Associations between imprinted gene differentially methylated regions, appetitive traits and body mass index in children.

BACKGROUND: Knowledge regarding genetic influences on eating behaviours is expanding; yet less is known regarding contributions of epigenetic variation to appetitive traits and body mass index (BMI) in children. OBJECTIVE: The purpose of this study was to explore relationships between methylation at differentially methylated regions (DMRs) of imprinted genes (insulin-like growth factor 2/H19 and Delta-like, Drosophila, homolog 1/maternally expressed gene 3) using DNA extracted from umbilical cord blood leucocytes, two genetically influenced appetitive traits (food responsiveness and satiety responsiveness) and BMI. METHODS: Data were obtained from participants (N = 317; mean age = 3.6 years; SD = 1.8 years) from the Newborn Epigenetic STudy. Conditional process models were implemented to investigate the associations between DMRs of imprinted genes and BMI, and test whether this association was mediated by appetitive traits and birthweight and moderated by sex. RESULTS: Appetitive traits and birthweight did not mediate the relationship between methylation at DMRs. Increased insulin-like growth factor 2 DMR methylation was associated with higher satiety responsiveness. Higher satiety responsiveness was associated with lower BMI. Associations between methylation at DMRs, appetitive traits and BMI differed by sex. CONCLUSIONS: This is one of the first studies to demonstrate associations between epigenetic variation established prior to birth with appetitive traits and BMI in children, providing support for the need to uncover genetic and epigenetic mechanisms for appetitive traits predisposing some individuals to obesity.

Maternal pre-pregnancy obesity and child neurodevelopmental outcomes: a meta-analysis.

This review examined evidence of the association between maternal pre-pregnancy overweight/obesity status and child neurodevelopmental outcomes. PubMed and PsycINFO databases were systematically searched for empirical studies published before April 2017 using keywords related to prenatal obesity and children's neurodevelopment. Of 1483 identified papers, 41 were included in the systematic review, and 32 articles representing 36 cohorts were included in the meta-analysis. Findings indicated that compared with children of normal weight mothers, children whose mothers were overweight or obese prior to pregnancy were at increased risk for compromised neurodevelopmental outcomes (overweight: OR = 1.17, 95% CI [1.11, 1.24], I2  = 65.51; obese: OR = 1.51; 95% CI [1.35, 1.69], I2  = 79.63). Pre-pregnancy obesity increased the risk of attention deficit-hyperactivity disorder (OR = 1.62; 95% CI [1.23, 2.14], I2  = 70.15), autism spectrum disorder (OR = 1.36; 95% CI [1.08, 1.70], I2  = 60.52), developmental delay (OR = 1.58; 95% CI [1.39, 1.79], I2  = 75.77) and emotional/behavioural problems (OR = 1.42; 95% CI [1.26, 1.59], I2  = 87.74). Given the current obesity prevalence among young adults and women of childbearing age, this association between maternal obesity during pregnancy and atypical child neurodevelopment represents a potentially high public health burden.

Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway.

Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [(11)C]raclopride and [(11)C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, P<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, P<0.008; midbrain: r=0.41, P<0.005) and transporters (accumbens: r=0.35, P<0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor-and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.

Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study.

