Attention-deficit/hyperactivity disorder and dopamine receptor D4 (DRD4) exon 3 variable number of tandem repeats (VNTR) 2-repeat allele.

To investigate the association of attention-deficit/hyperactivity disorder (ADHD) with the 48-base pair (bp) variable number of tandem repeats (VNTR) in exon 3 of the dopamine receptor D4 (DRD4) gene, we genotyped 240 ADHD patients and their parents from Hong Kong. The 4R allele was most common, followed by 2R. We examined association between the 2R allele (relative to 4R) and ADHD by Transmission Disequilibrium Test (TDT). The odds ratio (OR) (95% confidence interval) was 0.90 (0.64-1.3). The p-value was 0.6. Examining subgroups revealed nominally significant association of 2R with inattentive ADHD: OR = 0.33 (0.12-0.92) and p = 0.03. Because our study used TDT analysis, we meta-analyzed the association of 2R with ADHD in Asians (1329 patient alleles), revealing results similar to ours: OR = 0.97 (0.80-1.2) and p = 0.8. To examine the association of 2R with inattentive ADHD, we meta-analyzed all studies (regardless of analysis type or ethnicity, in order to increase statistical power): 702 patient alleles, 1420 control alleles, OR = 0.81 (0.57-1.1) and p = 0.2. Overall, there is no evidence of association between ADHD and the 2R allele, but the suggestive association with the inattentive type warrants further investigation.

Methylphenidate dose-response in children with ADHD: evidence from a double-blind, randomized placebo-controlled titration trial.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

Treatment strategies for ADHD: an evidence-based guide to select optimal treatment.

Attention-deficit/hyperactivity disorder (ADHD) is a common and impairing disorder affecting children, adolescents, and adults. Several treatment strategies are available that can successfully ameliorate symptoms, ranging from pharmacological to dietary interventions. Due to the increasing range of available options, an informed selection or prioritization of treatments is becoming harder for clinicians. This review aims to provide an evidence-based appraisal of the literature on ADHD treatment, supplemented by expert opinion on plausibility. We outline proposed mechanisms of action of established pharmacologic and non-pharmacologic treatments, and we review targets of novel treatments. The most relevant evidence supporting efficacy and safety of each treatment strategy is discussed. We review the individualized features of the patient that should guide the selection of treatments in a shared decision-making continuum. We provide guidance for optimizing initiation of treatment and follow-up of patients in clinical settings.

Measuring strengths and weaknesses in dimensional psychiatry.

BACKGROUND: The Extended Strengths and Weaknesses Assessment of Normal Behavior (E-SWAN) reconceptualizes each diagnostic criterion for selected DSM-5 disorders as a behavior, which can range from high (strengths) to low (weaknesses). Initial development focused on Panic Disorder, Social Anxiety, Major Depression, and Disruptive Mood Dysregulation Disorder. METHODS: Data were collected from 523 participants (ages 6-17). Parents completed each of the four E-SWAN scales and traditional unidirectional scales addressing the same disorders. Distributional properties, Item Response Theory Analysis (IRT), and Receiver Operating Characteristic (ROC) curves were used to assess and compare the performance of E-SWAN and traditional scales. RESULTS: In contrast to the traditional scales, which exhibited truncated distributions, all four E-SWAN scales had symmetric distributions. IRT analyses indicate the E-SWAN subscales provided reliable information about respondents throughout the population distribution; traditional scales only provided reliable information about respondents at the high end of the distribution. Predictive value for DSM-5 diagnoses was comparable to prior scales. CONCLUSIONS: E-SWAN bidirectional scales can capture the full spectrum of the population distribution of behavior underlying DSM disorders. The additional information provided can better inform examination of inter-individual variation in population studies, as well as facilitate the identification of factors related to resiliency in clinical samples.

Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.

We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.

Cigarette Smoking Progression Among Young Adults Diagnosed With ADHD in Childhood: A 16-year Longitudinal Study of Children With and Without ADHD.

