Lisa Feldman Barrett - US grants

DESCRIPTION (provided by candidate): The PI's goal is to develop a multilevel model for understanding emotional experience. Because there are no unqualified indices of direct experience, the PI began studying representations of emotional experience by examining the structure of self-reports. She discovered individual differences in the precision with which emotional experiences are represented over time, which she named emotional granularity. She chose the affective circumplex as a methodological tool to model individual differences in emotional granularity because its dimensions (valence and arousal) represent the causal processes associated with granularity. The PI defined two constructs, valence focus and arousal focus, to represent individual differences in these processes as they apply to generating representations of emotional experience. The PI's research has developed construct validity for valence and arousal focus using procedures from varying levels of analysis (social/personality, cognitive science, and psychophysiology); she plans to continue this work during the K02 funding period. In addition, the PI proposes an experimental research program to investigate the mechanisms that produce emotional granularity. Her goal is to directly model the processes that valence focus and arousal focus represent (rather than just measuring the indices as she has done to date). The PI will begin with behaviorally oriented studies utilizing methods from the cognitive neuroscience literature that have well-established functional neuroanatomical correlates. The result will provide a strong test of her hypotheses and will provide her with a clear functional platform upon which to move to the next phase of her research program (involving fMRI research). Moreover, the PI has developed her conceptual analysis of valence focus and arousal focus into a theory of how emotional experience is actually computed. Specifically, she hypothesizes that discrete emotional experiences are generated and represented by applying declarative emotion knowledge (associated with arousal focus) to core affective feelings of valence (associated with valence focus) via working memory. On this view, valence focus and arousal focus contribute to the granularity of felt experience itself. This hypothesis will be tested using fMRI experiments (in large part because fMRI methods provide the only way to test her hypotheses about felt experience at the present time). If successful, this work will call into question the assumption that emotional experience is epiphenomenal to emotion itself. Emotional experiences will come to be viewed as fluid, emergent phenomena that are constructed and elaborated via mental representations. In the broadest context, it has the potential to impact research where emotion plays some role.

[unreadable] DESCRIPTION (provided by applicant): The United States currently has the largest number of older adults at any time in its history, and this number is expected to rapidly increase over the next 20 years. This rapid increase in the aged population highlights the need to better understand changes that accompany aging and which may contribute to mental health and well-being in later life. One important and relatively unexplored aspect of aging relates to the changes that occur with decision making in the social and emotional realms. Making the correct social and emotional decisions during the lifespan is an essential contributor to well-being. One model that describes social and emotional flourishing with aging is Socioemotional Selectivity theory. According to Socioemotional Selectivity theory, there is an increasing focus on positive emotion over the adult lifespan such that older individuals selectively choose social interactions where the likelihood of positive emotional experience is high. In this setting, social contacts are limited to good friends and family, and greater satisfaction and well-being is achieved while the number of social contacts decreases. The underlying neural mechanisms that support this enhanced Socioemotional decision-making have received relatively little attention, but are important as they may protect from social isolation and mental illness. The specific purpose of the current proposal is to examine how the brain correlates of two well defined aspects of Socioemotional decision making - primary appraisal and affective learning about social objects (i.e., people) - are altered with aging. We will focus on two specific brain areas involved in these decision-making processes, the ventromedial prefrontal cortex and the amygdala. We plan to collect and analyze structural and functional magnetic resonance imaging data and self-report measures of social network characteristics and well-being. The overarching hypothesis is that age-related differences in ventromedial prefrontal cortex-amygdala circuitry during Socioemotional decision- making are closely related to Socioemotional selectivity and well-being in aging. Aim 1 will investigate age-related changes in the structure-function relationships between the ventromedial prefrontal cortex and amygdala during different aspects of Socioemotional decision making. Aim 2 will investigate how the ventromedial prefrontal cortex-amygdala circuitry relates to social network characteristics and well-being across the lifespan. The results of these studies will elucidate the neural bases of healthy Socioemotional decision-making and well-being in aging. [unreadable] [unreadable] [unreadable]