OBJECTIVE: To examine the associations between attention-deficit/hyperactivity disorder (ADHD) symptoms, obesity and hypertension in young adults in a large population-based cohort. DESIGN, SETTING AND PARTICIPANTS: The study population consisted of 15,197 respondents from the National Longitudinal Study of Adolescent Health, a nationally representative sample of adolescents followed from 1995 to 2009 in the United States. Multinomial logistic and logistic models examined the odds of overweight, obesity and hypertension in adulthood in relation to retrospectively reported ADHD symptoms. Latent curve modeling was used to assess the association between symptoms and naturally occurring changes in body mass index (BMI) from adolescence to adulthood. RESULTS: Linear association was identified between the number of inattentive (IN) and hyperactive/impulsive (HI) symptoms and waist circumference, BMI, diastolic blood pressure and systolic blood pressure (all P-values for trend <0.05). Controlling for demographic variables, physical activity, alcohol use, smoking and depressive symptoms, those with three or more HI or IN symptoms had the highest odds of obesity (HI 3+, odds ratio (OR)=1.50, 95% confidence interval (CI) = 1.22-2.83; IN 3+, OR = 1.21, 95% CI = 1.02-1.44) compared with those with no HI or IN symptoms. HI symptoms at the 3+ level were significantly associated with a higher OR of hypertension (HI 3+, OR = 1.24, 95% CI = 1.01-1.51; HI continuous, OR = 1.04, 95% CI = 1.00-1.09), but associations were nonsignificant when models were adjusted for BMI. Latent growth modeling results indicated that compared with those reporting no HI or IN symptoms, those reporting 3 or more symptoms had higher initial levels of BMI during adolescence. Only HI symptoms were associated with change in BMI. CONCLUSION: Self-reported ADHD symptoms were associated with adult BMI and change in BMI from adolescence to adulthood, providing further evidence of a link between ADHD symptoms and obesity.

SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families.

Haplotype-tagging SNP analyses were conducted to identify molecular genetic substrates of quantitative phenotypes derived from performance on a Continuous Performance Task (CPT). Three hundred sixty-four individuals were sampled from 152 families ascertained on the basis of at least one child having ADHD. Probands, their affected and unaffected siblings, and parents were administered a CPT. Four different components of performance were analyzed and tested for association with SNPs from 10 candidate genes involved in monoaminergic function. After correcting for multiple comparisons and controlling for multiple individuals from the same family, significant associations were identified between commission errors and SNPs in the DRD2 gene (rs2075654, rs1079596), and between reaction time variability and a SNP in the NET gene (rs3785155). These findings suggest that commission errors and reaction time variability are excellent candidates as ADHD endophenotypes based on previously published criteria. Results also shed light on the molecular genetic basis of specific processes that may underlie the disorder.

Temporal discounting: basic research and the analysis of socially important behavior.

Recent basic research on human temporal discounting is reviewed to illustrate procedures, summarize key findings, and draw parallels with both nonhuman animal research and conceptual writings on self-control. Lessons derived from this research are then applied to the challenge of analyzing socially important behaviors such as drug abuse, eating and exercise, and impulsiveness associated with attention deficit hyperactivity disorder. Attending to the broader temporal context in which behavior occurs may aid in the analysis of socially important behavior. Applying this perspective to the study of behavior in natural environments also highlights the importance of combining methodological flexibility with conceptual rigor to promote the extension of applied behavior analysis to a broader array of socially important behaviors.

Assessing the abuse potential of methylphenidate in nonhuman and human subjects: a review.

Methylphenidate (MPH) is widely used for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children, adolescents, and adults. Methylphenidate is clearly effective for the treatment of ADHD, but there is controversy as to whether it has significant abuse potential like other psychostimulants (e.g., D-amphetamine and cocaine). In general, the drug is believed to be abused at rates much lower than those for other stimulants. The present review examines studies that investigated the behavioral pharmacological profile of methylphenidate and discusses how results from these studies address its abuse liability. Using MEDLINE search terms methylphenidate, drug discrimination, reinforcement, self-administration, subjective effects, subject-rated effects, abuse potential, and abuse liability, along with a review of the references from identified articles, 60 studies were located in which the reinforcing, discriminative-stimulus, or subjective effects of methylphenidate were directly assessed in nonhumans or humans. Forty-eight (80.0%) of the studies reviewed indicate that methylphenidate either functions in a manner similar to D-amphetamine or cocaine (e.g., functions as a reinforcer, substitutes fully in drug discrimination experiments), or produces a pattern of subjective effects suggestive of abuse potential. The results are discussed as they pertain to factors that may account for the apparent discrepancy in abuse rates between methylphenidate and other stimulants, including characterization of actual abuse rates, defining abuse and misuse, pharmacokinetic factors, and validity of abuse liability assays.

