AIRC Users
Following is a partially updated project list supported by AIRC.
We have many projects on-going not listed.
Title: Imaging the central nervous system with iron oxide
particle MR contrast agents
Superparamagnetic iron oxide nanoparticle MR contrast agents are
gaining use in the CNS. The purpose of these studies is to evaluate
the imaging characteristics, time course, and neurotoxicity of iron
oxide based agents that have shown potential in the CNS, with the
goal of characterizing particle delivery, monitoring trafficking of
particles and cells, and visualizing intracerebral tumors. These
iron oxide-based agents include the laboratory preparation MION-46,
the clinically approved agent ferumoxides (Feridex I.V ®), the
investigational agent ferumoxtran-10 (Combidex ®), and the new agent
ferumoxytol. The agents consist of an iron oxide core with a
variable coating that determines cellular uptake and biological half
life. On MR scans the iron oxide agents demonstrate hypointense
signal drop out at all concentrations on T2-weighted images, but may
show hyperintense (bright) signal on T1-weighted images in areas of
low concentration. After MR of CNS delivery, the iron oxide
particles may be identified at the light and electron microscopic
levels, allowing evaluation of their exact location within tissues.
Osmotic BBB disruption is performed to assess transvascular
delivery, time course for imaging, and neurotoxicity of the iron
oxide contrast agents. After transvascular delivery, transient (1-3
d) T1 enhancement is seen with ferumoxtran-10 or ferumoxytol, while
ferumoxides induce long term (28 d) GRET2* signal dropout.
Inoculation of the iron oxide compounds into rat brain is performed
to assess the distribution, time course, and cellular uptake of the
agents. The distribution of T2 signal drop out approximates the
histological distribution of iron staining, while the T2* images
shows approximately double the apparent area. No pathological brain
cell or myelin changes are detected after either intracerebral
inoculation or BBB disruption, even 3 months after iron oxide
particle administration. Intracerebral tumor models include the LX-1
and CALU6 SCLC metastasis models, and U87 glioblastoma model.
Ferumoxtran-10 rapidly enhances the LX-1 model, which correlates
with iron staining in cells with macrophage morphology at the tumor
margin, but little enhancement is seen with the other models. We
hypothesize that tumor imaging requires the presence of imflammatory
cells at the tumor margin or in necrotic areas.
Title: Hypothalamic fMRI Response to Nutrients
- PI: Jonathan Q. Purnell, MD
- Co-I: Alexander Stevens, PhD
- Co-I: Michael Cowley, PhD
Nuclei within the hypothalamus and the brain stem integrate
inputs from adipose tissue reflecting body fat stores and the
gastrointestinal tract reflecting the amount and types of food
ingested. These afferent signals trigger changes in food intake and
energy expenditure through mechanisms involving both immediate
alterations in neuronal cell electrical activity and relatively
slower effects mediated via hormone-receptor binding. While these
concepts of a central integrative center controlling weight
regulation are well studied in animal models, the importance of
these findings to humans is less clear. The present study uses fMRI
to study hypothalamic signaling in response to nutrients in lean and
obese subjects in order to better understand the neurological
mechanisms leading to unwanted weight gain as a result of changes in
macronutrient content of the diet.
Title: Functional Organization of Posterior Cortex in Blindness
We are using fMRI to study how occipital, temporal and parietal
cortical areas that usually are involved in visual processes in
sighted people are reorganized in the blind. A growing body of
research indicates that blind individuals have greater auditory
perceptual abilities than sighted individuals. What is unclear is if
these perceptual abilities are related to the reorganization of
occipito-temporal brain regions that are involved in visual
processing in sighted individuals. We are attempting to determine
the extent of these superior auditory abilities and if they relate
to the reorganization of occipito-temporal and occipito-parietal
pathways by examining the relationship of neural reorganization and
auditory processing skills in early and late onset blind individuals
as well as sighted controls. One ongoing project is looking at
auditory perceptual consolidation in blind and sighted individuals.
