Terrence R. Stanford - US grants

[unreadable] DESCRIPTION (provided by applicant): Decisions about where to look within a typical visual scene are governed by the relative salience of individual stimuli and current behavioral objectives. To date, the majority of studies examining the cognitive control of visual orienting have targeted frontal cortex. However, there is growing evidence to suggest that signals related to working memory and decision-making are critically dependent on interactions between frontal cortex and subcortical structures such as the basal ganglia, cerebellum, and thalamus. Thalamus is unique among these subcortical structures; in addition to providing direct input to cortex, its constituent nuclei mediate the influences of both the basal ganglia and cerebellum on their respective cortical targets. Despite its critical anatomical position, virtually nothing is known about the nature of the information represented in central thalamus. The current experiments seek to fully characterize the central thalamic representations of cognitive factors relevant for producing visually-guided saccadic eye movements. The proposed studies will be the first to examine the potential importance of central thalamic nuclei, and the subcortical-cortical interactions they mediate, to the cognitive control of goal-directed saccadic eye movements. In doing so, these experiments will help to define the essential neural substrates for visuomotor cognition. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The size of the prefrontal cortex has increased dramatically in primates compared to other vertebrates and its evolutionary expansion mirrors the development of attention, memory, and executive function in these species. Developmentally, the prefrontal cortex undergoes a long maturation process that extends through puberty and into early adulthood. A number of mental illnesses have onsets linked to the maturation of the prefrontal cortex, most notably schizophrenia, which manifests itself in early adulthood. Impulse control also improves in adulthood, and failure to develop adequately is associated with delinquency, drug abuse, and other conditions of health and social significance. Little is known about the physiological changes that the prefrontal cortex undergoes during puberty and early adulthood so as to mediate increased cognitive control. Taking advantage of recent methodological and conceptual advances, we propose to investigate the changes of prefrontal cortical physiology and functional connectivity that occur after puberty. We propose to use a non-human primate model which will allow us to conduct neurophysiological recordings in the prefrontal cortex of juvenile and adult animals. Our studies will also sample the posterior parietal cortex, an area interconnected with the prefrontal cortex. This will serve as a control area allowing us to determine what is unique about the maturation of the prefrontal cortex, and it will also allow us to study changes of functional connectivity between the prefrontal cortex and posterior parietal cortex. Our study will make use of monkeys trained to perform behavioral tasks that require attention, working memory, and executive control. These experiments will offer insights on how development of the prefrontal cortex alters its physiological responses which will be essential for understanding and treating mental illnesses associated with problems of prefrontal cortical maturation. PUBLIC HEALTH RELEVANCE: The proposed research will determine how the functions of prefrontal cortex neurons change between adolescence and adulthood. Knowledge drawn from these experiments will elucidate the development of higher cognitive processes such as attention and memory, which is necessary for understanding the biological basis of conditions such as Attention Deficit Disorder and mental illnesses such as schizophrenia.

