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Director's Report to the National Advisory Council on Drug Abuse - May, 2004

Research Findings - Treatment Research and Development

High Levels of Prize Reinforcement makes a Difference for Treating Cocaine Users

Dr. Nancy Petry and colleagues at University of Connecticut Health Center and Yale University randomly assigned cocaine users to three levels of a motivational incentive intervention. In the first condition participants received standard counseling for drug abuse. In the second condition participants received standard counseling plus they could earn up to $80 worth of prizes through random drawings. In the third condition participants could earn up to $240 worth of prizes through random prize drawings. Prize drawing opportunities were contingent upon submitting a cocaine-free urine sample. Individuals in the high value ($240) condition achieved more abstinence from cocaine than those in the other conditions. Individuals who initiated treatment with negative urinalysis generally remained abstinent regardless of treatment condition assignment. Participants with positive urinalysis were most responsive in the high pay condition. These results suggest that relatively low cost motivational incentive programs may be appropriate for use in community treatment programs but that results may be magnitude dependent. Petry, N.M., Tedford, J., Austin, M., Nich, C., Carroll, K.M., Rounsaville, B.J., Addiction, 99(3), pp, 349-360, March, 2004.

Improvements in Counseling Session Punctuality with Contingency Management during Methadone Treatment

Dr. Charles Schuster at Wayne State University and colleagues conducted two studies to investigate the effectiveness of contingency management techniques in promoting punctual counseling attendance among methadone maintenance patients. In the first study, on-time attendance was reinforced with the chance to draw for prizes ranging in value from 0-$100.00. Those methadone maintenance patients who exhibited poor attendance initially demonstrated a significant positive response during the contingency management intervention phase. In the second study, participants were randomized to either a fixed or random value of voucher reinforcement. There were no differences between either group. Overall the results indicate that targeting poor attendance with contingency management may be effective. This is significant because attendance is consistently linked with abstinence outcomes. Rhodes, G.L., Saules, K.K., Helmus, T.C., Roll, J., Beshears, R.S., Ledgerwood, D.M., Schuster, C.R., Am J Drug Alcohol Abuse, 29 (4) pp, 759-773, 2003.

Pilot Study Shows Integrated Group Therapy May Improve Drug Use Outcomes for Bipolar Substance Dependent Patients

Dr. Roger Weiss and colleagues at McLean Hospital conducted surveys of bipolar patients showing that many initiate substance use because of at least one bipolar disorder symptom and most believe their drug use improves their bipolar symptoms. Among those who believe drug use improves their bipolar disorder symptoms, a new treatment, Integrated Group Therapy in which bipolar and substance dependence symptoms are concurrently treated produced fewer days of drug use. These results are preliminary due to design and sample size limitations. Weiss, R.D., Kolodziej, M., Griffin, M.L., Najavits, L.M., Jacobson, L.M., Greenfield, S.F., J. Affect. Disord, 79 (1-3), pp. 279-283, April 2004.

Smoking Among Female Prisoners: An Ignored Public Health Epidemic

The Mississippi Department of Corrections surveyed 866 female prisoners about tobacco use and interest in a smoking cessation program with a 27-item questionnaire. The majority of female inmates (73.9%) were current tobacco users with a mean of 14.6 cigarettes per day. Approximately 12.5% of current smokers reported a tobacco-related medical problem. Most (60.6%) had made at least one attempt to quit smoking and only 24.5% felt "very confident" that they could quit if they made an attempt. Overall, 64.2% of the smokers reported interest in participating in the smoking cessation program, with heavier smokers (71.4 %) reporting the most interest in enrolling in the program. The high percentage of current tobacco users, high level of interest in smoking cessation, and presence of smoking-related health problems indicate a tremendous public and correctional health problem that is being ignored. Cropsey, K., Eldridge, G.D., and Ladner, T. Addictive Behaviors, 29, pp. 425-431, 2004.

Disulfiram and Cognitive Behavior Therapy Effectively Reduce Cocaine Use

Dr. Kathleen Carroll and colleagues at Yale University evaluated the efficacy of disulfiram in general populations of cocaine users in a randomized placebo-controlled trial. They also compared the effectiveness of two active behavioral therapies, cognitive-behavioral therapy (CBT) and interpersonal psychotherapy (IPT). Participants (n=121) meeting criteria for current cocaine dependence were assigned to receive either disulfiram (250mg/day) plus CBT, disulfiram (250mg/day) plus IPT, placebo plus CBT, or placebo plus IPT. Both behavioral therapies were manual-guided and delivered in individual sessions for 12 weeks. Participants assigned to disulfiram reduced their cocaine use significantly more than those assigned to placebo, and those assigned to CBT reduced their cocaine significantly more than those assigned to IPT (P<.01 for both). Findings were consistent across all study samples (e.g., intention to treat, treatment initiators, and treatment completers). Benefits of disulfiram use and CBT were most pronounced for participants who were not alcohol dependent at baseline or who fully abstained from drinking alcohol during treatment. Thus, disulfiram and CBT are effective therapies for general populations of cocaine-dependent individuals. Further, disulfiram seems to exert a direct effect on cocaine use rather than through reducing concurrent alcohol use. Carroll, K.M., Fenton, L.R., Ball, S.A., Nich, C.N., Frankforter, T.L., Shi, J.S., and Rounsaville, B.J. Arch Gen Psychiatry. 61, pp. 264-272, March 2004.

