James A. Waltz - US grants

DESCRIPTION (Applicant's abstract): The proposed project is designed to investigate the nature of reasoning impairments in dementia of Alzheimer's type, and related disorders. In addition, by integrating neuropsychological data with brain imaging data, the study seeks to determine the roles of different brain regions in reasoning. The performance of three groups of patients will be compared on tests of working memory, declarative memory, and reasoning: 1) a group of patients with focal damage to prefrontal cortex, 2) patients with damage limited to anterior regions of temporal cortex, and 3) patients with damage to posterior cortical areas, producing dementia of Alzheimer's type. A group of age-matched control subjects will also be tested. Items from reasoning tests systematically vary in the number of relational representations they require reasoners to simultaneously manipulate. It is proposed that intact prefrontal cortex is essential for successful reasoning because it is required for the integration of relations between objects and events. Thus, it is hypothesized that patients with damage to prefrontal cortex will show significant impairment, relative to patients with Alzheimer's disease, on items which require relational integration. Additionally, it is predicted that a double dissociation will be found between relational reasoning and declarative memory abilities in patients with damage to prefrontal cortex and patients with Alzheimer's Disease. Finally, I hypothesize that significant correlations will be observed between scores on measures of working memory and relational reasoning in all participant groups.

DESCRIPTION (provided by applicant): It is widely known that patients with schizophrenia (SZ) show a reduced tendency to engage in goal- directed behavior that could lead to rewards. It has often been thought that motivational deficits in schizophrenia stem from a reduced ability to experience pleasure, called anhedonia. A number of recent studies challenge this view, however, finding that SZ patients frequently report normal hedonic experience. The reduction in reward-seeking behavior in schizophrenia is thus likely to have a more complicated explanation, possibly related to the physiology of reward processing. Abnormalities in brain regions involved in reward processing are, in fact, evident from neuroimaging studies of schizophrenia. These findings point to an important contradiction in the literature: schizophrenia patients report normal hedonic experience, but often show evidence of abnormal physiological associated with reward processing. In order to investigate the reasons for this apparent contradiction, we propose to adapt a paradigm from the experimental literature, which has been used, in conjunction with functional magnetic resonance imaging (fMRI), to identify the part of the brain (orbitofrontal cortex) whose activity most closely tracks the reported experience of food rewards. In this paradigms, participants receive small squirts of liquid food rewards, like tomato juice and chocolate milk, in the MRI scanner, while periodically rating the experience of pleasure associated with each food on a visual analog scale. This paradigm will allow us to determine, in a more graded fashion, correspondences between brain physiology and reported hedonic experience in schizophrenia, and the extent to which these relationships resemble those observed in healthy volunteers. Our prediction is that the correspondence between self- reports of pleasure and neural responses to food rewards in orbitofrontal cortex will be significantly weaker in schizophrenia patients than in healthy volunteers. Furthermore, we hypothesize that MRI responses to food rewards will relate more systematically to clinical ratings of negative symptoms, such as avolition, in schizophrenia. These results would potentially have important implications for understanding motivational deficits in patients, and for developing better treatments for the negative symptoms of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a complex mental disorder affecting approximately 1% of the population, that results in chronic disability for more than 3 of affected individuals through their adult lives, as well as a tremendous public health burden, in terms of the extremely high rate of unemployment in individuals with schizophrenia and the enormous financial costs to public health care system. Because of the close relationship between functional disability in schizophrenia and negative symptoms of the disorder, such as anhedonia (the inability to experience pleasure) and avolition (reduced motivation), it is critical that progress be made in understanding and developing therapeutic mechanisms for treating this class of symptoms. The goal of the proposed project is to investigate the neural processes associated with the experience of pleasure in schizophrenia, in order to increase our knowledge of the origins of negative symptoms, and to identify potential treatment targets.