INTRODUCTION: Children with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for smoking cigarettes, but there is little longitudinal research on the array of smoking characteristics known to be prognostic of long-term smoking outcomes into adulthood. These variables were studied into early adulthood in a multisite sample diagnosed with ADHD combined type at ages 7-9.9 and followed prospectively alongside an age- and sex-matched local normative comparison group (LNCG). METHODS: Cigarette smoking quantity, quit attempts, dependence, and other characteristics were assessed in the longitudinal Multimodal Treatment Study of Children with ADHD (MTA) eight times to a mean age of 24.9 years: ADHD n = 469; LNCG n = 240. RESULTS: In adulthood, the ADHD group had higher rates of daily cigarette smoking, one or more quit attempts, shorter time to first cigarette of the day, and more severe withdrawal than the LNCG. The ADHD group did not appear to have better smoking cessation rates despite a higher proportion quitting at least once. Smoking quantity and nicotine dependence did not differ between groups. The ADHD group reported younger daily smoking onset and faster progression from smoking initiation to daily smoking across assessments. Finally, ADHD symptom severity in later adolescence and adulthood was associated with higher risk for daily smoking across assessments in the ADHD sample. CONCLUSIONS: This study shows that ADHD-related smoking risk begins at a young age, progresses rapidly, and becomes resistant to cessation attempts by adulthood. Prevention efforts should acknowledge the speed of uptake; treatments should target the higher relapse risk in this vulnerable population. IMPLICATIONS: Although childhood ADHD predicts later smoking, longitudinal studies of this population have yet to fully characterize smoking behaviors into adulthood that are known to be prognostic of long-term smoking outcome. The current study demonstrates earlier and faster progression to daily smoking among those with a childhood ADHD diagnosis, as well as greater risk for failed quit attempts. Prevention efforts should address speed of smoking uptake, while treatments are needed that address smoking relapse risk. The current study also demonstrates ADHD symptom severity over development increases daily smoking risk, implicating the need for continuous ADHD symptom management.

Predictive utility of childhood diagnosis of ICD-10 hyperkinetic disorder: adult outcomes in the MTA and effect of comorbidity.

Diagnostic guidelines differ between DSM attention-deficit/hyperactivity disorder (ADHD) and ICD hyperkinetic disorder (HKD). Only 145 of 579 children age 7-9 in the Multimodal Treatment Study of ADHD (the MTA) with combined-type DSM-IV ADHD met criteria for ICD-10 HKD, because major internalizing comorbidities and more stringent symptom count/pervasiveness requirements excluded most. The 145 HKD had significantly better 14-month medication response than the rest. We explored whether HKD had greater adult symptom persistence and/or impairment than other ADHD. Multi-informant assessments were done for 16 years. We used the 12/14/16-year assessments, in young adulthood. The post-attrition 109 with baseline HKD had no greater adult persistence of ADHD symptoms/impairment than 367 without HKD, but had more cumulative stimulant use, more job losses, lower emotional lability, and fewer car crashes. However, those excluded for internalizing comorbidity but otherwise meeting HKD criteria had significantly more persistence. Only 6 of the 109 (5.5%) with baseline HKD met ICD-10 criteria for HKD in adulthood, compared to 25 of 367 (6.8%) without a childhood HKD diagnosis. Despite greater initial symptom severity, HKD had no worse 16-year young adult outcome than others, except for job losses, balanced by less emotional lability and fewer crashes. Comorbid internalizing disorder seems to have worse prognosis than initial severity/pervasiveness of ADHD symptoms.

Meeting Report: The Role of Beliefs and Perception on Body Size. Proceedings of the 26th Aschauer Soiree, Held at Aschauhof, Altenhof, Germany, May 26th, 2018.

