Tamara Hershey, Ph.D. - US grants

DESCRIPTION: (Applicant's abstract) The broad objective of this project is to understand the pathophysiology of dopa-induced dyskinesisas in Parkinson's disease. By defining the functional brain abnormalities in patients with dopa-induced dyskinesias, pharmacological and surgical treatment techniques for Parkinson's disease can be more rationally developed and refined. In addition, these results will have implications for current models of basal ganglia-thalamocortical physiology. Using functional neuroimaging (PET) and pharmacological activation techniques, we have identified specific abnormality in the activation of the ventrolateral thalamus in patients with dopa-induced dyskinesias. By examining these patients' cerebral blood flow responses to levodopa before and after surgical lesion to the internal pallidum (performed for clinical purposes entirely unrelated to this study) specific hypothesis regarding the inputs responsible for this thalamic over-activation can be tested.

DESCRIPTION (provided by applicant): The applicant is a clinical neuropsychologist with graduate training in neuropsychology and postdoctoral training in neuropharmacology and positron emission tomography (PET). The goal of this career development award is to integrate and advance these two areas of interest to answer questions about the neuropharmacological and neurophysiological basis of cognitive dysfunction in movement disorders such as Parkinson's disease (PD). This award will provide the applicant with training in the technical and theoretical issues related to using cognitive and pharmacological activation techniques in functional magnetic resonance imaging (fMRI). Long-term objectives are to address questions about the neural basis of cognitive dysfunction in movement disorders related to dopaminergic and/or basal ganglia dysfunction, such as PD, Tourette's syndrome and Huntington's disease. In addition, questions about the effects of dopaminergic treatments for these and other disorders (e.g. dystonia) on cognitive and neurophysiological functioning are also of interest. Cognitive dysfunction in these diseases, either due to the disease process itself or its treatments, can be limiting and disabling. Understanding the neurophysiologic basis for these symptoms may aid in assessing the effectiveness of current treatments or in developing better treatments. During the award period, the applicant will develop expertise in the use of fMRI, cognitive and neuropharmacological techniques to study these disorders, and will continue to hone her clinical skills in the neuropsychological assessment of movement disorders. The applicant will apply these new techniques to investigate the role of dopamine in working memory. The specific aims of the proposed studies are to test the hypothesis that 1) PD affects prefrontal cortex involvement in working memory and 2) dopaminergic modulation of working memory primarily occurs due to changes in lateral prefrontal cortical activity. To test these hypotheses, the applicant will first perform a behavioral study examining the effects of a steady-state infusion of levodopa, a dopamine precursor, on verbal and spatial working memory in PD patients and controls. The results of this study will then guide the choices of working memory tasks for an fMRl study. Subjects will be asked to perform working memory tasks before and during a steady-state infusion of levodopa. Modulation of the lateral prefrontal cortex is predicted during levodopa infusion. The degree of modulation is predicted to depend on baseline dopaminergic status (PD vs control) and the degree of memory load (low vs high).

[unreadable] DESCRIPTION (provided by applicant): A common difficulty in managing type 1 diabetes mellitus (T1DM) is hypoglycemia (low blood sugar). This complication is particularly common during childhood. Extreme hypoglycemia can cause coma or death, but less severe hypoglycemia can have consequences for cognitive function. However, it is not well understood how specific these cognitive consequences are and what their neural mechanisms might be, nor how these effects may differ across neural development. We propose to address these important questions. We hypothesize that severe hypoglycemia has a deleterious and specific effect on the hippocampus, a region particularly sensitive to metabolic insults, and on long-term memory, a skill that relies upon the integrity of the hippocampus, in children with T1DM. Using both retrospective and prospective methods, we will determine if the hippocampus is smaller in children with a history of repeated severe hypoglycemia. These measures will be obtained with high resolution structural magnetic resonance imaging and reliable volumetric measurements. We also will determine if reduced hippocampal volumes correlate with reduced long-term memory function. Memory function will be measured in part by a well-validated spatial delayed response measure that we have previously shown to be sensitive to repeated severe hypoglycemia in children with T1DM. We hypothesize that these effects will follow a developmental trajectory, with greater vulnerability in children who experienced hypoglycemia at younger ages due to interruption of critical developmental processes or to increased susceptibility for neuronal impact. The information obtained in this study will be important for the development of optimal treatment regimens for T1DM that minimize cognitive risk and maximize clinical benefit across the lifespan. [unreadable] [unreadable]

