Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00283647 |
| Other study ID # |
11261-CP-004 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
January 27, 2006 |
| Last updated |
April 13, 2015 |
| Start date |
October 2002 |
| Est. completion date |
September 2006 |
Study information
| Verified date |
April 2015 |
| Source |
National Institute of Environmental Health Sciences (NIEHS) |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Federal Government |
| Study type |
Observational
|
Clinical Trial Summary
Exposure to lead during pregnancy, infancy, and childhood increases the individual
likelihood of impaired school performance, increased impulsiveness, aggression, and
delinquent behavior. Disorders that result from exposure to environmental neurotoxicants are
a complex web of interactions between genetic, neurochemical, biochemical, environmental and
social factors that influence children during critical periods of development. To date,
research in the area of human developmental neurotoxicology focuses primarily on global
measures of sensory-motor development and cognition. However, studies elucidating the
biological basis for developmental and behavioral disorders due to environmental toxicant
exposure are lacking. Although gross brain structure appears normal, underlying problems
exist at a neural level. Our proposal seeks to relate childhood environmental lead exposure
at various levels and stages of development with detriments in brain structure and
neurochemical functioning assessed with magnetic resonance imaging (MRI) and magnetic
resonance spectroscopy (MRS). Cortical and subcortical brain volumes will be determined with
high resolution MRI. Neuronal and glial cell markers will be measured using proton MRS.
These structural and chemical measures will also be correlated with behavioral measures from
the young adult participants of the Cincinnati Lead Study (CLS). These participants
represent a unique and ideal cohort of approximately 240 subjects with detailed histories of
exposure and behavioral outcomes in lead exposed children monitored for approximately 20
years. A pilot study examining language, working memory and attention in combination with
functional magnetic resonance imaging (fMRI) will also be performed to better understand the
functional and behavioral deficits.
Description:
Overview of Imaging
All MRI and MRS investigations will be acquired on a 1.5 clinical MR scanner. The MRI and
MRS procedures will take approximately a half-hour to complete. Subjects also having fMRI
performed will require another scanning session on the research 3T MR scanner with one hour
for completion. Orientation to the scanning procedures will take place during the visit to
the Imaging Research Center, upon completion of informed consent. The subject will be given
a brief introduction to the general MR scanning procedures and demonstration of the MRI
machinery. Prior to beginning studies, subjects will be allowed to familiarize themselves
with the scanner to decrease anxiety about the experiment. Subjects will receive instruction
and practice in the appropriate behaviors necessary for a successful MR study. The research
MR technologist has over 10 years experience in pediatric neuroimaging and takes great care
to make subjects comfortable in the head coil so that they can remain as motionless as
possible for the duration of the scan. The subject is asked to select a video to watch and
is given the video goggles to focus and adjust to fit, immediately upon entering the scanner
room. Once on the table, the subject's head is restrained within a padded head holder with
additional foam pads, while the subject is watching the video. This arrangement is snug but
not uncomfortable. The subject is asked to hold a button box in one hand; this will be used
to make responses that will provide performance data used for validity checks on task
engagement as well as correlation with the activation results. A "panic ball" will also be
provided to each subject. The subjects will be carefully oriented to the equipment and
environment and will engage in explicit practice of all of the task requirements.
Anatomical Localizer and High Resolution Imaging Acquisitions
After subjects are positioned in the scanner, the scanner will be shimmed to provide a
homogeneous magnetic field for image acquisition. An initial alignment scan is done in 3
orthogonal planes simultaneously using a fast gradient echo sequence developed for the
scanner. This scan takes approximately 30 seconds and provides a quick view of the subject's
head position. Next, a high-resolution T1-weighted 3-D neuroanatomic scan will be obtained
using a inversion recovery, fast spoiled gradient echo (IR-prepped FSPGR) protocol to
provide images for morphometric studies, localization of MRS and anatomical localization of
the activation maps. The acquisition takes approximately 6 minutes and yields a minimum
spatial resolution of 1mm x 1mm x 1.5mm with sufficient signal to noise ratio and contrast
between gray and white matter for both manual and semi-automated segmentation of regional
brain volumes.
