RECENTLY COMPLETED STUDIES

Traumatic Brain Injury (TBI) Studies

MRS Biomarkers of Treatment Response in TBI
(KUMCRI Lied and Clinical Pilot Program)
PI: William M. Brooks, PhD, Janna Harris, PhD

The broad goal of this project is to validate magnetic resonance spectroscopy (MRS) biomarkers representing specific pathological mechanisms that contribute to cognitive outcome in human survivors of TBI.

Inflammation and traumatic brain injury in the elderly
(5 R01 AG031140-02)
PI: Nancy Berman, PhD (Co-Inv: Phil Lee, PhD)

Major Goals: To provide a rationale for specific treatments to improve outcomes of traumatic brain injury in the elderly and to test the effectiveness of treatments based on this rationale.

Diabetes and Oxidative Stress Studies

Quantitative in vivo biomarkers of oxidative stress in diabetes
(NIH R21 DK081079)
PI: In-Young Choi, PhD (Co-Inv: Phil Lee, PhD, Jeanne Drisko, MD, David Robbins, MD, Henry Yeh, PhD)

The overall aim of this proposal is to develop and characterize direct, objective in vivo biomarkers of oxidative stress occurring in diabetes mellitus. Such biomarkers would be valuable for monitoring long-term ongoing changes and complications that result from prolonged hyperglycemia and associated oxidative stress. We focus on two major antioxidants, glutathione (GSH) and vitamin C (ascorbate, Asc), that have received interest from the medical community as potential markers of oxidative stress to elucidate their role in diabetes and to provide new insights into diabetes care.

Glutathione as a measure of oxidative stress in magnetic resonance spectroscopy (MRS) in brains of multiple sclerosis patients
(National Multiple Sclerosis Foundation)
PI: Sharon G. Lynch, MD (Co-Inv: In-Young Choi, PhD, Phil Lee, PhD)

The goal of this study is to measure glutathione (GSH) in the brains of patients with secondary progressive multiple sclerosis (SPMS) to understand the role of oxidative stress in the disease.

Oxidative stress is an important component of the disease process, both in the animal model of multiple sclerosis (MS) and in MS itself. Measuring oxidative stress in the living person or animal has been very difficult in the past. GSH, a powerful antioxidant, may be lost in many diseases in which oxidative stress is implicated. GSH reduction may serve as an indicator of oxidative stress. We have developed a technique through magnetic resonance spectroscopy (MRS) that can measure GSH levels in living brains. Using this technique, we have compared GSH levels in healthy individuals with patients with Alzheimers disease. We have found a reduction of GSH in patients compared to healthy individuals. We believe that a reduction in GSH may also be measured in people with Secondary Progressive MS (SPMS) and that this can act as a marker in this disease process.

Disorders and Motivational Behavior Studies

A Pilot Study of Biological Signals of weight Loss in African American Women
PI: Cary Savage, PhD

The purpose of this study is to examine whether or not there are differences in how African American's women's brains react to food pictures depending on whether the6y are healthy weight or obese

Neural Processing of Emotion in Music among Individuals with Major Depression
PI: Cary Savage, PhD

Specific Aims and Study Summary: The proposed study will use functional MRI (fMRI) and a music-processing probe to determine whether patterns of brain activation elicited by emotionally evocative auditory stimuli differ between groups with major depressive disorder (MDD) and non-depressed controls.

Neural Responses to Faces
PI: Cary Savage, PhD

Specific Aims: To clarify the nature of unconscious emotional processing in SA, the proposed research will use neuroimaging (fMRI) measures in conjunction with backward masking. The specific aim of this study is to investigate the neural underpinnings of unconscious emotional face processing in people with and without SA. The study is specifically focused on amygdala activation during the presentation of masked angry faces.

Studies of Reward Processing and Impulsivity in Nicotine Addiction and Obesity
(NIH R00 R00DA025153)
PI: Laura Martin, PhD

The R00 project will extend the K99 findings by employing functional magnetic resonance imaging (fMRI) to investigate how the brain responds in healthy weight smokers and non-smokers as well as obese smokers and non-smokers when they choose between smaller immediately available rewards compared to larger delayed rewards.