Thirty-one scientists met at Aschauhof, Germany to discuss the role of beliefs and self-perception on body size. In view of apparent growth stimulatory effects of dominance within the social group that is observed in social mammals, they discussed various aspects of competitive growth strategies and growth adjustments. Presentations included new data from Indonesia, a cohort-based prospective study from Merida, Yucatan, and evidence from recent meta-analyses and patterns of growth in the socially deprived. The effects of stress experienced during pregnancy and adverse childhood events were discussed, as well as obesity in school children, with emphasis on problems when using z-scores in extremely obese children. Aspects were presented on body image in African-American women, and body perception and the disappointments of menopause in view of feelings of attractiveness in different populations. Secular trends in height were presented, including short views on so called 'racial types' vs bio-plasticity, and historic data on early-life nutritional status and later-life socioeconomic outcomes during the Dutch potato famine. New tools for describing body proportions in patients with variable degrees of phocomelia were presented along with electronic growth charts. Bio-statisticians discussed the influence of randomness, community and network structures, and presented novel tools and methods for analyzing social network data.

Methylation of the dopamine transporter gene in blood is associated with striatal dopamine transporter availability in ADHD: A preliminary study.

Dopamine transporters (DAT) are implicated in the pathogenesis and treatment of attention-deficit hyperactivity disorder (ADHD) and are upregulated by chronic treatment with methylphenidate, commonly prescribed for ADHD. Methylation of the DAT1 gene in brain and blood has been associated with DAT expression in rodents' brains. Here we tested the association between methylation of the DAT1 promoter derived from blood and DAT availability in the striatum of unmedicated ADHD adult participants and in that of healthy age-matched controls (HC) using Positron Emission Tomography (PET) and [11 C]cocaine. Results showed no between-group differences in DAT1 promoter methylation or striatal DAT availability. However, the degree of methylation in the promoter region of DAT1 correlated negatively with DAT availability in caudate in ADHD participants only. DAT availability in VS correlated with inattention scores in ADHD participants. We verified in a postmortem cohort with ADHD diagnosis and without, that DAT1 promoter methylation in peripheral blood correlated positively with DAT1 promoter methylation extracted from substantia nigra (SN) in both groups. In the cohort without ADHD diagnosis, DAT1 gene expression in SN further correlated positively with DAT protein expression in caudate; however, the sample size of the cohort with ADHD was insufficient to investigate DAT1 and DAT expression levels. Overall, these findings suggest that peripheral DAT1 promoter methylation may be predictive of striatal DAT availability in adults with ADHD. Due to the small sample size, more work is needed to validate whether DAT1 methylation in blood predicts DAT1 methylation in SN in ADHD and controls.

Substance use through adolescence into early adulthood after childhood-diagnosed ADHD: findings from the MTA longitudinal study.

BACKGROUND: Inconsistent findings exist regarding long-term substance use (SU) risk for children diagnosed with attention-deficit/hyperactivity disorder (ADHD). The observational follow-up of the Multimodal Treatment Study of Children with ADHD (MTA) provides an opportunity to assess long-term outcomes in a large, diverse sample. METHODS: Five hundred forty-seven children, mean age 8.5, diagnosed with DSM-IV combined-type ADHD and 258 classmates without ADHD (local normative comparison group; LNCG) completed the Substance Use Questionnaire up to eight times from mean age 10 to mean age 25. RESULTS: In adulthood, weekly marijuana use (32.8% ADHD vs. 21.3% LNCG) and daily cigarette smoking (35.9% vs. 17.5%) were more prevalent in the ADHD group than the LNCG. The cumulative record also revealed more early substance users in adolescence for ADHD (57.9%) than LNCG (41.9%), including younger first use of alcohol, cigarettes, marijuana, and illicit drugs. Alcohol and nonmarijuana illicit drug use escalated slightly faster in the ADHD group in early adolescence. Early SU predicted quicker SU escalation and more SU in adulthood for both groups. CONCLUSIONS: Frequent SU for young adults with childhood ADHD is accompanied by greater initial exposure at a young age and slightly faster progression. Early SU prevention and screening is critical before escalation to intractable levels.

Defining ADHD symptom persistence in adulthood: optimizing sensitivity and specificity.