Emotional states are central to mental and physical health. NIH invests[unreadable] tremendous resources in research on emotion, much of it devoted to animal models.[unreadable] Ironically, this research is guided by a scientific paradigm that is grounded in human[unreadable] experience. People experience fear and see it in others, so scientists assume there[unreadable] must be a literal (modular) neural circuit for fear in the mammalian brain. Rats freeze[unreadable] when they hear a tone paired with a foot shock, so they are presumed to be in a state of[unreadable] fear (versus surprise, anger, or even a general state of alarm) and undergoing ?fear[unreadable] learning.? Scientists also presume that a map of the neural circuitry of freezing behavior[unreadable] will yield a neural mechanism for fear that is largely preserved in humans, and a decade[unreadable] of neuroimaging studies have focused on locating a homologous neural circuit in the[unreadable] human brain. In the last five years, I have traced the roots of this ?natural kind? model,[unreadable] conducted a comprehensive review of the literature to examine its veracity, and found it[unreadable] wanting (Barrett, 2006a).1 In response, I have fashioned a new systems-level model,[unreadable] called the Conceptual Act Model, grounded in the neuroanatomy of the human brain. My[unreadable] model parsimoniously incorporates neuroscience findings from rats, primates, and[unreadable] humans, and explains the mechanisms that produce the range and variety of behavioral[unreadable] and introspective instances that we call ?emotion? (Barrett, b, c; Barrett, Mesquita,[unreadable] Ochsner, & Gross, 2007; Barrett, Ochsner, & Gross, 2007; Duncan & Barrett, 2007).[unreadable] The Conceptual Act Model asks different ? and perhaps better ? questions about what[unreadable] emotions are and how they function in mental and physical health. The NIH Director?s[unreadable] Pioneer Award will allow me the intellectual freedom and resources to continue building[unreadable] evidence for the Conceptual Act Model of emotion, thereby shaping a new paradigm to[unreadable] guide the scientific study of emotion.[unreadable]

Abstract Emotional states are central to mental and physical health. NIH invests tremendous resources in research on emotion, much of it devoted to animal models. Ironically, this research is guided by a scientific paradigm that is grounded in human experience. People experience fear and see it in others, so scientists assume there must be a literal (modular) neural circuit for fear in the mammalian brain. Rats freeze when they hear a tone paired with a foot shock, so they are presumed to be in a state of fear (versus surprise, anger, or even a general state of alarm) and undergoing [unreadable]fear learning.[unreadable]Scientists also presume that a map of the neural circuitry of freezing behavior will yield a neural mechanism for fear that is largely preserved in humans, and a decade of neuroimaging studies have focused on locating a homologous neural circuit in the human brain. In the last five years, I have traced the roots of this [unreadable]natural kind[unreadable]model, conducted a comprehensive review of the literature to examine its veracity, and found it wanting (Barrett, 2006a).1 In response, I have fashioned a new systems-level model, called the Conceptual Act Model, grounded in the neuroanatomy of the human brain. My model parsimoniously incorporates neuroscience findings from rats, primates, and humans, and explains the mechanisms that produce the range and variety of behavioral and introspective instances that we call [unreadable]emotion[unreadable](Barrett, b, c;Barrett, Mesquita, Ochsner, &Gross, 2007;Barrett, Ochsner, &Gross, 2007;Duncan &Barrett, 2007). The Conceptual Act Model asks different [unreadable]and perhaps better [unreadable]questions about what emotions are and how they function in mental and physical health. The NIH Director's Pioneer Award will allow me the intellectual freedom and resources to continue building evidence for the Conceptual Act Model of emotion, thereby shaping a new paradigm to guide the scientific study of emotion.

