Imaging the Long-Term Effects of Drug Exposure in Utero - Emory ...

Albert Einstein College
of Medicine
May 16, 2011
Claire D. Coles, Ph.D.
Departments of Psychiatry and Behavioral Sciences and Pediatrics
Emory University School of Medicine, Atlanta, GA

• Departments of Psychiatry
and Behavioral Sciences
and Pediatrics, Emory
University School of
Medicine
• Fetal Alcohol and Drug
Exposure Center, at the
Marcus Autism Center of
Children’s Health Care of
Atlanta

• Biomedical Imaging
Technology Center, Wallace H.
Coulter Center
Emory University & Georgia Institute of
Technology
• Xiaoping P. Hu, Ph.D.
(Director)
• Zhihao Li, Ph.D.
• Longchaun Li, Ph.D.
• Xiangchuan Chen, PhD.
• Priya Santhanam, PhD
• Gopikrishna Deshpande, PhD
(Auburn University)
• Maternal Substance Use and
Child Development Laboratory
Emory University School of Medicine
• Mary Ellen Lynch, Ph.D.
• Julie A. Kable, Ph.D.
• Department of Neurology
• Felicia Goldstein, PhD.
• Department of Psychology
• Stephan Hamann, Ph.D.

Some of the Research discussed today was supported by:
National Institute on Alcoholism and Alcohol Abuse, R01
AA014373
National Institute on Drug Abuse, R01-DA 07362
Georgia Department of Human Resources

%
30
25
20
15
10
5
0
Marijuana Cocaine Other Alcohol Cigarettes
Ebrahim, SH, & Gfroerer, J (2003) Obstetrics and Gynecology, 101, p374-378

State-Specific Weighted Prevalence Estimates of Alcohol Use
(Percentage of Any Use/Binge Drinking)
Among Women Aged 18 – 44 Years — BRFSS, 2008
CA
Guam
28.6
7.1
OR
WA
43.3
12.8
53.1
14.8
53.0
12.9
AK
51.7
18.0
46.1
12.0
NV
MT
ID
45.0
12.9
UT
20.4
6.5
51.6
15.5
AZ
WY
54.4
19.3
NM
49.1
15.0
CO
56.6
14.7
42.6
10.0
44.7
15.5
TX
HI
ND
SD
NE
54.0
23.0
57.0
19.4
53.2
18.9
KS
49.2
12.8
OK
40.9
11.3
43.6
11.6
MN
56.9
19.3
IA
58.2
22.9
49.2
16.0
MO
WI
39.8
11.1
68.4
23.9
AR
55.4
19.4
35.3
45.6
8.9
10.7
LA
41.7
6.1
IL
MS
51.1
MI
NY 12.8
58.8
18.7
PA
52.5
OH
47.6
54.5
18.9
16.3
12.3
WV
28.8
IN
49.5
38.0
6.9
14.7
9.9
VA
KY
40.4
31.7
NC
TN
11.8
8.0
SC
40.8
AL GA
11.4
38.1
47.1
9.5
12.5
U.S. Virgin Islands
25.2
7.7
Puerto Rico
FL
64.0
17.9
NJ
VT
ME
58.7
18.2
61.2
NH 12.5
63.1
MA
19.5
CT 58.0
63.9
18.1
RI
52.3
16.0
14.9
55.2
DE
53.8
17.1
MD
14.9
Washington, D.C. 62.1
21.9
Any Use
47.7
10.9
Binge
TM

Alcohol is a TERATOGEN:

FAS
• Prenatal
Alcohol
Exposure
• Face
• Growth
• Brain

• General Cognitive/Learning Skills (IQ)
• Executive Functioning Skills
• Attentional regulation
• Memory,Planning and organization
• Motor skills
• Visual/spatial skills
• Academic Achievement
• Adaptive Behavior
• Social Behavior
• Mental Health/Behavioral Disorders

• Adult Follow-up of Prenatally Identified Cohort-M
age 22.5 Years
• Predominantly African-American, Born 1980 to
1986
• Documented exposure to EtOH and other drugs
• High levels of exposure (M=10+ AAoz/wk= 20+
drinks)
• Longitudinal vs Clinical sample; not biased by
behavior problems, etc
• Developmental and social history known

• Controls- Recruited prenatally, same hospital and
SES, no alcohol exposure.
• Dysmorphic -Recruited prenatally, alcohol
exposed, Dysmorphic Checklist score 1 SD above
group mean.
• ARND - Recruited prenatally, alcohol exposed, no
dysmorphia, IQ

