1. NIAAA July 20, 2010 Adolescent Neurodevelopment and Alcohol (ANA) Robert J. Thoma, Ph.D. Associate Professor and Clinical Neuropsychologist University of New Mexico School of Medicine Department of Psychiatry, Center for Neuropsychological Services 021511 UNM Research

2. NIAAA July 20, 2010 Specific Aims Aim 1: To discriminate pre-morbid brain and behavioral impairment from that resulting from alcohol use. Aim 2: To clarify the course of alcohol effects on adolescent brain function. We will address this gap in current knowledge by measuring neuropsychological performance and brain function in all study groups over time. Aim 3: To clarify neuroanatomic and neurochemical substrates of alcohol-related impairment in adolescents. Aim 4: To clarify neurodevelopmental and neuroplastic changes associated with relapse to and recovery from alcohol abuse. Subjects (ages 12-18) (Group 1) Healthy alcohol-naïve control subjects (N = 10) (Group 2) Healthy alcohol-naïve subjects at high risk for alcohol use (N = 10) (Group 3) Adolescents who meet DSM-IV diagnostic criteria for alcohol abuse and dependence (N = 20). 021511 UNM Research

3. NIAAA July 20, 2010 Parent Assessment Demographics Locator, BAC, Slossen Oral Reading Test, Brief Family Questionnaire, BASC-2 (Parent Version) Adolescent Assessment Alcohol Assessment (Kid SCID, DrINC, Form-90) Psychological/Psychopathology Assessment (BASC-II) Neuropsychological Test Battery (WASI, Conner’s CPT, Trail Making Test, RBANS, COWAT, WCST, ACT, Digit Span Test, D-KEFS Tower Test). Electroencephalography (EEG; auditory oddball, sensory gating, resting) Magnetoencephalography (MEG; simultaneous with EEG) Structural MRI (sMRI; voxel-based morphometry; Freesurfer) Magnetic Resonance Spectroscopy (MRS) Diffusion Tensor Imaging (dti) Functional MRI (fMRI; resting) Methods 021511 UNM Research

4. NIAAA July 20, 2010 Neuropsychology Results Higher number of drinks per drinking day predicted poorer attention and executive function. Similar to studies of adults with alcohol use disorders, heavy drinking in adolescents appears to negatively affect neuropsychological functions associated with the frontal lobes. Greater frequency of marijuana use was associated with decrements in memory. This finding concurs with previous animal and human studies reporting detrimental effects of marijuana on learning and memory. Frequency of alcohol and nicotine use were not significant predictors of neuropsychological performance when accounting for intensity of drinking and frequency of marijuana use. Among adolescents without substance use disorders, having a parent with an alcohol use disorder was associated with poorer visuospatial ability. 021511 UNM Research

5. NIAAA July 20, 2010 sMRI Voxel-Based Morphometry Results Effect of DPDD within the AUD Group Baseline 1-Year Followup Group Comparison at Baseline Cluster 1 3629 voxels Right fusiform gyrus/right middle temporal/right inferior temporal Cluster 2: 2916 voxels Left superior occipital Cluster 3: 1677 voxels Right superior occiptal/right calcarine Cluster 4: 952 voxels Right superior temporal Cluster 5: 931 voxels Left superior occipital/left calcarine Cluster 6: 644 voxels Left Precuneus/Left calcarine Cluster 7: 278 voxels Right Fusiform/Right inferior occipital gyrus Cluster 8: 271 voxels Left superior orbital gyrus/left inferior frontal gyrus Cluster 9: 222 voxel Left inferior occiptal Cluster 10: 197 voxels Left insula lobe Cluster 11: 192 voxels Right superior area Cluster 13: 181 Left Middle area Cluster 14: 159 voxels Right Precuneus 021511 UNM Research

6. NIAAA July 20, 2010 MEG Results #1, P300 Oddball Experiment The frontal P300m effect was successfully induced in the control and high-risk adolescents. No frontal P300m was evident in the adolescents with AUD. Analysis of response times indicated no group differences in effort. The high-risk adolescents displayed a right hemispheric activation bias. Such an imbalance is notably similar to the EEG resting power bias in anxious and depressed subjects seen in the meta-analysis of Thibodeau, Jorgensen, and Sangmoon (2006). Across groups, better scores on tests of attention and executive functioning correlated with greater frontal P300 strength. 021511 UNM Research

7. NIAAA July 20, 2010 Multiple Voxel Spectroscopy (Chemical Shift Imaging) Gray matter glutamateGray matter glutamate + glutamine Gray matter creatine + phosphocreatine Healthy Control vs. High Risk t(25) = 2.69, p =.013t(25) = 2.75, p =.011t(25) = 2.05, p =.051 Healthy Control vs. AUD t(27) = 2.63, p =.032t(27) = 2.53, p =.017t(27) =.86, ns High Risk vs. AUD t(26) = -.138, nst(26) = -.184, nst(26) = -1.10, ns In the control group, glutamate+glutamine showed marginal or significant bivariate correlations with the Visuospatial Ability composite (r = -.528, p =.052), with number of commission errors on the CPT (r = +.554, p =.040), with reaction time on the CPT (r = -.619, p =.018). The relationship with reaction time was observed at a trend level in the high risk group (r = +.522, p =.067). None of these relationships were replicated in the AUD sample. 021511 UNM Research

8. NIAAA July 20, 2010 Conclusions Abnormalities associated with alcohol use: –Less Gray matter overall in AUD, and noteable regional reduction in hippo-amyg, etc. –Neuropsychological abnormalities in attention and executive function –Abnormally low frontal lobe activation during P300m oddball task –Greater cortical delta activity in fronto-parietal regions –Abnormally low glutamate level –Greater depression, anxiety and negative emotions in female adolescents with AUD High Risk for AUD (one or more parent with AUD) was associated with: –Poor performance on neuropsychological tests of visual-spatial functioning –Reduced volume of pre-frontal, limbic, and cerebellar gray matter. –Right hemispheric activation bias during P300m oddball task. –Reduced frontal striatal-cortical connectivity on fMRI 021511 UNM Research