DESCRIPTION (provided by applicant): Successful aging appears to relate in part to a variety of behaviors that require processing of motivated, goal- directed, and personally relevant (i.e., salient) information. For the most part, current research on salience has focused on the cognitive factors that allow attention to relevant information in the external environment. In our research, we focus on age-related changes in affective salience and their implications for social functioning. In our original grant, we examined age-related changes in the processing of novel and affectively potent stimuli, with a focus on the human amygdala [(R01 AG030311), Neural Mechanisms of Social Decision Making in Aging, August 1, 2006 - July 31, 2011)]. We found that amygdala responses to novelty, valence, and arousal are less robust and the functional connectivity between the amygdala and other affective brain structures is reduced in older individuals than in younger people. These findings indicate that information in the world is less affectively salient to older individuals. This is despite the fact that there appear to be few anatomical changes in the network that we have identified underlying affective salience (other than normal age-related reductions in amygdala volume). In the competing renewal, we will expand on these findings anatomically, functionally, and behaviorally. Using high resolution scanning, we will examine with more sophistication and precision, and in a larger sample, the extent to which both the structural integrity and intrinsic connectivity of brain regions within th affective salience network are maintained (or change) with age (Aim 1). In the context of spared anatomy and intrinsic connectivity within the affective salience network, task- related affective assemblies within this network are less robust with age, and we will examine the extent to which age-related reductions in sensory information from the body (in the form of reduced interceptive sensitivity) are responsible for task-related reductions in affective salience (Aim 2). Perhaps objects and events in the world are less salient because the bodily perturbations they produce are not detected and represented as efficiently in the aging brain. Furthermore, we will examine the extent to which these reductions in affective salience and interception underlie or contribute to normal age-related changes in memory for novel, neutral material (Aim 3) and in social engagement (Aim 4). Finally, using a longitudinal design, we will confirm that any age-related stability or decrements in affective salience can be disentangled from the substantial individual differences that exist, and also examine the extent to which strong affective reactivity is a protective factor, resulting in better memory for novel material and/or maintained social engagement as people age (Aim 5). PUBLIC HEALTH RELEVANCE: As people age, memory declines and the risk for social isolation (as well as the health related risks of social isolation) increases. Successful aging in these domains appears to relate, in part, to the ability to be affectively engaged by the world. In this renewal, we examine the age-related anatomical, brain function, autonomic and behavioral changes that occur in affective engagement, and examine the extent to which strong affective reactivity is a protective factor as people age.

DESCRIPTION (provided by applicant): It is well-established that the rate of disorders of affect exhibits a pronounced sex difference, such that susceptibility to disorders such as depression and post-traumatic stress is twice as high in women when compared to men. At present, however, the neural basis of this difference is not well understood. It has been suggested that women are at higher risk for these disorders due to a more general sex difference in the processing of affect. Multiple neuroimaging studies have supported this view, showing regional differences between men and women in the magnitude of the response to affective material. However, these studies have not converged on a consistent pattern of sex differences, nor have they related neural sex differences to pathological symptoms. Preliminary evidence from our lab has revealed a novel sex difference in affective processing, found not in the magnitude of the affective response, but rather in the persistence of that response over multiple repetitions. Our data indicate that while the response of the affective circuitry to negatively valenced stimuli does not differ between the sexes when those items are novel, the response to negative items that have been familiarized through repeated presentation is significantly greater in women than it is in men. This suggests that the affective systems of women habituate significantly more slowly to negative stimuli than do men's. Studies of individuals with high anxiety have shown similarly sustained activity in the affective network during the extinction of fear relative to healthy controls. Thus, it may be the case that the persistence of the affective response in women explains their greater susceptibility to affective disorder. In this proposal, we will test that possibility. Using fMRI, we will first fully characteize the habituation curves for the response to emotion-inducing material in various affective regions of interest in women and men, confirming the sex difference. These data will then be compared to various measures of affective disruption, including multiple inventories measuring depression and anxiety, tests of HPA axis responsiveness, and self-reported rumination. We predict that women will show longer-lasting responses in regions including amygdala, insula, and anterior cingulate relative to men, and that the magnitude of these responses after numerous repetitions will correlate with measures of affective dysfunction, such that those with the most persistent affective responses will also show the most symptoms. We further predict that women will have greater responses in the affective network than men when familiar affective material is visualized one week later. If these predictions are confirmed, it would indicate that the rate of habituation to negative stimuli predicts symptoms of affective disorder. Thus, as a slower rate of habituation is more common in women, they are more susceptible to disorders of affect as a group. A better understanding of the factors underlying sex differences in affective disorder could lead to more personalized and effective treatment.

