Project Leader: Steven D. Forman, M.D., Ph.D.

Heroin dependence remains a major public health problem in the United States. Opiate maintenance is the most effective treatment modality with and estimated 115,000 individuals currently receiving methadone maintenance. Despite its demonstrable effectiveness and widespread use, very little is known about the cognitive effects of chronic methadone maintenance. The overall goal of this research program is to investigate prefrontal cortical functioning in heroin addicts before and during the course of opiate maintenance.

Using a variant of the Go/no Go task and functional magnetic resonance imaging, we can assess whether prefrontal cortical activity increases with clinical improvement, both in dorsolateral regions associated with delay-dependent processing and in ventral areas associated with inhibitory processing. We plan to additionally use a combined fMRI/microdialysis system in a rat model to measure the neurochemical changes in those relevant brain areas identified in the clinical investigation. We hypothesize that intermittent exposure to short-acting opiates leads to oscillating levels of dopaminergic modulation in the prefrontal cortex that produces dysfunction. We further hypothesize that long acting agents in maintenance allow the system to stabilize by dampening the oscillation.

To test these hypotheses that opiate exposure attenuates activation of prefrontal cortex, we will use functional magnetic resonance imaging to assess regional brain activation with variable dose IV injection of amphetamine to acutely stimulate the brain. Experiments are ongoing to establish baseline response to amphetamine infusion. Once completed, testing the effect of intermittent opiate exposure will commence.

Cell Therapy for Congestive Heart Failure Using Skeletal Muscle-Derived Stem Cells

Project Leaders: William R. Wagnor, Ph.D. and Tetsuro Sakai, M.D., Ph.D.

Congestive heart failure is a major killer in developed countries. Various kinds of surgical and medical therapies have been available, however there is still an increased demand for new therapeutic options. This research seeks to investigate the feasibility of utilizing skeletal muscle-derived stem cells for cardiac cell transplantation as a means to improve impaired cardiac function resulting from myocardial infarction.

Using a pre-planting technique, muscle derived stem cells are cultured from muscle for injection. The recipient will undergo myocardial infarction surgery with direct coronary artery ligation. At one week after infarction, cultured cells are injected into the scar of the ligation. At four weeks after injection, MRI is used for cardiac functional assessment. Ventricular size, wall thickness are assessed, and cine imaging with cardiac tagging is used to assess regional wall motion. The results from this research will provide the basis for future research toward the cellular and tissue engineering approach for congestive heart failure patients.

Brain Changes in Craniosynostotic Rabbits

Project Leader: Wendy Fellows-Mayle, M.A.

Craniosnostosis is the premature fusion of one or more of the calvarial sutures and has been estimated as a problem in 3 in 10,000 live births. The premature closure of a suture has two main consequences: esthetic impairment and the possibility of damage to the growing brain. Neurological injuries that result from craniosynostosis include cascular malformation, changes in intracranial volume, and increased intracranial pressure. For these reasons, surgical repair is commonly performed within the first year of life.

Mainly because of small sample sizes and heterogeneous sampling the relationship between the brain and vault growth is lacking, and furthermore, the mechanisms behind craniosynostosis are not clearly understood. The study of the natural progression of uncorrected craniosynostosis could provide valuable information regarding the brain and its ability to compensate for skull restrictions if present. This study is designed to follow the progression of craniosynostosis from early development until a time when brain growth is complete in a colony of rabbits with a naturally occurring coronal suture (CS) synostosis.

This colony of rabbits has coronal suture synostosis of varying degrees. Based upon radiological measurements taken at 10, 25 and 42 days of age, two types of synostosis are found: delayed onset CS synostosis in which CS growth falls below the 95% confidence intervals for normal rabbits, and early onset CS synostosis which is diagnosed if there is no growth detected at the coronal suture. Early onset CS is further divided into unilateral complete and bilateral complete coronal suture synostosis.

The use of magnetic resonance imaging in this study provides anatomic detail of soft tissue that is not available in computerized tomography due to the small size of the rabbit brain. The MR images allow delineation of regional anatomic structure within the brain such as brain parenchyma, the ventricles, and the subarachnoid spaces, in addition to the intracranial volume.

Mechanism of Embolism Reversal In Vascular Plants: Studies at the Level of Individual Vessels

Project Leader: N. Michelle Holbrook, Ph.D.

This study investigates the integrated mechanism of embolism removal in vascular plants. The ability of return cavitated vessels to their functional state has profound implications for understanding the structure and physiology of vascular plants. Our goal is to test the hypothesis that embolism is a locally reversible phenomena made possible by the interaction of xylem arenchyma, vessel wall properties, and geometry of intervessel pits. Because maintenance of the water transporty capacity is a central feature in the growth and survival of plants, we believe that substantial scientific investment into the study of cavitation repair before we can understand fully the diversity of developmental and physiological response of plants to water availability. Because MRI can be used to visualize the distribution of mobile water, vessels containing embolisms are easily distinguished from filled vessels.

From time-lapsed data, the time-dependent populations of filled and embolized vessels can readily be quantified. Images are acquired using two-dimensional gradient echo protocol with an in-plane resolution of 20 x 20 mm. Signal averaging was required to obtain satisfactory signal-to-noise ratio, this limited the temporal resolution to 20 minutes. The plant is illuminated and watered during the experiment to visualize cavitation and refilling of vessels. Because MRI can also be used to image flow velocities, as well as water density, further studies will determine whether refilled vessels are able to subsequently transport water during periods of active transpiration. The results of this study will provide new insights into functional wood anatomy, the role of living cells in stems, and interspecies differences in water use strategies.

NMR on a Chip: A Micro-NMR Device for In Situ Detection of Chlorides in Concrete

Project Leader: Irving J. Lowe, Ph.D.

This project involves three parts, NMR micro-probe design, magnet design, and RF transmitter-receiver design, all of which to be fabricated on an integrated circuit. The objective of this project is aimed at designing a micro-NMR probe for the detection of chlorine in concrete. Chlorine is corrosive to iron reinforcing bars in concrete and is introduced by winter salting of roads and bridges as well as salt water in marine structures. Such a probe can be integrated in the concrete during setting to monitor the diffusion of destructive ions into critical structural areas.

Successful detection using inductive coil or coupling the magnetic force to a cantilever can induce corrective measures before the concrete approaches structural failure. We have successfully recorded Cl-35 NMR signals at 2.35 Tesla from various samples of concrete and have used these measurements to guide the design parameters. Several NMR chip designs are currently being constructed and tested.