Pilot Study of Reward Processing and Exercise Adherence
PI: Cary Savage, PhD, Joseph Donnelly (Co-Inv: Laura Martin, PhD)

An fMRI study examining the neural systems of reward and exercise adherence to a 9-month exercise program. Preliminary results indicate differences between reward and punishment in the middle frontal gyrus of the prefrontal cortex (PFC) at both anticipation and delivery. During anticipation, adherers show greater PFC activation than non-adherers to rewards compared to punishments. During delivery, non-adherers showed greater PFC activation than adherers when expected rewards compared to punishments were delivered. However when unexpected outcomes were delivered, PFC responded more to punishments compared to rewards among non-adherers.

Pilot Study of Reward Processing and Binge Eating Disorder
PI: Cary Savage, PhD (Co-Inv: Laura Martin, PhD)

This is an fMRI study examining the reward processing among obese participants who have binge eating disorder. Specifically this study examines similarities and differences in brain responses to rewards among obese participants with and without binge eating disorder compared to healthy weight participants. Data is currently being collected and analyzed.

Brain function predictors and outcome of weight loss and weight loss maintenance
NIH (R01 DK080090)
PI: Cary Savage, PhD (Co-Inv: William Brooks, PhD)

Obesity rates are on the rise and associated with serious public health consequences and rising health care costs. Eating behavior is influenced by a convergence of processes in the brain, including homeostatic factors and motivational and reward processing. Motivational and reward processing are especially important contributors to overeating in humans. Our initial functional imaging studies have identified brain regions that respond differently to visual food cues in obese and healthy weight individuals, and are positively correlated with reports of hunger in obese participants. While shedding some light on mechanisms of overeating, many important questions remain. For instance, it is not yet known whether brain activation patterns change after dieting, or if they change differentially in successful and unsuccessful dieters. In addition, little is currently understood regarding biological processes that contribute to long-term maintenance of healthy weight.

We will scan obese and healthy weight participants with a food motivation fMRI paradigm during a baseline state and after obese participants have completed a twelve-week diet-based weight loss intervention. Obese participants will then be followed though a 6-month weight maintenance period. The study will address three Specific Aims:

1. Characterize brain activation underlying increased food motivation and impulsive eating in obese individuals.
2. Identify brain activation changes and predictors of initial weight loss.
3. Identify brain activation predictors of weight loss maintenance.

Findings from this study will have significant implications for understanding mechanisms of obesity, weight loss, and weight maintenance, and may ultimately lead to more effective interventions.

Pupillary Responses and Neural Activation to Face and Non-Face Pictures in Children with ASD
PI: Cary Savage, PhD

This is a two stage study. The first measures pupillary response in children with Autism Spectrum Disorder (ASD), while they examine pictures of faces and toys. The second stage is an fMRI study in which these children are scannes while they undergo this task. The goal is to identify brain networks underlying blunted social repose in children with ASD.

Developing a verbal memory paradigm for fMRI in children at risk for psychiatric disorders
(Institutos Nacionais de Ciência e Tecnologia (Brazil))
(The National Institute for Developmental Psychiatry (Brazil))
PI: Euripides Miguel (Co-Inv: Cary Savage, PhD)

This project uses fMRI to examine brain activation during verbal learning in children at risk for obsessive-compulsive disorder (OCD; but not yet diagnosed), children with OCD, and healthy control children who are not at risk for OCD.

Incorporation of a protein-rich breakfast and its impact on appetite control and body weight management in overweight and obese adolescent girls
(KUMC BIRCWH Career Development Award)
PI: Heather Leidy (Mentor: Cary Savage, PhD)

This award supported Heather Leidy in fMRI studies of food motivation in breakfast skipping adolescent girls.

Other Ongoing Pilot Studies

Pilot studies for stimulus validation in fMRI study of response to advertising logos
PI: Amanda Bruce, PhD

The purpose of this pilot research study is to develop a set of relevant stimuli to use in a future functional magnetic resonance imaging (fMRI) study. In order to determine the most applicable logos to use, we need to determine which logos are the most familiar, pleasant, and exciting to children. In this study, we will ask children to rate commercial logos on familiarity, pleasantness (valence), and excitement (intensity). These ratings will then be used to select the most suitable images of food-related (McDonald's arches) and nonfood-related logos (Nike swoosh) to use in a neuroimaging study. We will be displaying two categories of logos: food and nonfood. It is important to make certain that the two groups of logos are matched as closely as possible on familiarity, valence, and intensity. Thus, we will aim to use the data from this pilot study to select 160 food and nonfood logos matched on familiarity, valence, and intensity that can be used in the future fMRI study.

