Michael N. Shadlen - US grants

[unreadable] DESCRIPTION (provided by applicant): The neurobiology of vision has emerged as the premier model for understanding higher cognitive processes such as decision-making. Indeed much is now understood about the neural mechanisms that underlie both the speed and accuracy of simple decisions between two alternative interpretations of an ambiguous visual stimulus. In a motion discrimination task, for example, neurons in the parietal cortex of the monkey accumulate evidence for the alternatives by integrating, as a function of time, the responses of neurons in the visual cortex. The decision process is thought to terminate when the accumulation of evidence reaches a criterion level. Although these neurons lend insight into the brain's computations, it is not known whether they actually cause the brain to commit to a decision. Nor is it known how they govern more complex decisions. The proposed research tests the hypothesis that neurons in parietal cortex play a causal role in decisions, and it examines the role of these neurons in more complicated decisions that are more like the ones humans rely on to perform cognitive tasks. The experiments combine neural recording and stimulation in rhesus monkeys with behavioral measurements in both monkeys and humans. Three specific aims are planned. 1) Microstimulation of the lateral intraparietal area (LIP) will elucidate how changes in the activity of LIP neurons affect perceptual decisions about an ambiguous motion stimulus and whether these neurons cause the brain to commit to a decision. 2) Neural recordings in area LIP along with behavioral testing in monkey and man will reveal the mechanism underlying perceptual decisions when there are more than two alternatives to choose among. 3) Neural recordings in area LIP along with behavioral testing in monkey and man will reveal how the brain combines information from several sources to reach a decision in a probabilistic classification task. Understanding the neural mechanisms that underlie decisions will help to elucidate the principles of neuroscience that give rise to cognition and its disorders. The proposed experiments leverage a solid foundation of knowledge of visual neuroscience toward an understanding of cognitive reasoning. Such understanding promises to provide the means to promote recovery of both sensory and intellectual function in the face of neurological disease. [unreadable] [unreadable] [unreadable]

Primates; Mammalia;

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DESCRIPTION (provided by applicant): The neurobiology of decision making has emerged as a model platform to understand fundamental brain mechanisms that underlie cognition. The remarkable progress in this area is attributed to its strong quantitative and empirical foundation in the study of visual perception and visual neuroscience in human and nonhuman primates. Thus, visual perceptual decision-making in nonhuman primates has begun to expose key principles of higher brain function and their underlying mechanisms - integration of sensory evidence, flexible timing, and setting criteria to terminate a process. These mechanisms comprise the rudiments of complex cognitive functions. They make a normal brain not confused: able to reason, prioritize, infer causes and consequences, assign authorship to one's own thoughts, explore, avoid distractions and engage with the environment. It seems likely that advances in the treatments of diseases affecting higher brain function will one day rely on an ability to manipulate circuits in order to affect the expression of these mechanisms. The research proposed in this application represents a step in this direction. The three scientific aims develop traditional electrical stimulation tools and emerging light-activation tools (optogenetics) for manipulating brain activity during decision making. The experiments will elucidate the neural mechanisms that explain the process of deliberation leading to a choice, the likelihood that such a choice is the correct one (i.e., accuracy), the amount of time it takes o make the choice (i.e., reaction time), and the confidence that a decision-maker has in a choice before the outcome is known. The first experimental aim examines the effect of electrical microstimulation of ~100 neurons in the visual cortex of a monkey (M. mulatta) during a difficult perceptual decision. Microstimulation is known to affect choice and reaction time in this setting, but the experiments will assess, for the first time, whether the manipulation reduces or enhances confidence in a decision. The second and third aims introduce emerging optogenetic methods in the same decision-making task. These experiments exploit a new capacity to induce neurons in the adult macaque brain to express channelrhodopsin (ChR2) and other light sensitive ion pumps. Aim 2 examines the effect of photostimulation on choice-accuracy and reaction-time. Aim 3 recapitulates the confidence measurements using light instead of electrical current to stimulate neurons. These studies promise to elucidate neural mechanisms of perception and decision-making. Moreover, by advancing optogenetic methods in the macaque, the proposed research will facilitate the study of sophisticated neural mechanisms at a more refined level than was hitherto possible.

