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:
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
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.