DESCRIPTION (provided by applicant): The bonding between mothers and their infants have critical long term impacts on the child's physical and mental well-being across lifespan. Thus the social and biological mechanisms that support optimal bonding are critical for the child's optimal development. Prior work from our team has shown that BOLD activation in the nucleus accumbens (NAcc) is related to the level of behavioral synchronization between a mother and an infant, which is taken to be an indicator of optimal bonding. Among mothers who are synchronous with their infants, the response of the NAcc to the infant is stronger than among non-synchronous mothers, and is correlated with oxytocin plasma levels. The NAcc, along with several other key structures, belong to our recently discovered social affiliation network; strength of intrinsic connectivity within this network is linked to greater social connectedness. Synthesizing these findings, we propose an innovative model by which mother- infant synchrony leads to a oxytocin-dependent dopamine release in the NAcc and other regions of the social affiliation network. In this R21 application, we plan to use an innovative multi-disciplinary method as we begin to explore this model and measure its four components: behavioral assessments of mother-infant synchrony, which is linked to oxytocin (that will be measured in the plasma), which in turn is linked to endogenous dopamine secretion and social affiliation neural network connectivity (measured by combined fMRI-PET imaging). Together, they will allow us to assess the extent to which the anatomy, intrinsic connectivity, and functional response in this social affiliation network is linked to synchrony in a way that is mediated by dopamine and oxytocin, which are key neurotransmitters in this network. Specifically, we plan to examine if mothers with stronger connectivity in the social affiliation network are more synchronous with their infants (Aim 1). We will also evaluate whether synchronous mothers have a greater BOLD response in this network when viewing a film of their own infant for 20 minutes vs. when viewing an unfamiliar infant (Aim 2). Moreover, we will evaluate whether infant-related stimuli enhance endogenous dopamine release and whether synchronous mothers will have greater endogenous dopamine release that is correlated to oxytocin, in response to their infants. We will also explore which regions in the social affiliation network show the greatest dopamine binding (Aim 3). Understanding the neurobiological mechanisms in the mother that promote successful bonding may significantly reduce the prevalence of childhood illness and increases the child's wellbeing. Additionally, the proposed research will establish that social reward is a mechanism for human maternal affiliation, and it will begin to parse apart the neurochemistry involved in this mechanism. Last, this study plan to use a novel research methodology of combined PET and fMRI in the functional study of human behavior, and to utilize it in favor of children's development.

? DESCRIPTION (provided by applicant): Between 50-66% of deaths caused by cancer could be prevented through behavioral modification. Accumulating evidence points towards a family of basic, affective psychological processes related to emotion, stress, and pain that influence behavioral choices, facilitating healthful choices or promoting unhealthful choices, and that have the capacity to influence key aspects of successful survivorship. While the links between affect and cancer-related decision making are becoming well-known, the research remains largely descriptive. A mechanistic understanding of these links is hampered by a major barrier: the neural circuitry underlying affective processing is still largely underspecified. A further barrierto progress is that subdomains of affective science including stress, emotion, and pain, have largely been studied independently of one another even though they overlap tremendously as psychological constructs. The historical divides that pose a critical barrier to using affective processes to improve cancer-related decision-making are exacerbated by a tendency for researchers to focus either on peripheral and central biomarkers of affect, but not to study them simultaneously. Our goal is to unify subdomains of affective processes into a common neural framework centered on subcortical brainstem regions that are known to be critically involved in affective processes, with a particular emphasis on the periaqueductal gray (PAG) which non-human animal research shows is a critical hub controlling autonomic output, analgesic responses, and other physiological responses during emotion, pain, and stress. Affective research in humans relies primarily on non-invasive neuroimaging techniques, but the spatial resolution of these techniques in prior work has been too small to examine the brainstem and particularly the PAG and its connectivity with any degree of specificity. We have developed an ultra-high field magnetic resonance imaging procedure at 7 Tesla that overcomes this problem. In Specific Aim 1, we will map the structural and functional connectivity of the brainstem, with a focus on the PAG, within subcortical and cortical networks using anatomical, diffusion weighted, and resting state (task-independent) functional connectivity within a 7T imaging environment. In Specific Aim 2, we will examine the functional organization of these brainstem networks across tasks that evoke stress, pain, and emotional experience to assess the construct validity of these three affective processes from a unified neuroscience perspective, and we further examine how these brainstem networks participate in executive function using a working memory task. Finally, in the Exploratory Aim, we will examine the extent to which peripheral physiological measurements (e.g., heart rate variability, skin conductance, respiratory rate) mediate the relation between brainstem network structure / activity and behavioral responses in each affective domain. Our main deliverable at the end of this R01 is a working neural theory of affective processes that can be used by cancer researchers to study the influence of affect on cancer-related decision making.

