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

Transcription

1 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

2 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

3 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.

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

5 % Marijuana Cocaine Other Alcohol Cigarettes Ebrahim, SH, & Gfroerer, J (2003) Obstetrics and Gynecology, 101, p

6 State-Specific Weighted Prevalence Estimates of Alcohol Use (Percentage of Any Use/Binge Drinking) Among Women Aged Years BRFSS, 2008 CA Guam OR WA AK NV MT ID UT AZ WY NM CO TX HI ND SD NE KS OK MN IA MO WI AR LA IL MS 51.1 MI NY PA 52.5 OH WV 28.8 IN VA KY NC TN SC 40.8 AL GA U.S. Virgin Islands Puerto Rico FL NJ VT ME NH MA 19.5 CT RI DE MD 14.9 Washington, D.C Any Use Binge TM

7 Alcohol is a TERATOGEN:

8 FAS Prenatal Alcohol Exposure Face Growth Brain

9 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

10 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

11 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<84. Special Education (n=20) Recruited in adolescence, no alcohol exposure, Special Education services, Same SES.

12 Control ARND DYSM (n = 26) (n = 36) (n = 30) % Males % A-A 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 (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

13 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

14 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

15 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

16 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

17 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)

18 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

19 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

20 Control EtOH DYSM SpecED 0 Lcerebral Rcerebral Lc'bellum Rc'bellum p<006 P<.008 p=.07 p=.09 Coles, Li, et al Brain Region In Cerebral Cortex, both alcohol groups differ from both control groups and not from each other.

21 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

22 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.

23 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

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

25 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

26 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.

27

28 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

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

30 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

31 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.

32 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<0.05 and 10 contiguous voxels (multiple comparison correction of alpha<1%).

33 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

34 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

35 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.

36 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?

37 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.

38 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.