IMAGING THE LONG-TERM EFFECTS OF DRUG EXPOSURE IN UTERO

Claire D. Coles, Ph.D. Departments of Psychiatry and Behavioral Sciences and Pediatrics Emory University School of Medicine, Atlanta, GA IMAGING THE LONG-TERM EFFECTS OF DRUG EXPOSURE IN UTERO 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

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) Colleagues 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.

Acknowledgments 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

Drug Use During Pregnancy (% Women Reorting Use) % 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

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. Cortical regions exhibiting PAE effects 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

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 Cortex and Cerebellum volume in Alcohol Affected Adults and two control groups (N=78) 200000 150000 100000 50000 Control EtOH DYSM SpecED In Cerebral Cortex, Dysm<Controls, Left, p<.008; Right, p<.05, no other groups are significantly different. 0 LC Cortex RC Cortex LCB C'tex RCB C'tex p<.02 p<.03 p<.04 p<.04 Brain Region Coles, Li, et al. 2008

White matter volume in alcoholexposed adults and controls (N=78). 250000 200000 150000 100000 50000 Control EtOH DYSM SpecED 0 Lcerebral Rcerebral Lc'bellum Rc'bellum p<006 P<.008 p=.07 p=.09 Coles, Li, et al. 2008 Brain Region In Cerebral Cortex, both alcohol groups differ from both control groups and not from each other.

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

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.

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)

Functional 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. fmri results: Spatial Working Memory 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 Alcoholaffected 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 hemisphere A: Frontal Pole, B: Rostral Middle Frontal Gyrus, C: Precentral Gyrus, D: Inferior Parietal Lobule, E: Precuneus Cortex Right hemisphere F: 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 voxels in 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 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. 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.

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.