Robijanto Soetedjo, Ph.D. - US grants

DESCRIPTION (provided by applicant): The proposed research will characterize the role of saccade-related cerebellar output from the caudal fastigial nucleus (CFN), in long-term saccade adaptation. Cerebellum is strongly implicated in short-term saccade adaptation, but its role in long-term saccade adaptation is unknown. Long-term adaptation has not been extensively studied, but is essential for maintaining movement accuracy during growth, aging, and for permanent rehabilitation of impaired movements. Long-term adaptation of saccades will be produced by presenting an adapting stimulus to a monkey for many days. In the first experiment, behavioral tests and temporary inactivation of the CFN will be used to test our hypothesis that cerebellar contribution to adapted saccades decreases rapidly after the initial adaptation. In a second experiment, permanent bilateral CFN lesions will be used to test our hypothesis that CFN output drives long-term adaptation. In third experiment, injections of anterograde tracer in the CFN, and retrograde tracer in the frontal eye field (FEF) will test our hypothesis that CFN output reaches the FEF via a relay in the thalamus. This pathway may induce long-term adaptation by modifying saccade commands descending from the FEF. The proposed research has three specific aims: (1) To measure the contribution of CFN to adapted saccades at different times during long-term adaptation. (2) To measure the long-term adaptation after permanently lesioning the CFN bilaterally (3) To determine the anatomical pathway of Iong-term adaptation.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Adaptation of saccadic eye movements is necessary so that saccade accuracy can be maintained throughout life despite the changes caused by development, aging and trauma. The long-term objective of this grant is to study the possible role of the oculomotor vermis of the cerebellum in the adaptation process. We will approach this object with 3 sets of experiments. In the first, we will inactivate the vermis pharmacologically and determine the deficit in the behavioral adaptation of saccades to an intra-saccadic target step, which causes saccades to appear inaccurate. In the second, we will examine the behavior of simple spike activity in the Purkinje cells of the oculomotor vermis to determine how it changes during this behavioral adaptation. Finally, we will attempt to drive adaptation by stimulating the superior colliculus, which is the likely source of the error-related activity in the inferior olive. Because of the similarities of simian and human saccadic eye movement behavior, the results of this project should have considerable relevance in the diagnosis, treatment and rehabilitation of patients with saccadic eye movement disorders.

DESCRIPTION (provided by applicant): Motor adaptation refines our movements during development, adjusts them when we attempt to acquire a new skill, and repairs them if they are compromised by injury. Our long-term goal is to identify the neural mechanisms of the motor adaptation that maintains the accuracy of saccadic eye movements. Most, if not all, neurophysiological studies on saccade adaptation have used targeting (reactive) saccades made in response to the sudden appearance of a target that falls off the fovea, called here the retinotopic goal of the saccade. For targeting saccades, the vectors of the retinotopic goal and the initial motor error (the difference between the target and current eye positions [also called the desired saccade vector]) are congruent. However, saccades often must be coordinated with other saccades or other types of eye movement, which may intervene before a saccade to an intended goal is executed. Such interruptions dissociate the vector of the saccade to be executed and its retinotopic goal, so the brain must perform a spatial updating to re-compute the vector of the intended saccade. Our preliminary experiments using a double-saccade task (DST) revealed that (1) the saccadic burst of saccade-related neurons in the superior colliculus (SC) are modulated by the retinotopic goal, and (2) unexpectedly, adaptation of targeting saccades does not generalize i.e., transfer, to the second saccade of a DST, even when the two saccades have identical initial motor errors. These findings lead us to hypothesize that the SC uses different processing for targeting saccades and saccades that require spatial updating. We will examine the effect of this separate processing on saccade adaptation. We will use three approaches to test this hypothesis: 1. Behavioral experiments to infer the adaptation sites of targeting saccades and the second saccade of a DST on the basis of both the characteristics of each adaptation and its transfer to the other type of saccade. 2. single unit recording to reveal any changes in SC activity specific to the two different saccade types and their adaptations and 3. microstimulation and focal inactivation to test the difference of SC topographic activity during the execution of saccades in the two tasks . Because of the similarities of simian and human saccadic eye movement behavior, the results of this project should have considerable relevance in the diagnosis, treatment and rehabilitation of patients with saccadic eye movement disorders. Our proposed experiments aim to provide both behavioral and neurophysiological evidence that adaptation of saccades with the same vectors, but generated in different goal contexts, do not transfer to each other and hence involve different adaptation pathways. Understanding the limitation of the transfer of adaptation between saccades in different contexts may help to design a more specific repertoire of rehabilitation strategies for patients with saccade disorders, and perhaps general motor deficits.

The brain does not need the cerebellum to make movements. Rather, it needs the cerebellum to make accurate movements. The cerebellum endows the organism with the ability to internally monitor and correct ongoing motor commands. This monitoring requires the cerebellum to be able to predict errors that are about to happen, and correct for them before they occur. That is, the brain relies on the cerebellum to have accurate internal models that learn to predict sensory consequences of motor commands. However, it has been difficult to decipher how the cerebellum represents internal models: for many forms of behavior, including saccadic eye movements. By examining the relationship between simple spikes of Purkinje cells (P-cells) and behavior, this project will advance our understanding of computations in the cerebellum. Results of these studies could provide new avenues of rehabilitation for patients with cerebellar damage.