DESCRIPTION (provided by applicant): The neurobiology of choice behavior has been intensely studied with laboratory tasks in which a subject makes a perceptual judgement and indicates the result with a motor action. Combined psychophysical and neurophysiological experiments have thus characterized perceptual decision-making capacity as a function of signal quality, strength, and subjective value, and have revealed many of the underlying neural circuits and their specific roles. However, the fundamental question of timing has been much harder to tackle: how long does it take to make a perceptual judgment, versus executing a motor action to report that judgment? At what point in time is a subject committed to a particular choice, and what neural mechanisms determine that? These issues are relevant to many real-life situations that require quick choices; for instance, when a driver sees a traffic light and must rapidly decide whether to step on the brake or the accelerator, depending on the light's color. But making accurate timing measurements is complicated because they are affected by numerous sensory and motor factors, such as readiness, motivation, task difficulty and speed-accuracy trade-offs. Consequently, current knowledge about the temporal dynamics of perceptual decision-making is rather crude. The PIs in this project recently developed a task that eliminates these confounds and produces a new psychophysical measure, the tachometric curve, which isolates a subject's perceptual processing capacity and quantifies it with unprecedented temporal resolution. They have also constructed a computational model that reproduces the subjects' behavior with great detail. The new paradigm and the model will be used jointly to investigate the timing of perceptual judgments and its neural basis. Specific model predictions will be tested via single-neuron recording and microstimulation within the Frontal Eye Field (FEF) of monkeys trained to perform the task under a variety of conditions. There are three specific aims. Aim 1: To test the hypothesis that changes in perceptual processing speed are manifested as changes in the slope of the tachometric curve (psychophysically) and in the acceleration of the oculomotor activity associated with a saccadic choice (neurally). According to the model, the tachometric curve and the oculomotor activity associated with saccadic choices should depend in specific ways on perceptual difficulty. To measure this dependency, subjects will perform 3 versions of the same choice task that will vary in perceptual difficulty according to different stimulus features to be discriminated. Aim 2: To test the hypothesis that when perceptual processing speed remains constant, both the slope of the tachometric curve and the acceleration of the oculomotor activity will stay constant as well, even if other measures of psychophysical performance do change. These experiments are thus complementary to those of Aim 1. Subjects will perform 4 variants of the choice task in which perceptual difficulty will be fixed but the likelihoods and rewards associated with the two possible motor responses will vary. The subject's performance level, reaction times and proportions of choices are expected to change drastically across the 4 conditions, but the measured correlates of perceptual processing speed should not. Aim 3: To test the hypothesis that an overall increase in the level of activation in FEF alters the timing and accuracy of a subject's choices, but not the observed perceptual processing speed. Subthreshold microstimulation current will be injected into the FEF at different points in time during task performance. The question is whether the evoked activity is interpreted as a purely motor signal or if it has a direct impact on the subject's perceptual processing capacity. Intellectual merit: The proposed experiments track how a subject's perceptual performance unfolds in time, and open up an entirely new avenue for investigating how choices are made. It will be possible (1) to determine the specific contributions of various cognitive factors such as attention, motivation, motor preparation, and perceptual processing speed to a subject's measured psychophysical performance, (2) to investigate how neuronal activity is related to each of these factors during a choice task, and (3) to reveal how the time course of this neuronal activity correlates with the time course of a subject's choice accuracy. Broader impacts: (1) Teaching. The results of this study will be incorporated into courses taught by the PIs. (2) Education. Undergraduate students with a minor in neuroscience will be hosted for research academic credit in the PIs' laboratories. A graduate student and a postdoctoral fellow will develop combined electrophysiological and computational skills. (3) Scientific understanding. The results are expected to be widely discussed and disseminated. (4) Enhancement of infrastructure for research. Cutting-edge equipment will be acquired for use in this and future projects. (5) Benefits to society. The novel task design has the potential to be adapted to human subjects and become a powerful diagnostic tool for elucidating how specific neural circuits or brain 'modules' are compromised by a given mental disorder.