Perceptual consolidation refers to the time necessary to form a
stable representation of a stimulus that can be used to guide
behavior. Another study is examining the role of occipital area in
the blind in auditory and somatosensory perception and attention.
Ultimately, we hope to learn how developmental factors and
experience influence the organization of the brain and how this
organization affects perception and cognition.
Brain Imaging Signatures of Acute Withdrawal Susceptibility
- PI: John Crabbe, PVAMC
- CoPI: Bob Hitzemann, PVAMC
- CoPI: Xin Li, AIRC -OHSU
WSP mice have been selectively bred for alleles at withdrawal
susceptibility genes to display high alcohol withdrawal convulsions
after cessation of chronic ethanol vapor inhalation, and their
counterpart genotype, WSR, have been bred to display very attenuated
withdrawal. DBA/2J inbred strain mice also show high alcohol
withdrawal per accidental fixation of susceptibility genes, and
C57BL/6J mice are the comparison inbred strain that shows
genetically low withdrawal. Both WSP and DBA/2J mice also show
severe withdrawal from sodium pentobarbital, while WSR and C57BL/6J
show low pentobarbital withdrawal. These two drug withdrawal
phenotypes can be elicited by a single high-dose intraperitoneal
injection (4 g/kg ethanol, 20% v/v in saline, or 60 mg/kg
pentobarbital in saline, respectively). Withdrawal is usually
indexed behaviorally by exacerbation of the handling-induced
convulsion, a behavioral response seen 4-24 hr after acute drug
administration. We have been approved to study the behavioral
consequences of these acute or chronic withdrawal-inducing
treatments under protocols at OHSU and the VA for many years.
What is not known is the differential brain basis for the
genotype-specific changes in handling convulsion susceptibility.
While pharmacological studies have been performed, they have not
followed specific brain regions in detail due to the cost in numbers
of animals for such studies.
Functional magnetic resonance imaging (fMRI) is a method for
localizing brain activity indirectly by monitoring changes in blood
flow (BOLD technology). We propose to use the new Advanced Imaging
Research Center’s Siemens 3-Tesla MRI magnet to study the temporal
pattern of brain activity in mice after acute injection with ethanol
or pentobarbital. fMRI requires that animals remain immobile in the
fMRI scanner, which they are unlikely to do voluntarily unless
severely restrained. Restraint would cause high levels of stress,
which would compromise the experiment. Fortunately, the doses of
ethanol and pentobarbital that produce acute behavioral withdrawal
signs 4-24 hr later also produce clinical anesthesia, starting by 5
min after injection, and lasting until 3-5 hr after injection. After
3-5 hr, depending on the animal’s individual metabolic rate for the
drug, brain levels of drug fall below the anesthetic threshold and
animals will begin to move.
The proposed experiments will take advantage of the window of
anesthesia to acquire repeated images of blood flow between 5 min
and recovery from anesthesia. It is presumed that the genotypes that
will eventually express high withdrawal (WSP and DBA/2J) will show a
different temporal pattern of regional brain activation than the
corresponding low-withdrawal genotypes during the anesthetic period.
Ten mice per genotype, of either sex, (40 mice total) will be
studied following ethanol injection, and an additional 40 mice
followed after pentobarbital injection. Mice will be 6-8 weeks of
age when tested. Numbers of subjects per group are based on
published studies with rats.
We have no experience with this procedure, nor are there any
reported studies like this in the literature. Rats have been tested
successfully both with and without clinical anesthesia (e.g., after
high doses of diazepam). We will use blood oxygenation
level-dependent (BOLD) contrast determined by a gradient-echo
echo-planar imaging pulse sequence to be determined by Dr. Li. Based
on fMRI studies with rat, cerebral blood volume and flow will be
determined after injection of a monocrystalline iron oxide
nanocolloid (MION) contrast agent given by pulsed tail-vein infusion
at an initial dose of 12 mg/kg (Wu et al., Magn Res Med 2002
48:987). The tail vein infusion needle will be left in place during
the period of anesthesia and MION delivered as deemed necessary toi
enhance MRI signal strength. MION (or the alternative
superparamagnetic contrast agent, gadolinium-DTPA, which will be
used if MION fails to improve image signal) are non-toxic and are
eliminated readily from the blood.