Effects of methylphenidate on sensitivity to reinforcement in children diagnosed with attention deficit hyperactivity disorder: an application of the matching law.

The behavior of children diagnosed with attention deficit hyperactivity disorder (ADHD) has been hypothesized to be the result of decreased sensitivity to consequences compared to typical children. The present study examined sensitivity to reinforcement in 2 boys diagnosed with ADHD using the matching law to provide more precise and quantitative measurement of this construct. This experiment also evaluated the effects of methylphenidate (MPH) on sensitivity to reinforcement of children with ADHD. Subjects completed math problems to earn tokens under four different variable-interval (VI) schedules of reinforcement presented in random order under both medicated and nonmedicated conditions. Results showed that, in the medicated condition, the matching functions for both subjects resulted in higher asymptotic values, indicating an overall elevation of behavior rate under these conditions. The variance accounted for by the matching law was also higher under the medicated conditions, suggesting that their behavior more closely tracked the changing rates of reinforcement while taking MPH compared to placebo. Under medicated conditions, the reinforcing efficacy of response-contingent tokens decreased. Results are discussed with respect to quantifying behavioral changes and the extent to which the drug interacts with prevailing contingencies (i.e., schedule values) to influence behavioral variability.

The good, the bad, and the aggregate.

To evaluate progress and focus goals, scientific disciplines need to identify relations that are robust across many situations. One approach is the literature review, which characterizes generality across studies. Some writers (e.g., Baron & Derenne, 2000) claim that quantitative literature reviews, but not narrative reviews, violate the methodological precepts of behavior analysis by pooling data from nonidentical studies. We argue that it is impossible to assess generality without varying the context in which relationships are studied. Properly chosen data-aggregation strategies can reveal which behavior-environment relations are general and which are procedure dependent. Within behavior analysis, reluctance to conduct quantitative reviews may reflect unsupported assumptions about the consequences of aggregating data across studies. Whether specific data-aggregation techniques help or harm a research program is an empirical issue that cannot be resolved by unstructured discussion. Some examples of how aggregation has been used in identifying behavior-environment relations are examined.

Effects of training dose on the relationship between discriminative-stimulus and self-reported drug effects of d-amphetamine in humans.

The aim of the present experiment was to examine the relationship between the discriminative-stimulus and self-reported effects of drugs in humans. To accomplish this aim, nine healthy adult volunteers (four females, five males) were trained to discriminate between placebo and 10 mg d-amphetamine (low-dose group) or 20 mg d-amphetamine (high-dose group). After acquiring the placebo-amphetamine discrimination, a range of doses of d-amphetamine (1.25-20 mg) was tested to determine if they shared discriminative stimulus effects with the training dose. Participants in the low-dose group exhibited a significant leftward shift in the dose-response function for discrimination performance, which is concordant with previous preclinical and human drug discrimination studies that assessed the effects of training dose. Consistent with the drug discrimination findings, participants in the low-dose group exhibited a significant leftward shift in the dose-response function for several self-reported drug effects (e.g., Like the Drug and Stimulated). However, several other self-reported drug effect items were not significantly influenced by training condition (e.g., Anxious/Nervous and Bad Effects). These results suggest that the discriminative-stimulus and self-reported drug effects of d-amphetamine overlap, but are not isomorphic. Furthermore, these results illustrate that behavioral history significantly influences subsequent drug effects in humans.

Factors affecting the reliability of clinical judgments about the function of children's school-refusal behavior.

Conducted two studies to examine the interrater reliability, test-retest stability, and the effect of various clinician variables, such as years of clinical experience, theoretical orientation, and prior experience with children, on clinical judgments about the reinforcement functions of children's school-refusal behavior. Results indicated that the judgments by individual clinicians were of questionable reliability. Judgments aggregated across 3 clinicians yielded acceptable interrater and test-retest reliability in Study 1, but a greater number of clinicians were necessary to achieve acceptable reliability in Study 2. Years of clinical experience and training were the only clinician variables related to the reliability of judgments about reinforcement functions. Several recommendations for the clinical assessment of the function of children's school-refusal behavior are discussed.

