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Director's Report to the National Advisory Council on Drug Abuse - February, 2005

Research Findings - Behavioral and Brain Development Research

Interpersonal Maladjustment as Predictor of Mother's Response to Relational Parenting Intervention

This research team previously demonstrated that a Relational Psychotherapy Mothers' Group (RPMG) was more effective in improving parenting than standard drug counseling (DC) for mothers enrolled in methadone maintenance. The research team recently examined whether mother's interpersonal maladjustment predicted a differential response to RPMG in a sample of 52 mothers and 24 children ages 7 and 16 who had completed baseline, post-treatment, and 6-month follow-up assessments. Results indicated an interaction effect; as maternal interpersonal maladjustment increased, parenting problems improved for mothers in the RPMG group, but remained the same or worsened for DC mothers. Mothers' and children's reports of child maltreatment risk were in or near the normal range for RPMG mothers but in or near clinical range for DC mothers at post-treatment and follow-up. RPMG mothers reported improved affective interactions and the DC group reported no such improvements, regardless of mothers' level of interpersonal maladjustment. These findings highlight the importance of including parenting interventions in substance abuse treatment and the value of interpersonally oriented interventions for substance-abusing mothers and their children. Suchman, N.E., McMahon, T.J., and Luthar, S.S. Journal of Substance Abuse Treatment, 27, pp. 135-143, 2004.

Sensation Seeking and Symptoms of Disruptive Disorder: Association with Nicotine, Alcohol, and Marijuana Use in Early and Mid-Adolescence

This cross-sectional study examined the association of Sensation Seeking (SS) and symptoms of Disruptive Disorders and investigated the associations of each with the risk of nicotine, alcohol, and marijuana use in a sample of 127 boys and 81 girls aged 11-14 years recruited from child psychiatry, pediatric adolescent, and pediatric family clinics. Results indicated that sensation seeking was correlated with Conduct Disorder (CD) and Oppositional Defiant Disorder (ODD), however, when analyzed by gender, there was a significant correlation between SS and CD for boys, but no significant correlations between Sensation Seeking and any of the Disruptive Disorders for girls. Sensation seeking was associated with nicotine, alcohol, and marijuana use; ODD was associated with nicotine use; and Conduct Disorder was associated with alcohol and marijuana use for boys and girls, and smokeless tobacco use for boys. Results from a series of gender specific regression analyses found that SS and ODD predicted nicotine use by girls and SS and CD predicted alcohol and marijuana use by boys. For all other analyses of cigarette, alcohol, and marijuana use, SS was the only significant predictor. Measurement of Sensation Seeking and symptoms of Disruptive Disorder in clinic setting can help identify and characterize youth who are at increased risk for drug use during early and mid-adolescence. Martin, C.A., Kelly, T.H., Rayens, M.K., Brogli, B., Himelreich, K., Brenzel, A., Bingcang, C.M., and Omar, H. Psychological Reports, 84, pp. 1075-1082, 2004.

Risk-taking Propensity and Risky Sexual Behavior of Individuals in Residential Substance Use Treatment

This study examined the relationship between risk-taking propensity and risky sexual behavior (RSB) in a sample of 76 mostly male (76%), African American (91%) adult residents of inner-city residential substance-use treatment facilities. The study utilized self-report measures and a computer administered behavioral task of risk-taking propensity, the Balloon Analogue Risk Task or BART. Results indicated that impulsivity, self-esteem, and risk-taking propensity were independently related to RSB. The study reports that risk-taking propensity was significantly related to risky sexual behavior even after taking into account age, gender, impulsivity, self-esteem, and depressive symptoms. In this model, risk-taking propensity and self-esteem were the only significant predictors of RSB. This study suggests the importance of risk-taking propensity as a factor underlying RSB and risk for HIV/AIDS. Lejuez, C.W., Simmons, B.L., Aklin, W.M., Daughters, S.B. and Dvir, S. Addictive Behaviors, 29, pp. 1643-1647, 2004.

Depression, Negative Self-Image, and Suicidal Attempts as Effects of Substance Use and Substance Dependence

This study examined the degree to which cocaine/crack, marijuana, and alcohol use and dependence from 26.5 to 37 years of age predicted depression, negative self-image, negative personal outlook, and suicidal attempts by age 37 in an inner-city sample of 277 African American men and women. Results from this sample, derived from the National Collaborative Perinatal Project (NCPP), found that substance use and dependence predicted mental health outcomes, controlling for prior depression, psychiatric treatment, and suicide attempts and that these predictions differed by gender. Overall, measures of substance use and dependence demonstrated relatively more predictions of suicide attempts for the men and negative self-image and negative personal outlook for the women. For the female sample, making a suicide attempt was predicted by cocaine/crack use and substance dependence, number of suicide attempts was predicted by cocaine/crack use, and depression was predicted by marijuana use. Negative self-image was predicted by substance use, illicit drug use, and substance dependence, and negative personal outlook was predicted by cocaine/crack use, substance use, and illicit drug use. For the male sample, making a suicide attempt was predicted by illicit drug use and substance use, number of suicide attempts was predicted by cocaine/crack use, illicit drug use, substance use, and substance dependence, and depression was predicted by illicit drug use. Negative personal outlook was predicted by cocaine/crack use, substance use, and substance dependence. There were no significant predictors of negative self-image for males. This study highlights gender differences in the important role of substance use in mental health outcomes. Friedman, A.S., Terras, A., Zhu, W. and McCallum, J. Journal of Addictive Diseases, 23(4), pp. 55-71, 2004.

