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Director's Report to the National Advisory Council on Drug Abuse - May, 2006

Research Findings - Behavioral and Brain Development Research

Methamphetamine and Other Substance Use during Pregnancy: Preliminary Estimates from the Infant Development, Environment, and Lifestyle (IDEAL) Study

Methamphetamine use is a continuing problem in several regions of the United States yet few studies have focused on prenatal methamphetamine exposure. Dr. Barry Lester and his colleagues are conducting a study to estimate the prevalence and correlates of alcohol, tobacco, and other substance use-including methamphetamine-during pregnancy in four areas of the country (Los Angeles, CA; De Moines, IA; Tulsa, OK; and Honolulu, HI). The sample consists of the first 1632 eligible mothers who consented to participate in a large-scale multi-site study focused on prenatal methamphetamine exposure. This unselected screening sample includes both users and nonusers of alcohol, tobacco, methamphetamine, and other drugs. Substance use was determined by maternal self-report and/or GC/MS confirmation of a positive meconium screen. Overall, 5.2% of women used methamphetamine at some point during their pregnancy. One quarter of the sample smoked tobacco, 22.8% drank alcohol, 6.0% used marijuana, and 1.3% used barbiturates prenatally. Less than 1% of the sample used heroin, benzodiazapenes, and hallucinogens. Multivariate modeling results showed that tobacco smokers and illicit drug users were more likely to be single and less educated, have attended less than 11 prenatal visits, and utilize public financial assistance. IDEAL is the first large-scale investigation to report the prevalence of methamphetamine use during pregnancy in areas of the United States where methamphetamine is a notable concern. Given that this research extends and confirms previous findings showing that high-risk groups of pregnant women can be identified on the basis of basic demographic characteristics, targeted interventions are greatly needed to reduce serious adverse outcomes associated with prenatal alcohol and tobacco use. Arria, A.M., Derauf, C., Lagasse, L.L., Grant, P., Shah, R., Smith, L., Haning, W., Huestis, M., Strauss, A., Grotta, S. D., Liu, J. and Lester, B. Methamphetamine and Other Substance Use during Pregnancy: Preliminary Estimates from the Infant Development, Environment, and Lifestyle (IDEAL) Study. Maternal Child Health Journal, pp. 1-10, January 5, 2006 [Epub ahead of print].

Cocaine Exposure During Pregnancy and Neonatal Outcomes

Data in this report are for newborns in the Maternal Lifestyle Study, a multi-site longitudinal investigation of health and development following prenatal drug exposure. Associations between cocaine exposure in utero and newborn conditions were examined. One of the strengths of this study is its large sample size; these analyses were carried out for 717 cocaine-exposed infants and 7442 infants not exposed to cocaine. Cocaine-exposed infants were about 1.2 weeks younger, weighed 536 grams less, measured 2.6 cm shorter, and had head circumference 1.5 cm smaller than nonexposed infants. Results did not confirm previous reports in the literature of abnormal anatomic outcomes. Central and autonomic nervous system symptoms were more frequent in the exposed group (i.e., jittery/tremors, high-pitched cry, excessive suck, hyperalertness, and autonomic instability); they were usually transient. No differences were detected in organ systems by ultrasound examination. Exposed infants had more infections, including hepatitis, syphilis, and HIV. Exposed infants were also less often breastfed, had more child protective services referrals, and were more often not living with their biological mother. Bauer, C.R., Langer, J.C., Shankaran, S., et al. Acute Neonatal Effects of Cocaine Exposure During Pregnancy. Archives of Pediatrics and Adolescent Medicine, 159, pp. 824-834, 2005.