Our goal is to assess how affect regulation strategies are protective of cognitive and affective functioning in those who are at risk of suffering age-related disorders of mood and cognition. According to RFA MH-17-405, studies of maturational shifts in affect regulation often yield inconsistent findings and the neurobiological systems that support affect regulation remain largely untested. In this application, we propose to closely investigate the dynamics and mechanisms of two maturational trajectories that impact affect regulation: increasing age and beta-amyloid plaques within the brain. To date, most efforts have focused on age-related changes in valence regulation (e.g., the age-related positivity effect). Arousal is acknowledged as important, but very little is known about how older adults actively regulate their arousal states, or the proximal and longer- term consequences of such regulation attempts for risk of suffering age-related changes in mood and cognition. Recent findings from our team suggest that those who optimize for momentary comfort cultivate arousal-avoidance affect regulation trajectories, whereas those who optimize for mastery in memory and attention cultivate grit trajectories (the ability to tolerate momentary unpleasantness in the service of some goal that requires effort, which is often transiently experienced as an unpleasant aroused state). Our work also suggests that affect regulation is associated with both the structure and connectivity within two of the brain's core networks: the salience and default mode networks. In older adults, beta-amyloid (A?) plaques within these two networks are a key pathology?one of the two major molecular hallmarks of Alzheimer's disease (AD)? associated with elevated risk of cognitive decline, symptoms of depression, and dementia. With these observations in mind, our team will combine (a) innovative theory and methods from the study of normal maturational changes in situation-focused affect regulation, (b) structural, functional, and molecular brain imaging, and (c) innovative computational modeling of spatial and temporal dynamics in one large five year study designed to examine how arousal-regulation is associated with changing age and A? status. We will characterize situation-focused arousal regulation strategies and cognitive effort at various levels of difficulty using behavioral, experiential, and neurobiological levels of analysis, both in the behavioral lab and during brain scanning. Data analysis will involve constructing dynamic temporal trajectories across performance in each task to characterize arousal-avoidance and grit (i.e., tolerance of high arousal in the service of effort). We will characterize and compare arousal-avoiding and grit regulation trajectories in individuals who vary in age (from 40 to 90 years old), A? status, cognitive impairment, and mood symptomatology (distinguishing two types of symptoms: distress (negativity) and apathy (lack of effort or engagement). The findings from the proposed research will be used to develop a longer-term project to determine how the temporal dynamics of affect regulation predict developmental/maturational trajectories for mood disorders and cognitive impairment.

It is well established that women exhibit a significantly higher rate of affective disorders than men do. This difference is particularly strong in post-traumatic stress disorder, where women are more than twice as likely to experience PTSD than men. Recent evidence suggests that women?s susceptibility to PTSD varies with their levels of ovarian hormones. During the luteal phase, when progesterone is elevated, women are more than three times as likely to develop PTSD symptoms after trauma. Similarly, women are twice as likely as men to be diagnosed with depression, and depressive symptoms also vary by menstrual phase. Both of these disorders involve alterations of memory, stress responses, and resting connectivity in the brain?s intrinsic networks. In PTSD, individuals experience intrusive memories of traumatic events, while individuals with depression show a marked negative retrieval bias. Stress-evoked release of the stress hormone cortisol is also elevated in both disorders. Similarly, resting connectivity between the default mode network, a group of structures engaged during the retrieval of memories, and the salience network, a group of structures involved in processing emotion, is elevated in individuals suffering from both disorders. Recent research indicates that affective memory, stress responsiveness, and resting connectivity are all influenced by changes in ovarian hormone levels. Negative memories acquired during the progesterone-rich luteal phase are better retained than during other menstrual phases. Increased progesterone is also associated with increased stress-evoked cortisol secretion. Similarly, ingestion of progesterone pills increases the connectivity between key nodes of default and salience networks. No study to date, however, has assessed the influence of changes in ovarian hormones on inter-network connectivity over the menstrual cycle. We hypothesize that changes in hormone levels over the menstrual cycle produce natural windows of vulnerability to traumatic life events, during which changes in the connectivity of the brain facilitate stress responses and enhance memory for negative experiences. To test this hypothesis, we will measure resting connectivity, stress hormone levels, physiological responses, and memory for negative material learned at hormonally distinct phases of the menstrual cycle. We predict that connectivity between resting and default mode networks will be at highest levels during the luteal phase, and that material learned in a negative emotional state will be best retained during the luteal phase. Additionally, we predict that the amount of connectivity between these two networks will significantly predict the enhancement of memory by negative affect, as well as the physiological response to negative mood induction. The results of this study could help to identify periods of maximum vulnerability trauma, thus facilitating prevention, as well as point to new and more targeted drug treatments.