DESCRIPTION (provided by applicant): The goal of this project is to investigate the perceptual andmotor contributions of the superior colliculus (SC) to choice behavior; specifically, we propose to do this in the context of an urgent decision-making task that allows us to dissociate perceptual and motor performance with great, unprecedented effectiveness. Neuroscientists have intensely studied choice behavior with numerous tasks in which a perceptual judgement is made and is followed by a motor report. While highly successful, this approach has limitations. Most notably, various covert factors such as attention, anticipation, motivation or task difficulty can be traded against each other, creating ambiguities that cannot be resolved via standard psychophysical metrics, i.e., reaction time and choice accuracy. Thus, fundamental questions about the timing of choices remain poorly understood. How long does it take to make a perceptual judgement versus executing a motor action to report it? At what point in time is a subject committed to a particular option? When the success rate increases, is it because stimuli are processed more efficiently, or faster, or because more time is dedicated to their analysis? The PIs in this project recently developed an urgent-choice task with which these questions - and the underlying neural mechanisms - can be examined in a direct, unambiguous way. It produces a new psychophysical measure, the tachometric curve, which characterizes a subject's perceptual performance over time independently of motor execution. The PIs have also constructed a computational model that relates neuronal responses to the subjects' behavior with great quantitative detail. In the proposed experiments, neuronal activity in the SC will be recorded from monkeys trained to performthis novel saccadic-choice task. Two problems will be addressed. First, the participation of the SC in perceptual processing, which in contrast to the SC's firmly established role in saccade execution, remains less well characterized. The unique properties of the tachometric curve will be exploited to determine when perceptual information informs the SC activity, and how this correlates with the temporal evolution of the subject's percept during task performance (Aim 1). In addition, subthreshold microstimulation current will be injected into the SC using various spatial and temporal configurations to determine how the artificially evoked activity impacts perceptual and motor performance (Aim2). The second problemis how choice behavior changes when it is driven by multisensory stimuli; that is, by the simultaneous presentation of visual and auditory cues. The SC is known to respond most effectively to such stimulus combinations, but their impact during choice behavior has not been assessed. A multisensory variant of the task will be used to determine whether multisensory integration alters the speed of the perceptual judgements or of the saccadic motor plans (Aim 3). This work will provide critical insight about how perceptual information is dynamically translated into motor output, will characterize how multisensory integration at the neuronal level leads to enhanced behavioral performance, and will determine how the SC participates in these processes..

? DESCRIPTION (provided by applicant): Conditions that manifest as abnormalities of eye movement have etiologies ranging from peripheral muscle pathology (e.g., gaze palsy) to central cognitive impairment (e.g., schizophrenia). Because eye movements are the key mediators of visual perception, disorders of ocular motility have consequences ranging in severity from blindness and low vision to the inability to perform daily tasks such as reading or crossing the street. Understanding the mechanisms of how eye movements are generated and controlled in the service of visual function holds the key to reducing the public health burden of these pathological states. Our goal is to assemble both early-career and established oculomotor and vision scientists for the dual purpose of assessing the current state of our field and for mapping its future direction. Such timely and focused scientific interaction is a key to progress on ameliorating the impact of oculomotor and visual diseases. The Gordon Research Conference (GRC) format is renowned for promoting meaningful and productive interactions by creating an environment that is at once informal and intensely focused on the very latest, cutting-edge research in the field. The first ever GRC on eye movements was in 2005, followed by meetings in 2007, 2011, and 2013. Each meeting has witnessed both conceptual and physical growth in the field, with 2013 the most successful to date. In addition to a range of topics that expanded the scope of the oculomotor field, the 2013 meeting included the first ever eye movement Gordon Research Seminar (GRS) designed to promote the careers of trainees. Seizing on this momentum, we will hold our second GRS in concert with a 2015 GRC that will reveal fresh perspectives on core oculomotor issues. Oculomotor Biomarkers For Psychiatric Disorders, considers the clinical implications of ocular motility for understanding neurological impairment; The Why and Where of Looking: Eye Movements for Natural Vision, considers the rules that govern oculomotor interrogation of the visual world; Eye Fields in Nonhuman Primates and Humans, examines similarities and differences in the cortical control of volitional eye movements across species; Just Can't Wait: Anticipatory Visual Analysis before Saccades explores how ocular motility impacts visual perception from neurophysiological and behavioral perspectives; Hering or Helmholtz? Probing the Interactions between Conjugate and Disconjugate Gaze, examines fundamental questions relating to the neural control of the two eyes; Vision, Efference Copy, and Probabilistic Inference: Insights into Vestibular Function and Development, presents the latest insights into visual-vestibular interactions; and Optogenetics and Eye Movements: What have we Learned, What can we Learn? looks to the future to consider how the emergence of optogenetics could transform understanding of eye movement control. The present proposal requests support for a comprehensive and forward-looking program designed to disseminate the latest knowledge, foster novel collaborative efforts, and advance the careers of future oculomotorists, all in the service of enhancing the impact of oculomotor research.

