work will be complemented by studies involving patients with unilateral cerebellar damage. Here the focus is on a comparison between conditions in which the ataxic limb is required for either state estimation or control, providing strong tests concerning the necessity of this structure to one or both of these functions.

The study of bimanual skills is important given that the vast majority of our daily actions -- typing, driving, cooking -- typically require coordinating the movements of our two upper limbs. The current project should serve as an important step in developing a general theoretical framework for studying coordination across multiple parts of the body (e.g., coordinating movements of the head, eyes, and arms), or even between different individuals (e.g., dancing, basketball). While the research plan focuses on the cerebellum, the basic ideas offer a general approach for exploring the neural mechanisms underlying skilled actions. This project will also provide research training opportunities in cognitive neuroscience for undergraduate, graduate, and post-doctoral researchers. The work will bring together students with interests in engineering, psychology, and the neurosciences, providing unique interdisciplinary training opportunities and advancing our understanding of the human motor system.

Tele-immersive environments allow people separated by distance to physically interact and communicate in real time inside a shared 3D virtual environment through the use of large camera networks that enable the capture and reconstruction of 3D images and sound and the subsequent integration of this multimedia data from geographically distributed sites. This project develops and deploys a next generation tele-immersive environment built for the common user who does not have the luxury of expensive supercomputing facilities and dedicated networks. More particularly, the vision of this project is to create a geographically distributed and cost effective tele-immersive environment that facilitates ordinary people performing physical activities in their homes or schools or doctor''s offices or job training facilities under the supervision of a trainer, therapist, or teacher who is not co-located.

The broader impact of this project is in facilitating physical interaction and communication of the elderly and persons with disabilities in their homes and work places with relatives, health care providers, and other service providers, in particular whenever they need some interaction during a period of rehabilitation, recovery or training. This project will also examine multimedia distributed communication using common Internet connectivity, which does not require high bandwidth or extremely expensive equipment, and thus may promote wider use of tele-immersive environments.

0-11 years old; Address; Apoplexy; Architecture; Area; Basal Ganglia; Basal Nuclei; Behavioral; Brain; Brain Diseases; Brain Disorders; Cell Communication and Signaling; Cell Signaling; Cerebral Stroke; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Cerebrovascular accident; Chemical Fractionation; Child; Child Youth; Children (0-21); Choice Behavior; Cognitive; Collection; Complex; Computer information processing; Corpus Striatum; Corpus striatum structure; DA Neuron; Decision Making; Decision Modeling; Development; Disease; Disorder; Dopamine neuron; Dysfunction; Electrocorticogram; Encephalon; Encephalon Diseases; Encephalons; Engineering / Architecture; Environment; Epilepsy; Epileptic Seizures; Epileptics; Evaluation; Event; FRACN; Feedback; Fractionation; Fractionation Radiotherapy; Frontotemporal Dementia; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Human; Human, Child; Human, General; Idiopathic Parkinson Disease; Impairment; Influentials; Intracellular Communication and Signaling; Intracranial CNS Disorders; Intracranial Central Nervous System Disorders; Knowledge; Lateral; Learning; Lewy Body Parkinson Disease; MR Imaging; MR Tomography; MRI; MRI, Functional; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Functional; Man (Taxonomy); Man, Modern; Measures; Medial; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Method LOINC Axis 6; Methodology; Methods and Techniques; Methods, Other; Modeling, Decision; Monkeys; NMR Imaging; NMR Tomography; Negative Reinforcements; Nerve Cells; Nerve Unit; Nervous; Nervous System, Brain; Neural Cell; Neurocyte; Neurons; Nuclear Magnetic Resonance Imaging; Operation; Operative Procedures; Operative Surgical Procedures; Outcome; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson's; Parkinson's disease; Parkinsons disease; Patients; Physiopathology; Population; Prefrontal Cortex; Primary Parkinsonism; Probability; Process; Processing, Information; Psychological reinforcement; Range; Reinforcement; Reinforcement (Psychology); Reinforcements, Negative; Rewards; Science of neurophysiology; Seizure Disorder; Signal Transduction; Signal Transduction Systems; Signaling; Staging; Stimulus; Striate Body; Striatum; Stroke; Surgical; Surgical Interventions; Surgical Procedure; System; System, LOINC Axis 4; Techniques; Trauma, Brain; Traumatic Brain Injury; Traumatic encephalopathy; Vascular Accident, Brain; Work; Zeugmatography; abstracting; awake; biological signal transduction; brain attack; cerebral vascular accident; children; disease/disorder; dopaminergic neuron; electrocorticography; epilepsia; epileptiform; epileptogenic; fMRI; frontal cortex; frontal lobe; frontotemporal lobar dementia; goal oriented behavior; insight; neural; neural mechanism; neuroimaging; neuromechanism; neuronal; neurophysiology; neuropsychological; pathophysiology; relating to nervous system; striatal; stroke; success; surgery; traumatic brain damage; youngster