Changes in the Meaning of Sexual Risk Behaviors Among Gay and Bisexual Male Methamphetamine Abusers Before and After Drug Treatment

This study combined the quantitative and qualitative research methodologies to examine risk behaviors among gay and bisexual male methamphetamine abusers as they entered treatment and at 1-year follow-up evaluations. Findings from the quantitative follow-up data demonstrate that gay and bisexual men reduce sexual risk behaviors and sustain those reductions following substance abuse treatment, and qualitative data reveal the meaning of these behavior changes from the perspective of the participant. At 1-year follow-up evaluations, associated behaviors of methamphetamine use and sexual risk behaviors were lessened. Although condom use decreased slightly, participants reported fewer anonymous sexual partners, reductions in episodes of both receptive and insertive anal intercourse, and an increased sense of responsibility to disclose their HIV status. This study further demonstrates the value of coupling quantitative and qualitative data in understanding the meaning behind reductions in high-risk behaviors. Reback, C.J., Larkings, S., and Shoptaw, S. AIDS and Behavior, 8, pp. 87-98, 2004.

Targeting HIV-Related Outcomes with Intravenous Drug Users Maintained on Methadone: A Randomized Clinical Trial of a Harm Reduction Group Therapy

In this study, investigators from Yale University evaluated the efficacy of a 12-session harm reduction group intervention for injection drug users, based on the Information-Motivation-Behavioral skills model of behavior change, that focused on reducing both drug and sex risk. Two hundred and twenty patients entering an MMP were randomized to receive either standard care (SC)-2 hours of counseling per month and a single-session risk reduction intervention-or SC plus the harm reduction group (HRG). Results showed that during treatment, patients receiving HRG were most likely to be abstinent from cocaine and to report fewer unsafe sexual practices. Post-treatment, HRG patients scored higher on a sexual risk quiz and reported increased self-efficacy in high-risk sexual situations. Enhancing methadone maintenance with a weekly harm reduction group treatment was somewhat more expensive but can bring positive changes in behaviors and attitudes that are associated with the transmission of HIV. Avants, K., Margolin, A., Usubiaga, M., and Doebrick, C. Journal of Substance Abuse Treatment, 26, pp. 67-78, 2004.

Psychiatric Co-morbidity Among Adolescent Substance Abusers Effects Response to Behavioral Treatment

Dr. Cindy Rowe of the University of Miami and colleagues continue their work to clarify the connection between psychiatric co-morbidity and treatment of adolescent substance abuse. Building on previous work highlighting the importance of both externalizing and internalizing disorders among adolescent substance abusers, this newest study examined whether adolescents with different psychiatric co-morbidities differed in clinical presentation and treatment response. Among 182 adolescent drug abusers in a randomized clinical trial comparing family and individual cognitive-behavioral therapy, more severe co-morbidity was associated with greater family dysfunction and being female and younger at intake. Regarding treatment response, adolescents with mixed externalizing and internalizing co-morbidities initially responded to treatment but returned to intake levels of substance use by 1 year post-discharge. Rowe, C.L., Liddle, H.A., Greenbaum, P.E. and Henderson, C. Impact of Psychiatric Comorbidity on Treatment Outcomes of Adolescent Drug Abusers. Journal of Substance Abuse Treatment, 26, pp. 1-12, 2004.

Mothers Entering Drug Treatment Appear to be Successful at Maintaining or Re-establishing Co-residency with their Children

Dr. Danica Knight and colleagues at Texas Christian University conducted a study of the degree to which mothers who enter residential drug treatment are successful in maintaining or re-establishing their role as parents during the course of treatment. The sample included 152 female clients admitted to a residential drug treatment program for women with dependent children. Among the 152 women in the study, there was a significant increase in child co-residency from admission to follow-up. Women who entered treatment with all children, or who were reunited with children previously in others' care at admission, were over five times more likely to co-reside with all children at follow-up. At follow-up, mothers who reported complete co-residence were more likely to be 30 years old or younger, live independently, and have fewer than two parenting challenges. This study documents the status of child co-residence prior to, during, and following treatment, which may have implications for the practice of providing child care and family residency options in drug abuse treatment. Knight, D.K. and Wallace, G. Where Are the Children? An Examination of Children's Living Arrangements when Mothers Enter Residential Drug Treatment. Journal of Drug Issues, 33(2), pp. 305-324, 2003.

HIV-Risk Behaviors Appear to be Connected to Violence and Clinical Depression Among Some Female Drug Users

Drs. Johnson, Cunningham-Williams, and Cottler recently published a paper describing the connection between sexual HIV-risk behaviors and exposure to violence and/or depression among 420 African-American out-of-treatment female drug users. Sexual risk behaviors were compared for women in mutually exclusive groups based on exposure to violence and the presence of clinical depression. Results showed that women with a history of sexually transmitted diseases were more likely to experience violence and depression, both alone and jointly. Women who had two or more sexual partners in the last 30 days and women who had an early onset of alcohol use were at an increased risk for having drug use, violence and depression. Never being married was a protective factor for drug use, violence and depression. As expected, more risk factors were found among women who had the full tripartite than among women with one or two of the factors. Johnson, S., Cunningham-Williams, R.M. and Cottler, L.B. A Tripartite of HIV-risk for African-American Women: The Intersection of Drug Use, Violence, and Depression. Drug and Alcohol Dependence, 70(2), pp. 169-175, 2003.