Drug Injection Practices Among High-Risk Youths: The First Shot of Ketamine

Little is known about ketamine injection practices, associated risk behaviors, or the demographic characteristics of ketamine injectors. This study employed an ethno-epidemiological methodology and interviewed 40 young (<25 years old) ketamine injectors in New York during 2000-2002 about ketamine injection initiation as well as histories of other injection drug use and involvement in the street economy. Ninety percent of the sample had a history of sniffing ketamine and 63% had a history of selling ketamine prior to ketamine injection initiation. This study compared two groups of ketamine users: 23 ketamine initiates (youths who initiated injection drug use with ketamine) and 17 other initiates (youths who initiated injection drug use with another drug, such as heroin, and later transitioned into ketamine injection). Results indicated that intramuscular injections were more common among ketamine initiates, whereas intravenous injections were more common among other initiates. Drug form and local knowledge within injection groups were important factors underpinning this relationship: liquid ketamine was injected primarily intramuscularly; powder ketamine was injected primarily intravenously virtually irrespective of injection drug use history. In addition, the comparison between ketamine initiates and other initiates revealed differences regarding knowledge about injecting drugs; risk behaviors at initiation; involvement in the street economy, including homelessness and experience dealing drugs; and city or location of ketamine injection initiation. These findings suggest that ketamine injection is an emerging practice among a new hidden population of injection drug users in cities throughout North America. Ketamine injector's variable risk knowledge and injection practices suggest risk for HIV, HCV, and HBV. Lankenau, S.E. and Clatts, M.C. Journal of Urban Health, 81(2), pp. 232-248, 2004.

Prenatal Cocaine: Quantity of Exposure and Gender Influences on School-Age Behavior

Investigators at Wayne State University have reported that both level of prenatal cocaine exposure and gender were significantly associated with school-age behavioral outcomes. Prenatal cocaine exposure was defined in two ways: dichotomous and ordinal. The dichotomous measure consisted of no exposure or any pregnancy exposure. The ordinal measure had three levels (none, some, persistent), with persistent prenatal exposure defined as continued cocaine use up until delivery as evidenced by positive maternal and/or infant urine testing at delivery. Data analyses were based on a total of 473 children, 204 of whom were prenatally exposed to cocaine; 24 of the cocaine-exposed children were classified as having persistent exposure. Behavior at 6 years of age was assessed using a teacher-report scale involving fourteen problem behavior areas. Boys with any prenatal cocaine exposure scored significantly higher (more problem behaviors) than non-exposed boys on the hyperactivity item. No similar cocaine effect was observed for girls. Boys, but not girls, with persistent exposure had more problems in central processing, motor skills, handling abstract concepts, and passivity to the environment. Covariates controlled for include prenatal exposure to alcohol and other illicit drugs, and postnatal drug use in the home. Delaney-Black, V., Covington, C., Nordstrom, B., et al. Prenatal Cocaine: Quantity of Exposure and Gender Moderation. Developmental and Behavioral Pediatrics, 25(4), pp. 254-263, 2004.

Prenatal Cocaine Exposure and Language Development

Recently-published results from two separate projects provide new information regarding associations between prenatal cocaine exposure and aspects of language development. From the University of Miami, Vogel and colleagues report that when the children in their study were 3 years old (424 children, 226 cocaine-exposed, 198 non-cocaine-exposed), there was a decrease in expressive language score with increasing level of prenatal cocaine exposure. Receptive language was more modestly, and not significantly, related to prenatal cocaine exposure. Using the same language assessment scale, the Clinical Evaluation of Language Fundamentals - Preschool (CELF-P), Lewis and co-investigators at Case Western Reserve University report that for their sample of 4-year-olds (189 cocaine-exposed and 185 non-cocaine-exposed), children exposed to cocaine in utero had poorer expressive and total language scores, and had more mild receptive language delays than nonexposed children. In both studies, the analyses took into account several key variables (e.g., prenatal exposures to alcohol, tobacco, and marijuana). Morrow, C.E., Vogel, A.L., Anthony, J.C., et al. Expressive and Receptive Language Functioning in Preschool Children with Prenatal Cocaine Exposure. Journal of Pediatric Psychology, 29(7), pp. 543-554, 2004; Lewis, B.A., Singer, L.T., Short, E.J., et al. Four-Year Language Outcomes of Children Exposed to Cocaine in Utero. Neurotoxicology and Teratology, 26(5), pp. 617-627, 2004.