Alzheimer's Disease, Aging and Memory Program Studies

Effects of Delivery Mode of Cognitive Intervention in Early AD
(Alzheimer's Association)
PI: Patricia Pohl, PhD (Co-Inv: Cary Savage, PhD)

The aim of this study is to use fMRI and a verbal memory paradigm to identify changes in brain function after intensive cognitive rehabilitation in individuals with early AD.

Understanding the mechanism of disease progression of Alzheimer's disease and diabetes in the animal models
PI: Eva L. Feldman (Co-Inv: In-Young Choi, PhD, Phil Lee, PhD)

This study aims to investigate the effect of diabetes and AD progression in the living animal brains in collaboration with Dr. Eva L. Feldman at the University of Michigan, who is Director of Center for the Study of Complications in Diabetes. This study will (1) provide in vivo evaluation of brain glucose, neurotransmitters and antioxidant levels in the diabetic and AD animal brains, (2) determine the effect of high glucose levels in diabetes (i.e., hyperglycemia) in AD progression, and (3) provide improved understanding of the interplay between hyperglycemia and antioxidant defense system in the brain. The identification of cerebral biomarkers is crucial to characterize the diabetes-related AD progress in the brain and can be translated to human studies.

Clinical and biomarker relevance of cytochrome oxidase in Alzheimer's disease
(Lied Endowed Clinical Pilot Research Fund)
PI: Russell Swerdlow, MD (Co-Inv: In-Young Choi, PhD, Phil Lee, PhD, Jeffrey M Burns, MD)

This study aims to determine whether platelet cytochrome oxidase (CO) activity or gene polymorphisms correlate with brain biomarkers. We will use magnetic resonance spectroscopy and imaging to assess glutathione levels and brain volume in AD subjects. This study tests for correlations between peripheral tissue-derived and brain-derived data.

Cardiorespiratory Fitness and Executive Function in Early Alzheimer's Disease
PI: Eric Vidoni, PT, PhD (Mentor: Cary Savage, PhD)

This award supported Eric Vidoni in fMRI studies of motor learning in Alzheimer's disease.

Force Amplitude Modulation of Hand and Tongue Movements in Parkinson s Disease
PI: Jeff Searl, PhD

Specific Aims and Study Summary: The purpose of this study is to describe the role of the basal ganglia and other key brain structres in regulating the force of tongue (speech and nonspeech) and hand movements for individuals with Parkinson's Disease and healthy age- and gender-matched controls. Subjects will squeeze small plastic bulbs held in their hands and oral cavities to match various increments of their maximum force. Functional magnetic resonance imaging (fMRI) data will be collected throughout the behavioral tasks, which will also be measured via pressure transducers connected to the bulbs and surface EMG leads on the hand and submental musculature.

Hypothesis 1 (H1): Tongue force during speech and non-speech tasks is regulated by neural structures including both the basal ganglia and the brainstem in subjects with PD and healthy controls.

Hypothesis 2 (H2): The intensity and volume of activation during force regulation of hand and tongue movements will be decreased in the basal ganglia for those with PD compared to healthy subjects.

Hypothesis 3 (H3): Individuals with PD will show more variable patterns of target force production and slower motor unit recruitment during hand and tongue movements than normal subjects.

Fetal and Maternal Health and Magnetocardiography-related Studies

The Effects of Docosahexaenoic acid (DHA) on fetal cardiac outcomes.
(R21 HD059019 NICHD)
PI: Kathleen Gustafson, PhD (Co-Inv: Mihai Popescu, PhD)

The purpose of this research is to determine the effects of maternal DHA supplementation during the 2nd and 3rd trimesters of pregnancy on maternal and fetal cardiac autonomic control. 60 pregnant women will be enrolled in the study and randomized to either 600 mg per day of DHA or placebo oil capsules. Maternal/fetal magnetocardiograms (MCG) will be obtained at 24, 32 and 36 weeks gestational age. A newborn neurobehavioral assessment will take place at birth. Maternal and infant blood samples will be analyzed to determine total fatty acid content. At 2 months of age, an infant MCG will be obtained.

