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
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.
Multimodal Neuroimaging in Stroke Motor Rehabilitation
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
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.