Grantee Research Project Results
2005 Progress Report: Magnetic Resonance Assessment of Brain Function Altered by Lead Exposure
EPA Grant Number: R829389C005Subproject: this is subproject number 005 , established and managed by the Center Director under grant R829389
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: CECEHDPR - University of Cincinnati Center for the Study of Prevalent Neurotoxicants in Children
Center Director: Lanphear, Bruce
Title: Magnetic Resonance Assessment of Brain Function Altered by Lead Exposure
Investigators: Lanphear, Bruce , Ris, Douglas , Dietrich, Kim , Cecil, Kim , Hornung, Richard , Holland, Scott
Current Investigators: Cecil, Kim
Institution: Children Hospital of Cincinnati , University of Cincinnati
Current Institution: Children Hospital of Cincinnati
EPA Project Officer: Hahn, Intaek
Project Period: November 1, 2001 through October 31, 2006
Project Period Covered by this Report: November 1, 2004 through October 31, 2005
RFA: Centers for Children's Environmental Health and Disease Prevention Research (2001) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health
Objective:
The objective of this research project is to assess the effects of lead exposure on brain function. The hypotheses being investigated are the same as those in the grant proposal.
Hypothesis 1. Childhood exposure to lead disrupts neuronal circuitry, resulting in changes in brain structure, and metabolism as measured by magnetic resonance (MR) methods.
Hypothesis 2. Delinquent behavior and antisocial outcomes (e.g., crime, violence, drug abuse) associated with childhood lead exposure correlate with differences in quantitative MR measures of brain structure and metabolism.
Progress Summary:
Participation Rate
The participation rate has been excellent. A total of 143 subjects have completed the aims, and recruitment continues at the expected rate. As shown on Table 1, 42 of these subjects were enrolled during this reporting period. The anticipated recruitment of 40 subjects for the pilot functional magnetic resonance imaging (fMRI) study, was exceeded, with 42 subjects completing the study.
American Indian |
Asian or Pacific Islander |
Black, not of Hispanic Origin |
Hispanic |
White, not of |
Other or |
TOTAL |
|
Female |
0 |
0 |
15 |
0 |
1 |
0 |
16 |
Male |
0 |
0 |
25 |
0 |
1 |
0 |
26 |
Unknown |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
TOTAL |
0 |
0 |
40 |
0 |
2 |
0 |
42 |
Preliminary Results
Pilot fMRI Studies. This study examined language, attention, working memory, and inhibition with the subjects performing neuropsychological tests while being imaged. The first fMRI task analyzed employed a verb-generation task.
Verb-Generation Task fMRI Methods. The members of the Cincinnati Lead Study (CLS) cohort performed an integrated verb-generation/finger-tapping paradigm while being imaged in a Bruker 3T MR scanner using a T2*-weighted, gradient echo, Echo Planar Imaging (EPI) sequence (scan parameters TR/TE=3000/38 ms, FOV = 25.6 * 25.6 cm, matrix = 64 x 64, slice thickness = 5 mm). Twenty-four slices were acquired at 110 time points during the alternating 30-second periods of control (finger tapping) and activation (visual noun presentation) for a 5.5-minute scan duration. In addition, a whole brain T1-weighted scan was acquired for anatomical coregistration. fMRI image processing was performed with custom software. For each subject, a Z-score map was determined, on a pixel-by-pixel basis, by calculating the t-value and converting to a Z-score. Individual Z-maps are combined to generate a composite Z-map. A linear regression model was used to evaluate the correlation between brain activation and mean childhood blood lead levels with subject full-scale IQ (FSIQ) as a covariate. The demographics for the 43 members of the fMRI sub-cohort included 23 males and 20 females; 38 were African American with a mean age of 21 + 1 years, mean childhood blood lead levels of 13.9 + 6.6 μg/dL with a range of 4.8-31.1 μg/dL, and an FSIQ mean of 87.5 + 10.4 with a range of 63-105.
Results
A composite Z-map (N = 43 subjects) reveals the activation associated with the verb-generation task (Figure 1). The regions typically associated with language apparent in this cohort include the traditional Broca’s area, Wernicke’s area, and the dorsolateral prefrontal cortex with overall left hemispheric dominance. An R-map compares the Z-score for predefined language regions of interest (ROIs) with a lead exposure index based on the mean of analyzed blood samples collected quarterly from birth to 5 years and at 5.5, 6, and 6.5 years (Figure 2). After adjusting for FSIQ in 41 subjects, activation in the left frontal inferior gyrus, where the traditional Broca’s area is located, demonstrated a significant inverse correlation with the mean childhood lead level (R = -0.39, p = 0.01) (Figure 3). Activation in the right temporal region, the contralateral area to the traditional Wernicke’s area, showed a strong positive correlation with the mean childhood lead level (R = 0.35, p = 0.03) (Figure 4).
Figure 1. Composite fMRI Activation Map for the Verb-Generation Task (N = 43). The left hemisphere (image right side) demonstrates activation in the dorsolateral prefrontal cortex, Broca’s, and Wernicke’s areas with overall left-sided dominance.