levodopa; short term memory; dopamine; Parkinson's disease; Tourette's syndrome; brain imaging /visualization /scanning; brain mapping; patient oriented research; behavioral /social science research tag; human subject; clinical research;

disease /disorder onset; long term memory; insulin dependent diabetes mellitus; cognition; brain imaging /visualization /scanning; hypoglycemia; brain morphology; age difference; brain mapping; hippocampus; brain injury; developmental neurobiology; children; behavioral /social science research tag; clinical research; human subject; patient oriented research; bioimaging /biomedical imaging;

[unreadable] DESCRIPTION (provided by applicant): This proposal is a competitive renewal of R01 DK64832 previously titled "Neurocognitive effects of hypoglycemia in T1DM". That grant hypothesized that prior severe hypoglycemia would reduce memory and hippocampal volume in youth with type 1 diabetes mellitus (T1DM). In the process of addressing this relatively narrow question, we have collected a uniquely large developmental neuroimaging and cognitive dataset in youth with T1DM that now allows us to examine broader and more complex issues. In light of new data and hypotheses, we have renamed the grant "Glycemic control, brain structure and cognitive development in T1DM". We now are able to address whether there is a differential effect of severe hypoglycemia (Hypo) and chronic hyperglycemia (Hyper) on the developmental trajectories of brain regions and whether these structural effects are reflected in changes in cognitive function. In our analyses to date, we found that a retrospective history of severe Hypo in youth with T1DM was associated with reduced volume in the posterior temporal- parietal cortex and reduced memory skills. In contrast, a retrospective history of Hyper in these same youth was associated with reduced volume in medial occipital-parietal cortex and lower verbal intelligence. These results are consistent with growing evidence that exposure to glycemic extremes has permanent consequences for the structural and functional integrity of these cortical regions. However, these data have come from retrospective studies and so the direction of causality can only be hypothesized. To address this ambiguity, prospective data are greatly needed. Our prior grant enrolled and characterized a large sample of youth with T1DM and followed them for two years. We now have new preliminary prospective data that demonstrate altered developmental trajectories of gray and white matter in the brain related to Hyper exposure during a 2 year follow-up period. However, the low frequency of severe Hypo during this time did not allow us to test hypotheses about Hypo's effects on brain development. To capture a wider range of exposure and enhance our power to test hypotheses we propose to follow this uniquely characterized cohort for 3 more years to assess change in brain structure and cognitive function over a full 5 years of T1DM. In addition, on the basis of new preliminary data suggesting that exposure to Hyper affects white matter microstructural integrity (measured with diffusion tensor imaging or DTI) in addition to regional brain volume, we propose to add state- of-the-art DTI measures to complement our existing measures. Finally, in order to more conclusively determine whether there are any differences at baseline in T1DM, we will add a newly diagnosed cohort to our longitudinal study. This plan, combined with our neuroimaging expertise and well-characterized existing cohort, places us in a unique position to test strong hypotheses about how glycemic extremes, brain structural integrity and cognitive function are related in youth with T1DM. PUBLIC HEALTH RELEVANCE: The goal of this project is to help determine whether central nervous system structure and function should join the peripheral nervous system, retina and kidneys as systems at risk during development in T1DM. This knowledge would have significant clinical implications for the optimal care of youth with T1DM. [unreadable] [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Depression and anxiety are highly prevalent (25-40%) in individuals with Parkinson disease (PD) and are the main cause of decreased quality of life in this population. Admissions to nursing homes and caregiver strain are influenced most by the psychiatric comorbidities of PD, not the cardinal motor symptoms of PD. Thus, understanding the neural circuits and predictive variables for the development of depression or anxiety in PD is an important area of research with significant clinical implications. One method for investigating the vulnerability of neural circuits underlying mood complications in PD is to study individuals treated with deep brain stimulation of the subthalamic nucleus (DBS STN). Optimal treatment with DBS STN has significant motor benefits for many PD patients. However, DBS STN can have unintended consequences on mood, perhaps due in part to the location of the active contact(s) within the functionally heterogeneous STN. It is known that anatomical pathways connect ventromedial STN to emotional systems (e.g. ventral pallidum, ventral striatum, anterior cingulate) and dorsal STN to motor systems in the brain (e.g. putamen, primary motor cortex). Direct tests of the hypothesis that stimulation of ventromedial STN influences acute changes in mood more than dorsal STN have not yet been done. In addition, the significance of any acute mood changes in response to DBS STN for understanding the neuropathophysiology of chronic, clinically significant mood disorders in PD is not known. We will use DBS STN and a novel, validated method for locating the site of contacts within the STN to address questions about the neural circuitry underlying acute and chronic mood dysfunction in Parkinson's disease. These methods provide a unique opportunity to map the relationship between STN regions (e.g. dorsal vs. ventromedial;left vs. right) and mood responses. In addition, we will determine if acute responses to stimulation of emotional areas of the STN are influenced by past or predictive of future clinical mood disorders. These experiments cannot be addressed in normal volunteers or in nonhuman animals. In addition to the direct clinical relevance for PD patients both with and without DBS, a better understanding of the neural circuitry involved in mood changes may provide useful information for others as well (e.g. individuals with altered basal ganglia functioning such as Huntington's disease, patients with non- PD major depression or anxiety). PUBLIC HEALTH RELEVANCE Depression and anxiety are highly prevalent (25-40%) in individuals with Parkinson disease (PD) and are the main cause of decreased quality of life in this population. This research will help to determine the neural circuitry involved in mood changes in PD and may provide useful information for other populations as well (e.g. individuals with altered basal ganglia functioning such as Huntington's disease, non-PD patients with major depression or anxiety).

