Ralph Adolphs - US grants

DESCRIPTION (Applicant's abstract): This revised FIRST Award builds on the principal investigator's previous work on emotion, and takes advantage of the unique resources provided by the Department of Neurology at the University of Iowa. The proposed studies aim at elucidating the neural systems responsible for emotional memory in humans. The phrase "emotional memory" refers to the modulation of long-term memory by the emotional state of the subject at the time stimuli are encoded. This issue is of importance in the study of memory, because it addresses the critical question of selectivity: why are some events more memorable than others? Neutral, pleasant, and unpleasant audiovisual stimuli will be shown to subjects. Memory for the stimuli will be assessed 24 hours later with free recall tasks, verbal and visual recognition memory tasks, and by measuring autonomic responses to previously seen stimuli. Two main hypotheses will be tested with two complementary methods. 1) Amygdala, ventral prefrontal cortex, and right somatosensory cortices are hypothesized to modulate memory by emotion. This hypothesis will be tested with the lesion method, by comparing memory performances between control subjects and subjects with lesions in target structures specified in the hypothesis. 2) GABAergic and beta-adrenergic neurotransmitter systems are hypothesized to modulate memory by emotion. This hypothesis will be tested with pharmacological manipulation, by comparing within-subject performances with or without specific drugs. It is predicted that normal subjects will remember best those stimuli that they found the most emotional, but that there will be specific impairments in memory for emotional stimuli in brain-damaged subjects who have lesions in target structures, and in normal subjects who have been given pharmacological agents. The results will inform strategies for the treatment of patients with disorders of emotion and memory, such as those caused by stroke, anxiety, and depression, and will contribute to our understanding of traumatic memories and eyewitness testimony.

During the current funding period we have concentrated on the recognition of emotion from visually presented stimuli (mostly facial expressions of emotion), and on primary emotions (happiness, surprise, fear, anger, disgust, and sadness). Building on this foundation, we now propose an in-depth exploration of two unelucidated and elusive aspects of emotion processing, enactment (expression of emotion) and feeling (experience of emotion), while continuing the investigation of emotion recognition in greater detail. We also plan to enlarge the scope of our investigations, to include social emotions. We will test a series of specific hypotheses to address the following key questions: (a) What are the neuroanatomical systems responsible for processing different primary emotions (e.g., happiness, disgust)? (b) Are there identifiable neural systems responsible for processing different social emotions (e.g., pride, guilt)? (c) To what extent do overt and covert emotional processing draw on different neuroanatomical systems? A final aim of this project is to maintain and expand the component of the Program's Patient Registry concerned with disorders of emotion. Our approach relies on the hypothesis-driven investigation of groups of subjects with focal brain damage, using state-of-the-art neuroanatomical and neuropsychological methods. The rationale for the new phase of the program is threefold. First, emotion is a central aspect of neurobiology. It is not possible to have a comprehensive understanding of mind and brain processes without factoring in the role of emotion. Second, the impairments of emotion which follow brain dysfunction have devastating consequences in everyday life, extending from suffering at the personal level to major social burdens. Third, the investigation of emotion has lagged behind as a theme in neurobiology, and is only recently being explored in a systematic fashion. We believe that bringing the study of human emotion into mainstream neuroscience is a high priority, and that the lesion method can add uniquely to contributions made by functional imaging and electrophysiological approaches. The findings from the proposed studies will help improve diagnosis and treatment of neurological and psychiatric diseases in which impairments of emotion figure prominently.

The investigators will combine approaches from economics, decision science, and cognitive neuroscience. The goal is to develop a system to measure how well different people reason in strategic social situations, and to explore how specific parts of the brain may be involved in strategic decision making.

The investigators plan to develop a measure to summarize how specific individuals perform in a set of strategic tasks conducted in a laboratory environment. They will administer these tasks -- eg, test "strategic IQ" --to individuals in separate groups with distinct characteristics. Three groups are made up of people who we might expect to be especially good at strategic thinking: mathematically gifted undergraduate students, students trained in the formal analysis of strategic thinking (game theory), and experienced business managers. The fifth group are individuals with specialized brain lesions that have specific and well-documented effects on cognition.

Data from all groups will be combined to test a new theory developed by two of the PIs about how people learn to think strategically. An additional study will involve only members of the fifth group. These individuals will also complete strategic tasks while undergoing fMRI brain imaging scans. The goal is to link evidence about the "games" that these participants play poorly with evidence from brain images, to link specific kinds of errors to specific brain circuits.

