REDUCED METABOLISM IN BRAIN CONTROL NETWORKS FOLLOWING COCAINE-CUES EXPOSURE IN FEMALE COCAINE ABUSERS Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved. Method: We compared brain metabolism (using PET and 18FDG) between female (n=10) and male (n=16) cocaine abusers when they watched a neutral video (nature scenes) versus a cocaine-cues video. Results: Craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p <0.05);females decreased metabolism (-8.6%b10) whereas males tended to increase it (+5.5%b18). SPM analysis (Cocaine-cues vs Neutral) in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001) whereas males showed increases in right inferior frontal (BA 44/45) (p<0.005). Females showed greater decrements with Cocaine-cues than males (p<0.001) in prefrontal, anterior cingulate, posterior cingulate, inferior parietal and dorsomedial thalamus. Conclusions: Females showed greater brain reactivity to cocaine-cues than males but no differences in craving suggesting that gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation in females of control network regions (prefrontal, cingulate, inferior parietal, thalamus) could increase vulnerability to relapse through impaired control. METABOLISM IN ORBITOFRONTAL CORTEX IS ASSOCIATED WITH POSITIVE EMOTIONALITY Neurobiological processes underlying personality characteristics may shed light on the mechanisms by which personality can increase or decrease the risk for substance use disorders (SUD). Personality traits associated with greater vulnerability for SUD include impulsivity, novelty seeking and negative emotionality whereas positive emotionality (PEM) is associated with resilience. PEM has been associated with striatal DA D2 receptors in controls and in subjects at risk for alcoholism. Since striatal D2 receptors modulate activity in orbitofrontal cortex and cingulate (brain regions that process rewards) we hypothesized that these regions underlie PEM. Methods: We assessed the correlation between baseline brain glucose metabolism measured with PET and 18FDG and scores on PEM (Multidimensional Personality Questionnaire or MPQ) in healthy controls (n=47). Results: SPM revealed that PEM was positively correlated (pc<0.05, voxel corrected) with metabolism in orbitofrontal (BA 11, 47), cingulate (BA 23, 32) and other frontal (BA 10, 9), parietal (precuneus, BA 40) and temporal (BA 20, 21) regions that overlap with the brains default mode network (DMN). Correlations with the other personality dimensions (Negative Emotionality and Constraint) were not significant. Conclusion: Our results corroborate an involvement of orbitofrontal and cingulate regions in PEM. Since dysfunction of orbitofrontal cortex and cingulate is a hallmark of SUD these findings support a common neural basis underlying protective personality factors (PEM) and brain dysfunction underlying SUD. The association with the DMN suggests that PEM relates to brain processes active during rest (ie. introspection, mind wandering). EFFECTS OF CELL PHONE EXPOSURE ON BRAIN GLUCOSE METABOLISM The dramatic increase in cell phone use has generated concern about negative effects on the human brain. However the extent to which acute cell phone exposures affect the human brain is still unclear. Here we evaluated if acute cell phone exposure affects brain glucose metabolism. Methods: We used PET and 18FDG to measure brain glucose metabolism in 48 healthy participants twice, once with cell phone activated (ON with sound muted) and once with cell phone OFF. SPM analyses were performed to compare metabolism between ON and OFF conditions and to perform regression analysis with the estimated radiofrequencies. Clusters >1000 voxels (8cm3) and p <0.05 (corrected for multiple comparisons) were considered significant. Results: Metabolism was significantly higher with than without cell phone exposure in the brain region closest to the antenna, which was located in the lower orbitofrontal cortex and temporal pole (ON 35.7 0.9 micromol/100 grams/min;OFF 33.4 1;SPM Pc <0.05). The increases were significantly correlated with intensities of the estimated electromagnetic field amplitude both for absolute (r=0.63, P <0.0001) and normalized metabolism (r=0.91;P <0.0001). Conclusions: Our results give evidence that the human brain is sensitive to the acute effects of radiofrequencies emitted from cell phones. FUNCTIONAL CONNECTIVITY DENSITY MAPPING: GENDER AND AGING EFFECTS, AND LATERALITY Energy-efficient functional hubs (highly connected regions) are essential for brain function but these networks are still poorly characterized. Methods: We assessed functional connectivity from MRI time series collected in resting-state conditions (RSFC) in 1054 healthy subjects (from open access databasewww.nitrc.org/projects/fcon_1000) to map the strength of short- and long-range functional connectivity density (FCD). Results: Short-range FCD was maximal in cingulate/ventral precuneus;also high in visual areas, inferior parietal, premotor, and inferior and middle frontal cortices. Long-range FCD was maximal in visual cortex;also high in posterior cingulate/ventral precuneus, angular gyrus, superior and inferior parietal cortices. Long-range FCD was higher than short-range FCD in posterior cortical regions and lower in subcortical and anterior cortices. Short-range cortical hubs were associated to minimally coupled networks and long-range FCD with pronounced leftward lateralization. Females had higher FCD than males, especially in DMN. Aging was associated with pronounced decreases in strength of long-range FCD hubs in DMN and dorsal attention networks (DAN) and compensatory increases in long-range FCD in somatosensory network. Discussion: Functional brain networks have a scale-free organization that shows consistency across and within individuals. Gender differences in FCD may explain the higher prevalence of ASD (disease linked with decreased brain connectivity) in males than in females. The vulnerability of long-range FCD in DMN and DAN to aging could underlie the deterioration of attention with age. RADIOTRACER DEVELOPMENT FOR EPIGENTIC BIOMARKERS Epigenetic processes such as Histone deacetylase (HDAC), which induce gene silencing by deacetylating histones, are implicated in addiction. Currently, there are no PET radiotracers to monitor HDAC in brain. Methods: We have focused on new benzamides to optimize HDAC binding potency as well as BBB permeability chosing MS-275 (Entinostat) and CI-994 (Acetyldinaline) as the starting template structures. Systematic parallel synthesis generated 32 benzamides through 7-16 steps for each, which showed moderate to high in vitro binding potency up to IC50=1 nM. Derivatives of Piperazinyl and N,N-dimethylaminomethyl increased binding potency. Overall, 15 compounds were labeled through N-methylation with C-11 methyl iodide and methyl triflate and used for PET studies with 9 female baboons (brain and heart). Three compounds showed high brain uptake (0.012-0.015 %ID/cc) within 20 min, which is >10X higher than MS-275. Brain distribution was highest in cerebellum, moderate in thalamus and striatum. Their binding specificity for HDAC in vivo is underway.
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