Anthropometric and Dysmorphologic Assessments in 6-Year-Old Children

Anthropometric and dysmorphologic assessments were carried out for 154 6-year-old children prenatally-exposed to cocaine (PCE) and 131 high-risk controls of similar race and social class. Dose-response relationships were observed for adjusted mean height z scores and for weight-for-height z scores, with higher cocaine exposure associated with lower height and lower weight for height. Severity of marijuana use also predicted lower height for age but greater weight for height. Higher average alcohol exposure throughout pregnancy and 3rd trimester predicted lower head circumference and weight z scores, respectively. After controlling for covariates, higher average prenatal cigarette exposure predicted higher incidence of cranial facial abnormalities. First trimester alcohol exposure predicted greater rates of ear abnormalities and third trimester marijuana exposure predicted greater rates of chest and head shape abnormalities. There was not an increased rate of minor anomalies among the PCE cohort, nor was a consistent phenotype identified, leading the authors to conclude that prenatal cocaine exposure is negatively related to specific growth outcomes, including standardized height and weight-for-height, but is not associated with a systematic pattern of structural abnormalities. The dysmorphologic examination utilized a standardized checklist of presence or absence of 271 common dysmorphic characteristics. The authors discuss limitations of the study in detail, such as implications for generalizability as a result of exclusion of children with birth defects (including suspected or diagnosed fetal alcohol syndrome) prior to recruitment. Minnes, S., Robin, N.H., Alt, A.A., et al. Dysmorphic and Anthropometric Outcomes in 6-Year-Old Prenatally Cocaine-Exposed Children. Neurotoxicology and Teratology, 28, pp. 28-38, 2006.

Prenatal Marijuana Exposure Relative to Visuospatial Working Memory and Neural Activity in Young Adults

From their longitudinal cohort study of the long-term sequelae of prenatal marijuana exposure, Dr. Peter Fried and colleagues have reported on visuospatial working memory performance and neural activity in 18-22 year-old young adults followed since birth. Given the longitudinal nature of the data collection, detailed information is available in many areas, including prenatal drug history, detailed cognitive/behavioral performance from infancy to young adulthood, and current and past drug usage. Thirty-one participants (16 prenatally-exposed to marijuana and 15 prenatally nonexposed to marijuana) performed a visuospatial 2-back task while neural activity was imaged with functional magnetic resonance imaging (fMRI). No significant task performance differences were observed when comparing controls versus exposed participants. However, multiple regression analyses (including controls with no exposure) revealed that as the amount of prenatal marijuana exposure increased, there was significantly more neural activity in the left inferior and middle frontal gyri, left parahippocampal gyrus, left middle occipital gyrus and left cerebellum. There was also significantly less activity in right inferior and middle frontal gyri. Included among the factors controlled in the analyses was current drug use. The authors interpret the results to suggest that prenatal marijuana exposure alters neural functioning during visuospatial working memory processing in young adulthood. Smith, A.M., Fried, P.A., Hogan, M.J. and Cameron, I. Effects of Prenatal Marijuana on Visuospatial Working Memory: An fMRI Study in Young Adults. Neurotoxicology and Teratology, 28, pp. 286-295, 2006.

Prenatal Exposure to Substances of Abuse in Children Residing in Russian Orphanages