? DESCRIPTION (provided by applicant): The goal of this project is to investigate the neural mechanisms whereby perceptual information guides oculomotor choices; speci?cally, we propose to record neuronal activity in the context of urgent decision-making, which allows us to dissociate perceptual and motor performance with unprecedented effectiveness. Neuroscientists have successfully studied choice behavior with numerous tasks in which a perceptual judgment is made and is followed by a motor report, but this approach has limitations. First, it allows various covert factors such as attention, anticipation, or task difculty to be traded against each other, creating ambiguities that cannot be resolved via standard psychophysical metrics, i.e., reaction time and choice accuracy. And second, serialization suppresses the rapid, reciprocal interaction between perceptual-analysis and motor-planning processes from which informed saccadic choices normally arise. In contrast, our approach is based on a recently developed task in which decisions are urgent, minimizing both of these problems. Notably, our framework also includes a heuristic model that relates neuronal responses to the subjects' behavior in this task with great quantitative detail. Thus, we propose to study how perception informs motor planning during urgent saccadic choices, engaging these processes within their natural time scale and dynamics and accurately relating them to psychophysical performance over time (during a trial). In the proposed experiments, oculomotor activity will be recorded from monkeys trained to perform several variants of our urgent choice task. Three problems will be addressed. First, the internal organization of the Frontal Eye Field (FEF), and how distinct neuron types within it participate in choice behavior. The idea is to simultaneously manipulate temporal and attentional demands to avoid the arti?cial alignment between attention and eye movements that standard tasks typically impose, and which confounds their neural correlates. The goal is to determine the contributions of FEF visual, visuomotor, and motor neurons to key neural functions: perceptual discrimination, attentional deployment, and motor planning (Aim 1). The second problem is how separate sensory cues are integrated to in?uence a motor plan and the ensuing choice. So, when an urgent decision is based on two informative features (e.g., shape and color) rather than one alone, perceptual performance may increase either because the perceptual process starts sooner or because it becomes more ef?cient, for instance, but each mechanism will have distinct psychophysical and neuronal signatures (Aim 2). Finally, both the FEF and lateral intraparietal area (LIP) are crucial for generating eye movements, but establishing essential functional distinctions between them has been dif?cult. We propose that fundamental differences should be observed when both urgency and attentional demands are varied during saccadic choices. This work will provide critical insight about how perceptual information is dynamically translated into motor output, will characterize how sensory information is integrated to generate enhanced behavioral performance, and will determine the degree of specialization of FEF and LIP in these processes. 1

Project Summary/Abstract The choice of where to look next entails selecting one particular motor action from a repertoire of available options, with the selection process being guided primarily by current perceptual information and, more indi- rectly, by internal factors such as motivation, current goals, previous experience, etc. The goal of this project is to develop and test a mechanistic framework for describing how perceptual and motor-planning processes dynamically interact and give rise to saccadic choices. What is partiuclarly ambitious about this project is that it aims to provide a parametrically detailed framework that is applicable to a large family of tasks while being tightly constrained by neurophysiology. In traditional studies of choice behavior, a decision based on a sen- sory stimulus is made ?rst and is then followed by a motor report. Under such conditions, a choice is often conceived as a serial process of perceptual evaluation followed by action selection, where the perceptual judg- ment (e.g., a color or motion discrimination) is relatively slow (?hundreds of ms). However, in the case of saccadic choices this scheme is rather misleading, because under natural viewing conditions the median time between gaze ?xations is rather short (200?250 ms), and the next saccade is always being planned. Based on urgency manipulations, recent work from our laboratory has uncovered many details about how perception and attention guide the choice process under more temporally realistic conditions, i.e., when the perceptual evaluation occurs rapidly (< 50 ms) and