Control
ARND
DYSM
(n = 26)
(n = 36)
(n = 30)
% Males 46.2 27.8 46.7
% A-A 1 100 97.2 100
Age (yrs) 22.7 (1.7) 23.1 (1.6) 23.1 (2.2)
Ed (yrs) 12.3 (1.6) 11.7 (1.5) 11.8 (1.3)
Dysm Score
3.62 (3.3) 4.7 (3.8) 9.43 (7.8)*
FSIQ 2 84.0 (8.6) 80.5 (12.1) 76.0 (12.0)*
AA/oz/wk 0 (0) 7.7 (13.1)* 13.5 (13.6)*
1
. African-American; 2 . Full Scale IQ * Indicates a significant difference

• Structure-Identify structural
changes associated with
prenatal alcohol exposure
(PAE)-sMRI
• White matter integrity-Using
Diffusion Tensor Imaging (DTI),
identify effects of PAE on
structural connectivity
• Activation-Using fMRI, examine
differences in activation of
candidate ROIs-Math and
Attention Tasks
3T Siemens
Magnetom Trio
Scanner

• PAE is associated with structural changes in
brain
• PAE affects white matter integrity
• PAE is associated with alterations in BOLD
activation in areas responsible for Math
performance
• PAE affects brain networks responsible for
structural and functional connectivity

• 96 separate measurements of brain volume, ranging
from total Intracranial volume to subcortical structures
(e.g., hippocampus)using Free surfer
• Examined:
▪ Cortical regions
▪ Subcortical
▪ Corpus Callosum
• Compared:
• Alcohol exposure vs Nonexposed Controls
• Alcohol “affected” vs “non-affected” vs Controls

SFr: Superiorfrontal
RMF: Rostralmiddlefrontal
CMF: Caudalmiddlefrontal
PTr: Parstriangularis
POr: Parsorbitalis
LOF: Lateralorbitofrontal
PrC: Precentral
PoC: Postcentral
SuM: Supramarginal
SPa: Superiorparietal
STe: Superiortemporal
ITe: Inferiortemporal
LOc: Lateraloccipital,
CAC: Caudalanteriorcingulate
PCu: Precuneus
Cun: Cuneus
PCa: Pericalcarine
Lin: Lingual
Fus: Fusiform
PHi: Parahippocampal
RAC: Rostralanteriorcingulate
IPa: Inferiorparietal
POp: Parsopercularis.
Cortical regions exhibiting PAE effects (N=92)
Chen, et al., (2011) ) Understanding Specific Effects of Prenatal Alcohol
Exposure on Brain Structure in Young Adults, Human Brain Mapping

Cbr: Cerebral Cortex
Cbe: Cerebellum
Cortex
Tha: Thalamus Proper
Hip: Hippocampus
Put: Putamen
Pal: Pallidum
Amy: Amygdala
Cau: Caudate
Acu: Accumbens
Area.
R: Right Hemisphere,
L: Left Hemisphere.
Sub-cortical regions exhibiting PAE effects, (N=92)

Effects of Prenatal Alcohol Exposure on Corpus Callosum Volume
. Segmentation of the corpus callosum (A), in which some
portions (1, 4 and 5) exhibited the general PAE effect (B). 1:
Anterior, 2: Mid-Anterior, 3: Central, 4: Mid-Posterior, 5:
Posterior.
•Chen, X., C.D. Coles, M.E. Lynch, X. Hu (2011, in Pre ) Understanding Specific Effects of
Prenatal Alcohol Exposure on Brain Structure in Young Adults, Human Brain Mapping ss

250000
200000
150000
100000
50000
Control
EtOH
DYSM
SpecED
In Cerebral
Cortex,
Dysm

250000
200000
150000
100000
50000
Control
EtOH
DYSM
SpecED
0
Lcerebral Rcerebral Lc'bellum Rc'bellum
p

• White matter integrity-Using Diffusion
Tensor Imaging (DTI), identify effects of PAE
in corpus callosum
• Assumption, there are specific effects on
White Matter integrity in brain

• Diffusion Tensor Imaging examines white
matter integrity and white matter tracts.
• Behavioral data in alcohol-affected
individuals suggests a effect on white
matter integrity.
• Structural neuroimaging studies indicate
differences in white matter, particularly
loss of white matter in alcohol-affected
individuals.