Over 600,000 children reside in institutional care in Russia, most of them in baby homes and orphanages. The actual prevalence of fetal alcohol spectrum disorders (FASD) and exposure to drugs of abuse among these children is unknown. In this study, a team of researchers from Boston and the Murmansk Region of Russia, led by Dr. Laurie Miller from Tufts-New England Medical Center conducted a systematic survey of phenotypic features associated with prenatal alcohol exposure among institutionalized Russian children and related these findings to their growth, development, medical, and social histories. Phenotypic screening was conducted for all 234 children residing in three baby homes in the Murmansk region of Russia (mean age 21+12.6 months). These baby homes care not only for orphaned children but also abandoned and relinquished children and children whose parents' rights were terminated. Phenotypic expression scores were devised based on facial dysmorphology and other readily observable physical findings. Growth measurements from birth, time of placement in the baby home, and at present were analyzed. In addition, the charts of 64% of the children were randomly selected for retrospective review. Information collected included maternal, medical, developmental, and social histories. Thirteen percent of children had facial phenotype scores highly compatible with prenatal alcohol exposure and 45% had intermediate facial phenotype scores. These scores correlated with maternal gravidity and age. At least 40% of mothers in whom history was available ingested alcohol during pregnancy; some also used illicit drugs and tobacco. Z scores for growth measurements corresponded to phenotypic score, as did the degree of developmental delay. Children with no or mild delay had significantly lower phenotypic scores than those with moderate or severe delay (p = 0.04); more than 70% of children with high phenotypic scores were moderately or severely delayed. More than half of residents of the baby homes in Murmansk, Russia, have intermediate (45%) or high (13%) phenotypic expression scores suggesting prenatal exposure to alcohol. Despite good physical care, stable daily routine, availability of well-trained specialists, and access to medical care, these vulnerable children show significant growth and developmental delays compared with their institutionalized peers. Miller, L.C., Chan, W., Litvinova, A., Rubin, A., Comfort, K., Tirella, L., Cermak, S., Morse, B., Kovalev, I., and Boston-Murmansk Orphanage Research Team. Fetal Alcohol Spectrum Disorders in Children Residing in Russian Orphanages: A Phenotypic Survey. Alcohol: Clinical and Experimental Research, 30 (3), pp. 531-538, 2006.

Testing for Fetal Exposure to Illicit Drugs Using Umbilical Cord Tissue

This study investigated the feasibility of using umbilical cord tissue as a means of assessing fetal drug exposure. Comparisons were made for paired specimens of meconium and umbilical cord tissue from 118 pregnancies with high suspicion of illicit drug use by the mothers. Each specimen was tested for amphetamines, opiates, cocaine, cannabinoids, and phencyclidine using a screening assay, with confirmation assessment carried out using gas chromatography/mass spectrometry (GC/MS). The agreement of drug screening results between umbilical cord and meconium was above 90% for all drugs tested. Agreement was 96.6% for amphetamines, 94.9% for opiates, 99.2% for cocaine, and 90.7% for cannabinoids (no PCP-positive samples were detected). Using meconium as the standard, umbilical cord screening sensitivity ranged from 75 to 95.2% and specificity from 91.2 to 100%. The investigators conclude that umbilical cord tissue performed as well as meconium, and that cord tissue may have some practical advantages over meconium. This research group is continuing its investigations into testing of umbilical cord tissue. Montgomery, D., Plate, C., Alder, S.C., Jones, M., Jones, J., and Christensen, R.D. Testing for Fetal Exposure to Illicit Drugs Using Umbilical Cord Tissue vs. Mecomium. Journal of Perinatology, 26, pp. 11-14, 2006.

Caregiver Substance Abuse Associated with Violence Exposure among Young Urban Children

Dr. Delaney-Black and her colleagues at Wayne State University examined the relative importance of caregiver substance abuse as a correlate of child-reported exposure to violence in this study of 407 female African-American primary caregivers and their children 6 to 7 years of age. The association between child report of violence and exposure to substance abuse by others (both within and outside the home) was considered after controlling for variance accounted for by child characteristics, caregiver characteristics, home environment, and neighborhood environment (including neighborhood crime). Caregiver alcohol abuse, children's witnessing of drug use in the home, and children's witnessing of drug deals all explained significant additional variance in violence exposure. These findings suggest that for early elementary-age children, meaningful prevention of violence exposure may be possible via addressing their exposure to substance abuse in their home and community. Ondersma, S.J., Delaney-Black, V., Covington, C.Y., Nordstrom, B. and Sokol, R.J. The Association between Caregiver Substance Abuse and Self-Reported Violence Exposure among Young Urban Children. Journal of Traumatic Stress, 19 (1), pp. 107-118, 2006.