Proton MR Spectroscopy Acquisitions
Proton MR spectroscopy data is acquired using the point resolved spectroscopy localization
(PRESS) method. Graphically, 3D cubic volume elements "voxels" are positioned in the
anatomic locations based upon the 3D images. Voxel 1 is placed in the anterior cingulate,
voxel 2 the left dorsalateral prefrontal cortex, voxel 3 within the basal ganglia
encompassing the caudate, putamen and internal capsule and voxel 4 is placed along the
superior temporal gyrus. Voxel 5 is used as a control and is positioned in the left centrum
semiovale, a believed to be unaffected white matter region. Voxels 6 and 7 are positioned
within the cerebellum and vermis, respectively.
Functional MRI Acquisitions
The location of the 24 axial slices to be imaged in the fMRI procedures is identified from
the high resolution anatomical imaging sequence. These 24 slices, 5 millimeters thick (120
mm), are sufficient to cover areas extending superiorly from below the inferior aspect of
the cerebellum to the apex of the cerebrum in an adult brain. Subjects undergo the fMRI scan
sequence during which they will be asked to perform tasks which can involve language, memory
and attention. The protocol for the fMRI scans will be a T2 - weighted gradient -echo Echo
Planar Imaging (EPI) method. The time sequence of alternating periods (30 sec) of task
conditions is repeated 5.5 times for a total of 11 intervals with 10 acquisitions per
interval, resulting in 240 images. 24 image slices are acquired for each time point.
Synchronization of the fMRI scans with the video stimuli is fully automated so that when the
visual presentation commences on the Macintosh computer, it triggers the Bruker MR scanner
to begin acquisitions. The MacStim presentation and the fMRI scan timing are synchronized
from the trigger point to the end of the experiment. The high resolution MDEFT sequence
allows for the 24 fMRI scan planes to be extracted from this 3D anatomical data set by
interpolation for use as an anatomical underlay for the activation maps.
Testing paradigms
The Verb Generation task is based on that described by Binder et al. and involves the
auditory presentation of a series of nouns. The subject is required to generate verbs that
are associated with each noun. For example, if the noun "ball" is presented, the subject
might generate the verbs "throw," "kick," and "hit." The subject is instructed to think the
verbs silently, without saying them, in order to minimize the motion artifact associated
with speech. Task performance is monitored by a button push each time the subject thinks of
a verb. This expressive task is assumed to require the engagement of dominant frontal lobe
and parietal lobe language areas. This task is derived from the clinical literature as an
MRI analog of the procedure used in the Wada test. It is now widely used for testing
hemispheric dominance for language in adults. It is included in the current protocol partly
to provide a point of comparison with the existing literature as well as with our own
preliminary data from other populations. Finally, this is a difficult semantic task and fits
neatly into the scope of the language skills we are seeking to monitor with lead exposed
young adults.
For studies designed to examine working memory, the "n-back" tasks are administered using
MacStim software on a Macintosh PowerBook laptop computer. The "n-back" is a working memory
task in which subjects view numbers from one to four that consistently appear in one of four
quadrants on the screen. Subjects view the stimuli through the audiovisual goggle system and
respond using a button box on which the buttons had been arranged so as to correspond with
the numbers appearing on the screen. In the "zero back" condition, subjects press the number
that corresponds to the number then appearing. In the "two back" condition, the subject
presses the button corresponding to the number that appeared two places prior to the number
then on the screen. During the fMRI scans, subjects are asked to perform the "zero and two
back" tasks in a block-periodic design. During each condition, 15 numbers appear over a 30
second interval. In all, 11 intervals are presented over a 5 1/2 minute scan. The
"zero-back" task serves as the contrast for the "two back" tasks. Data from the first "zero
back" task interval is discarded during post-processing to avoid any non-equilibrium
intensity modulation effects.
In assessing attention, the CPT-IP is administered using MacStim software and MRI compatible
audiovisual system. During the fMRI scans subjects are asked to perform the CPT-IP task in a
block-periodic design. Participants alternate between two conditions. During the first
condition, subjects perform in a control task during which they view a four-digit number
repeating at a constant rate (0.75 sec.) and are instructed to simply look at the flashing
number without responding in any way. During the second condition, subjects watch a series
of high resolution four digit numbers appearing in a random sequence and are instructed to
press a response button when they see any number repeat twice in a row during the sequence.
Numbers again appear every 0.75 sec.