DESCRIPTION: A central feature of theories regarding cerebellar function is their emphasis on the role of this structure in motor learning. Damage to this subcortical structure produces impairments not only in the control of movement, but also in the acquisition and consolidation of new motor skills. A description of cerebellar function that emphasizes motor learning, however, is insufficiently constrained given the broad range of skills encompassed by this term. The proposed studies are designed to clarify the boundary conditions of the cerebellum in motor learning, seeking to identify those features that are dependent on the integrity of the cerebellum as well as those features that do not involve the cerebellum. A set of the experimental tasks will be employed in which the core component of skill acquisition requires learning novel spatial relationships or novel spatiotemporal patterns. These tasks will be used to test two primary hypotheses. First, cerebellar involvement in motor learning will be more pronounced for tasks that emphasize plasticity in the temporal domain compared to tasks that emphasize plasticity in the spatial domain. Thus, the cerebellum will be essential for the acquisition of skills that exploit temporal regularities in the environment or require the modification of the temporal relationship between a movement and the resulting sensory consequences. In contrast, this hypothesis predicts that the cerebellum will not be directly involved in the development of skills that depend on the establishment of novel spatial representations or transformations. Second, a cerebellar-prefrontal network is hypothesized to support the maintenance of stimulus-response associations, an action-oriented form of working memory. These representations are a prerequisite for many forms of motor learning. Tasks that tax this network will involve the cerebellum, even if the primary locus of learning is extracerebellar. The performance of patients with cerebellar disorders will be compared to that of matched control participants. This methodology will be complemented by neuroimaging studies involving neurologically healthy individuals. PUBLIC HEALTH RELEVANCE Identification of the functional domain of the cerebellum in motor learning is important for the development of models of cerebellar function and for understanding the patterns of connectivity between the cerebellum and the cerebral cortex. The results should be of clinical relevance, allowing therapists to design rehabilitation programs that are tailored to either target or minimize impaired functional capabilities.

DESCRIPTION (provided by applicant): Our long-range goal is to understand how different regions of the brain select, plan, and implement skilled actions. In the current proposal, the focus is on hand choice; how people select one hand or the other to reach for and interact with objects in the environment. This problem is encountered many times each day-- picking up a coffee cup, using the telephone, pointing to a landmark when giving directions -- and accomplished in a seemingly effortless manner. However, the psychological processes and neural mechanisms engaged in solving this simple decision process have received minimal attention in the literature. Similar to findings in research on perceptual choices, our recent studies demonstrate that hand choice involves a competitive process between representations associated with the selection of the left or right hand. To date, our work has generally focused on behavior, characterizing the psychological and physiological processes involved in hand choice. In the proposed work, the emphasis will be on identifying cortical and subcortical regions associated with this elementary, yet fundamental decision process. To this end, three specific aims will be addressed. 1) Identify the neural regions involved in hand choice during unimanual actions. 2) Use a reinforcement learning task to directly compare processes involving in using feedback when the outcomes are associated with variation in the participant's sense of limb control. As a point of comparison here, the data from the hand choice task will be compared to a more standard decision-making task involving object choice. 3) Identify the neural regions associated with inhibitory processes involved in hand selection and response initiation. The experimental plan entails the integrated use of functional imaging, brain stimulation, and neuropsychological studies. At the completion of this project, we expect to have made significant advances, not only in our understanding of action selection, but also in how we control and inhibit actions.