DESCRIPTION (provided by applicant): Emotionally arousing events are often remembered better and more vividly than neutral events. This phenomenon, emotional memory, has been studied extensively in normal subjects, and impairments in emotional memory are a hallmark of neurological and psychiatric diseases, yet little is known regarding the neural mechanisms whereby it occurs. Studies in humans and other animals have shown that emotional memory depends critically on the amygdala, and point to specific unanswered questions. At what point in information processing does the amygdala modulate emotional memory? Specifically, during what window of time does the amygdala exert its modulation of memory-- early during initial processing of stimuli, throughout an extended time while information about these stimuli is consolidated in memory, or even during retrieval? We aim to address these questions by examining memory for neutral and for emotional stimuli in over 60 subjects who have damage to the amygdala, and comparing their performances to those given by controls without such damage. We will monitor eye gaze and psychophysiology during different encoding conditions, and assess memory for the stimuli at various points in time subsequently. We will also experimentally directly manipulate eye movements to visual stimuli during encoding to examine their influence on subsequent memory, and directly manipulate somatic arousal with a cortisol-inducing stressor to examine its influence on subsequent memory. Moreover, we will investigate autobiographical emotional memory, in relation to the point in time at which amygdala damage was acquired in life. Additional analyses will examine whether impairments due to amygdala damage are dissociable from those due to hippocampal damage, whether the amygdala differentially affects memory for gist and for detail information, whether left and right amygdala make different contributions to emotional memory, and whether there are gender differences. Findings from the studies will inform our understanding of emotional memory dysfunction in neurological and psychiatric disease, can be compared to a large literature on the basic science of emotional memory from studies in animals, and will complement the correlations found in functional imaging studies by establishing a causal role for the amygdala in human emotional memory.

DESCRIPTION (provided by applicant): Emotionally arousing events are often remembered better and more vividly than neutral events. This phenomenon, emotional memory, has been studied extensively in normal subjects, and impairments in emotional memory are a hallmark of neurological and psychiatric diseases, yet little is known regarding the neural mechanisms whereby it occurs. Studies in humans and other animals have shown that emotional memory depends critically on the amygdala, and point to specific unanswered questions. At what point in information processing does the amygdala modulate emotional memory? Specifically, during what window of time does the amygdala exert its modulation of memory-- early during initial processing of stimuli, throughout an extended time while information about these stimuli is consolidated in memory, or even during retrieval? We aim to address these questions by examining memory for neutral and for emotional stimuli in over 60 subjects who have damage to the amygdala, and comparing their performances to those given by controls without such damage. We will monitor eye gaze and psychophysiology during different encoding conditions, and assess memory for the stimuli at various points in time subsequently. We will also experimentally directly manipulate eye movements to visual stimuli during encoding to examine their influence on subsequent memory, and directly manipulate somatic arousal with a cortisol-inducing stressor to examine its influence on subsequent memory. Moreover, we will investigate autobiographical emotional memory, in relation to the point in time at which amygdala damage was acquired in life. Additional analyses will examine whether impairments due to amygdala damage are dissociable from those due to hippocampal damage, whether the amygdala differentially affects memory for gist and for detail information, whether left and right amygdala make different contributions to emotional memory, and whether there are gender differences. Findings from the studies will inform our understanding of emotional memory dysfunction in neurological and psychiatric disease, can be compared to a large literature on the basic science of emotional memory from studies in animals, and will complement the correlations found in functional imaging studies by establishing a causal role for the amygdala in human emotional memory.

This Integrative Graduate Education and Research Traineeship (IGERT) award supports the development of a multidisciplinary graduate training program in Brain, Mind, and Society. Its purpose is to provide students with the analytical foundations and the experimental skills needed to pursue scientific careers at the intersection of neuroscience and the social sciences, who are capable of integrating neural, psychological, and economic approaches to attack basic and applied problems related to valuation, human decision making, and social exchange. Trainees will take a rigorously designed, largely team-taught course sequence, spanning from nervous system organization and function to mathematical models of decision making and social exchange. This coursework will be complemented by equal balance in cross-disciplinary laboratory research, thereby tightly integrating research training with scholarship to create true intellectual hybrids across both disciplines.
The Brain, Mind, and Society program emphasizes the inclusion of highly qualified underrepresented students through a four-tiered outreach program, Science Matters, involving a team-based mentorship program bringing together students from the this program, underrepresented undergraduate students at Cal State University, Los Angeles and underrepresented high school students in Los Angeles' Belmont Schools. The resulting diversity of the program's collaborative teams will reflect the program's broader impact in five key social application areas, which may ultimately provide a new scientifically-enriched discourse to help us understand critical social problems, in economic, therapeutic, educational, philosophical, and business and political applications. IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