There May be Variations in the Progression from Abuse to Dependence for Different Substances

Drs. Ridenour and colleagues conducted a study meant to clarify the degree to which progression from abuse to dependence for marijuana, cocaine, and opiates mirrors the progression for alcohol. Re-analyzing data from the DSM-IV Substance Use Disorders Work Group (n = 1226) using McNemar's chi2, configural frequency analyses and survival analyses, these investigators found variations in progression from abuse to dependence for different substances. While for all substances, lifetime dependence in the absence of lifetime abuse was rare, results were consistent with a progression occurring for alcohol and cannabis, but not for cocaine and opiates. For cocaine users, abuse and dependence occurred in the same year for 66% of the cocaine users who experienced both disorders (57% of users with any cocaine disorder). For opiate users, abuse and dependence occurred in the same year for 65% who experienced both disorders (46% of users with any opiate disorder). Ridenour, T.A., Cottler, L.B., Compton, W. M., Spitznagel, E.L. and Cunningham-Williams R.M. Is There a Progression from Abuse Disorders to Dependence Disorders? Addiction, 98, pp. 635-644, 2003.

The Minnesota Multiphasic Personality Inventory-Adolescent Version (MMPI-A) Detected Under-Reporting of Teens' Substance Abuse

Drs. Lynda Stein and colleagues continue to tackle the difficult issue of accurate assessment of drug use among adolescents. Incarcerated, substance abusing (n = 67) and non-substance abusing (n = 59) adolescents completed the MMPI-A under two different sets of instructions. Assessments completed according to standard instructions correctly classified 60 - 85% of substance abusers. Assessments completed when adolescents were instructed to "fake good" produced lower scores on substance abuse overall, although the Lie scale detected over 75% of the under-reported profiles. Additionally, when used in combination with the best substance abuse scale, the Lie scale detected 82% of substance abusers. Given that accurate assessment is vital to effective treatment and treatment research, this study suggests that the MMPI-A may be a tremendously useful tool in adolescent substance abuse research. Stein, L.A.R.and Graham, J.R. Ability of Substance Abusers to Escape Detection on the MMPI-A in a Juvenile Correctional Facility. Paper presented at the 38th Annual Symposium on Recent Developments in the Use of the MMPI (MMPI-2 and MMPI-A), Minneapolis, MN, June 2003.

Developing a Brief Version of the Marijuana Effect Expectancy Questionnaire (MEEQ)

Drs. Griffin and other NIDA-funded colleagues collaborated on the development of a brief version of the 70-item MEEQ for use with incarcerated teens. A single item was generated to represent each of the 6 scales of the original instrument. A total of 124 incarcerated teens completed the brief version of the instrument (MEEQ-B). Psychometric analyses suggested that the MEEQ-B had two factors: a positive expectancies factor accounting for 29% of the variance in responses, and a negative expectancies factor accounting for 23% of the variance in responses. Further, the internal reliabilities of each of these factor-scales were 61% and 38%, respectively. The investigators conclude that researchers should continue to use the longer version of the instrument, but that the brief version may be useful as a clinical tool to generate discussion about marijuana use expectancies. S. Griffin, L. Stein, S. Colby, N. Barnett, P. Monti, and C. Golembeske. Validation of a Brief Version of the Marijuana Effect Expectancy Questionnaire. Poster presented at the 8th Annual Research Symposium on Mental Health Sciences, Brown University, Providence, RI, March 2004. Assessment of Substance Use and Treatment Implications for Incarcerated Teens Dr. Lynda Stein of Brown University and colleagues assessed the substance use patterns, and other factors with potential treatment implications, of incarcerated teens. Among the 82 teens participating in the investigators' randomized treatment outcome study, there were high rates of alcohol, marijuana, and nicotine use, and high rates of depressive symptoms. Regarding drug use expectancies, overall, teens do not expect alcohol to have very much impact upon them, aside from "liquid courage," and teens felt confident in their ability to resist alcohol. However, teens expected marijuana to have a positive impact and very little negative impact on them, but they were not confident in their ability to resist marijuana use. Many teens appeared to be interested in changing their use of marijuana and/or alcohol. Stein, L.A.R., Colby, S., Barnett, N., Monti, P., Lebeau-Craven, R. & Golembeske, C. Assessment of Substance Use and Treatment Implications for Incarcerated Teens. Proceedings from the 65th Annual Meeting of the College on Problems of Drug Dependence, Bal Harbour, FL., June 2003.