Figure 2. R-Map. Z-score compared to childhood mean blood lead levels. In Broca’s area, a negative correlation to childhood blood lead level is shown in blue. In the homolog of Wernicke’s area, a (+) correlation to childhood blood lead level is shown in yellow and red.
Figure 3. Linear Regression. Mean activation levels in Broca’s area (left frontal ROI in Figure 2) compared with childhood mean blood lead levels adjusted for FSIQ (R = -0.39, p = 0.01).
Figure 4. Linear Regression. Mean activation levels in Wernicke’s area homolog (right temporal ROI in Figure 2) compared with childhood mean blood lead levels adjusted for FSIQ (R = 0.35, p = 0.03).
Significance of Findings
The results of the fMRI study of semantic language, specifically a verb-generation task, reveal that lead exposure during childhood alters brain activation. Reduced activation in Broca’s area, a recognized region of language function in the left hemisphere, correlated with FSIQ-adjusted, elevated childhood blood lead levels. Increased activation in the right temporal lobe, the homolog of Wernicke’s area in the left, correlated with FSIQ-adjusted, elevated childhood blood lead levels. These correlations suggest a damaging effect to the traditional language areas by childhood lead exposure. These findings are consistent with other neurobehavioral studies finding language deficits, such as word recognition, associated with elevated childhood lead exposure.
Childhood lead exposure strongly influences neural substrates of semantic language function demonstrated as a selective, deleterious effect on normal language areas with concomitant recruitment of contra-lateral regions, resulting in striking, exposure-dependent, atypical organization of language function.
Future Activities:
We are proceeding towards our goal of 150 subjects participating in the study. During the next period, we will finish enrolling subjects for the imaging examination. We anticipate imaging at least 6 subjects per month to exceed our intended recruitment of 150 subjects. We would like to collect data from as many subjects as possible. With the use of the Internet, we have been able to locate members of the cohort previously lost to followup. Final analyses, with respect to global and substructural volumes, and regional metabolic marker concentrations will begin upon completion of the recruitment.
Pilot fMRI Project
Additional neuropsychological paradigms (attention, working memory, and inhibition) were employed for the 45 subjects who completed the fMRI studies. We are beginning to analyze these studies for significance. We anticipate findings of comparable or greater significance than those found in the verb-generation task.
Future Studies
We successfully sought National Institutes of Health funding (R21 ES013524) to extend the significance of the project with two tangential projects. First, we will investigate a novel approach for assessing low-level manganese exposure and brain manganese deposition in the cohort of 150 young adults enrolled in the CLS. Our aim is to develop a noninvasive MRI brain biomarker useful for assessing manganese exposure. Erin Haynes will work with Kim Cecil, Kim Dietrich, Bruce Lanphear, and other scientists in the National Institute of Environmental Health Sciences-funded Center for Environmental Genetics to conduct the manganese study.
Second, we want to explore the relationship between striatal structure, function, neurochemistry, postural sway, and cerebellar structure revealed by MR imaging and spectroscopy upon elevated environmental lead exposure. A preliminary review of historic postural sway data and current basal ganglia and cerebellar MR spectroscopy-derived metabolite levels is ongoing. The postural sway study also will include the aforementioned Center scientists along with Amit Bhattacharya, Ph.D., Professor at the University of Cincinnati Department of Environmental Health.
Publications from the preliminary analyses of this project data are forthcoming later in the calendar year. We also have presented our preliminary fMRI findings with respect to lead exposure and language function at two national/international meetings.
Journal Articles:
No journal articles submitted with this report: View all 6 publications for this subprojectSupplemental Keywords:
toxicology, ADHD behavioral assessment, behavioral deficit, genetic susceptibility, pesticides, biomarkers, environmental agents, exposure, exposure assessment, hearing loss, lead, meconium, neurotoxicity, pesticide exposure, risk assessment, toxicants,, Health, RFA, Scientific Discipline, ENVIRONMENTAL MANAGEMENT, Health Risk Assessment, Risk Assessments, Chemistry, Biology, Children's Health, Toxicology, Risk Assessment, toxicity, biological markers, lead, behavioral deficits, behavioral assessment, neurotoxicity, children, biomarker, adult antisocial outcome, exposure assessmentRelevant Websites:
http://www.healthyhomestoday.com Exit
http://www.cincinnatichildrens.org/research/project/enviro Exit
Progress and Final Reports:
Original AbstractMain Center Abstract and Reports:
R829389 CECEHDPR - University of Cincinnati Center for the Study of Prevalent Neurotoxicants in Children Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R829389C001 Neurobehavioral Effects of Prevalent Toxicants in Children
R829389C002 Validation of Meconium Markers of Fetal Neurotoxicant Exposures
R829389C003 Community-Based Research Project Identifying Residential Hazards Using Home Test Kits
R829389C004 Early Exposure to Lead and Adult Antisocial Outcome
R829389C005 Magnetic Resonance Assessment of Brain Function Altered by Lead Exposure
The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.