DESCRIPTION (provided by applicant): Studies from our laboratory as well as others over the past decade have confirmed the important participation of the amygdala in social perception, such as processing faces, and generated hypotheses about its role in mental illness, such as autism. Yet the precise role that the amygdala might play in mediating an endophenotype for social dysfunction remains poorly understood. This revised application plans a systematic and in-depth investigation of this topic in three specific aims. Aim 1 will investigate eye movements and emotional response during real social interactions (over live video and during face-to-face interactions). This will quantify the amygdala's contribution to realistic social interactions, and the impairments arising from autism. Aim 2 will investigate in more detail processing of social scenes containing faces, and tease apart possible aversion to faces from lack of attraction to them. Aim 3 will use the "bubbles" method to investigate which features in faces drive discrimination at the behavioral, emotional, and neural level. These experiments will be complemented by detailed questionnaires and interviews to assess real-life social functioning, and to explore individual differences. The aims will be carried out in neurological subjects with focal lesions of the amygdala, in high-functioning subjects with autism, in parents of autistic children who have the Broad Autism Phenotype, as well as in neurotypical controls. Contrasts between these groups will test the overall hypothesis that amygdala dysfunction contributes to the social impairments seen in autism as well as in first-degree relatives of people with autism. An endophenotype for impaired amygdala function is likely to contribute to several psychiatric illnesses in which the amygdala is thought to be dysfunctional, including depression, anxiety disorders, schizophrenia and autism. It is also likely to contribute to individual differences in the healthy population on dimensions that predispose to these psychiatric diseases, especially in those who share substantial genetic variance with these diseases (such as first-degree relatives). Our stimuli and methods will be made available to researchers and clinicians studying mental illness, and will inform diagnosis as well as provide a basis for designing future interventions.

We often make choices without knowing why or in some cases even without being aware that we made a choice at all. Moreover, we sometimes find ourselves having made choices that, with hindsight, we do not believe we should have made. For example, we might find ourselves with a cookie in our mouth despite firm intentions to diet; or we might find ourselves strongly liking or disliking a person without any knowledge of why.

These examples are puzzling because we tend to think that all choices are deliberate and based on information of which we are fully aware. Clearly, this is not the case. In fact, it may be the exception. Yet there must always be some signature of our choice, and of the ingredients that went into it, in our brains. In this research project, the Principal Investigators will conduct a series of studies that systematically explore what happens our brains when we make various kinds of decisions, some conscious, some non-conscious, using state-of-the-art tools from cognitive neuroscience: high resolution magnetic resonance imaging, and rare electrical recordings of the brain from neurosurgical patients. These studies will result in an unprecedented dissection of the different components that contribute to how we make decisions and provide novel insights into the role of consciousness in human behavior.

The studies will help to answer some important outstanding questions in neuroscience, psychology, and economics. How quickly do we make decisions? Are consciously made choices slower than ones made in the absence of consciousness? Do animals make conscious choices? How conscious are the choices made by people who are addicted to drugs, to shopping, or to gambling? Can we consciously override strong preferences of which we are not aware? Answering these questions will allow us to understand the mechanisms behind decision-making. It will also give us a deeper understanding of the nature of consciousness and what it contributes to human behavior. Finally, the insights obtained from our studies will lay the groundwork for engineering intelligent decision-making in computers, robots, and distributed systems.

This three-year grant will purchase two pieces of equipment for magnetic resonance imaging of the brain at the California Institute of Technology. One equipment piece provides the best resolution in a horizontal orientation; the second provides imaging of behaving monkeys in vertical position. This will provide state-of-the-art tools for investigating brain structure and function in monkeys with noninvasive methods, and also provide opportunities for imaging post-mortem human brains. The technology will make possible a set of research studies on how the brain processes information, including how it sees faces, how it weighs different choices, and how it makes decisions and guides action. These are important questions in neuroscience, and the new equipment will greatly enhance science at the Caltech Brain Imaging Center. The grant will also provide opportunities for training of students and post-docs on the new equipment. This will include classes taught at Caltech as well as participation in individual research projects. The development of these new scientific tools will lead to a better understanding of how the brain works, and how it is "wired up." That knowledge, in turn, will contribute to efforts to build artificially intelligent systems. Taken together, the cutting-edge science enabled by the new equipment, and the training of the next generation of young scientists on it, will contribute substantially to cognitive neuroscience in America and worldwide.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5).