DESCRIPTION (provided by applicant): Central dopamine is thought to play a significant role in obesity. In support of this idea, animal studies and one human positron emission tomography (PET) study have found reduced postsynaptic D2-like receptor availability in the striatum in obesity, with lower D2 receptor availability associated with higher weight. In addition, reward sensitivity, known to be related to dopamine function, has also been implicated in obesity and obesity-related eating behavior. These reports have led to the concept that dopaminergic abnormalities (e.g. reduced D2-like receptors) influence reward sensitivity, leading to altered eating behaviors and eventually obesity. However, there are several critical limitations that limit the strength of their conclusions and thus the interpretations and speculations embedded in literature that relies on this work. First, estimates of D2-like receptors in humans have been confounded by potential differences in endogenous dopamine release since the PET ligand (raclopride) used is known to be displaceable from receptors by endogenous dopamine. Second, failure to rigorously screen obese individuals for diabetes confounds conclusions, since diabetes has been independently associated with dopaminergic abnormalities. Finally, no human studies have addressed whether reduced D2-like receptor levels are a risk factor for obesity, a consequence of engaging in obesity related behaviors or being obese or all of the above. To clarify these issues, we propose to measure postsynaptic D2-like receptor binding with a PET ligand that, unlike raclopride, does not compete with endogenous dopamine and thus provides an unconfounded measure of D2-like receptors (NMB). Obese and lean subjects will be scanned and tested for behavioral features thought to be associated with dopamine and obesity (e.g. reward sensitivity) (Time 1). Obese subjects then will be assigned to a weight loss program that includes intensive monitoring and dietary and behavioral education. At the end of this year, all subjects will be scanned and tested again (Time 2). Results will determine if obesity status is associated with unconfounded measurements of reduced D2-like receptors in specific brain regions (e.g. ventral striatum and hypothalamus), whether individuals' D2-like receptor status is associated with dopamine-linked personality traits and with weight loss. This information is essential for accurately defining the role of the central dopamine system in obesity and for linking animal and human literature in this field. PUBLIC HEALTH RELEVANCE: This project will address the neurobiological underpinnings of obesity. We will determine whether dopamine receptors in the brain are reduced in obesity and whether they are affected by weight loss. In addition, we will determine whether dopamine receptors are related to behaviors that are associated with obesity. This information will be useful in devising new interventions for obesity and understanding the full effect of obesity on the brain.

