IMAGING THE LONG-TERM EFFECTS OF DRUG EXPOSURE IN UTERO

Claire D. Coles, Ph.D.Departments of Psychiatry and Behavioral Sciences and PediatricsEmory University School of Medicine, Atlanta, GA

International Society for Magnetic Resonance in Medicine, Montreal, Canada

May 10, 2011

Dr. Coles’ Affiliations

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

Colleagues 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 LaboratoryEmory 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

Acknowledgments

Drug Use During Pregnancy(% Women Reorting Use)

Ebrahim, SH, & Gfroerer, J (2003) Obstetrics and Gynecology, 101, p374-378

%

TM

U.S. Virgin Islands

State-Specific Weighted Prevalence Estimates of Alcohol Use

(Percentage of Any Use/Binge Drinking)

Among Women Aged 18 – 44 Years — BRFSS, 2008

State-Specific Weighted Prevalence Estimates of Alcohol Use

(Percentage of Any Use/Binge Drinking)

Among Women Aged 18 – 44 Years — BRFSS, 2008

Puerto Rico

53.1

14.8

53.1

14.8

53.0

12.9

53.0

12.9

43.3

12.8

43.3

12.8

51.7

18.0

51.7

18.0

45.0

12.9

45.0

12.9

54.4

19.3

54.4

19.3

49.1

15.0

49.1

15.0

56.6

14.7

56.6

14.7

42.6

10.0

42.6

10.0

20.4

6.5

20.4

6.5

51.6

15.5

51.6

15.5

54.0

23.0

54.0

23.0

57.0

19.4

57.0

19.4

53.2

18.9

53.2

18.9

49.2

12.8

49.2

12.8

43.6

11.6

43.6

11.6

40.9

11.3

40.9

11.346.1

12.0

46.1

12.0

56.9

19.3

56.9

19.3

58.2

22.9

58.2

22.9

49.2

16.0

49.2

16.0

39.8

11.1

39.8

11.1

45.6

10.7

45.6

10.7

35.3

8.9

35.3

8.9

31.7

8.0

31.7

8.0

38.0

9.9

38.0

9.9

55.4

19.4

55.4

19.4

68.4

23.9

68.4

23.9 58.8

18.7

58.8

18.7

47.6

12.3

47.6

12.3

54.5

16.3

54.5

16.328.8

6.9

28.8

6.9

38.1

9.5

38.1

9.547.1

12.5

47.1

12.5

40.8

11.4

40.8

11.4

40.4

11.8

40.4

11.8

49.5

14.7

49.5

14.7

51.1

12.8

51.1

12.8

52.5

18.9

52.5

18.9

58.7

18.2

58.7

18.264.0

17.9

64.0

17.9

61.2

12.5

61.2

12.5

63.9

16.0

63.9

16.0

58.0

18.1

58.0

18.1

63.1

19.5

63.1

19.5

55.2

17.1

55.2

17.153.8

14.9

53.8

14.9

62.1

21.9

62.1

21.9

Washington, D.C.

52.3

14.9

52.3

14.9

47.7

10.9

47.7

10.944.7

15.5

44.7

15.5

25.2

7.7

25.2

7.7

41.7

6.1

41.7

6.1

Any Use

Binge

CA

DE

MD

RICT

MA

ME

NH

VT

NJ

NY

PAOH

WV

VAKY

INIL

MI

WI

MN

TNNC

SC

GA

IA

HI

AK

NV

ND

SD

OR

WA MT

AZ

ID

WY

UT

CO

NM

OK

TX

NE

KS

ALMS

LA

MO

AR

FL

28.6

7.1

Guam

Epidemiology: Tobacco

27-33% of women of childbearing age

20-25% of expectant mothers continue use

27% were able to immediately quit use when told that they were pregnant

An additional 12% were able to quit by the third trimester of pregnancy

MANY, DIFFERENT, DEVELOPMENTAL AND BEHAVIOR PROBLEMS ARE NOTED IN CHILDREN, ADOLESCENTS, AND ADULTS EXPOSED TO ALCOHOL AND DRUGS PRENATALLY

The goal(s) of neuroimaging in the study of the effects of prenatal exposure…

Identify specific teratogenic outcomes of drugs of abuse and of the abuse of specific drugs….