This NSF Major Research Instrumentation (MRI-R2) Award will enable a three-year grant to purchase an upgrade for a single piece of equipment for imaging the human brain at the California Institute of Technology. The upgrade, a 32-channel Total Imaging Matrix upgrade of a Siemens 3.0 Tesla MRI scanner, will substantially improve the resolution, the speed with which experiments can be done, and the kinds of imaging sequences that can be programmed. Taken together, these major enhancements will enable a range of questions about the structure, connectivity, and functioning of the human brain. Researchers at Caltech, in collaboration with a national and international consortium of scientists, will use the equipment to investigate how the brain makes financial decisions, how social information such as faces are processed, and how brain-machine interfaces can be built to decipher information from the brain to guide robotic prostheses. These are important, big open questions in neuroscience, and the new equipment will greatly enhance science at the Caltech Brain Imaging Center.

The grant will also provide opportunities for training of students and post-docs on the new equipment. This will include classes taught at Caltech as well as participation in individual research projects. The development of these new scientific tools will lead to a better understanding of how the brain works, how it is wired up, and how it may dysfunction in disease. That knowledge, in turn, will contribute to efforts to build artificially intelligent systems. Taken together, the cutting-edge science enabled by the new equipment, and the training of the next generation of young scientists on it, will contribute substantially to cognitive neuroscience in America and worldwide.

Building on the prior Projects, this last Project will take our investigations of the social decision-making system to the network level and investigate the influences among its components using techniques such as pharmacological inactivation, rare human lesion subjects, diffusion imaging, BOLD coherence and spike-field coherence. It will pave the way for major future efforts, beyond the scope of the present application, eventually to understand the complete functional architecture for social decision-making implemented by a spatially distributed neural system. Specifically, we will focus on how the components of the system identified in the other Projects (e.g., amygdala, dorsolateral and orbital prefrontal cortex) interact. This requires investigations of two kinds: (1) demonstration of the functional effects on one another (Aims 1-2), and (2) characterization of their connectivity (Aims 3-4). This Project features a very close integration of studies in humans and monkeys, uses a diverse set of approaches ranging from diffusion imaging to tracer studies to pharmacological inactivation and spike-field coherence, and leverages many of the data collected under the other Projects. There are four Specific Aims: (1) to characterize interactions between prefrontal and amygdala regions in monkeys and humans using spike-field coherence (collaboration with Dr Doris Tsao); (2) to investigate causal influences of the amygdala on the prefrontal cortex using reversible pharmacological inactivation in monkeys and study of rare human lesion subjects (collaboration with Dr. Richard Andersen); (3) to describe structural and functional connectivity networks in monkeys (4) to describe structural and functional connectivity networks in humans. This final Project thus extends the studies from the prior Projects to the network level, and brings together many of the PIs from the prior Projects.

This Conte Center resubmission will use a multi-modal, multi-species approach to investigate the neurobiological underpinnings of social decision-making. Three cores provide administrative, neuroimaging, and participant recruitment and assessment resources for four Projects that are each directed by internationally renowned leaders in social neuroscience and decision neuroscience, all of whom have a track record of scientific collaboration, student training, and expertise in the topic of the planned studies. The Projects constitute a cohesive set of experiments in humans and monkeys that will use the resources of the Caltech Brain Imaging Center for fMRI studies of the brain, existing collaborations with three hospitals for intracranial recordings in neurosurgical patients, together with the resources of labs at Caltech and at Cambridge for electrophysiological recordings in nonhuman primates. Project 1 provides a foundational investigation of basic social reward processing (e.g., representing the value of emotional faces), and how this compares with nonsocial reward processing (e.g., the value of juice). Project 2 investigates how we can learn choices by observing other people's decisions. Project 3 investigates how we can make decisions that are based on another person's value (such as in altruistic behaviors). Project 4 investigates the connectivity of the brain structures revealed by the other Projects to underlie social decision-making, such as the amygdala and parts of the prefrontal cortex. Each Project includes both fMRI and electrophysiology, and studies in both humans and monkeys. This science is woven into a training and outreach program emphasizing dissemination and diversity; and all data are made available for data sharing. The uniform recruitment and assessment of participants, the tight integration and communication between Projects, and the collaborative track record of the team will leverage these studies to a systematic and coordinated investigation of the largest outstanding questions in social decision-making, an enterprise that only a Conte Center mechanism could make possible.