Wolfram syndrome (WFS; OMIM #222300) is a rare autosomal recessive disease clinically defined in 1938 as the combination of childhood-onset insulin dependent diabetes, optic nerve atrophy, diabetes insipidus and deafness 4-6. Based on early descriptions, neurological features were thought to appear later in the disease with death occurring in middle adulthood 6. Importantly, the major causative gene (WFS1) was identified in 1998 7. This discovery allowed researchers to determine that the WFS1 gene encodes the protein wolframin, which helps protect cells from endoplasmic reticulum (ER) stress-mediated apoptosis, potentially via intracellular calcium homeostasis 8-15. Pathogenic mutations in WFS1 can result in death or dysfunction of cells that are under high ER stress, such as insulin-producing pancreatic ? cells 16-18, causing insulin dependent diabetes. In addition, knowing the causative gene has allowed us to identify patients by their WFS1 mutation rather than the classic set of symptoms, leading to the increasing realization that the WFS1-related phenotype (including neurologic symptoms) is much more variable than previously understood. The first iteration of this grant (HD070855 ?Tracking Neurodegeneration in Early Wolfram Syndrome?) contributed to this shift in understanding. In this time, we have built a successful annual research clinic for WFS, met or exceeded our recruitment goals for patients and controls, validated a clinical severity rating scale for WFS 19, described an unexpectedly early neurophenotype of reduced balance, smell identification and ventral pons volume 20-27, identified alterations in traditional diffusion tensor imaging (DTI) metrics that suggest hypomyelination as a pervasive neuropathological feature of WFS 19-25,27 and provided justification for the selection of two primary outcomes (visual acuity and ventral pons volume) in a newly funded clinical efficacy study in WFS (Barrett, PI). Our findings suggest two lines of investigation going forward. First, we hypothesize that ER stress- related dysfunction could inhibit production of myelin during neurodevelopment in WFS, as active and developing oligodendrocytes (cells that produce myelin in the brain) are more vulnerable to ER stress than mature ones 28,29. However, standard DTI methods conflate inflammatory processes (which can also be associated with ER stress 30) in the extra-axonal space with metrics of axonal and myelin integrity, leading to potentially confounded measurements 31. We propose to collect novel, validated diffusion sequences on a new state of the art MRI scanner (Siemens Prisma) and apply cutting-edge analysis approaches to measure white matter integrity throughout the brain and in the optic nerve, improving our ability to draw conclusions about axonal and myelin integrity over time. Second, larger and more diverse samples are needed to determine the predictors of WFS degeneration. We will pool key variables from WU with baseline and placebo conditions from a new clinical trial in the UK, rapidly increasing our sample and allowing for more complex analyses. Findings from this work may indicate future targets for brain-specific intervention, identify outcome measures or high-risk subgroups for clinical trials targeting neurological symptoms and will lay the groundwork for additional international collaborations. These data will also greatly expand our understanding of the cross-sectional and longitudinal phenotype of WFS1-mutation related disorders, rather than classically defined Wolfram Syndrome. Such knowledge will have a significant impact on patients and families by allowing physicians to provide more accurate prognoses. Finally, forms of ER stress-mediated apoptosis have been implicated in more common neurodegenerative, endocrine and neurodevelopmental diseases 28,32, which may benefit from the insights gained here.

DESCRIPTION (provided by applicant): Up to 20% of all children have tics at some time in their life, and about 3% of all children have a chronic tic disorder such as Tourette syndrome (TS), making tic disorders a subject of substantial public health interest. Despite steadily increasing research, no treatment for TS works for more than half those treated, and the cause and pathophysiology of TS are poorly understood. Based on the observation that dopamine D2 receptor antagonists significantly reduce tic severity, one longstanding hypothesis has been that tics may involve abnormalities in transient (phasic) dopamine release in the striatum, while baseline (tonic) dopamine release may be normal. Several experiments in the past 15 years attempted to address this hypothesis by measuring striatal dopamine release in TS in response to amphetamine. One could argue, however, that this assessed only maximal possible dopamine release under nonphysiological conditions. The present proposal represents the first step in a plan to directly test phasic dopamine release in TS by measuring striatal dopamine release in response to a cognitive task with and without exogenous levodopa. The proposal will exploit the newly developed Siemens PET-MRI scanner to acquire rCBF simultaneously with the receptor imaging. The applicants have preliminary data on most aspects of this approach, considered individually, but none for the combined approach. This application proposes to test the full protocol on a small group of TS and matched control subjects, in order to demonstrate feasibility and estimate variance for a planned R01 application. The planned R01-funded follow-up study would include sample sizes adequate to test the effects of psychiatric comorbidity, past treatment, and demographic variables. PUBLIC HEALTH RELEVANCE: About 20% of all children have tics-sudden, unwanted movements or noises-at some time in their life, and about 3% of all children have a chronic tic disorder such as Tourette syndrome (TS), in which quality of life is substantially reduced. Unfortunately, how the brain generates tics is still not clear. Experts have hypothesized that the brain messenger dopamine, while released normally most of the time in TS, is not released normally when the brain sends a quick burst signal related to learning or movement. This project will use a new, cutting-edge brain scanner and a new experimental design to directly test whether such transient dopamine release is normal in TS. The present application will support first studying a small group of people with and without TS to show that the project is feasible and to clarify how many people need to be tested in the planned conclusive follow-up study. This new approach is expected to prove or lay to rest one of the key current theories about the cause of tics in Tourette syndrome.