informs oculomotor plans that are already ongoing. By combining our urgent-choice paradigms with neurophysiological and theoretical results, we have developed a modeling framework that (1) is applicable to a wide range of saccadic choice tasks, (2) replicates rich psychophysical data with exquisite detail, and (3) is ?rmly consistent with the oculomotor activity observed in the frontal eye ?eld (FEF). Here we propose to develop and test this framework and its predictions with a variety of saccadic choice tasks to be performed by human subjects. These tasks give rise to psychometric measurements that are unique in their temporal resolution, and based on such measurements, we will investigate how exogenous (saliency- driven) and endogenous (rule-driven) spatial attention relate to oculomotor activity, how they interact with and differ from each other, and how their dynamics relate to individual differences in task performance be- tween participants. Using the computational model to ?t the data, we will test speci?c mechanistic hypotheses about visuomotor interactions. The key innovations of this project are, ?rst, that it investigates eye movements in the rapid timescale that is relevant for naturally occurring visuomotor behaviors; second, that it is integra- tive, i.e., it aims to synthesize numerous neurophysiological and psychophysical results into a small number of principles whereby perceptuo-motor interactions give rise to saccadic choices; and third, that it identi?es robust psychometric properties that can serve to characterize fundamental cognitive functions in both healthy and clinical populations.

Project Summary/Abstract The goal of this project is to investigate the neural mechanisms whereby perceptual information guides the choice of where to look next; speci?cally, we propose to record neuronal activity during urgent decision making to examine with ?ne temporal resolution how perception informs motor planning. Neuroscientists normally study choice behavior with tasks in which a perceptual judgment is made and is followed by a motor report, but this approach has limitations. First, it allows various covert factors such as attention, anticipation, or task dif?- culty to be traded against each other, creating ambiguities that cannot be resolved via standard psychophysical metrics, i.e., reaction time and choice accuracy. And second, serialization suppresses the rapid, reciprocal inter- action between perceptual analysis and motor planning from which informed saccadic choices normally arise. Our approach is based on a recently developed task in which decisions are urgent and both of these problems are minimized. Our framework also includes a heuristic, physiologically grounded model that reproduces the subjects' rich behavior with great detail. Thus, we propose to study how perception informs motor planning using time pressure to engage these processes within their natural time scale and dynamics, and relate them quantitatively to psychophysical performance. Oculomotor activity will be recorded from monkeys trained to perform several variants of our urgent choice paradigm. In Aim 1 we will investigate the relationship between exogenous (or bottom-up) attention and motor planning by varying the relative salience of target and distracter during an urgent choice. We hypothesize that the re?exive, salience-driven form of attention acts through two speci?c mechanisms: acceleration of ongoing motor plans that are spatially congruent with it, and halting of those plans that are spatially incongruent. In Aim 2 we will investigate the relationship between attention, motor planning, and accumulation of sensory evidence by training monkeys to perform an urgent version of the well known random-dot motion discrimination task. In this case, because the locations of the two choice targets are dissociated from that of the stimulus to be discriminated, we expect to observe a tradeoff between stimulus-driven activity (signaling the deployment of attention to the stimulus) and target-driven activity (sig- naling the impending eye movement). Our previous and current preliminary results indicate that we will be able to resolve exquisitely orchestrated interactions between perceptual signals and ongoing motor activity that unfold very rapidly, within a few tens of ms, and are otherwise experimentally inaccessible. We will exploit this capability to draw essential functional distinctions between the frontal eye ?eld (FEF) and the lateral intra- parietal area (LIP), and to determine the distinct contributions of classical cell types (visual, visuomotor, and motor) to perceptually guided choices within each of these key oculomotor structures. This work will provide critical insight about how perceptual information is dynamically incorporated into ongoing motor activity, and how this interaction determines saccadic-choice performance.