DESCRIPTION (provided by applicant): Although negative symptoms, such as anhedonia (the blunted experience and/or anticipation of pleasure) and avolition (a reduced tendency to engage in goal-directed behavior), are among the debilitating and treatment-resistant aspects of the psychopathology of schizophrenia (SZ), little is known about their neural basis and their inter-relationships. It has often been thought that avolition stems from a blunted experience of pleasure in SZ, but, despite the intuitive appeal of this idea, direct evidence for it is limited. Recent work from our group indicates that brain responses to reinforcers correlate with ratings of negative symptoms in SZ patients. Furthermore, we have found that SZ patients with high ratings for negative symptoms also show a reduced willingness to explore response alternatives when uncertain. Our primary goal is to contribute to a mechanistic understanding of negative symptoms in SZ by investigating neural processes underlying value-based decision making (DM) and the updating of value representations based on prior outcomes, in SZ patients and their first-degree relatives. We posit that abnormal neural responses to rewards lead to degraded representations of expected value (EV) in the schizophrenic brain. Furthermore, based on recent findings of a role for uncertainty in modulating learning and DM, we will investigate a possible contribution of aberrant uncertainty processing to motivational impairments in SZ. Specifically, uncertainty is thought to influence learning by modulating the impact of surprising outcomes, called prediction errors, on changes in the strength of associations. A role for uncertainty has also been established in driving exploration in the service of maximizing the information obtained. Neuroimaging studies have implicated both dorsal anterior cingulate cortex (dACC) and parietal cortex in the processing of uncertainty. Importantly, neuroimaging findings from studies of DM in SZ point to dysfunction in these areas. We propose a set of MRI experiments designed to examine: (i) the relative impact and gains and instances of loss-avoidance on learning; (ii) the impact of uncertainty on value updating; (iii the neural basis of value- based choice; and (iv) neural processes underlying uncertainty-driven exploration. We hypothesize that avolition in SZ is, in part, driven by an attenuated neural response to positive outcomes and a consequent reduced anticipation of rewards. We further propose that, even if outcomes were experienced normally, motivational deficits could still arise in SZ if neural signals related to uncertainty were aberrant, leading to abnormal value updating and erratic, or reduced, exploration. Finally, we anticipate that many of the aberrant neural signals observed in SZ patients will be present in first-degree relatives of SZ patients We propose that the results of our proposed experiments will contribute to a mechanistic understanding of anhedonia and avolition in SZ. Such a mechanistic understanding would have important implications for developing better treatments for the negative symptoms of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a complex mental disorder affecting approximately 1% of the population, that results in chronic disability for more than 3 of affected individuals through their adult lives, as well as a tremendous public health burden, in terms of the extremely high rate of unemployment in individuals with schizophrenia and the enormous financial costs to public health care system. Because of the close relationship between functional disability in schizophrenia and negative symptoms of the disorder, such as anhedonia (a reduced ability to experience pleasure) and avolition (reduced motivation), it is critical that progress be made in understanding and developing therapeutic mechanisms for treating this class of symptoms. The goal of the proposed project is to investigate the neural processes underlying reward-based learning and motivation in patients with schizophrenia, and their first-degree relatives, in order to increase our knowledge of the origins of negative symptoms and to identify potential treatment targets.

7. Project Summary It is well-established that both childhood trauma and stressful recent life events can bring about and worsen the symptoms of mental illness. However, the underlying mechanisms by which stressors exert these effects remain unclear. The overarching goal of the proposed project is to investigate candidate neural pathways linking stressful life events to the symptoms of psychotic illness, in particular. There is strong evidence that early-life adversity can increase reactivity to acute stress later in life. This effect is believed to be mediated by ?sensitization? of brain dopamine pathways projecting to critical frontal and subcortical structures. However, both early-life and acute stress have been shown to reduce responsivity to rewards and positive experiences, as well. We will investigate how specific circuits connecting frontal, limbic, and subcortical structures ? especially circuits involved in the processing of rewards and other salient stimuli and events ? may mediate relationships between cumulative stress exposure and both the positive and negative symptoms of psychotic illness. Another goal is to examine how brain responses to acute stressors, as well as the effects of brain changes resulting from early-life adversity, vary across the spectrum of psychotic illness. In pursing these goals, we will use clinical assessment tools, self-report measures, experimental behavioral paradigms (including those for the induction of acute stress), computational modeling, and functional Magnetic Resonance Imaging (fMRI). We will also obtain, from study participants, ecological momentary assessments (EMA) of naturalistic stressors, rewards, and symptoms, as encountered and experienced in everyday life. We will enroll a sample of 164 individuals, made up of three subsamples: 82 individuals with schizophrenia or schizoaffective disorder, 41 first-degree relatives of schizophrenia patients, and 41 healthy volunteers. It is expected that participants from such a sample will have a range positive and negative symptoms. We regard this work as important, in that it is designed to contribute to a better understanding of the mechanisms by which both lifetime and acute stress impact psychopathology, thus contributing to the NIMH's stated mission of ?defining the mechanisms of complex disorders.? The proposed project is strongly aligned with the strategic plan of the NIMH, in that it seeks to link advances in biology ? our increased understanding of the functional roles of specific frontal-subcortical and limbic circuits, in particular ? with a major environmental factor known to influence mental disorders: stress. Finally, it is expected that the results of this work would inform our ability to develop biomarkers for prediction of psychosis risk and course, and to use pharmacological and non-pharmacological interventions in individuals with psychotic illness.