Relative immaturity and ADHD : findings from nationwide registers, parent- and self-reports

BACKGROUND: We addressed if immaturity relative to peers reflected in birth month increases the likelihood of ADHD diagnosis and treatment. METHODS: We linked nationwide Patient and Prescribed Drug Registers and used prospective cohort and nested case-control designs to study 6-69 year-old individuals in Sweden from July 2005 to December 2009 (Cohort 1). Cohort 1 included 56,263 individuals diagnosed with ADHD or ever used prescribed ADHD-specific medication. Complementary population-representative cohorts provided DSM-IV ADHD symptom ratings; parent-reported for 10,760 9-year-old twins born 1995-2000 from the CATSS study (Cohort 2) and self-reported for 6,970 adult twins age 20-47 years born 1959-1970 from the STAGE study (Cohort 3). We calculated odds ratios (OR:s) for ADHD across age for individuals born in November/December compared to January/February (Cohort 1). ADHD symptoms in Cohorts 2 and 3 were studied as a function of calendar birth month. RESULTS: ADHD diagnoses and medication treatment were both significantly more common in individuals born in November/December versus January/February; peaking at ages 6 (OR: 1.8; 95% CI: 1.5-2.2) and 7 years (OR: 1.6; 95% CI: 1.3-1.8) in the Patient and Prescribed Drug Registers, respectively. We found no corresponding differences in parent- or self-reported ADHD symptoms by calendar birth month. CONCLUSION: Relative immaturity compared to class mates might contribute to ADHD diagnosis and pharmacotherapy despite absence of parallel findings in reported ADHD symptom loads by relative immaturity. Increased clinical awareness of this phenomenon may be warranted to decrease risk for imprecise diagnostics and treatment. We speculate that flexibility regarding age at school start according to individual maturity could reduce developmentally inappropriate demands on children and improve the precision of ADHD diagnostic practice and pharmacological treatment.Swedish Research Council (2010-3184)Karolinska Institutet Center of Neurodevelopmental Disorders (KIND)Accepte

Childhood neurodevelopmental problems and adolescent bully victimization : population-based, prospective twin study in Sweden

Bully victimization is a common problem among children with neurodevelopmental disorders, including attention deficit/hyperactivity disorder and autism spectrum disorder. Previous research was mostly cross-sectional and seldom accounted for co-morbid psychopathology, which makes it difficult to draw conclusions about causality and specificity of any association. Using a genetically informative prospective design, we investigated the association between various neurodevelopmental problems (NDPs) in childhood and bully victimization in adolescence, and the relative contributions of genetic and environmental factors to this association. We obtained parent-reports of NDPs at age 9/12 years and self-reported bully victimization at age 15 for 3,921 children participating in the The Child and Adolescent Twin Study in Sweden (CATSS). Structural equation modelling was used to control for NDP co-morbidity and bully victimization at baseline. Cholesky decomposition was used to analyse genetic and environmental contributions to observed associations. Because most of the NDPs were associated to later bully victimization, a common effect of all NDPs was summarized into a general NDP factor. Controlling for this general factor, only problems with social interaction and motor control uniquely predicted subsequent bully victimization in girls. General and unique associations were influenced by both genetic and unique environmental factors. NDPs in general and social interaction and motor problems in particular predicted later bully victimization. The longitudinal design and twin analyses indicated that these associations might be causal. Knowledge of these vulnerabilities may be important when designing risk assessment and prevention strategies.The Swedish Council for Working Life and Social ResearchThe Research Council of the Swedish National Alcohol MonopolyThe Söderström-Königska FoundationFunds under the ALF agreementThe Swedish Research CouncilAccepte