Compelling evidence demonstrates that the brain's capacity to utilize glucose and respond to insulin is impaired in Alzheimer's disease (AD). A striking finding from human studies is the unique susceptibility of particular brain regions, particularly the default mode network (DMN) of the brain, to A? deposition in AD and cortical volume loss in diabetes. Although the cause of this regional disparity is unknown, understanding characteristics common to these regions could elucidate mechanisms of selective vulnerability in AD and perhaps lead to new treatment strategies. The DMN is a set of widespread but interconnected brain regions, with increased glucose uptake in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water, which we refer to as glycolysis. It has been hypothesized that the DMN's high rate of glycolysis augments an activity-dependent or metabolism-dependent cascade that is conducive to the formation of brain pathology in diseases such as AD, thus leading to the observed preferential vulnerability of this network. It is unclear whether increased glucose/insulin levels can increase glycolysis within the DMN above a certain threshold that could make brain tissue more vulnerable to A? deposition, damage or dysfunction. Data suggest that brain insulin dysregulation may be a critical aspect of AD risk. These relationships are of particular interest given the increased risk of AD in patients suffering from diabetes. Project 1 tests whether hyperglycemia and/or hyperinsulinemia affect glycolysis (as measured through PET imaging) in the DMN and whether the precuneus region is preferentially affected in the brains of controls and of those at higher risk for developing AD (older adults and in patients with Type 2 Diabetes (T2DM) with defective insulin signaling). Results will address fundamental questions about normal human brain metabolism as well as provide systems-level neurobiological data implicating alterations in glucose and insulin in DMN vulnerability.

Optical imaging is a non-invasive imaging modality that can visualize functional dynamics of blood volume and oxygen consumption associated with brain physiology and pathology. The Culver group has developed a novel high-density diffuse optical tomography (HD-DOT) system that achieves fMRI-comparable image quality and sensitivity and can detect cortical resting state networks (RSN) using functional connectivity and cortical blood flow responses to tasks. This technological innovation now opens up new avenues of research into patient populations that cannot be imaged with fMRI. A prime example of this new opportunity is individuals with implanted deep brain stimulators (DBS). The systems-level impact of DBS responsible for clinical benefit and potential side-effects is still not fully understood and could be useful in optimizing DBS, potentially providing short-cuts to the current trial-and-error approach to programming and electrode selection. Currently, investigations into the brain networks involved in DBS are difficult due to the significant limitations of conventional neuroimaging techniques. Due to contraindications from implanted hardware, these patients cannot be safely imaged with MRI for research purposes. Although blood flow can be measured by PET in these patients, studies are limited due to radiation exposure limits and poor temporal resolution (e.g. minutes). In contrast, HD-DOT allows us to measure cortical hemodynamics in response to task or DBS conditions and measure resting state networks with comparable temporal and spatial resolution to fMRI and with greater comfort (patients sit in a comfortable chair during scanning) and no radiation exposure. We have previously shown the feasibility of assessing cortical RSNs and task-induced responses in a small number of patients with subthalamic nucleus (STN) DBS. The work proposed here will establish the utility and sensitivity of HD-DOT to answer important clinical and theoretical questions in two different DBS populations.