Longitudinal Mapping of Cortical Thickness and Brain Growth in Normal Children

Using computer-matching algorithms and new methods of measuring cortical thickness, Dr. Elizabeth Sowell and her colleagues recently published an article in which they mapped changes in brain morphology in a sample of 45 children scanned two years apart from the ages of 5 to 11 years. Measurements of brain size over this age range showed that the greatest growth occurs in the prefrontal cortex, as well as the temporal and occipital cortices. Measures of the thickness of gray matter and white matter showed that over the age range scanned there is considerable variability in changes that occur in different areas of cerebral cortex. The thickness of the gray matter increases in the areas in the frontal and temporo-parietal cortices associated with language and gray matter thickness decreases in many other cortical areas. Since the gray matter thinning actually takes place in cortical areas in which cortical volume is increasing, it is likely that there is a corresponding increase in white matter development in these areas, possibly reflecting the maturation of connectional pathways. Significantly, the decrease in gray matter thickness in the left dorsal frontal and parietal lobes was strongly correlated with improved performance on a test of verbal skills. This paper represents the first report of changes in gray matter thickness, brain size, and structure/function relationships in children followed longitudinally during a time of rapid cognitive development. Data such as these can serve as the basis for defining relationships between brain morphology and cognitive changes in disrupted development. Sowell, E.R., Thompson, P.M., Leonard, C.M., Welcome, S.E., Kan, E. and Toga, A.W., The Journal of Neuroscience 24(38), pp. 8223-8231, 2004.

The Fate of Perfluoro-Tagged Metabolites of L-DOPA in Mice Brains

Dopamine occurs in quantities in the mammalian CNS too small to be detected by current magnetic resonance neuroimaging methods. Fluorine atoms, however, can be detected by magnetic resonance spectroscopy (MRS). In an effort to render dopamine detectable with MRS, Dr. Sherry Dingman and colleagues have developed isomers of L-DOPA tagged with multiple fluorine atoms. In this study, Dr. Dingman has demonstrated that these tagged isomers, when injected into mice intraperitoneally, are taken up into brain tissue and converted into molecules of fluorine-tagged dopamine. Thus it may be possible to use fluorine-tagged neurotransmitter precursors, such as those used here, to allow for the study of transmitters and transmitter systems in vivo using magnetic resonance imaging. Dingman, S., Mack, D., Branch, S., Thomas, R., Guo, C., and Branch, C., Journal of Immunoassay and Immunochemistry 25(4), pp. 359-370, 2004.

Differential Cingulate and Caudate Activation Following Unexpected Nonrewarding Stimuli

Considerable research has been devoted to the investigation of reward processing and much of this research, conducted in nonhuman primates, has demonstrated that cells in some dopamine-rich areas of the brain respond to differences between expected and actual rewards. In this study, Dr. B.J. Casey has used functional magnetic resonance imaging to examine the activation patterns of cortical and subcortical brain areas to the occurrence of an unexpected event or the absence of an expected event. It was found that the anterior cingulate region and the caudate nucleus were responsive to these stimulus conditions, with activity in the anterior cingulate increasing when an unexpected event occurred and activity in the caudate decreasing when an expected event did not occur. These findings demonstrate that neural activity in dopamine-rich regions of the brain can be activated by a variety of stimuli, including those not specifically associated with reward. Davidson, M.C., Horvitz, J.C., Tottenham, N., Fossella, J.A., Watts, R., Ulug, A.M. and Casey, B.J., NeuroImage. 23, pp. 1039-1045, 2004.

Mapping Cortical Change in Alzheimer's Disease, Brain Development, and Schizophrenia

Dr. Elizabeth Sowell and her colleagues have described a sophisticated image analysis algorithm, based on data collected from many individuals that can identify patterns of brain structure and function during the course of development and in populations in which the brain has been altered by aging, disease, or abnormal development. The methods that they describe use pattern-matching and can be used to compare and pool data across different populations and over time. These methods may also prove useful in demonstrating the effects of therapies aimed at ameliorating the progression of disease or the sequelae of abnormal development. Thompson, P.M., Hayashi, K.M., Sowell, E.R., Gogtay, N., Giedd, J.N., Rapoport, J.L., de Zubicaray, G.I., Janke, A.L., Rose, S.E., Semple, J., Doddrell, D.M., Wang, Y., van Erp, T.G., Cannon, T.D. and Toga, A.W. NeuroImage 23, S2-S18, 2004.

In Utero Marijuana Exposure Associated with Abnormal Amygdala Dopamine D2 Gene Expression in the Human Fetus

Dr. Yasmin Hurd and her colleagues, using in situ hybridization histochemistry, have published the first description of neurobiological effects of in utero exposure to cannabis in the human fetus. Their results demonstrate that cannabis exposure during prenatal development causes a decrease in dopamine D2 mRNA expression in the amygdala and that the magnitude of this decrease was positively correlated with the level of exposure. Importantly, this decrease in D2 mRNA was gender-specific, occurring in males but not in females. This alteration in the mesocorticolimbic dopaminergic brain circuitry during development may contribute to the emotional and cognitive deficits that have been reported in children prenatally exposed to cannabis. Wang, X., Dow-Edwards, D., Anderson, V., Minkoff, H., Hurd, Y.L. Biological Psychiatry 56, pp. 909-915, 2004.


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