CORE 1 will provide the administrative coordination, oversight, and logistical support for the entire Conte Center It will hire a part-time administrative staff who is currently laboratory administrator for the PI and whose duties already entail grant management, coordination with the Caltech Brain Imaging Center, and supervision of other staff. This Core includes support for visits of all the PIs to NIH for annual meetings, visits for the Advisory Board to Caltech annually, travel for off-site collaborators to attend NIH site visits, and maintenance of a website dedicated to the Conte Center. There are three Aims: to coordinate and communicate internally among all the investigators of the Conte Center to facilitate the science proposed; to coordinate the best teaching and training of graduate-students, post-docs, and undergraduates; and to coordinate and communicate between the investigators of the Conte Center and the outside research community, NIH, and the larger public.

Core 1. Project Summary. Core 1 will provide the administrative coordination, oversight, and logistical support for the entire Conte Center. It will hire a part-time administrative staff (Dr. Remya Nair) who is currently laboratory administrator for the PI and whose duties already entail grant management, coordination with the Caltech Brain Imaging Center, and supervision of other staff. This Core includes support for visits of all the PIs to Caltech for annual meetings, visits for the Advisory Board to Caltech annually, and continued maintenance of our website dedicated to the Conte Center. There are three Aims: to coordinate and communicate internally among all the investigators of the Conte Center to facilitate the science proposed; to coordinate the best teaching and training of graduate-students, post-docs, and undergraduates; and to coordinate and communicate between the investigators of the Conte Center and the outside research community, NIH, and the larger public.

This NSF Major Research Instrumentation (MRI) Award will enable a three-year grant to purchase a major upgrade to the magnetic resonance imaging scanner used for studying the function and structure of the human brain by neuroscience researchers at the California Institute of Technology and their national and international collaborators. The award will support the upgrade of the existing Siemens Tim Trio 3T scanner at the Caltech Brain Imaging Center to the latest Siemens Prisma platform. The upgraded scanner will provide clearer and more detailed images of the human brain. Such an improvement in imaging capabilities will enable Caltech researchers to address fundamental problems such as how the brain learns from experience, how the brain makes decisions and how brains support the ability to learn from and interact with other people in social contexts. This new equipment will ultimately help Caltech researchers obtain a better understanding of how the brain works, how it is wired up, and how it may dysfunction in disease. That knowledge, in turn, will contribute to efforts to build artificially intelligent systems. The grant will also enable students and post-docs to obtain experience in using state-of-the-art brain imaging equipment, through classes taught at Caltech that offer hands-on-experience as well as through the participation of trainees in research projects that utilize the equipment. Taken together, the cutting-edge science enabled by the new equipment, and the training of the next generation of young scientists on it, will contribute substantially to cognitive, decision and social neuroscience at Caltech, in the US and worldwide.

To advance understanding about how the brain supports the capacity of humans to learn, make decisions and mediate social interactions it will be necessary to make progress in three distinct domains. First, there is a need to develop a much more detailed circuit-level understanding of the neural mechanisms underlying these various computational processes by resolving the functional properties of discrete neuroanatomical sub-divisions within each of the relevant brain areas of interest such as the amygdala, ventromedial prefrontal cortex, striatum and midbrain. Second, it is necessary to address how the various sub-processes that are implemented in these distinct sub-systems are ultimately integrated together at the systems level to drive complex behavior. Third, it will be important to characterize how the various computations and neural implementations differ across time, tasks and individuals. The Siemens Prisma scanner provides technical capabilities that are uniquely suited to advance progress in each of these three domains at the California Institute of Technology. The new platform will offer significant improvements in the quality of high resolution fMRI scans obtained from brain structures of interest, by minimizing dropout and geometric distortion, and by increasing signal-to-noise. These capabilities will also enhance the stability of the images obtained and hence improve test-retest reliability, while the improved gradient set will offer major gains in the quality of diffusion weighted imaging, and of functional connectivity data.