Improving Parenting and Drug Use Among Drug-Dependent Mothers

Dr. Suchman of Yale University and colleagues developed and tested a 12-week parenting intervention for drug-dependent mothers. The investigators compared 20 mothers receiving Emotionally-Responsive Parenting (ERP) to a historical control group of 23 mothers that received standard treatment. Mothers receiving ERP mothers had better weekly attendance, and completion rates, and were more compliant with clinical advice. At post-treatment, 83% of women receiving ERP vs. 70% of comparison mothers were abstinent, but this difference was non-significant. Importantly, ERP mothers' capacity to acknowledge their own and their children's cognitive and affective states also improved significantly. This pilot study suggests that a parenting intervention focused on increasing parents' emotional availability to children can be effective in contributing both to abstinence and to emotional responsiveness. Suchman, N. E., Altomare, M., Moller, F., Slade, A., & Mayes, L. Emotionally Responsive Parenting: A New Parenting Intervention for Drug Dependent Mothers. Invited poster presentation, College on Problems of Drug Dependence Annual Meeting, Bal Harbour, FL, June 2003.

Social Relationships Appear to be Integral to Successful Treatment for Women in Drug Abuse Treatment

Dr. Danica Knight and colleagues at Texas Christian University presented a paper on the role of social relationships for women in drug abuse treatment. Findings documented significant associations between interpersonal relationship measures and key treatment process indicators among 152 women in long-term residential drug abuse treatment. For example, clients who were motivated at treatment entry were more likely to develop healthy relationships with fellow clients during treatment, and those who reported healthier family relationships were more likely to complete treatment requirements. Relationships with peers were important in the development of counselor rapport, and in perceived support for treatment. Relationships with family members impacted psychosocial functioning and completion, and relationships with counselors facilitated compliance, longer retention, and completion. This study provides additional evidence for the importance of building and maintaining positive social networks during the course of treatment. Knight, D.K., Joe, G.W, and Simpson, D.D. Is the Treatment Process Different for Women in Residential Treatment? Presented at the annual meeting of the American Psychological Association, Toronto, Canada, August 2003.

Genetic and Environmental Influences on Substance Initiation, Use, and Problem Use in Adolescents

Dr. Thomas Crowley and colleagues at the University of Colorado conducted a sibling/twin/adoption study of substance initiation, use, and problem use, estimating the relative contribution of genetic and environmental influences on these phenotypes in adolescents. The participants were 345 monozygotic twin pairs, 337 dizygotic twin pairs, 306 biological sibling pairs, and 74 adoptive sibling pairs. Results showed that there were moderate to substantial genetic influences, with the exception of alcohol use and any drug use, and modest to moderate shared environmental influences on substance initiation, use, and problem use. For alcohol and any drug, heritability was higher and the magnitude of shared environmental influences was lower for problem use than for initiation or use. Environmental influences shared only by twin pairs had a significant effect on tobacco initiation, alcohol use, and any drug use. For tobacco use, tobacco problem use, and marijuana initiation, heritability was higher and the magnitude of shared environmental influences was lower in female than in male adolescents. There was no evidence for sex-specific genetic or shared environmental influences on any variable. The moderate to substantial heritabilities found for adolescents in the present study are comparable to those found in twin studies of adult substance use and substance use disorders. The finding that problem use is more heritable than initiation and use is also consistent with the results of adult twin studies. The significance of environmental influences shared only by twin pairs on tobacco initiation, alcohol use, and any drug use suggests the influences of peers, accessibility of substances, and sibling interaction. Soo Hyun Rhee, S.H, Hewitt, J.K, Young, S.E., Corley, R.P., Crowley, T.J. and Stallings, M.C. Archives of General Psychiatry, 60, pp. 1256-1264, 2003.

Affect Differences Between Non-Abusers of Drugs Who Made a Preferred (Blind) Selection of Amphetamine Over Placebo

Dr. Frances Gabbay at the Uniformed Services University of Health Sciences (USUHS) compared a group of self-selected choosers of amphetamine over placebo to those who avoided amphetamine on a series of questions assessing subjective feelings. While taking amphetamine (blinded), choosers had increased ratings on energy, cognitive efficiency and well being, with reduction of fatigue and sedation. Non-choosers reported none of these effects though had an increase in dysphoria. Under placebo the ratings decrease while sedation ratings increased. The fact that these groups react to amphetamine differently (without knowing what it is they are ingesting) could be related to important differences in risk for drug use. Gabbay, F.H. Experimental and Clinical Psychopharmacology, 11(1), pp. 91-101, 2003.

Reduced Serotonin Uptake Sites among Cocaine Patients: Negative Correlation with Aggression, Impulsivity, and Sensation Seeking

Dr. Ashwin Patkar and associates at Thomas Jefferson University assessed binding (Bmax) values of paroxetine in platelets-a measure of serotonin uptake sites-in treatment-seeking male and female cocaine dependent patients. While Kd between subjects and controls were not different, Bmax was significantly (p < .001) lower in the patients while higher were several measures of aggression (Buss-Durkee battery), depression (Beck Depression Inventory), impulsivity (Barrett) and sensation seeking. The results may have limited generalizability since the subjects were all African-American. There was no difference in craving. These results suggest that the densities of serotonin uptake sites may be reduced among cocaine abusers and related to impulsive-aggressive behavioral dimensions. Patkar, A.A., Gottheil, E., Berretini, W.H., Hill, K.P., Thornton, C.C. and Weinstein, S.P. The American Journal of Addictions, 12, pp. 432-447, 2003.