OBJECTIVE: Longitudinal studies of children diagnosed with ADHD report widely ranging ADHD persistence rates in adulthood (5-75%). This study documents how information source (parent vs. self-report), method (rating scale vs. interview), and symptom threshold (DSM vs. norm-based) influence reported ADHD persistence rates in adulthood. METHOD: Five hundred seventy-nine children were diagnosed with DSM-IV ADHD-Combined Type at baseline (ages 7.0-9.9 years) 289 classmates served as a local normative comparison group (LNCG), 476 and 241 of whom respectively were evaluated in adulthood (Mean Age = 24.7). Parent and self-reports of symptoms and impairment on rating scales and structured interviews were used to investigate ADHD persistence in adulthood. RESULTS: Persistence rates were higher when using parent rather than self-reports, structured interviews rather than rating scales (for self-report but not parent report), and a norm-based (NB) threshold of 4 symptoms rather than DSM criteria. Receiver-Operating Characteristics (ROC) analyses revealed that sensitivity and specificity were optimized by combining parent and self-reports on a rating scale and applying a NB threshold. CONCLUSION: The interview format optimizes young adult self-reporting when parent reports are not available. However, the combination of parent and self-reports from rating scales, using an 'or' rule and a NB threshold optimized the balance between sensitivity and specificity. With this definition, 60% of the ADHD group demonstrated symptom persistence and 41% met both symptom and impairment criteria in adulthood.

Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression.

BACKGROUND: The Multimodal Treatment Study (MTA) began as a 14-month randomized clinical trial of behavioral and pharmacological treatments of 579 children (7-10 years of age) diagnosed with attention-deficit/hyperactivity disorder (ADHD)-combined type. It transitioned into an observational long-term follow-up of 515 cases consented for continuation and 289 classmates (258 without ADHD) added as a local normative comparison group (LNCG), with assessments 2-16 years after baseline. METHODS: Primary (symptom severity) and secondary (adult height) outcomes in adulthood were specified. Treatment was monitored to age 18, and naturalistic subgroups were formed based on three patterns of long-term use of stimulant medication (Consistent, Inconsistent, and Negligible). For the follow-up, hypothesis-generating analyses were performed on outcomes in early adulthood (at 25 years of age). Planned comparisons were used to estimate ADHD-LNCG differences reflecting persistence of symptoms and naturalistic subgroup differences reflecting benefit (symptom reduction) and cost (height suppression) associated with extended use of medication. RESULTS: For ratings of symptom severity, the ADHD-LNCG comparison was statistically significant for the parent/self-report average (0.51 ± 0.04, p < .0001, d = 1.11), documenting symptom persistence, and for the parent/self-report difference (0.21 ± 0.04, p < .0001, d = .60), documenting source discrepancy, but the comparisons of naturalistic subgroups reflecting medication effects were not significant. For adult height, the ADHD group was 1.29 ± 0.55 cm shorter than the LNCG (p < .01, d = .21), and the comparisons of the naturalistic subgroups were significant: the treated group with the Consistent or Inconsistent pattern was 2.55 ± 0.73 cm shorter than the subgroup with the Negligible pattern (p < .0005, d = .42), and within the treated group, the subgroup with the Consistent pattern was 2.36 ± 1.13 cm shorter than the subgroup with the Inconsistent pattern (p < .04, d = .38). CONCLUSIONS: In the MTA follow-up into adulthood, the ADHD group showed symptom persistence compared to local norms from the LNCG. Within naturalistic subgroups of ADHD cases, extended use of medication was associated with suppression of adult height but not with reduction of symptom severity.

Late-Onset ADHD: Understanding the Evidence and Building Theoretical Frameworks.

