David H. Zald - US grants

Two Pet studies are proposed to elucidate the specific contributions of the orbitofrontal cortex (OFC) and amygdala to olfactory and hedonic processing in humans. Study 1 examines whether activity in the amygdala, OFC and pyriform cortex varies in a concentration dependent manner. 15 subjects will be exposed to four concentrations of butanol and four concentrations of phenylethyl alcohol while cerebral blood flow (rCBF) is measured with PET. Study I also examines whether attention modulated rCBF) is measured with PET. Study 1 also examines whether attention modulated rCBF in these regions by imaging subjects while attend to and ignoring ordorants. In study 2,25 subjects will be exposed to highly aversive, pleasant and neutral stimuli to examine if rCBF in the OFC and amygdala varies with the hedonic meaning or emotional responses induced by odorants. These studies represent the first steps in a research program aimed at elucidating the functions of the OFC and amygdala in humans, with a long-term goal of determining the role of these structures in normal and abnormal emotional behavior.

Abstract

With National Science Foundation support, Dr. Zald and colleagues will conduct a three-year project aimed at developing a novel program of research that fuses cognitive neuroimaging techniques with neuroimaging of neurotransmitter release. A wealth of neuropharmacological evidence indicates that dopamine (DA) exerts a profound influence on affective, motor, and cognitive processes. A full understanding of DA.s influence on neurobehavioral systems requires knowledge of how and when DA is released. Recent advances in PET imaging make it possible to safely measure DA release in humans during different cognitive or behavioral tasks. Such data provide novel insights into the functions of DA, and allows assessment of DA during cognitive functions for which animal models are lacking. However, because of the interdisciplinary nature of such studies, few cognitive neuroscientists have exploited these techniques. The project includes: 1) a learning component to facilitate the acquisition of the methodological skills necessary to perform studies of DA release using [11C]raclopride PET; 2) a program of studies aimed at testing specific hypotheses about when endogenous DA is released; and 3) continuing development of teaching skills, including the development of a course on the cognitive neuroscience of emotion. Specific studies focus on 1) the influence of task response demands and reward contingencies on DA release, 2) the impact of novelty on DA release, 3) whether DA is released during tasks involving set shifting (which is disrupted by DA depletions), and 4) the relationship between BOLD fMRI responses and DA release in striatal subregions.

The proposal establishes collaborations between two major academic centers that will allow the exchange of ideas and technical developments in this emerging field. Because the field is in its infancy, dissemination of these ideas and techniques at meetings and symposium is likely to have substantial effects in guiding how others approach this area. Moreover, the interdisciplinary nature of the work allows for the integration of ideas across different fields of neuroscience. The grant also provides the opportunity to facilitate training at the graduate level including participation of minority M.D. trainees through the Vanderbilt-Meharry Medical college alliance. At the institutional level, it furthers the department of psychology's goal of becoming a leader in cognitive neuroimaging and will facilitate the expansion of the types of PET studies performed at Vanderbilt.