The new idea in this proposal is that the basic unit of computation in the cerebellum may not be a single P-cell or a randomly selected population of P-cells, but rather a specific group of P-cells wherein all the P-cells share the same preference for prediction error. Using this idea, the collaborative team of investigators from Johns Hopkins University and University of Washington has found that during saccades, the simple spikes of P-cells predict with exquisite accuracy future behavior of the eyes. The aim of this project is to understand how the cerebellum learns to make such accurate predictions. The investigators present a new paradigm, one in which sensory errors are perpendicular to the direction of motion of the eyes. This paradigm is interesting because behavior shows considerable richness: motor commands that arrive early in the movement appear to change little following error, but those that come late show both high learning and rapid forgetting. Using a combination of experiments and computational modelling, the investigators will test ideas that behavioral changes are due to the neural changes in the P-cells: micro-clusters that do not prefer the error express their learning in the acceleration phase of the movement, whereas those that prefer the error express their learning in the deceleration phase.

Project Summary/Abstract The accuracy and precision of saccades are important to vision. Our long term goal is to identify the neural mechanisms that underlie saccade motor control. As with other movements, the cerebellum plays a key role in fine tuning saccadic eye movements. Specifically, intact oculomotor vermis (OMV) and caudal fastigial nucleus (cFN) is critical for producing accurate saccades. Much of our understanding of the physiology of neurons in the cFN and Purkinje (P-) cells in the OMV during saccades has relied on saccades made to single targets that appear in the visual periphery. In such a visually guided saccade task, the vectors of the retinotopic target and the saccade motor command are congruent. However, in real life, saccades often must be coordinated with other saccades or other types of eye movement that intervene between the programming and execution of a saccade. Such interruptions dissociate the vector of the saccade to be executed from its retinotopic target vector. The brain must update the vector of the upcoming saccade by combining the retinotopic target vector with information about the intervening movement. Oculomotor areas of cerebral cortex account only partially for the spatial updating of saccades, implying significant contribution from subcortical structures. We hypothesize that the OMV and the cFN to which it projects play critical roles in this process. These structures receive motor command feedback from brainstem saccade premotor neurons. The feedback signal could be used to adjust the motor command of the final saccade during spatial updating via cFN projection to saccade premotor neurons. We will test this hypothesis in a monkey performing a double-step saccade task (DST). In this task, the monkey makes two sequential saccades in the dark to previously flashed visual targets. The task requires the brain to combine the motor command of the first saccade with the retinotopic location of the flashed second target to produce an accurate second saccade. Specifics Aims 1 and 2 examine the activity of neurons in the cFN and OMV P-cells during spatial updating of saccades. We will test the hypothesis that by combining the retinotopic target signal in the SC with the feedback motor command of the first saccade of a DST, the cerebellum computes a corrective signal. This corrective signal is represented in the saccade-related activity of the neurons. Specific Aim 3 perturbs the processing of spatial updating of saccades before the second saccade is launched. We will briefly increase P-cell activity by using optogenetic activation triggered by the first saccade, and examine the effects on the second saccades. Overall Impact: The cerebellum plays an important role in the accuracy, precision, and temporal sequencing of movements. We will study the cerebellum?s contribution to the coordination of a sequence of saccades?well understood movements that provide a platform for understanding motor coordination more generally. The results of our studies will improve our understanding of the neural basis of motor coordination and will guide the development of behavioral strategies to rehabilitate patients with cerebellar diseases.

Project Summary/Abstract The accuracy and timely execution of rapid saccadic eye movements are crucial for effective vision. Therefore, an accurate measure of where the eye is aimed is required to understand not only the effect on visual processing but also the neuronal mechanisms that underlie the generation of the eye movements themselves. For more than 40 years, much of our understanding of the oculomotor system has relied on the scleral search coil system. This system has the advantages of operating in real time and having low noise and high accuracy. However, it requires an invasive surgery to implant the eye coil and bulky high power AC electromagnetic field coils. Unfortunately, as far as we are aware, there are no longer manufacturers that supply the scleral search coil system. The shifting focus of the electronics industry toward digital switching technology obsoletes most linear parts required to build the power oscillator that feeds the field coils and the detector. The optical eye movement transducers, which do not require attachment to the eye, are limited by the long latency of their video processing. Also, the fast high-end devices suffer from ringing artifacts at the end of a saccade that may mislead the interpretation of saccade kinematics. These problems could be a barrier for a new oculomotor neurophysiology lab. With the recent development of optogenetics, a technique that allows light to manipulate the activity of specific neurons with high temporal precision and then examine the effects on eye movements, the availability of an eye tracking device with a real-time characteristics is necessary. This real-time, low latency requirement is necessary in a closed-loop optogenetics experiment in which the laser light pulse is triggered and modulated by the kinematics of the eye movement while a saccade is unfolding. To address the need for a non-contact eye movement transducer with high spatial and temporal resolution, we propose to develop an eye tracking device that senses the asymmetric geometry of the ocular globe. The device will be based on a capacitive sensor that measures the proximity between the globe and the sensor. A capacitive proximity sensor has a wide bandwidth in excess of 1MHz and the signal processing stage can be designed using small-signal analog/digital circuits that allow for real-time operation. The capacitance sensor is composed of a fractured carbon nanotube-paper composite (CPC). Unlike other planar capacitive sensors, the fractured CPC relies on the total surface area resulting from the stretching of numerous multi-walled carbon nanotubes (MWCNTs). The surface area of MWCNT networks can be large enough to provide measurements that are orders of magnitude more sensitive than that of planar capacitors. The performance of the proposed sensor will be evaluated in a non-human primate and compared to that of a scleral search coil system.