Katherine H. Karlsgodt - US grants

DESCRIPTION (provided by applicant): The purpose of this project is to use cognitive neuroscience techniques to explore schizophrenia as a connective disorder. A verbal memory task will be used to investigate semantic and phonological representations of information in working memory, and the extent to which maintenance of this information may differ in schizophrenia. The task will then be used to probe functional connectivity in patients and controls. The first phase will be a behavioral study in which a set of target words will be encoded, followed by a recognition period when the subject will see phonetic foils, semantic foils, unrelated foils, and target matches, and decide whether the items were part of the initial list. The goal of the behavioral component is to ensure the behavioral profile is well characterized in patients before moving the task to a functional imaging environment. The second phase will be a functional magnetic resonance imaging (fMRI) study of the same task. In this study, functional activation associated with responses to phonological probes is expected to include frontal and parietal regions while that associated with responses to semantic probes is expected to include frontal and temporal regions. Since this task has been shown to activate multiple regions, fMRI data will be analyzed to assess functional connectivity (correlation of activity) between these regions. Since schizophrenic patients are impaired on verbal working memory tasks, and previous studies have demonstrated disruptions in the coordination of neural activity in other domains, it is hypothesized that cerebral connectivity during this task will be disturbed in patients.

DESCRIPTION (provided by applicant): Adolescence is a critical neurodevelopmental period in which life decisions start to be taken over by the adolescent. However, decision making ability may be limited. For instance, reward and executive functions may be modulated differently, or by different factors, during adolescence and as a result may be imbalanced, leading to risky or non-optimal decisions. Adolescents are also at risk for psychiatric illness, including schizophrenia (SZ) and bipolar (BP) disorder. Individuals with SZ and BP show decreased decision making ability, although deficits appear to be driven by executive dysfunction in SZ and reward dysfunction in BP. Given the demonstrated importance of executive and reward networks to decision making in adolescence as well as SZ and BP, we take the novel approach of deconstructing this complex process and testing the independent contributions of reward and executive networks to decision making behavior. We will longitudinally assess a sample of adolescents with affective and non-affective psychosis and bipolar disorder, as well as healthy controls, using multimodal neuroimaging. To functionally define the two circuits of interest, we will use a working memory task to localize a fronto-parietal executive network and a reward responsivity task to localize a ventrostriatal-orbitofrontal network. Task-based regions of interes (ROIs) will be used as seeds for diffusion tensor imaging tractography and as ROIs in which to probe grey matter (GM) thickness. To assess structural development we will use a combination of within and between subject data to plot the trajectory of structural and behavioral change from age 12-21 in patients and controls, as well as whether structural change (white matter (WM) and GM) in each circuit mediates behavior. Then, we will test whether there is a differential impact of illness on development of the two circuits, such that mood symptom severity (across all diagnoses) is associated with reward circuit alterations while severity of positive symptoms is associated with changes in executive networks. We will further test whether a traditional categorical analysis or our symptom spectrum analysis can account for more of the variance in the structural measures. Finally, we will determine the neural biosignatures that describe individuals at high and low ends of the symptom spectrums by performing a profile analysis based on data from ROIs in both networks. We will also test the degree to which baseline lab-based decision making performance longitudinally predicts real life behavior, as well as if WM and GM maturation between baseline and 1 year follow up can predict behavior at the 2 year follow up. This work may help identify novel treatment opportunities specifically appropriate for developing adolescents, who may be amenable to treatments that would not be as effective in adults. Further, if we can identify specific aspects o decision making that are affected in individuals with different symptom profiles, that may provide important traction on how to uniquely tailor cognitive remediation approaches. Finally, if we can predict later real life behavior with measures from laboratory visits, we can identify individuals n need of social or cognitive intervention.

Project Summary A number of neuropsychiatric disorders, including psychotic spectrum disorders (PSD), have been associated with developmental changes in brain structure and function. Adolescence is a period of special importance, with alterations of synaptic pruning and myelination trajectories proposed as neural mechanisms underlying PSD. There is also a growing interest in ways that neurodevelopmental changes may be leveraged as treatment targets. Unfortunately, such efforts are limited by the technology currently available for monitoring microstructural change. Neuroimaging is ideal for investigating in-vivo developmental changes, due to its non- invasive nature. However, the measures used are often indirect, and the extent to which they are sensitive to neural microstructure is not always clear. Accordingly, the imaging methods community continues to develop increasingly sophisticated techniques to improve our estimation of tissue characteristics, but there is often substantial delay in translating new methodologies to clinical populations. One modality that has the potential to improve our understanding of brain microstructure is multishell diffusion weighted imaging (mDWI). One emerging mDWI method is neurite orientation dispersion and density imaging (NODDI), which can yield sophisticated estimates of microstructural architecture. In particular, NODDI allows estimation of three factors relevant to development: neurite orientation, reflecting dendritic density and the complexity of dendritic branching, neurite density, which is correlated with myelination, and cellular density. Although these measures are relevant to many neuropsychiatric disorders, this technique has not been broadly adopted, with little existing work using NODDI in PSD and no work in adolescent or young adult patients. This project will employ NODDI as well as standard structural grey and white matter imaging measures in a sample of healthy adolescents and adolescents with PSD (age 12-18), in order to establish the utility of NODDI as a measure of synaptic pruning and myelination. First, the degree to which NODDI measures are similar or different to standard measures of grey matter thickness and white matter integrity will be assessed. Secondly, whether NODDI measures are sensitive to differences in pruning across adolescence by comparing cross sectional age related differences between groups. And the final assessment will be whether NODDI is more or differently sensitive than standard measures by testing if it is more predictive of chronological age, functional connectivity, and patient status. If successful, this project would establish evidence that NODDI provides unique information that may be valuable for investigating neuropsychiatric disorders, and further, that the measure can detect maturational differences between diagnostic groups, which could impact how clinical researchers perform diffusion imaging moving forward. In addition to the impact on the larger clinical imaging field, these analyses can also have an impact on the field of psychosis in particular, by helping to fully and accurately characterize microstructural neurodevelopment to target new avenues of treatment for psychosis.