Both personality and genetic factors are reliably associated with vulnerability for developing psychostimulant drug abuse. Some of this vulnerability is likely expressed as individual differences in the cognitive and subjective response to psychostimulants. PET and SPECT imaging studies of striatal dopamine (DA) binding indicate the presence of significant individual differences in the amount of DA released by psychostimulants. these differences in DA release are associated with the subjective effects of these agents. Studies also suggest that baseline variables, such as basal D2/D3 binding in the striatum, and novelty/sensation seeking personality traits may predict responsiveness to psychostimulants. Unfortunately, this literature has been limited to measurement of striatal DA functioning due to difficulties imaging extrastriatal DA with most available DA receptor ligands. However, substantial evidence indicates that extrastriatal regions are also involved in processes related to drug abuse. We propose to examine the relationship between extrastriatal DA functions, personality and responsiveness to oral amphetamine (d- AMPH) using [18F]Fallypride in 54 healthy human subjects. [18F]Fallypride is a high affinity D2/D3 ligand that labels both striatal and extrastriatal receptors and is sensitive to endogenous DA levels allowing it to index the amount of endogenous DA released by psychostimulants. Preliminary data using [18F]Fallypride PET in healthy subjects indicate that d-AMPH produces significant DA release in the striatum. The amount of DA released in both the striatum and extrastriatal regions was associated with objective psychomotor improvements on d-AMPH. However, significant associations between DA release and subjective effects of d-AMPH localized to extrastriatal regions, especially portions of the cingulate. Consistent with animal models, the data indicate that individuals high on sensation seeking have lower basal D2/D3 binding levels in both the striatum and midbrain DA producing regions (likely reflecting reduced autoreceptor density). The present proposal aims to confirm and extend these findings in a large sample of subjects. We additionally aim to test hypothesis that the catechol-o-methyltransferase val158met polymorphism effects DA release. This will be assessed by specifically recruiting equal numbers of met/met, val/met and val/val subjects. We will additionally provide an initial exploration of whether several additional candidate genes that are related to risk for drug abuse have a measurable effect on either baseline D2/D3 binding and/or DA release. Finally, in order to better understand the regional regulation of DA, we will examine the inter-relations between DA functioning in the midbrain, striatum, thalamus and cortex. Taken together, the study will provide unique information on how individual differences in the organization of the human DA system are associated with personality, genetics and the subjective and cognitive effects of psychostimulants.

DESCRIPTION (provided by applicant): Increasing data indicate that emotional stimuli gain preferential access to attentional resources. This effect can be instantiated as improved detection time, enhanced cortical responses, and greater disruption of the processing of concurrent or immediately subsequent stimuli. The amygdala has been hypothesized to play a critical role in the emotional guidance of attention. This influence figures prominently in several neuro-behavioral models of anxiety disorders. However, direct evidence for this hypothesis is extremely limited, and little is known regarding the aspects of attentional modulation that are affected by selective lesions of the amygdala. Preliminary data from our laboratory indicate that patients who have undergone selective unilateral removal of the amygdala and anterior hippocampus for intractable epilepsy show deficits in specific attentional tasks. These deficits include a failure to show an attentional blink in response to aversive emotional pictures, a slowed visual search for emotional stimuli, and a failure to show any slowing of performance during presentation of emotional words in the Emotional Stroop paradigm. The present proposal aims to elucidate the specific components of attention that are affected by amygdala lesions in humans. Additionally, we propose to test recent theories that posit that the left and right amygdala are differentially involved in processing conscious vs. unconscious stimuli and conditioned vs. innately emotional stimuli. Towards this end, we propose to study 38 patients before and after they undergo unilateral (half right-half left) amygdalohippocampectomies for intractable epilepsy. We will additionally study 38 age-, gender-, handedness- and education-matched controls, and 38 nonsurgical epilepsy patients who are matched with the amygdalohippocampectomy patients for anticonvulsant usage. Participants will receive a battery of tests to determine the specific effects of amygdala lesions on attentional guidance in response to different types of emotional stimuli. The study represents the first research to thoroughly examine the role of selective amygdala lesions on different tasks of attention modulation. It is unique in the emotion literature in its examination of patients both pre- and post-surgery and its ability to rule out confounds of anticonvulsant medications. Thus, the study will be able to address the effects of amygdala lesions with a degree of precision that has been unattainable in previous research on the human amygdala.