Sex Differences in rCBF Induced by Cue-induced Craving

Using verbal scripts to induce craving in patients with cocaine dependence (most, but not all who were in treatment), Kilts and colleagues at Emory University found, using PET, rCBF increases in the superior temporal gyrus, dorsal anterior and posterior cingulate cortex, nucleus accumbens area, and the central sulcus. However, in comparison to an identical study in men, women showed less activation of the amygdala, insula, orbitofrontal cortex, and ventral cingulate cortex but greater activation of the central sulcus and widely distributed frontal cortical areas. These findings suggest sex differences in the functional anatomy associated with cue-induced cocaine craving. Whether these differences are physiological or perceptual or both cannot be determined but once characterized may have implications for treatment. Kilts, C.D., Gross, R.E., Ely, T.D. and Drexler, K.P.G. American Journal of Psychiatry, 161(2), pp. 233-241, 2004.

Linkage Evidence for Two Chromosomal Regions Associated with Substance Dependence Vulnerability

Drs. Stallings, Crowley, and collaborators found a location on chromosome 3 (3q24-25, near markers D3S1279 and D3S1614) and chromosome 9 (9q34, near marker D9S1838) that had LOD scores above 1.0 suggesting possible linkage and providing a basis for a replication study. The measure "phenotype" used was determined empirically-having the greatest heritability as determined in their twin and community samples-and based on responses to diagnostic interviews. Specifically, it was the average number of symptoms of substance use over all substances (i.e., total number of symptom counts for all substances divided by the number of substances used). These results were obtained on adolescents and match findings reported by others on adults. Stallings, M.C., Corley, R.P., Hewitt, J.K., Krauter, K.S. Lessem, J.M. Mikulich, S.K., Rhee, S.H., Smolen, A., Young, S.E. and Crowley, T.J. Drug and Alcohol Dependence, 70, pp. 295-307, 2003.

Linkage Evidence for One Chromosome Region: Suggestive for Several Others for Nicotine Dependence

Dr. Ming D. Li and collaborators analyzed data from the Framingham Heart Study population using number of cigarettes smoked from on time period and a genome scan of 401 markers at an average spacing of 7.5 cM. Significant linkage was found at locus GGAA5C04 &GATA90D07 on chromosome 11 with suggestive loci found on 4, 7, 9, 14, & 17 by one of two methods. Loci on 7, 11, and 17 were found by both methods. Li, M.D., Ma, J.Z., Cheng, R., Dupont, R.T., Williams, N.J., Crews, K.M., Payne, T.J. and Elston, R.C. BMC Genetics, 4(Suppl 1) S103, 2003.

Opiate Addicts Lack Error-Dependent Activation of Rostral Anterior Cingulate

Dr. Steven Forman and colleagues at University of Pittsburgh used functional Magnetic Resonance Imaging (fMRI) to determine whether brain regions involved in error detection, such as the anterior cinglulate cortex, are dysfunctional in substance abusers. Normal individuals performing response suppression tasks activate anterior cingulate cortex with occurrence of false alarm error responses to non-targets. In contrast, methadone maintained opiate addicts exhibited an attenuated anterior cingulate cortex error signal and significantly poorer task performance. In controls but not opiate abusers, the individual level of event-related anterior cingulate cortex activation accompanying false alarm errors positively predicted task performance, particularly sensitivity in discriminating targets from non-targets. These results suggest that the attenuation of error signals in anterior cingulate cortex may play a role in loss of control in addiction and other forms of impulsive behavior. Forman, S.D., Dougherty, G.G., Casey, B.J., Siegle, G.J., Braver, T.S., Barch, D.M., Stenger, V.A., Wick-Hull C., Pisarov L.A. and Lorensen, E. Biological Psychiatry, 55(5), pp. 531-537, 2004.

Prefrontal Responses to Drug Cues: A Neurocognitive Analysis

Dr. Julie Fiez and colleagues at the University of Pittsburgh reviewed neuroimaging studies of cue-elicited craving in the context of a framework drawn from behavioral research indicating that perceived drug use opportunity significantly affects responses to the presentation of drug cues. They report that activation of the prefrontal cortex was consistently found in studies using non-treatment seeking substance abusers. In contrast, prefrontal activation was largely absent in studies using treatment-seeking subjects. Using this framework provides a way to reconcile discrepant findings among brain imaging studies of cue-elicited craving. Wilson, S.J., Sayette, M.A., Fiez, J.A. Nature Neuroscience, 7(3), pp. 211-214, 2004.