DHA Supplementation and Pregnancy Outcome
R01 HD047315 NICHD (KUDOS study):
PI: Susan Carlson, PhD (Co-Inv: Kathleen Gustafson, PhD)

This research is designed to determine whether 600 mg of DHA a day will improve pregnancy outcomes and enhanced visual and cognitive performance in children up to 18 months of age. Dr. Gustafson serves as the vision scientist and electrophysiologist in this project and is responsible for obtaining sweep visual evoked potentials, visual stereoacuity and analyzing heart rate (HR) and heart rate variability (HRV) from the cognitive tasks. 360 women will be enrolled in the study and will be randomized to DHA or placebo oil. Visual assessments will take place at 6 weeks, 4, 6, 9, 12 and 18 months of age. Cognitive assessments with ECG will take place at 4, 6, and 9 months of age. Dr. Gustafson is responsible for obtaining and analyzing the 3,240 data sets that will be generated from these 2 assessments and for reporting the results.

The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid
(Mead Johnson Nutritionals, DIAMOND study follow-up)
PI: Susan Carlson, PhD (Co-Inv: Kathleen Gustafson, PhD)

The first phase of the DIAMOND study is complete. This study compared the effects of 4 different levels of DHA supplementation in infant formula on visual and cognitive outcomes. This was a multi-center study with 160 infants enrolled at the Kansas City site. We are currently funded by MJN to follow the remaining cohort to determine the effects of supplementation on brain event related potentials during a Go/NoGo task. We are also collecting ECG during the task to determine the effects of supplementation on HR and HRV. There are approximately 80 children available for this follow up study. The assessments are performed at 4 and 5 years of age. Dr. Gustafson is responsible for the analysis and reporting of the ERP and cardiac assessments.

Effects of Maternal Exercise on Fetal Cardiac Outcomes
(Kansas City University of Medicine and Biosciences)
PI: Kathleen Gustafson, PhD, Linda May, PhD

The purpose of this study is to determine the effects of maternal exercise during pregnancy on maternal, fetal and infant HR and HRV. Approximately 50 women have been recruited into this pilot study which has resulted in four APS abstracts presented in 2008 and 2009 and featured on the APS Lifeline TV Podcast in August 2009.

Advanced Source Reconstruction Techniques for Fetal Magnetocardiography
(NIH/NBIB R21 EB006776)
PI: Mihai Popescu, PhD (Collaborators: Kathleen Gustafson, PhD, Anda Popescu, M.Sc.)

This investigation aims to optimize fetal magnetocardiography (fMCG) for studying cardiac development and electrophysiological abnormalities. The study focuses on the development of advanced source reconstruction algorithms, which use the multichannel fMCG data and 3D ultrasound images of the feto-abdominal anatomy to provide reliable measures of fetal cardiac electrophysiology. As part of the study, we will test the novel methodology for fetuses with an abnormal increase in ventricular wall thickness. A successful validation will recommend fMCG as an investigational tool for studying cardiac electrophysiology in a broad range of conditions associated with increased risk of ventricular hypertrophy, e.g. intra-uterine growth retardation, diabetus, pulmonary valve and aortic stenosis, closure of the ductus arteriosus, tetralogy of Fallot, or ventricular septal defect.

Brain/Behavior profiles to distinguish individual differences in Asperger Syndrome
(Kansas Center for Autism Research and Training - KCART)
PI: Winnie Dunn, PhD (Collaborators: Kathleen Gustafson, PhD, Mihai Popescu, PhD)

This investigation aims to identify valid methods for behavioral assessment and to study their correlation with brain activity within the Autism Spectrum Disorders (ASD). Validating behavioral methods will enable us to characterizing the neurobehavioral characteristics of ASD, which in turn will provide insights about individual differences within this heterogeneous disorder. As part of the study, we will investigate the potential of MEG brain imaging to characterize the sensory-gating mechanisms, and to providing evidence-based measures for distinct sensory processing-temperament profiles. This aim of the study fits well within a growing consensus that developmental abnormalities of the limbic system might play a major role as a biological substrate for autism spectrum disorders.