Establish the brain basis for behavioral changes observed in affected individuals

Facilitate diagnosis of the effects of prenatal exposure.

Many other factors that may affect outcomes……………..

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

Focus of Presentation

Specific Drugs of Abuse

Alcohol

Stimulants (Cocaine/Methamphetamine)

Methods-Status of knowledge

sMRI

DTI

fMRI

And, yes, there are lots of other methods….

Recent reviews of Imaging literature on Alcohol Exposure (Neuropsychology Review, 2011, 21 (2)

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?

Prenatal Alcohol Exposure and Brain Structure (see Lebel,et al, 2011)

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.

Structural effects of Prenatal Alcohol Exposure: an example

Young adults identified prenatally and followed longitudinally. Matched for ethnicity and SES.

96 separate measurements of brain volume, ranging from total Intracranial volume to subcortical stuctures(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 Male and female differences in alcohol effects

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.

Chen, et al., (2011) ) Understanding Specific Effects of Prenatal Alcohol

Exposure on Brain Structure in Young Adults, Human Brain Mapping

Cortical regions exhibiting PAE effects

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

. 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.

Effects of Prenatal Alcohol Exposure on Corpus Callosum Volume

•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

Cortex and Cerebellum volume in Alcohol Affected Adults and two control groups (N=78)

0

50000

100000

150000

200000

250000

LC Cortex RC Cortex LCB C'tex RCB C'tex

Control

EtOH

DYSM

SpecED

Brain Region

p<.02 p<.03 p<.04 p<.04

In Cerebral

Cortex,

Dysm<Controls,

Left, p<.008;

Right, p<.05, no

other groups are

significantly

different.

Coles, Li, et al. 2008

White matter volume in alcohol-exposed adults and controls

(N=78).

0

50000

100000

150000

200000

250000

Lcerebral Rcerebral Lc'bellum Rc'bellum

Control

EtOH

DYSM

SpecED

Brain Region

p<006 P<.008 p=.07 p=.09

In Cerebral

Cortex,

both

alcohol

groups

differ from

both

control

groups and

not from

each other.

Coles, Li, et al. 2008

Prenatal Alcohol Exposure and DTI (see, Wozniak & Muetzel, 2011)

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.

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

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

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.

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.

Prenatal Alcohol Exposure and Functional Imaging(see, Coles & Li, 2011) Limited research (ERP=5 studies; fMRI=9 studies)

Overall-global decrement in processing resources/neural efficiency

Regional localization not best way to understand alcohol-related deficits?

Experimental parameters affect activation(e.g., subject characteristics, task difficulty)

Specific issues (e.g., microcephaly, IQ, comorbidities)

fMRI results: Spatial Working MemoryFunctional brain

activation differences (bottom frame) between the PAE (top-left frame) and control (top-right frame) subjects in a spatial working memory task. The exposed group exhibited greater activation in extended brain regions.

This figure is adapted from Spadoni, et al, 2009 with permission.

Spadoni, A. D., Bazinet, A. D., Fryer, S. L., Tapert, S. F., Mattson, S. N., & Riley, E. P. (2009). BOLD response during spatial working memory in youth with heavy prenatal alcohol exposure. Alcoholism: Clinical And Experimental Research, 33(12), 2067-2076.

Studied DMN in Alcohol Exposed young adults during Math Task

Reduced DMN deactivations found in other clinical conditions, particularly those associated with attentional deficits

Activities of this network can be used to examine functional synchrony (fMRI)

Functional correlations in DMN can be correlated with evidence of Structural connectivity identified using DTI

Hypotheses regarding Effects of Alcohol

DMN deactivation reduced in Alcohol-affected groups

White matter integrity in DMN reduced

Synchonization reduced between MPFC and PCC (fMRI activation)

Correlation between FA (DTI) and fMRI results reduction associated with PAE

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<0.001, only positive correlation (red-yellow was noted with the seeding region regardless of regression method. Seeding was in the PCC region defined in Figure 1.