DESCRIPTION (provided by applicant): Anhedonia has long been recognized as a core symptom of major depressive disorder (MDD). Preclinical animal models of effort-based decision-making provide a strong basis for hypotheses regarding the neural and neuropharmacological substrates of anhedonia. Such models indicate the importance of mesolimbic dopamine projections to the nucleus accumbens in overcoming response costs in order to obtain rewards, and the importance of the anterior cingulate in evaluating response costs. On the surface, the behaviors displayed by dopamine depleted animals appear similar to the motivational deficits that characterize anhedonic MDD. However, it has been difficult to integrate these preclinical models with clinical studies of MDD, because of: 1) a failure to distinguish between deficits in hedonics (pleasure) and motivation in the clinical literature, 2) the lack of objective experimental measures of motivational deficits in humans, and 3) the dearth of studies specifically targeting patients with motivational or hedonic deficits. To address this issue, we have developed and validated a novel behavioral paradigm for exploration of motivational elements of anhedonia in humans. The Effort Expenditure for Rewards Task (EEfRT) measures individual differences in the willingness to expend effort for a given level of monetary reward. The EEfRT was carefully adapted from effort-based decision-making paradigms used in animal studies of the mesolimbic dopamine system and anterior cingulate. In humans, peformance on the EEfRT has been shown to predict individual differences in trait anhedonia and dopamine function in healthy controls. The present proposal seeks to:1) use event-related fMRI to elucidate the neural correlates of effort-based decisions in healthy controls (n =24), and test hypotheses regarding the specific roles of the ventral striatum and anterior cingulate in predicting effort-based decisions; (2) validate the sensitivity of the EEfRT for detecting behavioral deficits in individuals with MDD and self-reported motivational deficits (n=24); and (3) test the hypothesis that patients with MDD and self-reported motivational deficits will show abnormal ventral striatal and anterior cingulate activations during performance of the EEfRT. If successful, the proposed research will significantly enhance our ability to identify specific behavioral deficits of anhedonic symptoms in MDD, as well as their neurobiological substrates, and provide the basis for future studies on the utility of the EEfRT and fMRI to serve as a behavioral or biomarker for clinical and clinical outcome research. PUBLIC HEALTH RELEVANCE: MDD is predicted to become the second leading cause of death and disability in the United States by the year 2020, and anhedonia remains among the most difficult symptoms to treat in MDD. This proposal provides a unique translation of preclinical models to attempt to both understand the neural substrates of anhedonia and to develop an objective biomarker that could be used to develop treatments particularly tailored for addressing motivational deficits in MDD.

Neuroeconomic research demonstrates that temporary suppression of the right dorsolateral prefrontal cortex (DLPFC) with repetitive transcranial magnetic stimulation (rTMS) leads experimental subjects to choose riskier, but potentially larger reward options over a less risky reward options. This finding has been interpreted as suggesting that the ability to override or inhibit the drive to choose tempting but riskier choices lies in a specific region of the brain ? the lateral prefrontal cortex. However, the findings reveal that, in addition to choosing more risky options following prefrontal suppression, the probability of choosing a particular option approaches chance level. Thus, an alternative interpretation of the evidence is that, as a result of suppression of the DLPFC, subjects have greater difficulty discriminating between the subjective values of the two options and choosing the highest valued alternative. This Doctoral Dissertation Improvement grant will enable the co-PI to test these alternative hypotheses of lateral prefrontal cortex function against each other by suppressing activity in this brain region with rTMS immediately before healthy human participants perform a choice task in which they must make choices between certain and risky options with varying relative subjective values. The results will reveal whether disruption of the lateral prefrontal cortex specifically modulates risk taking or helps individuals compare subjective values and select the most valued option.

In terms of broader impacts, this research will inform solutions for improving maladaptive decision making in the wide range of situations (e.g. insurance, investing, health decisions) that depend upon perceptions of risk.