Effects of Fast-ForWord Language on Children's Language Processing
(NIH/NIDCD R21 DC007214)
PI: Marc Fey, PhD (Collaborator: Mihai Popescu, PhD)

The broad objectives underlying this investigation consist in developing and testing language interventions or sequences of interventions that not only change the language performance of children with specific language impairment (SLI), but fundamentally change their ability to learn new language from the input to which they are exposed. As part of the study, we aim to compare the neurophysiologic effects of Fast ForWord Language (FFW-L) with those of a less intensive, conventional Narrative Based Language Intervention (on their own and in combination) on a battery of auditory and auditory-verbal tests. To achieve this objective, whole-head magnetoencephalography (MEG) is combined with high-density electroencephalography (EEG) to provide a detailed spatio-temporal profile of the brain's response to simple and complex auditory stimuli before each of the planned interventions or control periods.

MEG spatio-temporal source localization using the Source Affine Image Reconstruction (SAFFIRE) algorithm
PI: Shannon Blunt (Collaborator: Mihai Popescu, PhD)

This study focuses on the development and evaluation a new non-parametric iterative algorithm that aims to improve performance in reconstructing sparse solutions for the biomagnetic source imaging problem. The new method is derived as a recursive implementation of a Minimum Mean-Square Error (MMSE) estimation algorithm and uses a generalized affine scaling transformation in an iterative scheme. We use theoretical and empirical approaches to assess the role of the initialization of the iterative algorithm, and to test its sensitivity in the presence of noisy data.

MEG registration of short-term cortical adaptation to TAC-Cell inputs to human hand and face
PI: Steve Barlow (Collaborator: Mihai Popescu, PhD)

This study uses magnetoencephalography (MEG) to characterize the short-term adaptation of the primary somatosensory cortex (S1) in response to tactile inputs to the human hand and lips. The cortical response to pneumatic tactile stimuli consisting of pulse-trains delivered at different frequencies is used to testing whether the magnitude of short-term adaptation in S1 reflects differences in mechanoreceptor representation for these two sensorimotor control systems

Other HBIC Studies

MRI-Based Modeling to Evaluate Risk of Osteoarthritis
(NIH R01 EB008709)
PI: Kenneth Fischer, Ph.D. (Co-Inv: Phil Lee, PhD)

The major goal of this project is to validate MRI-based in vivo joint contact modeling and to develop predictive indices from MRI-based modeling for risk of osteoarthritis following injury.

Bone-renal regulation of energy metabolism
PI: Peter Rowe, PhD (Co-Inv: Phil Lee, PhD)

The goal of this study is to understand calcium regulation in kidney diseases using MR imaging techniques. The proposed molecular studies intend to unravel the role of the PHEX, FG23, and ASARM-peptide axis in regulating energy metabolism. The aims are 1. Determine whether ASARM-PHEX interactions contribute to fat mass and energy metabolism in vivo. Integral to this aim will be the use of XLH, MEPE transgenic (MEPE tgn), ASARM transgenic (MEPE-tgn), DMP1 null and MEPE null mice, 2. Unravel the molecular pathways in vitro using adipocytes, bone cells, pancreatic beta cells and renal cells in coculture models, 3. Use our well established PHEX synthetic peptides as tools (in vitro and in vivo) to probe the role of ASARM peptides and PHEX in regulating fat mass and energy metabolism. NIH R01 grant was submitted in October, 2009, to be resubmitted.

The role of dietary antioxidants and caloric restriction and exercise in slowing aging in mice
PI: Daniel Aires, MD (Co-Inv: In-Young Choi, PhD, Phil Lee, PhD, Russell Swerdlow, MD, Hao Zhu, PhD)

This study investigates the effects that the caloric restriction alone or in combination with dietary antioxidants have on murine life span and evaluates whether the above mentioned interventions work better when combined together than caloric restriction through the measurements of brain chemicals using in vivo magnetic resonance spectroscopy and imaging (MRS/MRI) in combination with histopathologic analyses.