Project 2. Project Summary. This Project 2 is a renewal of Project 3 in our current Conte Center. It has Ralph Adolphs (overall Center Director) and Cendri Hutcherson (formerly post-doc on current Project 3, now faculty) as co-PIs and includes a modest subcontract to the University of Toronto, Canada (Hutcherson). Its overall goal is to understand how social inference and context (the focus theme of this Conte Center) guide social decision-making, with a specific focus on prosocial (altruistic) decisions. A counterpart to this is Project 3, which will investigate how social inference and context guide decisions related to social threat. Project 2 will focus on how we represent the internal states of another person (social inference representations, Aim 1), how such representations are then used to make altruistic social decisions (Aim 2), and where in these processes we find individual differences that may correlate with measures like autistic traits, empathy, or social network size (Aim 3). As with Projects 1 and 3 in this Conte Center renewal, this Project 2 focuses on fMRI studies in healthy individuals. Also as with Projects 1 and 3, this Project 2 has links to Aims under other Projects that offer a complementary approach. Specifically, it features computational models (drift-diffusion models) that will also be leveraged in Project 3, and it will develop a battery of social inference tasks (versions of the RDoC-listed ?why/how? task) that will also be administered to patients with focal lesions of the prefrontal cortex under Project 5. As well, we plan to make specific comparisons between the neural systems for social inference revealed under this Project 2 with social neuroscience tasks such as the ?why/how? task, and the systems revealed with computational fMRI investigated for observational learning in Project 1 (using cross-task decoding in overlapping subjects). The strong links between Project 2 and others is reflected in its personnel: it lists PIs from other Projects (O'Doherty, Tranel, Camerer) and shares post-docs with other Projects. The first two Aims will develop tasks for two focused fMRI studies that will each be conducted in 100 healthy participants recruited through Cores 2 and 3. A subset of 30 of these will be retested in future years to investigate stability over time. Aim 1 will develop six tasks that probe how specific contexts modulate social inference: through task set, for facial expressions or actions, for social or nonsocial events, as a function of cognitive load, and whether the person we are observing seems to be in need or to have merit. This latter need/merit context factor is further developed in relation to altruistic decision-making in Aim 2, which expands a task and approach we recently published, using drift-diffusion modeling to better understand how specific parameters influence the temporal evolution of the choice process.

Project 5. Project Summary. Project 5 will conduct behavioral and fMRI studies in people who have focal lesions to the prefrontal cortex, recruited from the lesion registry at the University of Iowa. It is a major extension of our current Conte Center, and has a subcontract to PI Daniel Tranel at Iowa. Its three Aims focus on dissociation of basic decision-making systems (continuous with Project 1 in our current Conte Center), studies of social inference (the same tasks as under the renewal Project 2, Aim 1), and fMRI studies probing compensatory processing. Given the strong links to other Projects, it also includes as personnel several PIs from other Projects (Adolphs, O'Doherty) as well as shared post-docs. The overarching goal of Project 5 is to use the lesion method to investigate the necessary role of specific sectors of the prefrontal cortex, the brain region most important for social decision-making. We are particularly interested in medial regions of the PFC, known to be critical for representing value and social inference, and in dorsolateral prefrontal cortex, known to be important for context-dependent regulation. How damage to these regions may dissociate specific components of the social decision-making process, let alone how it may engage compensatory processing through remaining intact network components, is largely unexplored. This will be a crucially important complement to all other studies under this Conte Center, since it provides a window into the necessary role of brain regions. Aim 1 focuses on the role of the ventromedial prefrontal cortex in goal-directed or habit-based control in instrumental choice. We will build on strong pilot data that shows, for the first time in humans, that the vmPFC is essential for goal-directed, but not habit-based choice. Aim 2 will use the full battery of tasks developed under Aim 1 of Project 2 to probe the necessary role of the prefrontal cortex in social inference. This task battery probes inferences made to social or nonsocial stimuli, as a function of cognitive load, to facial expressions or hand actions, and other factors. Finally, Aim 3 will analyze the tasks under Aims 1 and 2 done in fMRI experiments, to examine the neural regions responsible for possible compensatory task performances. The studies will be executed in 30 patients with focal, chronic lesions to the prefrontal cortex, 30 subjects with lesions elsewhere, and 30 healthy comparison subjects, using a combination of ROI-based and voxel-based lesion mapping. Some of the ROIs we will specifically query are those generated from the fMRI studies in Projects 1, 2 and 3: those fMRI studies tell us which regions are activated in healthy brains, but only Project 5 can tell us if damage within those same regions also compromises social inference and decision- making performances.

OVERVIEW. Project Summary. This renewal application of a basic research Conte Center aims to elucidate the neurobiological mechanisms for social decision-making in humans. While our current Conte Center investigated the basic systems for decision-making, and did so in both humans and monkeys, this renewal now focuses only on humans, and on more translationally relevant questions. In particular, we now focus on how social inference and context come into play. How do we attribute internal states, such as values, beliefs, and intentions, to other people? How does this depend on the context in which we observe those other people? How does it influence how we can learn from others, how we make altruistic decisions about them, how we deal with social threat? This set of new questions builds directly on our current Conte Center, and is of critical translational importance for understanding deficits in social decision-making such as those that occur in autism spectrum disorders and other psychiatric illnesses. Three cores provide administrative, neuroimaging, and participant recruitment and assessment resources for five Projects that are each directed by internationally renowned leaders, all of whom have a track record of scientific collaboration, student training, and expertise in the topic of the planned studies. Unique innovative strengths of this application are the combination of neuroimaging, intracranial electrophysiology, and lesion studies in human subjects. Cross-cutting questions can be addressed with this multimodal approach, which includes neuroimaging in the very same subjects from whom we record electrophysiologically, and in lesion subjects. Project 1 begins by investigating how social inference and context guides social learning. Projects 2 and 3 examine how social inference modulates social decision-making, in either prosocial, altruistic contexts (Project 2) or under social threat (Project 3). Project 4 examines these questions in relation to how we represent other people and ourselves, using single-unit recordings. Project 5 focuses on lesion studies of the prefrontal cortex, which is the brain region most closely involved in the processes under investigation. This science is woven into a training and outreach program emphasizing dissemination and diversity; and all data are made available for data sharing. The uniform recruitment and assessment of participants, the tight integration and communication between Projects, and the collaborative track record of the team will leverage these studies to a systematic and coordinated investigation of the largest outstanding questions in social decision-making. Progress on this topic will be an essential component for better diagnoses and treatments for a range of psychiatric disorders, including autism, addiction, and mood disorders.