Oral D-Amphetamine Causes Prolonged Displacement of [C-11]Raclopride as Measured by PET Source

Dr. Usula Busto and colleagues at the University of Toronto used PET imaging to determine whether orally administered D-amphetamine would inhibit [C-11]raclopride binding to the same extent as intravenously administered D-amphetamine. Twelve healthy human volunteers were scanned at baseline and 2 hrs after D-amphetamine administration (n = 5); at baseline, 2 and 6 hrs post drug (n = 4); or at baseline, 2 and 24 hrs post drug (n = 3). The study found that orally administered D-amphetamine caused a reliable and prolonged [C-11]raclopride displacement, the magnitude of which is similar to that observed after intravenous administration. Orally administered D-amphetamine caused a significant decrease in [C-11]raclopride binding at 2 h (13% +/- 5%). Receptor availability was still decreased at 6 hrs (18% +/- 6%), even though physiological effects of amphetamine had completely returned to baseline. [C-11]Raclopride binding returned to baseline at 24 hrs. The percentage of [C-11]raclopride displacement was not correlated with plasma D-amphetamine concentrations. Cardenas, L., Houle, S., Kapur, S. and Busto, U.E. Synapse, 51(1), pp. 27-31, 2004.

Attributes of Long-term Heavy Cannabis Users: A Case-control Study

Dr. Harrison Pope and colleagues at McLean Hospital examined the attributes of long-term heavy cannabis users. Using a case-control design, they obtained psychological and demographic measures on 108 individuals, age 30-55, who had smoked cannabis a mean of 18,000 times and a minimum of 5,000 times in their lives and compared these heavy users to 72 age-matched control subjects who had smoked at least once, but no more than 50 times in their lives. Although no significant differences between the two groups were found with respect to reported levels of income and education in their families of origin, heavy users reported significantly lower educational attainment (P<0.001) and income (P=0.003) than the controls, even after adjustment for a large number of potentially confounding variables. The majority of heavy users (66-90%) also reported that cannabis had a 'negative effect' on cognition, memory, career, social life, physical health and mental health. Finally, heavy users also reported significantly lower levels of satisfaction than controls on several measures of quality of life. It remains to be determined why heavy cannabis users continue to smoke regularly for years, despite acknowledging these negative effects on their quality of life. Such an understanding may guide the development of strategies to treat cannabis dependence. Gruber, A.J., Pope, H.G., Hudson, J.I. and Yurgelun-Todd, D. Psychological Medicine, 33(8), pp. 1415-1422, 2003.

What Is Odd in the Oddball Task? Prefrontal Cortex Is Activated by Dynamic Changes in Response Strategy

Drs. Scott Huettel and Gregory McCarthy at Duke University used functional Magnetic Resonance Imaging (fMRI) in normal human subjects to determine whether the transient activation in the prefrontal cortex in response to infrequent target stimuli is due to selection of an infrequent response or to changes in response strategy. Subjects viewed a series of circles and squares that required left and right button presses, respectively. On 90% of trials ("standard" trials), the stimuli were presented in the same visual hemifield as the hand of response, but on 10% of trials ("strategy-change" trials) they were presented in the opposite visual hemfield. Behavioral results indicated that subjects developed a position-based response strategy during the standard trials, which was inhibited on the strategy-change trials. Significant activation to the infrequent strategy-change trials was found in the anterior middle frontal gyrus (MFG), the posterior inferior frontal gyrus (IFG) and adjacent insular cortex, and in the anterior cingulate gyrus (ACG). Activity within the MFG and ACG was much greater on error trials than on correct trials, while IFG activity was similar between error and correct trials. These results suggest that the dorsolateral prefrontal cortex (dlPFC) is associated with dynamic changes in the mapping of stimuli to responses (e.g. response strategies), independently of any changes in behavior. These findings provide a basis for interpreting the functional changes in these brain regions observed in substance abusers in brain imaging studies of drug action, craving, and response inhibition deficits. Huettel, S.A.and McCarthy, G. Neuropsychologia, 42(3), pp. 379-386, 2004.

Conformationally-Flexible Benzamide Analogues as Dopamine D-3 and Sigma(2) Receptor Ligands

Dr. Robert Mach and colleagues at Wake Forest University have determined the affinities of a new series of ligands for D2-like dopamine (D-2, D-3 and D-4) receptors using receptor binding assays. One compound was identified that bound with high affinity (Ki value = 2 nM) and moderate selectivity (30-fold) for D-3 compared to D-2 receptors. A number of the compounds also showed high affinity and excellent selectivity for sigma(2) versus sigma(1) receptors. These novel compounds may useful platforms for developing novel PET ligands for imaging D-3 receptors and sigma receptors. Mach, R.H., Huang, Y.S., Freeman, R.A., Wu, L., Vangveravong, S. and Luedtke, R.R. Bioorganic & Medicinal Chemistry Letters, 14(1), pp. 195-202, 2004.

Impaired Decision Making Related to Working Memory Deficits in Individuals with Substance Addictions

Drs. Antoine Bechara of University of Iowa and Eileen Martin of University of Illinois at Chicago examined whether impaired performance of substance abusers on a laboratory test of decision-making is related to impairments in working memory. Decision-making was indexed by the gambling task (GT) paradigm and working memory was indexed using a Delayed Non-Match to Sample task (DNMS). Impaired performance on the Gambling Task was seen in 11% of healthy control participants and 61% of substance abusers. Substance abusers performed significantly lower than controls on the DNMS task, irrespective of whether substance abusers were impaired on the GT, even if the substance abusers were matched with controls who were equally impaired on the GT. Substance abusers were impaired across all delay times on the DNMS task, suggesting the deficit may not lie in working memory per se, but rather in the "executive" processes. The results suggest that there are multiple distinct mechanisms of decision-making and inhibitory control and that substance abusers may be affected in any one or combinations of them. Bechara, A. and Martin, E.M. Neuropsychology, 18(1), pp. 152-162, 2004.