Pathogenic and therapeutic mechanisms in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis
(National Multiple Sclerosis Foundation)
PI: Steven M. LeVine, PhD (Collaborators: In-Young Choi, PhD, Phil Lee, PhD)

Multiple sclerosis (MS) is a progressive disease that remains difficult to treat. Axonal and neuronal damage are key components underlying the progressive nature of this disease but the mechanisms that lead to these changes are not established. MRI images and pathological examinations reveal the accumulation of abnormal iron deposits in several areas of MS brains. Studies have established that iron has the potential to cause tissue damage, but it is unknown whether iron actually has a role in the pathogenesis of MS. We plan to test the hypothesis that iron deposits, and/or elevated iron levels, in MS brain tissue exacerbate the disease process. The studies will be performed on mice with experimental autoimmune encephalomyelitis (EAE), a model of MS, since it enables a systematic investigation of the development of pathological events, and mice are the least sentient species that can get EAE. Furthermore, MRI is an important tool for the monitoring of disease in MS patients, and studies utilizing MRI to detect iron deposits in EAE mice will further the understanding of MRI findings as they relate to pathological changes that are induced by iron. Besides advancing the understanding of pathologenesis in MS, these studies should help identify new therapeutic approaches.

The Molecular Mechanism of Proinflammatory Cytokine Regulation in Hypoxemia Fetal Guinea Pig
PI: Carl P. Weiner, PhD (Co-Inv: In-Young Choi, PhD, Phil Lee, PhD, Yafeng Dong, PhD)

The purpose of this study is to investigate the effect of hypoxia duration and intensity on proinflammatory cytokine regulation in the brain of newborn guinea pigs. Glutathione is a sensitive hypoxia indicator, thus glutathione quantification will allow us to know the level of brain oxidative stress directly in the living brain. In this study, we will quantify brain glutathione levels and structural changes using magnetic resonant spectroscopy (MRS) and magnetic resonant imaging (MRI) techniques at 9.4 T.

In vivo modulation of intercellular tight junctions in the blood brain barrier to improve delivery of anti-cancer drugs
PI:Teruna Siahaan, PhD

Specific Aims and Study Summary: To study the porosity of tight junctions after modulation using MRI in rats in vivo

Detection of BBB leakines in EAE mouse using MRI
PI: Teruna Siahaan, PhD

Specific Aims and Study Summary: The leakiness of the BBB and the immune cell infiltration due to inflammation from Experimental Autoimmune Encephalomyelitis (EAE) will be evaluated using high-resolution spin-echo T1-weighted MRI with the help of MRI contrast agents at 9.4 T MR. EAE will be induced in SJL/J mice on day 0 with PLP in CFA at the KU-Lawrence campus following an IACUC approved protocol. The brains and the spinal cords of the animals will be observed by MRI after I.V. injection of the animals tail veins with 0.5 mmol/kg of Gd-DTPA or 600 μmol Fe/kg USPIO agent 7228. The animals will be observed under anesthesia (a mixture of 1.5 % isoflurane, 1:1 of air and oxygen) by MRI using a standard immobilizer with temperature controller. The MRI data will be collected on day of maximum disease (~ day 15) on mice treated with our therapeutic peptide as well as non-treated mice.

PREVIOUS STUDIES CONDUCTED AT HBIC

Traumatic Brain Injury (TBI) Studies

Predicting Response to Memory Training in TBI with fMRI
(NIH R21 HD050534)
PI: Cary Savage, PhD (Co-Inv: William Brooks, PhD, Phil Lee, PhD)

The overall goals of this project are to use fMRI and a verbal memory paradigm to examine predictors of cognitive and daily functioning in individuals with traumatic brain injury. This project aims to identify mechanisms of recovery from TBI by examining brain systems supporting the use of semantic strategies during non-cued and cued verbal learning using functional magnetic resonance imaging (fMRI). The study addresses two Specific Aims: 1. Assess the ability of TBI patients and matched healthy control (HC) participants to utilize semantic strategies under both non-cued and cued conditions and define how patterns of brain activation change to support this process. 2. Examine specific patterns of brain activation with fMRI in predefined regions of interest (ROI) in TBI and HC groups and determine how individual differences in brain activation relate to cognitive functioning and behavior in natural settings.

An experimental model of white matter infarct
(NIH 5R21NS052355)
PI: Shawn B. Frost, PhD (Co-Inv: Phil Lee, PhD)

The goal of this project is to develop an animal model of white matter infarct that will be valuable in the understanding of the underlying mechanisms of subcortical ischemic stroke, neuronal reorganization leading to motor recovery and most importantly, the evaluation of therapeutic interventions. Focal injections of the potent vasoconstrictor endothelin-1 will be used to develop a model for future evaluation of potential therapeutic treatments for disabilities resulting from focal infarcts in posterior limb of the internal capsule; a common site for clinical strokes in the cerebral white matter. This dense fiber bundle contains corticofugal axons originating in the motor cortex (including the corticospinal tract), as well as ascending fibers conveying cutaneous and proprioceptive information to the somatosensory cortex. In clinical stroke, injury to the posterior limb of the internal capsule results in substantial sensorimotor deficits. This animal model of white matter infarct will be extremely valuable in future development of therapeutic interventions in stroke treatment of white matter stroke. This will be an important, and unique, animal model for research into pharmaceutical and physical therapeutic effects on recovery of function following white matter infarct and subcortical stroke.