DESCRIPTION (provided by applicant): This R21 proposal aims to employ a magnetic resonance spectroscopy (MRS) protocol to examine the relationship between the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the frontal cortex and motor system dynamics during the selection and initiation of movements as measured with transcranial magnetic stimulation (TMS) of the motor cortex. TMS studies conducted in the PI's laboratory have dissociated two inhibitory mechanisms that contribute to the selection and initiation of responses. One mechanism helps to resolve competition among co-activated responses and is associated with lateral prefrontal cortex. The other mechanism helps prevent impulsive execution of a selected response and is associated with dorsal premotor cortex. However, the relationship of these two inhibitory processes to levels of GABA within their associated frontal cortical regions has not been investigated. The proposed project will investigate this relationship through the study of individual differences at the neurochemical and neurophysiological level. The project represents a new research direction for the PI, yet is highly feasible. The PI is an expert on the motor system and the use of TMS as a tool for investigating the dynamics of response preparation. The co-investigator Dr. Richard Maddock is an expert in the use of MRS methods, specifically for measuring GABA. With Dr. Maddock's guidance, and the recent installation of MRS software at UC Berkeley, the infrastructure is in place for this work.

? DESCRIPTION (provided by applicant): This proposal explores the interaction of processes involved in action selection and action execution. This interaction is essential for understanding how people learn to make optimal decisions and develop complex skills, as well as for explicating how disorders of the motor system may impact cognition, a question that has been of central interest in studies of degenerative diseases of the cerebellum and basal ganglia. The interaction can be appreciated by considering that successful decision making requires (at least) two fundamental abilities. First, an agent must be able to evaluate the value of different options in the environment, using that information to choose the option that will maximize reward. Second, the agent must be able to execute a response to indicate the selected option. Traditionally, models of decision making have focused on the former and ignored the latter. However, in many real-world situations, errors in execution are the primary impediment to successful outcomes. A tennis player may correctly opt to use a backhand swing instead of a forehand to return a serve, but fail to execute the action properly. Or in a more mundane example, a person might choose to take a sip from the wine glass rather than the water glass, but fail to reap the expected reward because she knocks over the glass by reaching in a clumsy manner. In this example, the issue is whether a person values wine less (due to the failure to obtain the expected reinforcement) after the clumsy reach, or whether the error is attributed to the execution system, with the outcome precluded from influencing future choice behavior (assuming we are equally competent in reaching for water or wine). The proposed work will examine the psychological processes and neural systems through which action execution and action selection interact. To this end, two specific aims will be addressed. 1) Our pilot work demonstrates a striking difference in choice behavior depending on whether failed outcomes are attributed to a property of the object or a limitation of the execution system. A series of computational models will be developed that have the potential to account for this difference. In a symbiotic manner, behavioral data from a series of experiments will be used to evaluate the models, and the models will be used to generate and test specific predictions. 2) Identify the neural regions involved in the interaction of action errors and selection processes. Of special note here is the idea that cerebellar-based representations of action execution errors might serve a dual-purpose, improving future action execution and providing a gating signal to constrain learning processes that underlie action selection dynamics. The experimental plan for this aim entails the integrated use of functional imaging and neuropsychological studies. At the completion of this project, the studies will help provide an integrated picture of how action selection and action execution processes interact in the human brain to optimize behavior.