Event-Related Functional Magnetic Resonance Imaging of Reward-Related Brain Circuitry in Children and Adolescents

Dr. Julie Fiez and colleagues at the University of Pittsburgh used functional magnetic resonance imaging to investigate the brain reward systems of normal children and adolescents. Regions and time-courses of reward-related activity were similar to those observed in adults with condition-dependent BOLD changes in the ventral striatum and lateral and medial orbital-frontal cortex. Reward-related activity in these regions exhibited larger responses to positive than to negative feedback. These results provide further a baseline from which to understand the pathophysiology of reward-related disorders, such as substance abuse, in youth. May, J.C., Delgado, M.R., Dahl, R.E., Stenger, V.A., Ryan, N.D., Fiez, J.A. and Carter, C.S., Biological Psychiatry, 55(4), pp. 359-366, 2004.

Trend Detection Via Temporal Difference Model Predicts Inferior Prefrontal Cortex Activation During Acquisition of Advantageous Action Selection

Dr. Martin Paulus and colleagues at the University of California, San Diego used functional magnetic resonance imaging (fMRI) to investigate the role of the inferior prefrontal cortex in detecting changes in the association between an action and an outcome. FMRI scans were conducted on normal subjects while the performed a task based on the common game of Rock Paper Scissors (RPS) that required the development of an advantageous strategy over trials. Activations in the medial frontal gyrus (BA 10) left ventrolateral frontal gyrus (BA 11/47), and left pallidum were significantly higher during trials in which subjects acquired the advantageous action. The time course of individually derived trend detection functions was found to be time-locked to the hemodynamic changes in the inferior frontal gyrus. These findings are consistent with the hypothesis that the inferior prefrontal cortex computes a trend from previously experienced action-outcome sequences based on a value function derived from the temporal difference model. These findings have important implications for the understanding of substance abuse since substance abuse is characterized by an inability to alter drug-taking behavior based on adverse outcome, and since substance abusers have been found to exhibit impairment in activation of the inferior prefrontal cortex. Paulus, M.P., Feinstein, J.S., Tapert, S.F. and Liu, T.T. Neuroimage, 21(2), pp.733-743, 2004.

Artifactual fMRI Group and Condition Differences Driven by Performance Confounds

Drs. Hugh Garavan and Kevin Murphy of the Medical College of Wisconsin and Trinity College examined how differences in task performance across groups could confound functional imaging results. Specifically, the presence of disproportionate numbers of errors in one group may either introduce noise into the signal of interest or confound the signal of interest with an additional signal associated with specific error-related processes. To test this possibility two inhibitory task datasets involving young and aged subjects were analyzed twice using event-related techniques. In one analysis, correct and error response trials were analyzed separately. In the other analysis, error responses were treated as if they were correct. It was found that the activation maps differed considerably, with the inclusion of errors leading to many false positive and false negative activation clusters. These differences were not corrected with an analysis of covariance (ANCOVA) using performance as a covariate. Data simulations that varied the number of errors included in the analyses found that surprisingly few errors could significantly alter activation maps. Consequently, brain-imaging investigations that do not accommodate error contributions to functional signals are at risk of misinterpreting activation patterns. Given that studies have shown that substance abusers may exhibit higher error rates than normal subjects, these findings suggest that brain imaging studies of drug addiction that combine correct and incorrect trials in a single analysis need to be interpreted with caution. Murphy, K. and Garavan, H. Neuroimage, 21(1), pp. 219-228, 2004.

Modulation of Caudate Activity by Action Contingency

Dr. Julie Fiez and colleagues at the University of Pittsburgh used functional Magnetic Resonance Imaging (fMRI) to determine whether human striatal activation is driven solely by the hedonic properties of rewards or whether such activation is reliant on other factors, such as anticipation of upcoming reward or performance of an action to earn a reward. Normal human subjects performed a task during fMRI scans in which monetary gains and losses were displayed either 1) randomly in time, 2) following an anticipatory cue, or 3) following a button press response. Robust and differential activation of the caudate nucleus occurred only when a perception of contingency existed between the button press response and the outcome. This finding suggests that the caudate is involved in reinforcement of action potentially leading to reward, rather than in processing reward per se. Tricomi, E.M., Delgado, M.R. and Fiez, J.A. Neuron, 41(2), pp. 281-292, 2004.