As soon as the animal is visibly moving, which will be apparent
from the breakdown in the fMRI signal quality, the animal will be
removed from the scanner and quickly euthanized by CO2 asphyxiation
(>5 minutes exposure to 70% CO2).
John Crabbe and Bob Hitzemann are affiliated with the Department
of Behavioral Neuroscience and with the Portland Alcohol Research
Center as well as the Research Service at the Portland VA Medical
Center.
Neuropsychiatric Recovery from Methamphetamine Dependence
- PI: William F. Hoffman, Ph.D., M.D.
- Co-I: Alexander Stevens, PhD
- Co-I: Suzanne Mitchell, Ph.D
This project has the principal aim of establishing the cortical
basis of a measure of impulsivity (the Delay Discounting task) and
assess its utility in the comparison of methamphetamine abusers to
non-users. Plan: This study will test the hypothesis that the
cognitive performance we have found in methamphetamine abusers
(working memory and impulsivity) is related to activation specific
brain regions likely to be involved in the performance of those
tasks. Specifically, we hypothesize that impulsivity (a preference
for immediate over delayed rewards on the Discount Delay task) is
related to failure to activate the orbitofrontal cortex and
dorsolateral prefrontal cortex. Methods We will study 10 to 20
chronic methamphetamine abusers, who have been abstinent only a
short time and a comparable number of controls who have never used
illicit drugs. Subjects are interviewed to establish a diagnosis
according to DSM-IV criteria and severity of current symptoms on
standard rating scales. We use paper and pencil tests to thoroughly
characterize the subjects' cognitive abilities and functional
magnetic resonance imaging to link the activity of specific brain
regions to performance on the Delay Discounting task. Findings to
Date: Sixteen normal subjects have been imaged. The data on these
subjects establishes that Delay Discounting task activates a
cortical network consisting of lateral and dorsolateral prefrontal,
anterior cingulate and posterior parietal regions. The left side is
activated more than the right. MeSH terms: amphetamine, functional
magnetic resonance imaging, cognitive disorder
Title: Prefrontally-mediated memory in Phenylketonuria
- Local PI: Robert Steiner, MD
- Overall PI: Desiree White, PhD
- Co-I: Urick Szumowski, PhD
This study will be conducted to address the following questions:
(1) Do children with phenylketonuria (PKU) have memory problems
related to the function of specific areas of the brain? (2) Do
problems in these aspects of memory worsen as individuals with PKU
age? (3) Do problems in the white matter of the brain contribute to
memory problems in individuals with PKU?
The following hypotheses will be tested: Children with PKU
exhibit impairments in prefrontally-mediated aspects of memory. To
achieve this aim, we will evaluate working memory and strategic
memory processing in children with early-treated PKU who range from
7 to 18 years of age. Comparisons will be made with a
demographically matched group of typically developing children.
Impairments in prefrontally mediated aspects of memory emerge as
children with PKU age. To achieve this aim, we will evaluate working
memory and strategic memory processing longitudinally. By doing so,
we will define the developmental trajectory of prefrontally-mediated
aspects of memory at the level of individual children.
White matter abnormalities contribute to impairments in
prefrontally-mediated aspects of memory in children with PKU. This
aim will be achieved through the use of diffusion tensor imaging
(DTI), a neuroimaging technique permitting refined examination of
white matter integrity. Dopamine deficiency also will be examined by
assessing blood phenylalanine levels and blood
phenylalanine:tyrosine ratios. Findings from DTI, phenylalanine
levels, and phenylalanine:tyrosine ratios will be examined in
relation to our memory findings.
Both PKU and non-PKU children will complete the memory and
related ability tests and the MRI at study entry, approximately 2
years following study entry, and approximately 4 years following
study entry. Performance on tests of memory and related abilities
will be done on children with PKU and they will be compared with the
performance of children without PKU over time. |