Quantitative integration of single-subject studies: Methods and misinterpretations.

Derenne and Baron (1999) criticized a quantitative literature review by Kollins, Newland, and Critchfield (1997) and raised several important issues with respect to the integration of single-subject data. In their criticism they argued that the quantitative integration of data across experiments conducted by Kollins et al. is a meta-analysis and, as such, is inappropriate. We reply that Kollins et al. offered behavior analysts a technique for integrating quantitative information in a way that draws from the strengths of behavior analysis. Although the quantitative technique is true to the original spirit of meta-analysis, it bears little resemblance to meta-analyses as currently conducted or defined and offers behavior analysts a potentially useful tool for comparing data from multiple sources. We also argue that other criticisms raised by Derenne and Baron were inaccurate or irrelevant to the original article. Our response highlights two main points: (a) There are meaningful quantitative techniques for examining single-subject data across studies without compromising the integrity of behavior analysis; and (b) the healthiest way to refute or question findings in any viable field of scientific inquiry is through empirical investigation.

Comparison of acute behavioral effects of sustained-release and immediate-release methylphenidate.

The rate of onset of a drug's effect is an important determinant of its abuse potential. This experiment examined the acute behavioral effects of orally administered sustained-release methylphenidate (SR; 20-40 mg), immediate-release methylphenidate (IR; 20-40 mg), and placebo in 10 healthy volunteers. Drug effects were assessed before drug administration and periodically afterwards for 6 hr using drug-effect questionnaires and performance measures that are sensitive to the acute effects of stimulants. The IR formulation produced stimulant-like drug effects (e.g., increased ratings of "good effects") that generally varied as a function of dose and time. The SR formulation produced only transient effects on these measures. These findings are consistent with previous research on the influence of rate of onset using other drugs and suggest that the abuse potential of IR methylphenidate may be greater than that of SR methylphenidate.

Discriminative-stimulus and participant-rated effects of methylphenidate, bupropion, and triazolam in d-amphetamine-trained humans.

The discriminative-stimulus and participate-rated effects of a range of doses of d-amphetamine (2.5-20 mg), methylphenidate (5-40 mg), bupropion (50-400 mg), and triazolam (0.0625-0.5 mg) were tested in 5 humans trained to discriminate between oral d-amphetamine (20 mg) and placebo. d-Amphetamine and methylphenidate generally dose dependently increased drug-appropriate responding. Bupropion and triazolam on average occasioned less than or equal to 40% drug-appropriate responding. d-Amphetamine, methylphenidate, and bupropion produced stimulant-like participant-rated effects, while triazolam produced sedative-like effects. These results further demonstrate that the acute behavioral effects of d-amphetamine and methylphenidate overlap extensively in humans, which is concordant with preclinical studies. Bupropion produced some d-amphetamine-like, participant-rated drug effects but did not occasion significant levels of d-amphetamine-appropriate responding. These findings are concordant with previous findings of a dissociation between the discriminative-stimulus and participant-rated effects of drugs.

Human sensitivity to reinforcement in operant choice: How much do consequences matter?

The results of many human operant conditioning experiments appear to show that humans are less sensitive than nonhumans to operant consequences, suggesting species discontinuities in basic behavioral processes. A reanalysis of 31l data sets from 25 studies employing variable-interval schedules of reinforcement designed to assess sensitivity to reinforcement corroborates the claim that human behavioral allocation among alternatives often deviates from predictions based on rates of experimentally programmed consequences. Close inspection of the studies in question, however, suggests that methodological issues contribute heavily to the differences noted so far between humans and nonhumans and that an explanation based upon species discontinuities is not tenable.