Study Suggests Methamphetamine Withdrawal is Associated with Brain Changes Similar to Those Seen in Depression and Anxiety

Dr. Edythe London and her colleagues at the UCLA, UCI, and NIDA's IRP used positron emission tomography (PET), to compare glucose metabolism in the brains of 17 methamphetamine abusers (MA) who had stopped using the drug 4-7 days before their participation in the study, and 18 non-abusers. The PET scans identified regional brain differences in glucose metabolism. In MA, glucose metabolism was lower in the limbic and paralimbic regions that are linked to depressive disorders, depressed mood, and sadness and higher in brain regions linked to anxiety and drug cravings. The ACG appears dysfunctional in MA abusers compared to healthy subjects. The most robust group difference in rCMRglc was in the infragenual ACG, where MA abusers showed relative hypoactivity compared with control subjects, and the ventral striatum, where MA abusers showed relative hyperactivity. MA provided higher self-ratings of depression and anxiety than control subjects, and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula; higher in the lateral orbitofrontal area, mid- and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA, self-reports of depressive symptoms co-varied positively with relative metabolism in limbic regions (e.g., perigenual anterior cingulate gyrus and amygdala), and ratings of state and trait anxiety covaried negatively with relative activity anterior cingulate cortex and left insula. London, E.D., Simon, S.S., Berman, S.M., Mandelkern, M.A., Lichtman, A.M., Bramen, J., Shinn, A.K., Miotto, K., Learn, J., Dong, Y., Matochik, J.A., Kurian, V., Newton, T., Woods, R., Rawson, R., and Ling, W. Mood Disturbances and Regional Cerebral Metabolic Abnormalities in Recently Abstinent Methamphetamine Abusers. Archives of General Psychiatry, 61, pp. 73-84, January 2004.

Gray Matter Differences Between Smokers and Non-Smokers

Imaging studies have shown structural changes (i.e., ventricular enlargement and atrophy) in cigarette smokers when compared to nonsmokers. Functional differences appear in the lateral prefrontal cortex (PFC), anterior cingulate cortex (ACC), ventral striatum, and thalamus. Using magnetic resonance imaging, one group of NIDA supported researchers at UCLA evaluated brain regions for differences in gray matter between smokers and nonsmokers. Results showed smokers had smaller relative cortical gray matter volumes and lower gray matter densities than nonsmokers in the prefrontal cortices at the dorsal and ventral lateral levels. Smokers also had smaller left dorsal ACC volumes and lower right cerebellar gray matter densities than nonsmokers. No regions were significantly larger or had significantly higher gray matter densities in smokers when Regions of Interest (ROI's) were compared with nonsmokers. There was also a positive association between pack-year smoking history (9-70 pack years) and gray matter density, with smokers who had a greater number of pack years having smaller cortical densities. Strengths of the study included the use of relatively stringent thresholds for significance, and similarities in study findings with the use of two independent methods of MRI analysis. Results indicate significant regional gray matter volume and density differences between smokers and nonsmokers, a potentially important association with smoking behavior that has not yet been widely studied. Brody, A.L., Mandelkern, M.A., Jarvik, M.E., Lee, G.S., Smith, E.C., Huang, J.C., Bota, R.G., Bartzokis, G. and London, E.D. Differences Between Smokers and Non-smokers in Regional Gray Matter Volumes and Densities. Biological Psychiatry, 55(1), pp. 77-84, January 2004.

Parametric Manipulation of Conflict and Response Competition Using Rapid Mixed-trial Event-related fMRI

Dr. B.J. Casey and colleagues investigated the fMRI activation patterns of a number of brain areas while subjects performed a task in which they were to signal an incompatibility in a presented stimulus. A goal in this study was to determine how the preceding context (i.e., the number of compatible or incompatible trials) affected the response to an incompatible stimulus and the regions of the brain that contributed to the response. It was found that reaction times increased as the number of preceding compatible trials increased and that an increase in activation in the anterior cingulate, dorsolateral prefrontal, and superior parietal cortices paralleled this change. The temporal aspects of the changes in activation differed, however, with increased activity in the anterior cingulate cortex preceding that in the dorsolateral prefrontal cortex, which, in turn, preceded that in the superior parietal cortex. These findings are consistent with the theory that the anterior cingulate cortex detects conflict, the superior parietal cortex controls attention to the stimulus and the prefrontal cortex modulates the latter's influence. Durston, S., Davidson, M.C., Thomas, K.M., Worden, M.S., Tottenham, N., Martinez, A., Watts, R., Ulug, A.M., and Casey, B.J. NeuroImage, 20, pp. 2135-2141, 2003.

Tissue Immunoassay for 19F-tagged 5-Hydroxytryptophan

Dr. Sherry Dingman and colleagues have synthesized a new tool for magnetic resonance imaging, L-6-heptafluorobutyryl-5-hydroxytryptophan, that has the potential for greatly increasing the detection of the neurotransmitter, serotonin. To assess whether this compound would be useful as an imaging agent, experiments were performed to determine if it crossed the blood brain barrier and became concentrated in vesicles in serotonergic neurons. This is a necessary step if the compound is to accumulate in sufficient quantity for in vivo detection. L-6-heptafluorobutyryl-5-hydroxytryptophan was administered in ova to domestic chicks (Gallus domestics) to investigate its bioavailability and uptake dynamics. It was found that the compound accumulated in higher quantities in neural and liver tissue than in heart tissue and that, in the brain, the midbrain contained more tagged compound than the frontal lobe, and the frontal lobe contained more than the occipital or cerebellum samples, thus demonstrating that the compound follows the pathway of endogenous serotonin. Dingman, S., Hurlburt, L., Thomas, R. and Guo, C. J Immunoassay Immunochem., 24(4), pp. 325-344, 2003.


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