Project Summary Sensorimotor learning is an essential feature of human competence, allowing people to flexibly move in novel and variable environments. The cerebellum is a critical structure in sensorimotor pathways as evidenced by the fact that deficits in sensorimotor learning and control are the prominent features of ataxia, a neurological condition observed in individuals who suffer from degenerative disorders of the cerebellum. The over-arching goal of this project is to advance our understanding of the role of the cerebellum in sensorimotor learning. Recent experimental work has shown that sensorimotor learning entails the operation of multiple learning processes, some of which are under volitional control and others that operate in an automatic and implicit fashion. Identifying the contribution of these different processes has been hindered by the use of experimental methods that confound information arising from different feedback signals. The key experimental manipulation to be used in the proposed research will entail a new method, designed to isolate cerebellar-dependent error based adaptation, a learning process that serves to ensure the calibration of sensorimotor maps. This method involves a manipulation of visual feedback such that the error signal remains invariant despite changes in behavior. Preliminary results with this method reveal fundamental inadequacies with current computational models of sensorimotor adaptation. To address these limitations, the proposed work entails the integrated use of behavioral, neuroimaging, and computational methods to develop new models of sensorimotor adaptation. The research plan centers on three specific aims. The first aim is to iteratively use computational and behavioral methods to develop and test new computational models of sensorimotor adaptation. Psychophysical experiments with healthy young adults will be conducted to specify the constraints on error-based adaptation, with this information used to inform model refinement. The goal of the second aim is to characterize the contribution of the cerebellum to error-based learning, testing key predictions from the modeling work concerning the sensitivity of this structure to error information. This work will entail behavioral studies in patients with cerebellar degeneration and, as a point of contrast, patients with Parkinson's disease, as well as functional neuroimaging (fMRI) studies in healthy young adults. The goal of the third aim is to examine constraints on the error signal that drive adaptation, and in particular, explore how adaptation may interact with systems sensitive to task outcome. Various manipulations will be employed that may modulate the the strength of error information, or put this information in conflict with reinforcement signals. Taken together, this project should provide a new framework for understanding the contributions of the cerebellum to sensorimotor adaptation and gain insight into the behavioral changes observed in individuals with ataxia arising from cerebellar degeneration.

The past two decades have witnessed an exponential increase in the use of non-invasive brain stimulation (NIBS) methods. The two most commonly used methods, transcranial electrical stimulation (tES) and transcranial magnetic stimulation (TMS), provide tools to manipulate activity in targeted brain regions, and this give cognitive neuroscientists a method to test functional hypotheses. Despite this potential, there are substantial concerns about the reliability and robustness of the physiological and behavioral changes resulting from these NIBS methods, especially when used to induce modulatory perturbations in the state of neural excitability. The purpose of this project is to create a new and more robust method for modulatory NIBS in human participants. The method, referred to as kilohertz transcranial magnetic perturbation (kTMP), will open a new experimental electromagnetic subspace for perturbing brain function. This method will open several new opportunities for cortical stimulation: larger electrical fields, more precise timing, better spatial control, and both a greater range and a more precise delivery of stimulation frequency.