Project Summary We recently reported that levels of midbrain dopamine (DA) autoreceptors are inversely related to self-reported impulsivity. This finding suggests that individuals with reduced autoregulatory control of DA release are susceptible to impulsivity because of a reduced ability to control the approach-related motivational drive provided by DA neurotransmission. However, self-report measures do not allow for a direct examination of the core processes of behavioral control that are thought to be weakened in impulsivity. At present, the relation between DA autoreceptors and specific processes underlying impulsivity is unknown, as impulsivity is a multi- faceted construct and behavioral measures of impulsivity are only modestly associated with self-report scales. To clarify the link between DA functioning and impulsivity, we propose to measure midbrain DA autoreceptor availability and behavioral and fMRI indices of impulsivity in a group of 28 healthy adults. Midbrain autoreceptor availability, as well as D2-like receptor availability in the striatum and cortex will be assessed with the high affinity PET D2/D3 ligand [18F]fallypride. All participants will complete a rewarded stop signal task (SST) and a temporal (delay) discounting (TD) paradigm in order to provide objective measures of behavioral control. The SST and TD paradigms capture two distinct aspects of impulsivity (stopping and reward decision- making), which engage distinct, albeit overlapping neural networks. By completing these tasks during fMRI, we will be able to test whether individual differences in midbrain DA autoreceptor levels influence the responsivity of brain areas involved in self-regulation (e.g., anterior cingulate, ventral striatum, right inferior frontal gyrus). We will also test whether D2-receptor availability in the target behavioral control regions is predictive of the degree of BOLD activation during task performance, thus providing an ability to examine mechanistic models of the link between individual differences in DA functioning and the engagement of areas involved in behavioral control. In the case of TD, we will assess the hypothesis that lowered autoreceptor control leads to greater BOLD responses in the nucleus accumbens for immediate rewards, leading to more impulsive choice. In order to bridge current theories of DA functioning and the cognitive science of stopping, we have developed a novel, reward version of the SST that assesses the extent to which go and stop reaction times are altered by reward context. This may prove critical for defining the specific nature of DA's impact on behavioral control. Such reward manipulations have not been widely examined in the SST paradigm, despite the fact that most real-life impulse control problems arise in the context of high motivation. One hundred additional participants (and the 28 scanned participants) will complete the rewarded SST and a battery of self-report and behavioral measures of impulsivity to further characterize this new paradigm. Overall, this project bridges cognitive and affective science and neuroscience, behavioral economics, neuropharmacology and personality research to provide a framework for understanding reward influences on behavioral control and self-regulation.

DESCRIPTION (provided by applicant): In the human pursuit of financial well-being, social satisfaction, and physical health the decisions we make require the integration of a number of features. Nearly all decisions require the weighing of expected benefits with any associated costs, such as varying amounts of temporal delay until outcomes are realized, the exertion of physical effort required to achieve various outcomes, or uncertainty about the outcome of a choice. Despite their ubiquity in everyday life, scientists have only recently started to examine how these features may be differentially integrated for decision making across adulthood and into old age. Emerging theories suggest that changes in cognition, emotion, motivation, and experience across adulthood influence age differences in decision making. However, there is currently very little empirical evidence directly linking specific changes in psychological (cognitive or affective) processes and neural system function with age differences in choice. The overarching goal of this grant is to significantly advance the field by broadening the initial body of work on decision making over the adult life span in order to create a foundation for future research. Our integrative approach, which includes measurement of cognitive and affective individual differences, decision making behavior and functional and structural brain imaging (MRI, fMRI, PET), will be applied to the study of individual and age differences in preferences for time, effort, and uncertainty across a range of decision making domains (financial, social, health). Using radioligand PET imaging of dopamine D2-like receptors with [18F]fallypride in a large life-span sample of healthy adults between the ages of 20 and 85, the project will provide the first whole-brain (midbrain, subcortical, and cortical) examination of the specific role of dopamine receptors in supporting the core motivational valuation processes underlying decision making. All participants will complete decision making tasks while undergoing fMRI to test whether differences in choice behavior and functional neural activity are influenced by age differences in D2-like receptor levels. We expect individual differences in the functional activation and dopaminergic function of these structures to be related to the decision preferences of individuals. We further theorize that mesolimbic aspects of the dopamine system will show smaller age differences when compared to anterior lateral cortical regions. We expect these mesolimbic regions (a ventromedial corticostriatal-midbrain network) to play a primary role in the integration of decision costs across domains. Beyond contributions to the study of human aging, the work will clarify the neural substrates of subjective valuation processes across adulthood. This multimodal, adult developmental approach has the potential to more precisely characterize the neurobiological systems involved in integrating motivational and cognitive processes in decision making. This work will provide a necessary foundation from which to understand and treat potential decision-making impairments across adulthood by identifying focused targets for future interventions. PUBLIC HEALTH RELEVANCE: The proposal aims to characterize individual and age differences in motivation, cognition, and decision making over the adult life span using multimodal neuroimaging techniques. This work will form the basis of a translational research program on decision making over adult development and aging, and has the potential to eventually facilitate identification of specific markers for suboptimal decision making in adults o all ages to inform the design of appropriate interventions. The long-term goal of this line of research is to improve the physical, emotional, and financial health of all adults by improving decision making at the individual level.