PURPOSE OF REVIEW: The traditional definition of Attention-Deficit/Hyperactivity Disorder (ADHD), assuming onset in childhood, has been challenged by evidence from four recent birth-cohort studies that reported most adults with ADHD lacked a childhood categorical ADHD diagnosis. RECENT FINDINGS: Late onset of symptoms was evaluated in the long-term follow-up of the Multimodal Treatment study of ADHD (MTA). In most cases, other factors were present that discounted the late onset of ADHD symptoms and excluded the diagnosis of ADHD. We offer two theoretical frameworks for understanding the ADHD trajectory throughout the life cycle: (1) the complex phenotype model, and (2) the restricted phenotype model. We conclude that (a) late onset (after age 12) is a valid trajectory for ADHD symptoms, (b) the percentage of these cases with onset after adolescence is yet uncertain, and

Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder.

Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc.

Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia.

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases.

Mutations in ECEL1 cause distal arthrogryposis type 5D.

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ~50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ~70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.

Clinical practice: Adult attention deficit-hyperactivity disorder.

Short-term trials involving adults with ADHD have shown significant improvements in symptoms with stimulants and atomoxetine; however, data on long-term benefits and risks of these medications, particularly among older persons, have been insufficient.

Improving Methylphenidate Titration in Children with Attention-Deficit/Hyperactivity Disorder (ADHD): A Randomized Controlled Trial Using Placebo-Controlled Titration Implemented in Clinical Practice.

BACKGROUND AND OBJECTIVES: Concerns exist regarding the rising use of methylphenidate. A double-blind, placebo-controlled methylphenidate titration (PCT) for children with attention-deficit/hyperactivity disorder (ADHD) has shown potential to improve titration (i.e., detection of placebo responders and larger ADHD symptom improvement) in experimental settings. This study aims to determine if these advantages can be transferred to clinical settings. METHOD: Children (aged 5-13 years) with an ADHD diagnosis and an indication to start methylphenidate (MPH) treatment were recruited. Participants were randomized to PCT or care as usual (CAU) in a 1:1 ratio followed by a 7-week randomized controlled trial (T1) and 6-month, naturalistic, open-label follow-up (T2). Parents, teachers, and physicians rated ADHD symptoms, ADHD medication use, MPH dosing, and treatment satisfaction using questionnaires. RESULTS: A total of 100 children were enrolled and randomized to PCT (n = 49) or CAU (n = 51). In the PCT group, we found 8.2% placebo responders, 16.3% non-responders, and 65.3% responders to MPH. With PCT compared with CAU, a significantly larger number of children discontinued MPH (T1: 24.5 vs 5.9%, p = 0.009; T2: 41.7 vs 10.4%, p < 0.001) and refrained from using other pharmacological treatment (T1: 20.4 vs 3.9%, p = 0.013; T2: 20.83 vs 6.25%, p = 0.002). At both timepoints, there were no significant differences between the groups in the average dose of MPH, ADHD symptoms, or treatment satisfaction. CONCLUSIONS: PCT can be used to improve detection of children who do not benefit from MPH, and may therefore potentially reduce overtreatment of ADHD with MPH.

Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder.

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [(11)C]raclopride (D(2)/D(3) receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D(2)/D(3) receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.

Maternal perspectives on the return of genetic results: context matters.

The objectives of this study were to study maternal preferences for the return of their child's genetic results and to describe the experiences, perceptions, attitudes, and values that are brought to bear when individuals from different racial and cultural backgrounds consider participating in genetic research. We recruited women with diverse sociodemographic profiles to participate in seven focus groups. Twenty-eight percent of participants self-identified as Hispanic; 49% as White, non-Hispanic; and 21% as Asian or Asian American. Focus groups were conducted in English or Spanish and were audio-recorded and transcribed verbatim. Transcripts were analyzed using qualitative thematic methods. Results indicated that preferences and decisions regarding the return of results may depend on both research and individual contextual factors. Participants understood the return of results as a complex issue, where individual and cultural differences in preferences are certain to arise. Another key finding was that participants desired an interpersonal, dynamic, flexible process that accommodated individual preferences and contextual differences for returning results. Our findings indicate a need to have well-developed systems for allowing participants to make and change over time their choices regarding the return of their child's genetic results.