One of the greatest challenges to understanding variability in human behavior and cognition, in both health and disease, is the relative disconnection between scientific psychology and neurobiological knowledge. Not much is known of how personality, intelligence, and other variables are related, and we do not know how they arise from brain activity. The overarching, high-risk goal of this NSF-EAGER project is to use neuroscience data to discover the architecture of the mind: can we build a new psychology from knowledge about the brain? The starting point of this work is the notion that instead of personality, intelligence, positive mood, attention and other current psychological constructs, none of which were derived based on neuroscience data, one might end up with a very different inventory if these psychological variables were derived in a data-driven fashion from neuroimaging data. This project is exploratory, since there are no extant paths for approaching this issue. The project will use approaches from the field of causal discovery, essentially asking if we can identify features in neuroimaging data that best explain new, revised psychological variables. The results will be a proof-of-principle that such an approach could yield new psychological constructs, and if successful will provide an initial direction in which this new field could evolve. The project will also use open science practices throughout its activities.

This EAGER project investigates individual differences in psychology and brain function to address a high-risk, high-payoff question: can we use neuroscience to revise psychology? It will focus on probing two domains of utmost importance to functioning in the real world: personality and intelligence. There has been success in predicting classical derivations of personality dimensions and intelligence from neuroimaging data, but this approach is inherently limited by the particular psychological constructs used in the first place. The further step taken here is to optimally combine test results in light of neural predictability, based on causal graphs that are estimated from resting-state fMRI data. The project will also use a novel, entirely data-driven approach, Causal Feature Learning (CFL), to automatically derive candidate causal variables from the fMRI measurements that may explain the behavioral and psychometric measures used to determine personality and intelligence. CFL has been used successfully in this fashion to analyze climate data, but it has never been applied to neuroscience. The project intends to make substantial contributions to philosophical and psychological conceptualizations of mental variables and cognitive architecture.

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.

Understanding human brain function requires knowledge of its connectivity: how one structure causally influences other components of the network. A wide range of neurological and psychiatric disorders prominently involve dysfunction of connectivity, including neurodegenerative diseases, autism, and mood disorders. Yet current methods provide only indirect measures of connectivity, and none can directly test how one brain structure causally influences another at the level of the whole brain. A unique opportunity to obtain such measures in the human brain comes from using experimental manipulation of activation through direct electrical stimulation, coupled with the whole-brain field-of-view of fMRI (es-fMRI). Our group has obtained IRB approval, and obtained strong initial data of concurrent es-fMRI in a series of 20 neurosurgical patients over the past two years. Here we intend to leverage this unique approach to the application of important open research questions in emotion, and to dissemination of protocols to a wider community of possible performance sites through this U01 mechanism. Three Aims progress through initial validation and quantification of the approach, mapping of brain networks involved in emotion processing (with a focus on the amygdala and medial prefrontal cortex), and convergent measures with ECoG and rs-fMRI. These Aims offer a mix of immediate implementation based on strong pilot data, more exploratory implementation during the grant, strong validation components, and future planning. The research focus of all Aims is on how emotion is caused by activity in brain networks. This is the topic with the strongest link to readily accessible brain structures for electrical stimulation in neurosurgical epilepsy patients (amygdala and prefrontal cortex). The work would have immediate implications for deep brain stimulation to treat diseases like depression, and long-term implications for eventually mapping out the effective functional connectome of the human brain. We will aim to provide the research community with short, feasible protocols that could be adopted by many other sites in a concerted effort to map effective connectivity in the human brain, eventually accumulating a database for understanding how individual differences in emotion, in health and disease, arise from differences in network connectivity.