Maternal Acceptance Moderates Relationship Between Community Violence Exposure and Child Functioning

Children in the United States are exposed to considerable community violence that has been linked to child functioning, however, not all those exposed experience negative outcomes. Dr. Delaney-Black and her colleagues examined the potential buffering or moderating role of maternal acceptance in the relationship between child-reported community violence exposure (reports of witnessing and being a victim of community violence) and internalizing and externalizing problems. In a sample of 268 urban African American first graders community violence exposure was significantly related to symptoms of post-traumatic stress, but did not correlate with either internalizing or externalizing problems for all children, after control for demographics, maternal mental health, and general life stress. However, children's perceptions of maternal acceptance moderated the relationship between violence exposure and internalizing and externalizing problems that included being withdrawn, anxious-depressed, and demonstrating delinquent behavior. Children with the lowest levels of self-reported maternal acceptance were most impacted by community violence. In this sample of urban first graders, low levels of maternal acceptance placed children at greater risk for adverse outcomes associated with community violence exposure compared to moderate and high levels of maternal acceptance. Bailey, B.N., Hannigan, J.H., Delaney-Black, V., Covington, C.Y., Covington, C.Y. and Sokol, R.J. The Role of Maternal Acceptance in the Relation between Community Violence Exposure and Child Functioning. Journal of Abnormal Child Psychology, pp. 1-14, February 9, 2006 [Epub ahead of print].

Maternal Behavior among Drug Using Mothers

In this report, Dr. Rina Eiden and her colleagues examined the association between maternal cocaine use and maternal behavior in an infant feeding context. The investigators also tested a conceptual model predicting maternal insensitivity during mother-infant interactions. The analyses involved 130 mother-infant dyads (68 cocaine-exposed and 62 noncocaine-exposed) recruited after birth and assessed at 4-8 weeks of infant age. Results indicated that when the effects of prenatal cocaine use were examined in the context of polydrug use, maternal psychopathology, maternal childhood history, and infant birth weight, only postnatal cocaine use and maternal depression/anxiety were unique predictors of maternal insensitivity during the mother-infant interactions. Eiden, R.D., Stevens, A., Schuetze, P. and Dombkowski, L.E. A Conceptual Model for Maternal Behavior Among Polydrug Cocaine-Using Mothers: The Role of Postnatal Cocaine Use and Maternal Depression. Psychology of Addictive Behaviors, 20, pp. 1-10, 2006.

Genomic Screen for Loci Associated with Tobacco Usage in Native American Population

The prevalence of tobacco usage in Native American adults and adolescents is higher than any other racial or ethnic group, yet biological risk and protective factors underlying tobacco use in this ethnic group remain unknown. A genome scan for loci associated with tobacco use phenotypes was performed with data collected from a community sample of Mission Indians residing in Southwest California. This study used a structured diagnostic interview to define two tobacco use phenotypes: 1) any regular tobacco usage (smoked daily for one month or more) and 2) persistent tobacco usage (smoked at least 10 cigarettes a day for more than one year). Heritability was determined and a linkage analysis was performed, using genotypes for a panel 791 microsatellite polymorphisms, for the two phenotypes using variance component methods implemented in SOLAR. Analyses of multipoint variance component log of the odds (LOD) scores for the two tobacco use phenotypes revealed two scores that exceeded 2.0 for the regular use phenotype: one on chromosomes 6 and one on 8. Four other loci on chromosomes 1,7,13 and 22 were found with LOD scores between 1.0 and 1.5. Two loci of interest were found on chromosomes 1 and 4 for the persistent use phenotype with LOD scores between 1.3-1.5. Bivariate linkage analysis was conducted at the site on chromosome 4 for persistent tobacco use and an alcohol drinking severity phenotype previously identified at this site. The maximum LOD score for the bivariate analysis for the region was 3.4; however, there was insufficient power to exclude coincident linkage. While results do not provide evidence for linkage to specific chromosomal regions these results do identify regions of interest in the genome in this Mission Indian population for tobacco usage, some of which were identified in previous genome scans of non-native populations. Additionally, these data lend support for the hypothesis that cigarette smoking, alcohol dependence and other consumptive behaviors may share some common risk and/or protective factors in this Mission Indian population. Ehlers, C.L. and Wilhelmsen, K.C. Genomic Screen for Loci Associated with Tobacco Usage in Mission Indians. BMC Medical Genetics, 7(9), 2006.