• FA-Fractional Anistropy-How strongly directional local
tract structure is. Responsive to conditions that affect
axon development or damage axons reflected in low FA
and Hi MD.
• MD-Mean diffusivity. Average Diffusion in all 3 directions.
• AD-Axial Diffusivity- Mean magnitude of water diffusion
parallel to axon direction within the voxel of axon tractsmeasures
axonal integrity
• RD-Radial Diffusivity-Mean magnitude of water diffusion
perpendicular to axon tracts-measures demylenization

LI, Coles, Lynch, & Hu, Human Brain Mapping, 2009

Using TBSS for DTI analysis, voxel-wise statistics on the skeletonized FA data reveal
subregions of the cingulum with significantly lower FA values in both PAE groups
versus control subjects.
Skeletonized FA difference between Control and Non-Dysmorphic PAE groups
(green=skeleton, purple=anatomically defined ROI, pink=region of significant
difference). Similar differences were seen between control and dysmorphic PAE
groups.
Santhanam, et al, 2011, in press

TBSS results for bilateral
cingulum. ROI shows
significant differences
between
(a) Control and Non
Dysmorphic PAE groups
(b) Control and Dysmorphic
PAE groups in FA.
Green indicates mean FA skeleton
and red indicates regions of
significant difference between
groups, with thickened red-yellow
for the bilateral cingulum ROI.
Axial slices shown are z=107 to
z=112.

Controls Non-Dys PAE Dys PAE
Left hand
response to
Opposite side
stimulation (LO)
*Significant difference between Dys-PAE and Control groups in premotor area
Controls Non-Dys PAE Dys PAE
Right hand
response to
Opposite side
stimulation (RO)
*Significant difference between Dys-PAE and Control groups in
primary motor (arrows) and premotor areas

Group maps of
task-related activation
Difference maps of
task-related activation
Control-NonDys
Control
Non-dys
PAE
Dys PAE
+
_
Control-Dys
29

Regions of default mode deactivation during arithmetic task (using
letter-matching task as baseline). MPFC and PCC clusters from these
group average activation maps were used for subsequent resting-state
analysis. Color bar indicates these regions are negatively activated.
Figure 1

Resting-state functional
connectivity (correlation)
group maps (a) with and (b)
without global signal
regression. At threshold
p

FIGURE 3: Difference correlation
maps of:
(a) Control-Non Dysmorphic PAE
(b) Control-Dysmorphic PAE
groups seeded at the PCC region
and masked at MPFC region
identified in Figure 1.
Control groups had more
correlation with the MPFC than
either exposure group (red-yellow
indicates positive difference).
Threshold used was p

• Task related reactivity in DMN affected by
PAE
• Structural Connectivity lower (DTI)
• Functional Connectivity affected (fMRI)
• Implies that structural connectivity deficit
affects functional network in system that
modulates attention and cognition

• Genetic differences that characterize women
who use drugs/alcohol during pregnancy
• Social factors, like nutrition, post natal
environment, social class, ethnic group…
• Polydrug exposure prenatally and postnatally
• Experimental characteristics-sample
selection, research design, and so forth

• Evidence for persistent, global deficits even
when SES and postnatal environment
accounted for.
• In addition to global deficits, there may be
specific cognitive problems in the following
areas: Motor functioning, visual spatial skills,
math, memory.
• MRI (and fMRI) suggest neurological basis for
behavioral findings.

• Coles CD; Li Z (2011) Functional neuroimaging in
the examination of effects of prenatal alcohol
exposure.
• Lebel C; Roussotte F; Sowell ER (2011) Imaging
the impact of prenatal alcohol expsure on the
structure of the developing human brain.
• Wozniak JR; Muetzel RL (2011) What does
diffusion tensor imaging reveal about the brain
and cognition in fetal alcohol spectrum disorders?

• 20 years of research
• Brain Volume -Smaller in Diagnosed cases
and prenatal exposure
• With total BV controlled, specific effects
noted in corpus callosum, caudate,
hippocampus, cerebellum. Other areas also
noted.
• Both white and grey matter affected but
white more affected.
• Sowell and colleagues-cortical thickening
• Reductions found more often in frontal,
parietal. Other areas less studied.

• 7 Studies, 2 with adults, 5 with older children
and adolescents.
• Microstructural anomalies found in many
regions studied, but particularly, Corpus
Callosum
• Structural and functional deficits appear related
• DTI seems sensitive to teratogenic effects of
alcohol; however, effects are not specific but
similar to those in other disorders
• Lack of developmental norms makes
interpretation difficult.