DESCRIPTION (provided by applicant): The central hypothesis of the Research Domain Criteria (RDoC) project is that categorical mental disorders do not line up one-to-one with variations in the functioning of neural circuits. Rather, neural circuits align with narrower neurobehavioral constructs that are themselves related to psychopathology in cross-cutting fashion: Dysfunction in each construct is related to multiple forms of psychopathology and most forms of psycho- pathology are related to dysfunction in more than one construct. Failure to refocus research with this is mind will continue to obscure the neurobiology of psychopathology. We endorse these hypotheses, and propose to test them. Our first aim is to test hypotheses regarding the association between specific neural circuits and five neurobehavioral constructs in the RDoC positive and negative valence and cognitive systems domains. Using fMRI, we will assay the functioning of a mesocorticostriatal system involved in approach motivation and reward attainment (pleasure), a limbic/paralimbic system involved in anticipation and response to aversive-threatening stimuli, and control systems involved in effortful response inhibition. Thi addresses the first goal of the RDoC initiative of mapping constructs to brain circuits. RDoC's second goal is to relate constructs to psychopathology to enable a new classification of psychopathology informed by neurobiology. To advance this goal, our second aim is to test the hypothesis that RDoC constructs are associated with psychopathology in a complex but tractable cross-cutting manner. We will map RDoC constructs to empirically-defined dimensional conceptions of psychopathology based on strong evidence that prevalent mental disorders are organized by their correlations (comorbidity) into distress, fears, and externalizing dimensions. Using structural equation modeling, we will test the hypothesis that the five selected RDoC constructs are related in cross-cutting fashion to these three dimensions of psychopathology. This reflects our hypothesis that the mental disorders that load on each broad dimension cluster together precisely because they share the same pattern of variations of these neurobiological constructs and etiologic influences. We will also test the possibility that relativ differences in the expression of RDoC constructs produces heterogeneity in the expression of symptoms within the three dimensions of psychopathology. Our third aim is to test the crucial hypothesis that variations in functioning of the neural circuits are associated with psychopathology in the same cross-cutting manner and their associations with psychopathology are mediated by the RDoC constructs. Our proposed study is based on a highly informative sample of 400 young adult twins strategically selected from a large representative cohort. Participants who exhibited psychopathology in adolescence will be steeply oversampled to greatly enrich the sample on psychopathology. Critically, the twins will allow us to determine the extent to which genetic influences are shared in common by the neural circuits, constructs, and dimensions of psychopathology.