Stroke Studies

Multimodal Neuroimaging in Stroke Motor Rehabilitation
(AHA-Heartland 0860041Z)
PI: Carmen M. Cirstea, MD, PhD (Co-Inv: William M. Brooks, PhD, Phil Lee, PhD)

This longitudinal interventional study evaluates the metabolite/functional (1H-MRS/fMRI) changes in remote primary and secondary motor areas following an arm-focused motor training. Neuroimaging paradigms are incorporated within kinematic measures of motor behavior to describe biological effects of the intervention in remote motor areas associated with "true" recovery or behavioral compensation - precisely, whether persistent participation of contralesional cortices reflects a less efficient type of plastic reorganization (so-called maladaptive plasticity). Identifying the optimal form of therapy for maximizing recovery by modulation of neuroplastic mechanisms is a significant challenge faced by the rehabilitation field. Thus, by using a multimodality approach we might open a new window into the neural mechanisms underlying recovery following a focal brain injury

Neural Predictors of Arm Motor Function in Stroke
Clinical Pilot Research & Lied Basic Science Program
PI: Carmen M. Cirstea, MD, PhD (Co-Inv: William M. Brooks, PhD, Sang-Pil Lee, PhD)

Since stroke is the leading cause of long-term disability worldwide, identifying stroke recovery predictors is of critical importance. Although neuroimaging has undergone spectacular development in recent years, no group of such predictors has been found. 1H-MRS research focused on potential predictors has received limited attention in any stage of stroke recovery despite its availability and reproducibility. Thus, the goal of this study is to investigate the prognostic value remote metabolite (1H-MRS) alterations in determining the subsequent recovered performance in sub-acute stroke. This study would be especially significant because restorative therapies are generally thought to be more effective when introduced at earlier time points post-stroke, and identification of predictive biomarkers in the sub-acute stage may become essential for screening patients who best benefit from such therapies. This study has been submitted to NIH, as R01 application in October 2009 (CMC-PI), and MWA Scientist Development Grant application in January 2010 (CMC-PI).

Motor Performance and Cortical Changes in Chronic Stroke
(K01 HD047148)
PI: Barbara Quaney, PhD (Mentor: Cary Savage, PhD)

This is an NIH Scientist Development Award designed to further Dr. Quaney's development in the use of fMRI.

Diabetes and Oxidative Stress Studies

MRI/MRS of Alcohol, Mitochondria and Oxidative Stress in Hyperglutamategic Mice
PI: Elias K. Michaelis, PhD, In-Young Choi, PhD (Co-Inv: Phil Lee, PhD)

This study aims to investigate the effect of over-expression of the gene for glutamate dehydrogenase (GLUD) in the mouse brains in collaboration with Dr. Michaelis at the University of Kansas at Lawrence. This study will (1) provide in vivo evaluation of the levels of the neurotransmitters and antioxidants in the wild type and the GLUD transgenic mouse brains, and (2) measure the effects of chronic alcohol intake and aging on the regional brain metabolism of GLUD transgenic mice. The overall goal of this protocol is to investigate the possible changes in GLUD transgenic mice with ethanol treatment. With this overall goal, we hypothesize that the GLUD transgene leads to selective hypersensitivity/vulnerability of the brain regions to the actions of ethanol, and the chronic ethanol treatment leads to morphological and physiological changes, and MR techniques can detect these changes. To this end, this study employs non- invasive MR techniques (MRS and MRI) to measure these changes in GLUD transgenic mice and wild type mice with ethanol treatment.