Gender Differences in the Prediction of Condom Use Among Incarcerated Juvenile Offenders

Dr. Angela Robertson and her colleagues at Mississippi State University examined the predictive value of the Information-Motivation-Behavioral Skills (IMB) model of HIV prevention for sexually active juvenile offenders at risk for substance abuse and explored gender differences in IMB model constructs for condom-protected vaginal intercourse. Self-report measures of HIV/AIDS knowledge, pro-condom peer influence, risk perception, condom attitudes, condom use self-efficacy, frequency of vaginal intercourse, and frequency of condom-protected vaginal intercourse were collected from predominantly African-American detainees 13-18 years of age. Analysis consisted of structural equation models for the combined sample (N = 523) and for separate gender groups (328 males and 195 females). In the combined model, condom use was significantly predicted by male gender, peer influence, positive condom attitudes, and condom self-efficacy. In separate gender analyses, condom use among adolescent males was predicted by peer influence (modestly) and by positive condom attitudes, whereas condom use among females was predicted by peer influence, self-efficacy, and condom attitudes. Compared with males, females reported significantly greater knowledge, less peer influence, higher perceived risk for infection, more positive condom attitudes, and more self-efficacy, but they reported less condom use. The authors conclude that females may find it difficult to use condoms consistently despite their awareness of their efficacy. Power imbalances or other dynamics operating in their relationships with males need further exploration. Gender differences in the relationship between condom self-efficacy and condom use were masked in the analysis of the total sample, indicating the value of testing theories of HIV prevention separately by gender. Robertson, A.A., Stein, J.A., and Baird-Thomas, C. Gender Differences in the Prediction of Condom Use among Incarcerated Juvenile Offenders: Testing the Information-Motivation-Behavior Skills (IMB) Model. Journal of Adolescent Health, 38 (1), pp. 18-25, 2006.

HIV and HCV Testing for Young Injection Drug Users in Rhode Island

Young injection drug users (IDU) are at risk for both human immunonodeficiency virus (HIV) and Hepatitis C infections (HCV). Rates of HIV testing have been widely documented, but limited information exists regarding HCV screening rates. Dr. David Pugatch and colleagues in Rhode Island recruited 86 IDUs 18-25 years of age from drug detoxification programs and street outreach to examine rates of HIV and HCV testing. Forty-nine percent of participants had been tested for HIV and HCV, 38.4% for HIV only, 2.3% for HCV only and 10.5% had not been tested for either HIV or HCV. Participants were more likely to have been tested for HIV than for HCV (87.2% vs. 51.2%, p < .001). Participants recruited through street outreach were more likely to have been tested for HCV than those recruited from drug detoxification programs (64.2% vs. 30.3%, p = .002). Results from this study suggest that young injectors may be under-screened for HCV. Pugatch, D., Anderson, B.J., O'Connell, J.V., Elson, L.C. and Stein, M.D., HIV and HCV Testing for Young Drug Users in Rhode Island. J of Adolescent Health, 38(3), pp. 302-304, 2006.

Neuropsychological Predictors of BOLD Response during a Spatial Working Memory Task in Adolescents: What Can Performance Tell Us About fMRI Response Patterns?

Dr. Susan Tapert and her colleagues at the University of California, San Diego explored the relationship between neuropsychological test performance and fMRI activation on a spatial working memory task in 49 typically developing adolescents. They found that neuropsychological performance negatively predicted fMRI activation, suggesting that those adolescents with better neuropsychological abilities needed to recruit fewer neural resources to perform the task. Nagel, B.J., Barlett, V.C., Schweisburg, A.D. and Tapert, S.F. J. Clin. Exp. Neuropsychol. 27(7), pp. 823-839, 2005.