This novel magnetic stimulation holds promise to produce meaningful focal physiological changes, for several reasons. First, subthreshold kilohertz (kHz) electrical stimulation has been shown to alter motor-evoked responses with an effect size similar to that of direct current electric fields. Second, suprathreshold kHz frequency electric fields robustly block nerve conduction in a reversible manner. Third, suprathreshold experiments have shown that kHz tES can mimic low frequency electric fields in the motor cortex of the mouse, presumably due to frequency intermodulation. This project will employ subthreshold electric fields, albeit at much higher amplitude than those presently available with tES and with the frequency specificity not possible with extant TMS methods. kTMP offers a hybrid subthreshold approach that will exploit strong midrange electric field amplitudes with frequency specificity, including frequency intermodulation effects, offering a new approach to perturb brain function. The initial empirical evaluation of kTMP will focus on modulating human motor cortex excitability, the "gold standard" approach for evaluating NIBS methods. Importantly, by substantially expanding the range of electric field induction, it should be possible to obtain dose-dependent functions, something that has proven elusive with other subthreshold NIBS methods. Once these benchmark tests are met, kTMP should be readily adopted for basic cognitive neuroscience research, providing a robust tool to perturb and modulate targeted cortical regions as a means to test functional hypotheses in physiological and behavioral studies. In the long term, kTMP has promise to be employed in the treatment of psychiatric and neurological disorders.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PROJECT SUMMARY The goal of this project is to extend our understanding of the cerebellum, and in particular, how this subcortical structure contributes to human cognition. Diverse lines of research provide compelling evidence that the cerebellum is not only involved in sensorimotor control, but also contributes to a range of cognitive functions. For example, the neuroimaging literature has produced maps of the cerebellum that exhibit a stable functional organization, with much of the cerebellar cortex showing hemodynamic changes that cannot be attributed to movement. Moreover, patients with cerebellar disorders exhibit behavioral impairments on tasks assessing cognitive and affective processing. However, our understanding of the functional role of the cerebellum in cognitive domains remains rudimentary: Functional hypotheses have either been largely descriptive or targeted to account for cerebellar function in a relatively narrow, task-specific manner. The research program outlined in this proposal is designed to address this issue, seeking to develop a mechanistic account of cerebellar function. Theoretically, the work will be guided by a novel hypothesis, namely that the cerebellum is essential for processing that requires the continuous transformation of an internal representation, or CoRT(continuous representational transformation). This hypothesis offers a parsimonious account of how the cerebellum supports performance in diverse task domains. In the context of sensorimotor control, CoRT would entail computations required to move a limb from one position to another and to anticipate the sensory consequences of that movement. In other task domains, the continuous transformation of an internal representation may optimize anticipatory behavior; for example, perception frequently involves the internal transformation of the sensory input to account for atypical viewpoints, and social judgments may benefit continuously simulating the intended actions of another individual. The research program will involve the integrated use of behavioral, computational, and neuroimaging studies. One major component of the behavioral work will focus on the performance of individuals with spinocerebellar ataxia (SCA). This work will involve traditional on-site experiments spanning a broad range of task domains to test the CoRT hypothesis, as well as an ambitious on-line testing program. Through an outreach program facilitated by SCA support networks and collaborations with an international team of researchers, the on-line program should produce a unique database to provide well-powered tests of functional hypotheses, and examine relationships between behavioral performance, etiology, and clinical ratings, and relate these measures with region-specific pathology in the cerebellum. A second major component will build on recent neuroimaging work with healthy young adults that has provided a comprehensive functional map of the human cerebellum though the use of a large battery of tasks. This approach will be used to explore constraints on the organization of the functional map by developing models of cortico-cerebellar connectivity and examining changes over the course of learning. As with the neuropsychological studies, the neuroimaging studies will yield a rich database to evaluate different functional hypotheses, as well as establish norms for comparison with atypical populations. !

Project Summary/Abstract Non-invasive brain stimulation (NIBS) has attracted considerable interest in the cognitive neuroscience community, providing an important basic research tool to study brain function, with emerging clinical applications to enhance cognitive function in individuals with neurological disorders. Despite this potential, an emerging literature has highlighted concerns regarding the reliability and robustness of transcranial electric stimulation (tES), the primary NIBS method used to induce changes in brain plasticity through the application of subthreshold stimulation. These problems are likely related to the fact that tES systems can only induce modest electrical fields (E-field) at the cortical surface given that safety/tolerance issues limit the intensity of tES stimulation that can be delivered at the scalp. We propose to develop a radically new NIBS device, one in which we will apply oscillating magnetic fields at kHZ frequencies. Theoretical analyses indicate that this device will produce a significant increase in the range of E-field induction, as well as provide a number of other advantages, relative to current NIBS methods. The two-year funding period will be used to perform the theoretical analysis of the system, construct the device to deliver kHz magnetic stimulation, perform bench tests to confirm theoretical estimates, and conduct initial testing with human participants to assess the feasibility of the system for producing changes in cortical physiology. If our expectations are confirmed, this system will provide a powerful new tool for modulating neural excitability.