? DESCRIPTION (provided by applicant): Type 1 diabetes mellitus (T1DM) is typically diagnosed in childhood and over time can lead to complications affecting the retina, heart, kidneys, peripheral nerves, and more recently appreciated, the brain. During childhood, the brain undergoes significant structural and functional changes and has a high and rapidly changing metabolic demand; these unique properties have led to the suggestion that the developing brain may be especially vulnerable to glycemic extremes. Accordingly, studies find that early age of onset, accumulated exposure to hyperglycemia and repeated severe hypoglycemia during development are associated with lower cognitive performance and altered brain structure in children with T1DM. Intriguing patterns have been identified, yet substantial individual variability in brain outcomes remains unexplained. More recently, our data and others' have suggested that clinical severity at diagnosis, particularly at younger ages, may contribute to cognitive and brain outcomes, even many years later. However, previous studies have not been designed to differentiate the effects of initial clinical presentation from the cumulative effects of subsequent glycemic extremes on the brain. Thus, the goal of this study is to determine how clinical features at the time of T1DM diagnosis shape the developmental trajectory of the brain and its responses to subsequent glycemic control. We propose to test this hypothesis explicitly by performing sensitive neuroimaging, cognitive testing and quantitative clinical measures on children with T1DM and their non- diabetic siblings at diagnosis and at 3 and 21 months post-diagnosis. Findings may highlight the need for programs aimed at early diagnosis of the disease, DKA prevention, and ?-cell preservation, particularly in at- risk youth, in order to minimize long-term negative consequences for brain health and development. Although recent exciting developments raise the possibility of better glycemic control using closed-loop insulin delivery systems or of curing T1DM through ?-cell transplants, the risks associated with clinical presentation of T1DM would still remain and need to be better understood.

Overall Center Summary The NINDS P30 center core at Washington University (WashU), which operates as the Neuroimaging Informatics and Analysis Center (NIAC), was established in 2004 to facilitate neuroimaging as a core research tool in the drive to better understand and treat neurological conditions and diseases. Neuroimaging-based research at Washington University covers the spectrum from preclinical small animal studies to large-scale clinical trials to translational use of novel imaging methods in the clinic. In recent years, this research has become more expansive to include larger patient cohorts, more complex imaging protocols, greater diversity of clinical, genetic, and behavioral measures, and more extensive quantitative post-processing and analysis. This research covers a diversity of neurological diseases and conditions, including stroke, traumatic brain injury, Parkinson's Disease, Alzheimer's disease, multiple sclerosis, and epilepsy. The overarching mission of the NIAC is to facilitate the full range of this research through a suite of innovative imaging physics, informatics, and analysis services supported by a rich consulting and educational program. With this continuation proposal, we will expand the Center's services to support the evolving practices of our investigators. Specific Aim 1 will facilitate large scale, interdisciplinary neuroimaging-based research by providing a comprehensive informatics infrastructure that provides data management and automated image processing services for small animal imaging and human imaging obtained at WashU facilities and in multi- center clinical studies. Specific Aim 2 will facilitate the development and adoption of new neuroimaging methods in clinical research and clinical practice by providing active expert consulting, MRI physics support, and advanced software development services. The NIAC will include three cores to achieve these aims. The Administrative Core will oversee the Center's operations and allocation of resources, operate an active outreach and education program, and ensure a high level of communication between the Center's faculty and staff and the neuroscience community. The Informatics Core will provide software and hardware to integrate the imaging facilities, provide database services, execute automated and semi-automated image processing pipelines, and share data within collaborative networks and the broader research community. The Imaging Core will provide direct user support through consulting services and training programs and will lead the effort to develop and transition new methods to the Center's users. The Center will be overseen by a Steering Committee composed of Center users and domain experts with deep and diverse experience. The three cores, under the Steering Committee's guidance, will work closely together to provide a comprehensive suite of services and resources to support the University's neuroimaging community.

