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Vanderbilt University research probes basic form and function

Best Practice
Gore, John, Ph.D. Nashville, Vanderbilt University Institute of Imaging Science USA
Avison, Calum Nashville, Vanderbilt University Institute of Imaging Science USA
Damon, Bruce, Ph.D. Nashville, Vanderbilt University Institute of Imaging Science USA
Yankeelov, Thomas Nashville, Vanderbilt University Institute of Imaging Science USA
Waddell, Kevin Nashville, Vanderbilt University Institute of Imaging Science USA
Anderson, Adam Nashville, Vanderbilt University Institute of Imaging Science USA
Welch, Brian Philips Healthcare USA

Since 2002, physicians and scientists at Vanderbilt University Institute of Imaging Science (VUIIS, Nashville, Tenn.) have been employing medical imaging modalities to perform far more than their traditional clinical tasks of detection and visualization. In the new discipline of imaging science, investigators are using MRI, PET, CT, SPECT, x-ray, optical imaging and ultrasound to explore the pathophysiology of many diseases and to develop and apply measures of treatment response. In human research, researchers led by VUIIS director John Gore, Ph.D., are using the center's Achieva 3.0T system in many studies, including brain function and structure, presurgical mapping, automated contrast kinetics imaging, muscle DTI fiber tracking and neurotransmitter spectroscopy.

 

 Vanderbilt University Institute of Imaging Science From left to right:
John Gore, Ph.D., Bruce Damon Ph.D., James Joers, Ph.D., Malcolm Avison, Ph.D., Adam Anderson Ph.D., Brian Welch, Ph.D., Kevin Waddell Ph.D., Thomas Yankeelov, Ph.D.
Vanderbilt University Institute of Imaging Science
From left to right: John Gore, Ph.D., Bruce Damon Ph.D., James Joers, Ph.D., Malcolm Avison, Ph.D., Adam Anderson Ph.D., Brian Welch, Ph.D., Kevin Waddell Ph.D., Thomas Yankeelov, Ph.D.

MR studies play major role in new frontier of imaging science

Medical imaging technology is being used in advanced research to help clarify biological and physiological processes, a major extension of traditional radiology that reflects advances in other areas, such as genomics, proteomics and molecular biology.

 

"In vivo imaging is being researched to measure tissue structure and for quantitative morphometry, such as assessing tumor growth or recession," says John Gore, Ph.D., director of VUIIS. "Imaging also is being developed to measure intrinsic tissue characteristics and composition, such as cell density or neural myelination and to map spatially varying metabolic and physiological properties, such as blood flow or oxygen use. Another application is being developed to detect and quantify specific processes at the molecular level - the expression of specific genes, for example."

 

Established in 2002, VUIIS is a transinstitutional center within Vanderbilt University, which invested more than $40 million in the facility's physical plant, equipment and personnel. Approximately 23 faculty, 15 staff and 54 trainees are engaged in VUIIS activities. A new fourlevel, 42,000 sq. ft. building was opened in November 2006 and now integrates all VUIIS disciplines and facilities under one roof.


Two important VUIIS facilities are the Center for Small Animal Imaging and the Center for Human Research Imaging. Equipment for the former includes 4.7T, 7.0T and 9.4T small bore MRI systems, microCT, microPET and microSPECT systems, optical imaging and ultrasound. The human research center houses researchdedicated Achieva 3.0T and 7.0T scanners. Included among the 3.0T research projects are those for GABA spectroscopy, DTI of muscle tissue, DCE and extended MultiVane motion correction techniques.


VUIIS's reputation has earned it the honor of hosting major international scientific meetings, including an International conference for biomedical imaging scientists: Frontiers of Biomedical Imaging Science, which convened in Nashville, June 27-29.


Immediately preceding this conference, June 24-26, VUIIS hosted the third meeting of Philips' Achieva 7.0T Users Group, which was attended by representatives of the Achieva 7.0T sites worldwide.