The Directorate of Social, Behavioral and Economic Sciences offers postdoctoral research fellowships to provide opportunities for recent doctoral graduates to obtain additional training, to gain research experience under the sponsorship of established scientists, and to broaden their scientific horizons beyond their undergraduate and graduate training. Postdoctoral fellowships are further designed to assist new scientists to direct their research efforts across traditional disciplinary lines and to avail themselves of unique research resources, sites, and facilities, including at foreign locations. This postdoctoral fellowship award supports a rising interdisciplinary scholar at the intersection of psychology, neuroscience and economics. In this project, the goal is to explore how decision-making is influenced by episodic memory, by using tools and theories from the above-mentioned fields, with the addition of computational modeling. Memory is essential to adaptive behavior, enabling organisms to draw on past experience to improve choices. Yet, the neural and cognitive mechanisms by which memory guides decision making are poorly understood. Despite substantial advances in understanding neural mechanisms of memory, on one hand, and those of decision making, on the other, remarkably little is known about a central adaptive aspect of memory function: how memory for the past is used to guide decisions. The proposed research aims to address this gap by bringing together three fields: psychology, neuroscience and economics. This NSF Fellow proposes a novel framework for beginning to understand how memory for specific episodes ("episodic memory") is used to guide value-based decisions. Our overarching hypothesis is that many value-based decisions involve sampling evidence from memory to inform the decision. This team will test their hypothesis by integrating computational modeling with eyetracking and functional imaging (fMRI) in humans to investigate the neural mechanisms by which episodic memory contributes to decision making. Determining the brain and cognitive mechanisms by which memory guides decisions will lay the foundation for potential future interventions which could radically shape policy. Poor decision making has been linked to poverty and aging with cascading effects on society more generally. The proposed results could help improve individual and collective decision making with clear implications for improving education and decision making across a diverse population.

Although it may seem obvious that many decisions are guided by memory, most studies on value-based decisions have focused on how repeated rewards incrementally form habitual decisions, which are distinct from pervasive more flexible and deliberative decisions that rely on episodic memory. This team's overall approach draws on advances in the neurobiological mechanisms of perceptual decision making. In perceptual decisions, such as deciding the direction of moving random dots, visual motion information is accumulated and when enough information is accumulated, a decision is made. This accumulation process is reflected in the firing rates of neurons in association and premotor cortices. Furthermore, the speed and accuracy of the decision are explained by a threshold (or bound) applied to the accumulation of information from the visual cortex. This team hypothesizes that a similar process accounts for how memories guide value-based decisions; in particular, we propose that sequential memory retrieval enters value based decisions in the same way that visual motion information is accumulated towards a perceptual decision. By linking memory, value and choice, this knowledge is expected to have important implications for multiple fields, including psychology, economics and neuroscience.

Abstract The neurobiology of perceptual decision-making elucidates fundamental neural mechanisms of higher cognitive function, the understanding of which will inspire new strategies to treat neurological and psychiatric diseases affecting thought, perception and awareness. The inquiry focuses on processes that intervene between the acquisition of sensory evidence and commitment to a proposition, behavioral choice, or plan. Progress was facilitated by the discovery of persistent neural activity in prefrontal and parietal association cortex of the monkey. By requiring a monkey to communicate its decision with an eye movement, the decision process is observable as an evolving neural commitment to one action or another. Much is now understood about the neural mechanisms that underlie the accumulation of evidence, the tradeoff between speed and accuracy, the assessment of confidence in a decision, and the incorporation of bias. However, it is unknown how these mechanisms can apply to more complex decisions that are not construed as a dedicated chain from a single source of evidence to action selection. A critical limitation to progress is a gap in knowledge about the flow of information between circuits when the path from evidence to action is indirect and flexibly controlled. The current proposal addresses this problem by developing new behavioral tasks in which the path from sensation to decision to action is diverted or elaborated, and it exploits emerging tools to measure and manipulate neural activity in order to characterize interactions between populations of neurons in the service parallel, serial and multiplexed computations. Aim 1 elucidates context-dependent interactions between two parietal areas that mediate decisions communicated by an eye or arm movement. Simultaneous multichannel neural recording from the medial and lateral intraparietal areas will expose patterns of serial inheritance or parallel processing of evidence, the decision and termination. Aim 2 elucidates the dynamical changes in the representation of a decision when the decision to action mapping changes during the decision itself. Neural recordings are obtained from the parietal cortex of monkeys during a perceptual decision that is suspended by an intervening eye movement task. If successful, Aim 2 will forge a connection between the stability of vision across changes of gaze and the integrity of a decision across changes of intention. Aim 3 investigates a processing bottleneck that arises when two streams of evidence support two distinct decisions about a single object, that is, a double decision. Behavioral evidence from humans and monkeys indicates that sensory evidence can be acquired in parallel, but is incorporated sequentially into the double-decision. Aim 3 thus promises to elucidate the neural mechanisms of this serial incorporation and thus begin to explain why mental operations take the time they do. Together the proposed research will open new areas of computational and mechanistic interrogation of circuit interactions in the service of decision-making and cognitive control.