Components of the Cerebellar Vermis Mediate Cocaine's Persisting and Acute Effects

The dopamine transporter (DAT) is thought to play a critical role in mediating the reinforcing and subjective effects of cocaine. It has been known for many years that the affinity of drugs for the DAT is positively correlated with their capacities to maintain self-administration behavior in animals. The knowledge that the primate cerebellar vermis (lobules II-III and VIII-IX) was reported to contain axonal dopamine transporter immunoreactivity (DAT-IR), and that this region has connections to midbrain dopaminergic cell body regions led a team of researchers at McLean Hospital in Boston to 1) apply BOLD-fMRI technology to determine whether cocaine-related cues activated DAT-IR-enriched vermis regions in cocaine abusers and 2) perform PET imaging in healthy subjects to determine whether the DAT-selective ligand [11C]altropane accumulated in those vermis regions. They found that cocaine-related cues selectively induced BOLD activation in lobules II-III and VIII-IX in cocaine users, and, at early time points after ligand administration, appreciable [11C]altropane accumulation was observed in lobules VIII-IX, possibly indicating DAT presence in this region. These findings, when combined with the established roles for the vermis as a locus of sensorimotor integration and motor planning, and findings of increased vermis activation in substance abusers during reward-related and other cognitive tasks, led the McLean team to propose that the vermis be considered one of the structures involved in cocaine- and other incentive-related behaviors. Anderson, C.M., Maas, L.C., Frederick, B. deB., Bendor, J. T., Spencer, T. J., Livni, E., Lukas, S.E., Fischman, A.J., Madras, B.K., Renshaw, P.F. and Kaufman, M.J. Cerebellar Vermis Involvement in Cocaine-Related Behaviors. Neuropsychopharmacology, advance online publication, pp. 1-9, October, 12 2005.

Visuospatial Memory Deficits Emerging During Nicotine Withdrawal in Adolescents with Prenatal Exposure to Active Maternal Smoking

Preclinical (animal) studies have previously shown that the effects of nicotine withdrawal are more pronounced in adolescents that were exposed to nicotine prenatally than in those that were exposed only in adolescence. In this study, Dr. Leslie Jacobsen and her colleagues examined visuospatial and verbal memory in 35 adolescent tobacco smokers with prenatal exposure to nicotine and 26 adolescent smokers with no prenatal exposure. They found that adolescents with prenatal exposure had greater deficits in visuospatial memory than adolescent smokers that had not been exposed to nicotine during gestation and that these deficits were accompanied by altered activation patters in the hippocampus bilaterally and the left parahippocampal gyrus. Jacobsen, L.K., Slotkin, T.A., Westerveld, M., Mencl, W.E. and Pugh, K.R. Neuropsychopharmacology. 2005.

A Shift from Diffuse to Focal Cortical Activity with Development

Dr. B.J. Casey and colleagues used fMRI to investigate the potential changes that occur in neural processing associated with performing a cognitive control task with developmental time. In this combined longitudinal and cross-sectional study, they found that performance on the task did not change between the ages of 9 and 11 although reaction time did. In terms of brain activation patterns, there was a decrease in diffuse activation in the dorsolateral prefrontal cortex and an increase in focal activation in ventral prefrontal regions, suggesting a refinement in the neural circuitry needed to perform the task. Durston, S., Davidson, M.C., Tottenham, N., Galvan, A., Spicer, J., Fossella, J.A., and Casey, B.J. Developmental Science. 9(1), pp. 1-20, 2006.

Mapping Brain Maturation

Dr. Elizabeth Sowell and her colleagues at the University of California Los Angeles have investigated the regional development of gray and white matter during the development of healthy children using structural MRI. This team of investigators has now extended these studies to structural brain development in early-onset schizophrenia, fetal alcohol syndrome, ADHD, and Williams syndrome. In this paper, Dr. Sowell and colleagues review their findings on brain development in these groups of individuals, comparing differences in the development of specific regions of the brain in the different groups and relating them to the possible cellular changes that underlie them as well as to the cognitive and behavioral changes that occur during childhood and adolescence. Toga, A.W., Thompson, P.M. and Sowell, E.R. Trends in Neuroscience. 29(3), pp. 148-159, 2006.


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