Deep brain stimulation of the subthalamic nucleus (STN DBS) can provide substantial motor benefit yet occasional mood and cognitive side effects in Parkinson disease (PD). Current literature hypothesizes that downstream network level effects are a critical mechanism of STN DBS?s influence on motor and non-motor behavior, however our ability to test this hypothesis has been limited. Common imaging modalities either do not have the temporal resolution necessary to discern resting state functional connectivity of cortical networks or are not suitable or safe for patients with implanted DBS. We have developed a novel high-density diffuse optical tomography (HD-DOT) system for measuring brain hemodynamics which can accurately map the functional connectivity of cortical resting state networks (RSN) or task-evoked responses within the first ~1cm of cortex. HD-DOT has comparable temporal and spatial resolution to fMRI, greater comfort than MRI or PET, no radiation exposure, no electrical artifacts, no metal artifacts and no contraindications or safety concerns for DBS patients. We have strong preliminary data showing the validity and feasibility of assessing cortical RSNs and task-induced responses in STN DBS patients. With our novel HD-DOT system, careful experimental design and rigorous analyses, this study will determine the nature of cortical RSN-level modulation induced by STN DBS and its relationship to DBS-induced motor and cognitive change. Controls and individuals with PD will be enrolled pre-surgically and scanned with HD-DOT and MRI (resting state BOLD, structural]). After implantation and optimization of DBS, PD individuals will be scanned with HD-DOT in several conditions. With these data, we will test hypotheses about networks that are responsive to important characteristics of STN DBS (e.g.location) and their relationship to motor and non-motor function. This information ultimately could provide methods for faster optimization of DBS parameters and help identify cortical nodes or networks involved in STN DBS-induced benefits or side effects that would provide future targets for less invasive neuromodulation. Finally, this work could reveal fundamental properties of cortical network physiology such as the capacity for plasticity in response to up-stream perturbations.

This proposal, from the Neuroscience Program in Washington University?s Division of Biology and Biomedical Sciences (DBBS), is a new application to the Jointly Sponsored Ruth L. Kirschstein National Research Service Award Institutional Predoctoral Training Program in the Neurosciences. The overarching goals of our Neuroscience program are to equip our trainees with a firm foundation in nervous system function and dysfunction, the ability to identify problems and design strategies to address them critically and rigorously, and the skills required to perform, present, and mentor others in research. The strengths of our current training program include a strong and evolving curriculum to address critical areas of modern neuroscience and the skills necessary for success in any neuroscience career, a focus on improving diversity of students in neuroscience and retaining diverse students in the program, a collegial and collaborative atmosphere, broad institutional support, multiple neuroscience-related opportunities for community outreach and teaching and a supportive administrative structure that facilitates all aspects of the educational process, from recruitment of students to thesis defense and beyond. This proposal builds on these features with ongoing and future initiatives aimed at improving quantitative, experimental and statistical thinking, facilitating interdisciplinary and/or advanced training in areas relevant to a student?s research, modernizing curriculum delivery, providing evidence-based ethics training to address well-publicized problems of rigor and reproducibility, and assessing the impact of these initiatives and modifying their implementation as needed. We are requesting 11 slots for students in their 1st and 2nd years. Students will emerge from this program with a stronger foundation in experimental and statistical thinking, ethics and methods to improve rigor and reproducibility. Faculty in the program will also benefit from exposure to emerging methods and approaches in these areas.

Type 2 diabetes mellitus (T2D) is a significant public health problem affecting ~30 million American. Obesity, insulin resistance, insulin deficiency (? cell dysfunction) and dysglycemia all precede the diagnosis of T2D and are known to promote inflammation and ultimately lead to microvascular complications. More recently, research has identified brain-related complications in adult-onset T2D, including reduced regional brain structure and function, impaired cognition, and increased lifetime risk for Alzheimer?s disease. Alarmingly, an increasing number of children and adolescents are being diagnosed with T2D, likely due to the growing prevalence and earlier onset of obesity. Youth-onset T2D appears to have a more aggressive course than adult-onset T2D, with earlier onset and more rapid progression of microvascular complications. In addition, studies of youth with obesity and youth-onset T2D have reported robust differences in regional brain structure and cognition, suggesting that brain effects may follow the same aggressive course as the more typical vascular complications. Unfortunately, little is known about the factors associated with poor brain structure and function in youth with T2D. To address this critical gap in knowledge, we propose to study youth across the spectrum of body mass index (BMI) and metabolic dysfunction. This approach will allow us to disentangle the relationship of key features of T2D risk (e.g. obesity) with intermediary physiologic changes that pose a risk for the brain (e.g. insulin resistance, inflammation, ?-cell dysfunction and dysglycemia) that may lead to reduced brain structure and function in T2D. We will determine which of these factors are most associated with differences in brain structure and function among groups, over time, and how these effects differ from normal neurodevelopment. Given that the disease occurs at a time when brains are undergoing dramatic developmental processes, the aggressive nature of youth-onset T2D progression and complications in other organ systems, these results may provide guidance and justification for longer follow-up, interventional or mechanistic studies and have important clinical implications.