MR spectroscopy research clarifying GABA, glutamate roles

GABA (gamma-aminobutyric acid) is the brain's principal inhibitory neurotransmitter, while glutamate is the main excitatory neurotransmitter. "Many psychiatric and neurologic disorders are suspected to have altered glutamate and/or GABA neurotransmission," says VUIIS Professor, Calum Avison, Ph.D. "For example, there is increasing recognition that altered cortical GABA levels are associated with clinical conditions, such as epilepsy, chronic alcoholism, schizophrenia and depression."


On MRS spectra, GABA and glutamate spectral peaks are small and often hard to discern among larger metabolic peaks in the brain (e.g., NAA, choline, etc.), even with 3.0T's high SNR and spectral resolution. Therefore, use of sophisticated editing methods are needed to pick out the GABA and glutamate peaks from the crowded background - allowing investigators to measure their levels in the human brain without contamination from other stronger brain metabolite signals.


"While the literature notes the potential for significant GABA and glutamate editing errors with even slight patient motion, we're making these measurements robust, so our technologists can run it on normal walk-in volunteers. We have about a 95 percent success rate gathering these GABA spectra," he says. "We credit this to the specific MRS  pulse sequences, our post-processing approach and artifact correction methods. The flexibility of the Philips Achieva platform has been essential in allowing us to develop these complex MRS methods, and the high homogeneity, stability and sensitivity of Achieva 3.0T will allow us to fully realize the potential of these exciting new probes of brain neurotransmitter status."

 

Neurotransmitter spectroscopy. By using sophisticated editing methods, the neurotransmitters GABA and glutamate peaks can be distinguished in these spectra collected from an 18 ml volume in the anterior cingulate cortex. Acquisition times were 10:40 min. for GABA and 5:20 min. for glutamate.

 


One of Dr. Avison's NIH grants is to study adolescents and young adults who have a history of cocaine and alcohol exposure in utero. "In cocaine-exposed animals, there are alterations in the cortical GABA neurons associated with executive function, and there is evidence that kids with a history of prenatal cocaine exposure have ADHD-like symptoms that persist for life, but interestingly may be unresponsive to Ritalin®," Dr. Avison observes.

 

Preliminary results include data on both glutamate and GABA editing in normal volunteers for validation purposes (Ref. 1). "The cocaine and schizophrenia studies are just beginning," he says. "But, we have spectra showing how GABA is edited from a typical volunteer - showing where it comes from and what spectra look like for both GABA and glutamate."

DTI fiber tracking finds extracranial application

Diffusion anisotropy applies to muscle tissue as well as to the brain's white matter fiber tracts. "Muscle fibers are about 50 ┬Ám in diameter and can be tens of centimeters long. Additionally, there is a network of protein filaments in muscle fibers that cause contraction and which also are longitudinally oriented," says Institute scientist, Bruce Damon, Ph.D. "This combination of elongated cellular geometry and longitudinal arrangement of contractual proteins causes water to move preferentially along the cell's long axis."


One basic aim of Dr. Damon's DTI research is explaining the role of muscle architecture in locomotion. "We developed a protocol to acquire the diffusion tensor of certain muscles - such as the hamstring, quadriceps and muscles comprising the calf - and determine how their architecture supports rapid shortening and the generation of high forces," he explains.

 

This figure shows a DT-MRI skeletal muscle fiber

tracking result. The images are T1-weighted axial

anatomical images taken at proximal (top image)

and distal (bottom image) locations of the thigh.

The gold and similarly shaded lines show the local

muscle fiber orientations of the vastus medialis

oblique muscle. These data are being used by Drs.

Herman Kan, M.D., Anneriet Heemskerk, Ph.D., and

Bruce Damon, Ph.D. As part of a clinical study of

the anatomical and phsyiological basis for patellar

subluxation syndrome.