Individual differences in cognitive abilities ultimately derive from differences in brain function. Recent studies have been able to predict, to some degree, individual differences in intelligence from the connectivity pattern among brain regions obtained at rest with functional magnetic resonance imaging (rs-fMRI). However, it remains unclear how reliable these findings are, how well they replicate, and to what extent they generalize to other samples. These questions have also limited our understand of what it is in the neuroimaging data that drives these predictions; for example, are there specific brain regions, or specific ways that the data are processed that make a difference? To address these questions this project will begin with a successful initial finding, predicting intelligence from rs-fMRI with a particular approach, in a large data set (the Human Connectome Project data, HCP). Building from this initial finding, a series of research aims will then investigate how different kinds of analyses might yield different results, how statistically reliable the findings are, how well they replicate, and how they generalize to databases other than the HCP. These findings will be high methodological value to all scientists working in this field and will also yield initial answers to important questions regarding the neural basis of intelligence. All work will use open-science practices including but not limited to pre-registration and data sharing of data and software.

This project capitalizes on recent success in predicting general intelligence (g) from resting-state fMRI (rs-fMRI) data in the Human Connectome Project dataset (HCP). Its principal aims are to investigate the reliability, reproducibility, and generalizability of this finding. A first aim will quantify the effect of brain alignment, rs-fMRI denoising, brain parcellation, and model-learning strategy on the prediction of intelligence from rs-fMRI in the HCP. The aim will quantify how choices at key intersections in this processing decision tree affect final prediction results. This investigation will provide a valuable inventory of possible processing pipelines, and the difference that different parameter choices make; aim to yield a single "best" combination of analytical choices; and explore which anatomical brain regions, and networks, can best predict intelligence. A second aim will add graph-theoretical summary features and externally driven brain states to improve the prediction of intelligence in the HCP. Do features derived from rs- or task-fMRI yield substantially better predictions? Do models built separately from each paradigm, and for different tasks, point to shared anatomical regions? Combining features from both paradigms, what is the best prediction we can obtain? To investigate the generalizability of results obtained, the results will be replicated across three independent datasets: the Enhanced Nathan Kline Institute - Rockland Sample (NKI-RS; target 1000 participants, 6-85 year-olds), the NIH Adolescent Brain Cognitive Development dataset (ABCD; target 10,000 participants, 9-10 year-olds), and the Cambridge Center for Ageing and Neuroscience (Cam-CAN; 700 participants, 18-88 year-olds). These pre-registered studies will quantify how robust are the brain predictors of intelligence (to different subject samples, and different MRI acquisition methods).

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.

An award is made to the California Institute of Technology to purchase state-of-the-art equipment for a 7-Tesla magnetic resonance imaging (MRI) instrument for brain imaging. This instrument will enable cutting-edge basic research, as well as research-intensive training, at the Caltech Brain Imaging Center (CBIC) aimed at investigating brain structure and function in a range of animal species. The research will engage more than a dozen different labs at Caltech pursuing basic scientific questions, including a large number of postdoctoral fellows, graduate students, undergraduates and high school summer students. Special emphasis will be placed on increasing the representation of women and underrepresented minority students in education and research. This includes Caltech's Ph.D. programs as well as its Summer Undergraduate Research Fellows program and WAVE program, which welcome students from outside Caltech and focus on increasing the participation of underrepresented students in science, technology, engineering and math. It also includes the Caltech Classroom Connection, a science education outreach program partnering Caltech scientists with K-12 teachers in the local public school system to provide summer research experiences for K-12 students. Additional educational impact will come from the use of this instrument in connection with courses. In addition, the MRI instrument will be made available to academic institutions in the Greater Los Angeles area. The insights into the structure and function of the brain obtained through this research and communicated through public outreach will contribute broadly to scientific literacy.

The specific goals of the supported research are to elucidate fundamental principles of brain structure, function and dysfunction; to test, develop, and compare synergistic technologies for investigating the brain; and to train the next generation of students and scientists in this endeavor. Specific aims will investigate the structural and functional connectivity of the brain, knowledge that is essential for formulating and testing computational models of brain function and allowing comparisons among species. Convergent technologies will also be used to investigate the brain, including the use of functional MRI, ultrasound and photoacoustic tomography. The research will develop the next generation of genetically encoded molecular probes for MRI, and will enable more precise imaging and manipulation of biological function at the cellular and circuit level. This research will leverage unique connections to studies conducted on Caltech's human MRI scanners, enabling novel advances in the study of brain structure and function across species. Results from the research will be disseminated in peer-reviewed publications and at scientific meetings.

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.