DESCRIPTION (provided by applicant): Vital financial decisions are made during pre-retirement age that can influence financial well-being for the rest of an individual's life. Howeve, very little psychological and neurobiological research has examined financial decision making in this pre-retirement late middle age range. An overarching goal of this grant is to begin to construct a more comprehensive model of the specific psychological and neural mechanisms that support financial decisions in young adulthood and late middle age. All aims seek to understand adult age differences in cost-benefit decisions and the specific role of dopaminergic neuro-modulation in supporting these preferences in young and late middle-age adults. We particularly focus on decisions with effort costs, but we will also examine the influence of dopamine (DA) on risky choice. A single multimodal neuroimaging study will examine age and individual differences in basic cognitive and motivational variables, decision making behavior, neural reward circuits using fMRI, multiple aspects of the DA system collected across three radio- ligand PET imaging sessions, and behavioral sensitivity to the drug amphetamine. Using radioligand PET imaging of D2-like receptors and release with [18F]fallypride and DA transporters (DAT) with [18F]FECNT, the project will provide the first examination of the specific role of multiple aspects of DA function in supporting the core motivational processes underlying cost-benefit decision making in healthy young and middle-aged adults. We expect to observe differential age effects in both functional neural activity assessed with fMRI and DA function assessed with PET. Across imaging methods, we expect to observe some level of preservation of function in the ventral striatum and midbrain in late middle age. However, we expect to observe larger age differences in lateral cortical D2 receptors, striatal and ventromedial prefrontal DA release, and DAT expression. We expect these neurobiological age differences, especially in medial prefrontal and striatal networks, to be associated with decision making, such that individual differences in the function of these systems are associated with individual differences in the tolerance of effort costs. We will also include an amphetamine challenge to examine the influence of DA release on decision preferences. This will be the first study of human age differences in DA release, and the first study of DA drug effects on decision making across adulthood. The parallel use of the DAT ligand [18F]FECNT will allow us to uniquely assess the relative and possibly synergistic impact of presynaptic and postsynaptic DA variables, and to further provide a unique assessment of the relations between DAT expression and amphetamine-induced DA release and the behavioral effect of amphetamine. Beyond contributions to the study of human aging, the work will clarify the neural substrates of cost-benefit decision making across adulthood. This multimodal, adult developmental approach has the potential to more precisely characterize the neurobiological systems involved in motivation and decision making, and has the potential to identify focused targets for future interventions.

A critical challenge for psychiatry is determining the best way to characterize psychopathology given the continuously distributed and highly correlated nature of most psychological symptoms. An increasing body of evidence on the structure of mental illness indicates the presence of a latent general factor of psychopathology (GF), also referred to as a P-factor, that explains a significant amount of the common variance in the expression of multiple psychiatric symptoms and disorders. The presence of a GF has substantial implications for psychopathology research and treatment because it suggests that a comprehensive understanding of mental illness requires an untangling of nonspecific risk factors from narrower, dimension-specific, risk factors or features. Caspi et al., (2014) suggest that schizophrenia symptoms are so highly correlated with the GF that they are mostly an expression of the GF. However, methodological limitations, such as the use of community and youth samples with few psychotic patients, restrict conclusions from the existing literature. We propose to test the hypothesis that schizophrenia spectrum and psychotic symptoms load heavily on both a GF AND a separate higher-order psychosis factor in a sample of 800 adult psychiatric and medical treatment seeking subjects that includes a substantial group of patients with psychotic disorders as well as patients with significant externalizing and internalizing symptoms. The potential utility of defining an accurate structural model of severe psychopathology lies in its ability to provide more accurate dimensional phenotyping than can be achieved by categorical diagnoses of primary and comorbid conditions. This may in turn aid in understanding mechanisms involved in the etiology and expression of illness as well as predicting its course and optimal treatment. Toward this end, we aim to determine the extent to which patient factor scores at different levels of the structure of psychopathology (GF, 2nd-order psychosis and narrower 1st order symptom dimensions) predict neural and neuropsychological features that have previously been associated with schizophrenia but have never been tested while statistically controlling for dimensional features of psychopathology outside of the schizophrenia spectrum. Using this quantitative approach in a subsample of 300 participants, we will explicitly test the hypothesis that some neural and cognitive correlates of schizophrenia, such as the volume of the anterior cingulate area, are nonspecific correlates of the GF, while others, such as temporal cortical sensory processing abnormalities, are specific to a 2nd-order psychosis factor, and will show associations that remain significant even after controlling for the GF. In order to assess the prognostic significance of the GF, we will test whether scores on the GF are predictive of the course of illness in 150 patients experiencing first-episode psychosis (even after controlling for previously defined prognostic indicators). Taken together, the study will provide the most comprehensive test to date of the relevance of GF model to understanding the expression and neural correlates of severe psychopathology.