Project Abstract Perceptual decision making relies on cognitive processes such as acquiring and integrating sensory information, holding information in working memory, incorporating biases, setting a speed-accuracy regime, and planning a motor response. Many of these processes are affected (compared to age-matched controls) in patients with early Alzheimer's disease (AD). The neural correlates of these cognitive processes have been identified in persistently active neurons in frontal and parietal association cortex. We will test the hypothesis that disruption of persistent activity underlies some of the deficits seen in decision making in AD. Our first aim is to characterize the ability of patients with AD to incorporate evidence, environmental biases, and time pressure into their decisions. We will leverage the insights into the neural and computational basis of these abilities obtained from a well-studied perceptual decision making task. By comparing the performance of patients in this task against age matched controls, we will gain insights into the nature of the neural computations that are disrupted in early AD. The experiments also have the potential to uncover new behavioral markers for early AD. Our second aim is to mimic the deficits seen in AD in the macaque monkey by manipulating persistent activity in parietal association cortex while they perform the same perceptual decision task. We will bilaterally express inhibitory chemogenetic DREADD receptors (Designed Receptors Exclusively Activated by Designer Drugs) in a subregion of parietal cortex with neurons that show persistent activity in this decision making task. Preliminary data shows that we can successfully change decision making behavior with this approach. We will build upon these results by investigating how integrating evidence, incorporating biases, and deciding under time pressure is affected by this manipulation in the same task as used with AD patients. Together, our results will provide insights into the computations that underlie decision making, their neural implementation in the primate brain, and how failure to sustain persistent activity in association cortex can lead to deficits in decision making in AD. Our long-term goal is to develop behavioral assays for early diagnosis and to gain insight into fundamental mechanisms that will ultimately lead to new therapeutic targets in AD.

Project Abstract Decision making is a core component of normal and abnormal cognitive function. Understanding the neural mechanisms of decision-making will lead to advances in the diagnosis, classification and future treatments of disorders affecting thought and control. Mathematical models of the decision process, based on bounded evidence accumulation, have been developed over decades and are being increasingly leveraged to gain deeper insights into the origins of cognitive deficits arising from a range of brain disorders. However, major gaps remain in our understanding of the neural mechanisms responsible for decision-making, thereby limiting the validity and utility of the models. A successful line of research on perceptual decision-making has established that neurons in the parietal and prefrontal cortex of the rhesus monkey (Macaca mulatta) encode the accumulating evidence bearing on the alternatives. These observations are mainly from neurons in areas of the macaque cortex that are associated with preparation of the actions (e.g. hand or eye movements) for reporting the decision alternatives. However, decisions are often formed without knowledge of what actions they might call for, and under such conditions, effector-selective neural activity does not appear to reflect accumulation dynamics. Recent studies, have identified a novel ?abstract? decision signal in non-invasive electrophysiological (EEG) recordings from human decision makers. The signal, termed the central parietal positivity (CPP), represents the accumulation of evidence for decisions irrespective of the sensory or motor requirements of the task, hence the designation, abstract. The neural circuits that give rise to the CPP are likely to explain the capacity to flexibly link decisions to various actions depending on context and goals. However, because the signal has thus far only been observed in EEG recordings from humans, its neural basis is unknown. The proposed aims will (1) establish the neural underpinnings of the CPP by establishing its analogues in single-neuron, multi-neuron, local field potentials and EEG of the macaque and (2) localizing its source in humans through the use of neuroimaging, and electrocorticography (ECoG) from patients undergoing neurosurgery. Both aims draw on an integrated computational effort that combines biophysical modeling, neural networks, and mathematical characterization of the decision process. The knowledge gained through these investigations will increase our understanding of core cognitive capacities whose deficiency contributes to major brain disorders while bridging long-standing methodological gaps in human versus non-human animal investigations.