Physiology and pathophysiology of central adenosine A1 and A2A receptors

The aim of this thesis was to further investigate the individual roles of central adenosine A1 and A2A receptors in the physiological and pathophysiological effects of adenosine. In addition, the characteristics of different adenosine receptor ligands were studied. For these purposes pharmacological tools as well as mice lacking adenosine A1 and/or A2A receptors were used. Both adenosine A1 receptor knock-out and adenosine A1/A2A receptor double knock-out mice survived fetal life and developed no major defects. No significant change in baseline motor activity was seen in these knock-out mice. In situ hybridization and receptor autoradiography confirmed that the adenosine A1 receptor knock-out did not express any central adenosine A1 receptors. Adenosine A1 receptor heterozygotes expressed half the amount of the receptor. The same was due for the adenosine A2A receptor heterozygote regarding the adenosine A2A receptor expression. The expression of adenosine A2A receptors was not affected by absence of the adenosine A1 receptors. Rats that were sleep-deprived for 3 or 6 hours had altered levels of both adenosine A1 and A2A receptor mRNA. Adenosine A1 receptor mRNA was up-regulated specifically in the horizontal limb of the diagonal band in the basal forebrain. This up-regulation was not seen at the protein level. On the contrary, adenosine A2A receptor mRNA was down-regulated, and this was accompanied with a decrease in receptor binding after 3 but not 6 hours of sleep-deprivation. The alterations of the adenosine A2A receptor expression was observed only in the olfactory tubercle. The sleep pattern and the response to sleep deprivation was studied in mice lacking adenosine A1 receptors. These mice did unexpectedly not differ from their wild-type siblings in these respects. Adenosine A2A receptor knock-outs were more sensitive to hypoxia-ischemia than wild-type mice. They developed an aggravated brain damage, which resulted in altered behavior later in life. Adenosine A2A receptor knock-outs exposed to hypoxia-ischemia showed altered behavior in the open field test and performed less well in the rotarod test. Chronic administration of the locomotor activity stimulating adenosine A2A receptor antagonist SCH 58261 was given to rats. In contrast to previous studies with the non-selective adenosine antagonist caffeine, no tolerance developed to the motor stimulating effect after repeated injections of the drug. The locomotor effects of caffeine were analyzed in mice lacking adenosine A1 receptors. The dose-response curve for caffeine seemed shifted to the left, whereas response to high dose caffeine was unaltered in the knock-out. No locomotor stimulating effect was observed in adenosine A1/A2A receptor double knock-out mice in congruence with mice lacking only the adenosine A2A receptor. Finally, the selectivity of the adenosine receptor ligands DPCPX (A1 antagonist), SCH 58261(A2A antagonist), ZM 241385(A2A antagonist) and CGS 21680(A2A agonist) were tested by means of receptor binding in adenosine receptor knock-out brains. DPCPX did not bind to brains from adenosine A1 receptor knock-outs, whereas SCH 58261 and ZM 241385 did not bind in brains from adenosine A2A receptor knock-outs. CGS 21680 did however not bind in the striatum from adenosine A2A receptor knock-outs, but extra-striatal bindin

Disrupted Attention to Other’s Eyes is Linked to Symptoms of ADHD in Childhood

Attention-deficit/hyperactivity disorder (ADHD) is associated with impaired social interaction. Other’s eyes are important for understanding the social world. Here, we examined concurrent and longitudinal links between attention to other’s eyes and symptoms of ADHD and comorbid externalizing and internalizing symptoms. Eighty-two 8 to 13-year-old children (40% with ADHD) participated. The latency to a first gaze shift to and away from the eye region of human faces, when primed to look at either the eyes or the mouth, was recorded with eye tracking. Parents rated ADHD, externalizing and internalizing symptoms at the time of testing and at 2-year follow-up. The results show that longer looking at the eyes before reorienting was specifically associated with concurrent and future symptoms of inattention, even when accounting for comorbid symptoms. We conclude that the temporal microstructure of attention to other’s eyes is altered in children with symptoms of ADHD, which may contribute to social impairments

The adenosine A1 receptor contributes to the stimulatory, but not the inhibitory effect of caffeine on locomotion: a study in mice lacking adenosine A1 and/or A2A receptors.