 

 

More clinically-oriented muscle DTI research focuses on muscle architecture in the vastus medialis and vastus lateralis muscles, which if functionally imbalanced relative to each other can cause patellar subluxation.


"In persons with patellar subluxation, the patella tends to be pulled out of alignment as they extend their leg," Dr. Damon says. "If the vastus muscles are imbalanced, the vastus lateralis pulls the patella from its natural position. We're doing fiber tracking to understand how the muscle architecture contributes to that problem."


This project is being spearheaded by Herman Kan, M.D., musculoskeletal radiologist at the Children's Hospital, and supported by additional fiber-tracking projects by Anneriet Heemskerk, Ph.D.


Another clinical study, headed up by postdoctoral fellow, Otto Sanchez, entails investigation of the diffusion properties of the hamstring muscle following acute strain. In T2-weighted imaging, clinicians would expect to see increased signal intensity from edema. "The problem is that edema is nonspecific - it happens every time you hurt yourself," he observes. "We're hoping that diffusion measures will be more sensitive to the muscle membrane's structural integrity and that in the long term we can develop a practical measurement method."


Collaborating on this project with Otto Sanchez are musculoskeletal radiologist John Block, M.D., and athletic trainers from Vanderbilt Sports Medicine.

Study of contrast kinetics contributes to understanding of lesion physiology

In the study of contrast kinetics, VUIIS researchers are clarifying the physiological mechanisms that determine why contrast moves through tissues or lesions at a given rate. From a clinical standpoint, the ultimate goal is to use these kinetic parameters to evaluate the patient after the first treatment cycle to assess the intervention's therapeutic value.

 

"We are developing a new mathematical model to analyze the contrast agent kinetics automatically in Dynamic Contrast Enhanced studies of volunteers," says Tom Yankeelov, Ph.D., VUIIS Director of Cancer Imaging. "Our model is more closely related to lesion physiology and we are combining it with measurements of water diffusion to provide ADC maps as well."

 

Water diffuses in adipose and granular tissues, he continues, but once a benign or malignant mass begins to grow, cell populations increase, generating more barriers to diffusion, thereby slowing down diffusion time.


"Researchers have shown in small animal models of cancer that ADC changes actually happen before the changes in the dynamic contrast-enhanced analysis. These studies are now beginning in patients," he says.

Dynamic contrast enhanced MRI (DCE-MRI) allows

for characterization of various relevant physiological

parameters including blood vessel perfusion and

permeability (characterized by the parameter Ktrans),

the extravascular extracellular volume fraction (ve) and

tumor cell size (ti). These parameters can be mapped

for each voxel in each slice of a DCE-MRI data set. The

figure depicts how each of these parameters estimates

(in a three dimensional rendering) the extent of tumor.

Each row of the figure corresponds to a different time in

the course of therapy and it is clear that these parameters

are sensitive to longitudinal changes. Of note is the reduction

in the Ktrans parameter while the ve and ti parameters still

indicate residual disease. (All panels are rendered at 50%

of the maximum value observe in the pre-treatment scan.)

 

 

VUIIS investigators are developing a PRIDE tool that will combine acquired ADC data with four other parameters. These are a T1 map, Ktrans (tissue perfusion and microvascular vessel wall permeability) ve (extracellular volume fraction, and ti (time constant measuring persistence of water molecules in a cell).

 

"We hope our model will provide a more comprehensive characterization of tumor response," Dr. Yankeelov says. "We see patients pre-therapy right after diagnosis, then after the first therapy cycle, and subsequently just before they go to surgery at therapy completion. The idea is to study the four parameters and the ADC map and determine if some combination or perhaps individual parameters can predict therapy response. You could individualize treatment that way."

 

 

Reference

  1. Waddell KW, Avison MJ, Joers JM, Gore JC.
    A practical guide to robust detection of GABA in human brain by J-difference spectroscopy at 3T using a standard volume coil.
    Magn. Reson. Imaging: in press (2007).


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