Resting State DMN correlations and Task Based DMN Deactivation

Control ARND Dysm

% Signal change in PCC

-0.585

(0.06)

-0.536

(0.05)

-0.425

(0.06)

Mean Corr. Coeff in MPFC

0.285

(0.03)

0.190*

(0.03)

0.206*

(0.03

*Significantly different from Controls, p<.05

Resuts: Default Mode

Task related deactivity 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

Effects of Prenatal Stimulant Exposure: Reviews

Roussotte F, Soderberg L, Sowell E. Structural, metabolic and functional abnormalities as a result of prenatal exposure to drugs of abuse: Evidence from neuroimaging. Neuropsychol Rev. 2010 Dec;20(4):376-97.

Derauf C, Kekatpure M, Neyzi N, Lester B, Kosofsky B. Neuroimaging of children following prenatal drug exposure. Semin Cell Dev Biol. 2009 Jun;20(4):441-54.

Stimulant Studies

Published studies of Cocaine very limited; Methamphetamine even fewer.

Results are inconsistent

In most studies reductions are noted in Brain Volume

Polydrug use is very common; Often effects of stimulants do not persist when other drugs are controlled.

Program #: 4344 PCE Effects on Brain Structures

Cortical regions affected by Prenatal Cocaine Exposure

• Left hemisphereA: Frontal Pole, B: Rostral Middle Frontal Gyrus, C: Precentral Gyrus, D: Inferior Parietal Lobule, E: Precuneus Cortex

• Right hemisphereF: Caudal Middle Frontal Gyrus, G: Rostral Middle Frontal Gyrus, H: Pars Triangularis, I: Pars Opercularis, J: Medial Orbital Frontal Cortex, K: Caudal Anterior Cingulate Cortex, L: Precuneus Cortex

Chen, X, Coles, CD, Lynch, ME, Li, Z, Hu, X (2011) Effects of prenatal cocaine exposure on human brain structures, Poster # 4344, Montreal, CA

Prenatal cocaine exposure and emotional arousal in adolescents: Neuroimaging and N-Back task

Bilateral amygdala area(brain images) comparing activation between Cocaine exposed and Controls (bar graphs). Activation level is the produce of mean regression coefficient (representing the fMRI signal amplitude) and number of activated voxelsin the ROI (representing the activation volume). With “NEU0” value as the baseline (zero). The error bars represent standard error.

Li, Z, Coles, CD, Lynch, ME, Hamann, S., Pelter, S, LaConte, S & Hu, X (2009) Prenatal cocaine exposure alters emotional arousal regulation and its effects on working memory, Neurotoxicology and Teratology, 31 (6), 342-348.

Cocaine exposed adolescents do not show the usual balance between cognitive and emotional arousal

Left dorsal lateral prefrontal area(brain images) and the activation amount comparison between groups (bar graphs). As in the previous slide, there is an interaction between Condition (Neuo.Neg) and Exposure Group.

Li, Z, Coles, CD, Lynch, ME, Hamann, S., Pelter, S, LaConte, S & Hu, X (2009) Prenatal cocaine exposure alters emotional arousal regulation and its effects on working memory, Neurotoxicology and Teratology, 31 (6),

342-348.

Summary The study of effects of prenatal exposure is in the

early stages (Alcohol>Cocaine>other drugs) There is a great deal of similarity in outcomes (e.g.,

reduced brain volume, inefficient neural processing on fMRI) that suggest non-specific effects or polydrug effects.

Sample sizes are not yet large enough to control for potentially confounding genetic and environmental factors.

“developmental norms” are not yet available to allow interpretation of some findings.

Current research findings based on group differences; Methods are not yet appropriate for diagnostic purposes

Nevertheless…

Neuroimaging, as experimental methods and imaging techniques continue to be refined, hold great promise both as a way of understanding the development and function of the prenatally exposed brain and as a method , eventually, for diagnosis of affected individuals.