Disorders and Motivational Behavior Studies

Studies of Reward Processing and Impulsivity in Nicotine Addiction and Obesity
(NIH K99 1K99DA025153-01A1)
PI: Laura Martin, PhD

The primary aim of this study is to examine neural responses to rewards and punishments in nicotine addicted, obese and healthy groups. Employing functional magnetic resonance imaging (fMRI), the study uses monetary rewards and self-reported impulsivity to clarify the degree to which nicotine addiction and obesity share mechanisms in the neural systems of reward. Preliminary results from this study show that cigarette smokers respond differently than non-smokers to rewards and punishments during the anticipation and the delivery of rewards and punishments, with larger activations in prefrontal regions during the anticipation of rewards compared to punishments, larger activations to the expected delivery of punishments compared to rewards, and larger deactivations to the unexpected delivery of rewards. Preliminary results in obese individuals compared to healthy weight individuals show greater prefrontal activations to rewards compared to punishments during both the anticipation and delivery stages. Preliminary results comparing obese non-smokers, healthy weight smokers and healthy weight non-smokers indicate that obese participants respond more to rewards than punishments during both the anticipation and delivery stages.

Alzheimer's Disease, Aging and Memory Program Studies

Quantitative in vivo measure of an AD drug treatment in transgenic mice
(Alzheimer's Association NIRG-07-60405)
PI: Phil Lee, PhD (Collaborator: In-Young Choi, PhD, Mary L Michaelis, PhD)

The goal of this study is to quantify the therapeutic effects of a microtubule stabilizing drug "TX-67" developed by Dr. ML Michaelis at KU on a triple transgenic (3xTg-AD) mouse model of AD using non-invasive MRI techniques. The Specific Aims for this project are (1) to establish completely non-invasive MRI/MRS techniques to visualize Aβ plaques and to quantify defects of the axonal transport system and neurochemical alterations in the mouse brain in vivo and (2) to quantify the in vivo effects of the novel AD drug treatment in Aβ plaque accumulations, axonal transport deficits and neurochemical levels in the transgenic AD mouse brain.

Intranasal Insulin and Memory in Early Alzheimer's Disease
(The Dana Foundation)
PI: Jeffrey M. Burns, MD (Co-Inv: Phil Lee, PhD)

This study seeks to understand how the brain, and in particular the memory system, responds to insulin. The study will provide valuable information about insulin's role in brain function in Alzheimer's disease (AD) and possibly identify a subset of AD patients (those without the ApoE4 gene) who are most likely to benefit from insulin. This information will guide our future efforts in more precisely defining the role of insulin dysregulation in AD and has the potential to lead to therapeutic interventions for AD, new strategies for promoting healthy brain aging, and the development of novel prognostic or diagnostic AD biomarkers. The primary aim of this study is to assess the effect of insulin on memory performance and the underlying neural response in the hippocampus in early-stage AD and nondemented controls (aim 1). Secondary objectives include assessing the role of apoE4 genotype in modulating brain insulin responses (aim 2) and global responses to insulin using MRI scans (blood flow and cortical activity; aim 3). Our overall hypothesis is that the acute administration of insulin to the brain, via the intranasal route, will have benefits on memory function related to increased functional activation in the medial temporal lobe, an area rich in insulin receptors. Additionally, we hypothesize that this effect will be most prominent in ApoE4 non-carriers and will not be explained by global effects (increased blood flow or alterations in the cortical activity) induced by insulin administration.

The role of dietary antioxidants and caloric restriction and exercise in slowing aging in mice
(Dept of Dermatology funding)
PI: Daniel Aires, MD (Co-Inv: In-Young Choi, PhD, Phil Lee, PhD, Russell Swerdlow, MD, Hao Zhu, PhD)

This study investigates the effects that the caloric restriction alone or in combination with dietary antioxidants have on murine life span and evaluates whether the above mentioned interventions work better when combined together than caloric restriction through the measurements of brain chemicals using in vivo magnetic resonance spectroscopy(MRS) in combination with histopathologic analyses.

Other HBIC Studies

Nannocarrier Based Intralymphatic Imaging and Therapy for Melanosa
(NIH (CCET COBRE) P20RR015563-08)
PI: Mark Cohen, MD (Co-Inv: Phil Lee, PhD)

The aim of this proposal is to investigate novel ways to image lymphatically spread tumors such as cutaneous melanoma while utilizing intralymphatic delivery of a contrast agent. The long term goal of the research is to develop therapies for melanomas of the extremities without invasive surgical removal of lymph nodes or isolated limb perfusion.