Caffeine has biphasic effects on locomotion, and blockade of the adenosine A(2A) receptor (A2AR) is necessary for the stimulatory effect of low doses of caffeine, but not for the locomotor depressant effect observed at high doses. We wanted to elucidate the role of the adenosine A(1) receptor (A1R) in mediating the locomotor effects of increasing doses of caffeine using wild-type mice (A1R(WT)), mice heterozygous for (A1R(HET)), and mice lacking the adenosine A(1) receptor (A1R(KO)). Caffeine had the typical biphasic dose-effect relationship in all three genotypes, but the stimulatory action of caffeine was facilitated in the A1R(KO) mice. In order to investigate the interaction between blockade of A1Rs and A2ARs, mice lacking both receptors (A1R(KO)/A2AR(KO)) were tested. Regardless of A1R genotype, animals lacking A2AR were not stimulated by caffeine, whereas animals heterozygous for A2AR were. As expected, the A1R is not crucial for the stimulatory effect of caffeine, but seems to modulate the effect of caffeine exerted via A2AR blockade. Furthermore, these results suggest that the inhibitory effect of high doses of caffeine is due neither to blockade of the A1R, nor of the A2AR, and an effect independent of these adenosine receptors is likely.Comparative StudyJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Internalizing symptoms in adolescence are modestly affected by symptoms of anxiety, depression, and neurodevelopmental disorders in childhood

Background: Internalizing disorders, such as anxiety and depressive disorders, are common mental disorders in young people, but a detailed understanding of the symptom continuity from childhood to adolescence that additionally includes a variety of neurodevelopmental disorder (NDD) symptoms is lacking. We therefore aimed to assess the extent to which parent-reported anxiety, depression, and NDD symptoms in childhood predict parent-reported internalizing symptoms in adolescence. Methods: We used the nation-wide population-based Child and Adolescent Twin Study in Sweden, comprising 4492 twins born in Sweden between 1998 and 2003 that were assessed at age 9, and then again at age 15. Linear regression in a structural equation modelling framework was used to analyze the data. Results: Overall, our results indicate that 15.9% of the variance in internalizing symptoms at age 15 can be predicted by anxiety, depression, and NDD symptoms at age 9. Anxiety and NDD symptoms in childhood predicted the largest amount of internalizing symptoms in adolescence. Conclusions: Adolescent internalizing symptoms are modestly affected by childhood symptoms of anxiety, depression, and NDDs, suggesting that they may represent different constructs across age. Future studies should further empirically investigate differences in etiology and trajectories of childhood versus adolescent internalizing symptoms

Aggravated brain damage after hypoxic ischemia in immature adenosine A2A knockout mice.

BACKGROUND AND PURPOSE: Cerebral hypoxic ischemia (HI) is an important cause of brain injury in the newborn infant. Adenosine is believed to protect against HI brain damage. However, the roles of the different adenosine receptors are unclear, particularly in young animals. We examined the role of adenosine A2A receptors (A2AR) using 7-day-old A2A knockout (A2AR(-/-)) mice in a model of HI. METHODS: HI was induced in 7-day-old CD1 mice by exposure to 8% oxygen for 30 minutes after occlusion of the left common carotid artery. The resulting unilateral focal lesion was evaluated with the use of histopathological scoring and measurements of residual brain areas at 5 days, 3 weeks, and 3 months after HI. Behavioral evaluation of brain injury by locomotor activity, rotarod, and beam-walking test was made 3 weeks and 3 months after HI. Cortical cerebral blood flow, assessed by laser-Doppler flowmetry, and rectal temperature were measured during HI. RESULTS: Reduction in cortical cerebral blood flow during HI and rectal temperature did not differ between wild-type (A2AR(+/+)) and knockout mice. In the A2AR(-/-) animals, brain injury was aggravated compared with wild-type mice. The A2AR(-/-) mice subjected to HI displayed increased forward locomotion and impaired rotarod performance in adulthood compared with A2AR(+/+) mice subjected to HI, whereas beam-walking performance was similarly defective in both groups. CONCLUSIONS: These results suggest that, in contrast to the situation in adult animals, A2AR play an important protective role in neonatal HI brain injury.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

The effect of autistic traits on response to and side-effects of pharmacological ADHD treatment in children with ADHD : results from a prospective clinical cohort

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition that globally affects an average of around 5% of children and is associated with several adverse life outcomes. Comorbidity with autism spectrum disorder (ASD) is highly prevalent. Pharmacological treatment for ADHD symptoms has been shown to be effective. However, the prevailing perception is that children with ADHD and concomitant ASD symptoms report poorer efficacy and more side effects. This has been supported by studies on this population, but prospective studies directly comparing children with ADHD and different levels of ASD symptoms are lacking. We aimed to assess if children with ADHD and concomitant ASD symptoms differ regarding effects and side-effects of pharmacological ADHD treatment compared to children with ADHD without ASD traits. This is to our knowledge the second study to directly compare the effect of ADHD medication between ADHD patients with different levels of ASD symptoms. METHODS: In a non-randomized, observational, prospective cohort study, 323 patients aged 6 to 17 years who were diagnosed with ADHD and starting pharmacological treatment were divided into two groups: one with high level of ASD symptoms (ASD group, N=71) and one with low level of ASD symptoms (non-ASD group, N = 252). Treatment outcome was measured as ADHD symptoms, and evaluated using the Swanson, Nolan and Pelham Teacher and Parent ADHD rating scale-version IV (SNAP-IV). Side-effects were evaluated using the Pediatric Side Effects Checklist (P-SEC), at 3 months follow-up. RESULTS: From baseline to 3 months, there was no significant difference in neither treatment effect nor number of clinically significant adverse events experienced between the ASD group and the non-ASD group. CONCLUSIONS: Our results did not implicate that ADHD patients with concomitant ASD symptoms have decreased treatment effect of ADHD medication than patients with ADHD without concomitant ASD symptoms. Neither did the results support that ADHD patients with ASD symptoms experienced significantly more side-effects than ADHD patients without ASD symptoms. Although, we did not analyze different medications separately, this is in line with the only previous study directly comparing methylphenidate treatment in children with or without ASD

Trends in childhood and adolescent internalizing symptoms : results from Swedish population based twin cohorts

BACKGROUND: Previous research has noted trends of increasing internalizing problems (e.g., symptoms of depression and anxiety), particularly amongst adolescent girls. Cross-cohort comparisons using identical assessments of both anxiety and depression in youth are lacking, however. METHODS: In this large twin study, we examined trends in internalizing symptoms in samples of 9 year old children and 15 year old adolescents, gathered from successive birth cohorts from 1998 to 2008 (age 9) and 1994-2001 (age 15). Assessments at age 9 were parent-rated, and at age 15 self- and parent-rated. We examined (i) the relation between birth cohorts and internalizing symptoms using linear regressions, and (ii) whether percentages of participants exceeding scale cut-off scores changed over time, using Cochrane Armitage Trend Tests. RESULTS: Among 9 year old children, a significantly increasing percentage of participants (both boys and girls) had scores above cut-off on anxiety symptoms, but not on depressive symptoms. At age 15, a significantly increasing percentage of participants (both boys and girls) had scores above cut-off particularly on self-reported internalizing symptoms. On parent-reported internalizing symptoms, only girls demonstrated a corresponding trend. CONCLUSION: In line with previous studies, we found small changes over sequential birth cohorts in frequencies of depression and anxiety symptoms in children. Further, these changes were not exclusive to girls

Adolescents on psychotropic treatment displayed longer corrected QT intervals than unmedicated controls when they rose rapidly from the supine position

Aim: Psychotropic medication can contribute to arrhythmia and identifying individuals at risk is crucial. This Swedish study compared the corrected QT (QTc) intervals of adolescents on psychotropic medication with unmedicated controls, when supine and after rising rapidly. Methods: The study was carried out at Östersund County Hospital in March 2022 and February to March 2023. It comprised 16 cases, aged 10–17 years and 28 controls. QTc intervals were measured with electrocardiography and calculated using Bazett's and Fridericia's formulas. Univariate and multiple linear regressions were used to assess differences in QTc intervals between the cases and controls and across sex, age and body mass index. Results: The mean QTc interval when supine, calculated with Bazett's formula, was longer for the adolescents on psychotropic medication than the controls (p = 0.046). The same was true for the mean QTc interval after rising rapidly from the supine position, calculated with both Bazett's formula (p = 0.009) and Fridericia's formula (p = 0.007). Mean QTc intervals varied by sex and age groups. Psychotropic medication prolonged QTc intervals, particularly in girls. Conclusion: Longer QTc intervals were found in adolescents on psychotropic medication, particularly after rising rapidly from the supine position