Do Poor Diet and Lifestyle Behaviors Modify the Genetic Susceptibility to Impulsivity in the General Population?

The present study investigated whether an unhealthy diet and other lifestyle behaviors may modify the genetic susceptibility to impulsivity. A total of 33,047 participants (mean age = 42.1 years, 59.8% females) from the Dutch Lifelines cohort were included. Each diet index and other lifestyle behaviors were tested for their interactions on the effect on the attention-deficit/hyperactivity disorder (ADHD) polygenic risk score (PRS) on impulsivity using a linear regression model with adjustment for covariates. The ADHD PRS was significantly associated with impulsivity (B = 0.03 (95% CI: 0.02, 0.04); p = 2.61 × 10-9). A poorer diet, a higher intake of energy, and a higher intake of fat were all associated with higher impulsivity, and a high intake of energy amplified the effect of ADHD PRS on impulsivity (e.g., for the interaction term of ADHD PRS and highest tertile on intake of energy, B = 0.038 (95% CI: 0.014, 0.062); p = 0.002. The other lifestyle factors, namely short and long sleep duration, current and past smoking, higher alcohol intake, and more time spent on moderate-to-vigorous physical activity were associated with higher impulsivity, but no interaction effect was observed. In conclusion, we found that a high intake of energy exacerbated the genetic susceptibility to impulsivity. Our study helps to improve our understanding of the role of diet and genetic factors on impulsivity.

Identifying populations at ultra-high risk of suicide using a novel machine learning method.

BACKGROUND: Targeted interventions for suicide prevention rely on adequate identification of groups at elevated risk. Several risk factors for suicide are known, but little is known about the interactions between risk factors. Interactions between risk factors may aid in detecting more specific sub-populations at higher risk. METHODS: Here, we use a novel machine learning heuristic to detect sub-populations at ultra high-risk for suicide based on interacting risk factors. The data-driven and hypothesis-free model is applied to investigate data covering the entire population of the Netherlands. FINDINGS: We found three sub-populations with extremely high suicide rates (i.e. >50 suicides per 100,000 person years, compared to 12/100,000 in the general population), namely: (1) people on unfit for work benefits that were never married, (2) males on unfit for work benefits, and (3) those aged 55-69 who live alone, were never married and have a relatively low household income. Additionally, we found two sub-populations where the rate was higher than expected based on individual risk factors alone: widowed males, and people aged 25-39 with a low level of education. INTERPRETATION: Our model is effective at finding ultra-high risk groups which can be targeted using sub-population level interventions. Additionally, it is effective at identifying high-risk groups that would not be considered risk groups based on conventional risk factor analysis.

Lifelong versus not lifelong death wishes in older adults without severe illness: a cross-sectional survey.

BACKGROUND: Some older adults with a persistent death wish without being severely ill report having had a death wish their whole lives (lifelong persistent death wish; L-PDW). Differentiating them from older adults without severe illness who developed a death wish later in life (persistent death wish, not lifelong; NL-PDW) can be relevant for the provision of adequate help and support. This study aims to gain insight into the characteristics, experiences, and needs of older adults with a L-PDW versus older adults with a NL-PDW and into the nature of their death wishes. METHODS: In the Netherlands, in April 2019, a cross-sectional survey study was conducted among a large representative sample of 32,477 citizens aged 55 years and older. Respondents with a L-PDW (N = 50) were compared with respondents with a NL-PDW (N = 217) using descriptive statistics, Kruskal-Wallis tests, and Fisher's exact tests. RESULTS: Respondents with a L-PDW were relatively younger and less often had (step)children. They less often looked back on a good and satisfying life with many good memories and more often reported trauma. Older adults with a NL-PDW more often reported loss and bereavement. Overall, the groups showed a lot of similarities. Both groups reported a death wish diverse in nature, numerous health problems, and a variety of needs for help and support. CONCLUSIONS: Some of the differences we found between the groups might be particularly relevant for the provision of adequate help and support to older adults with a L-PDW (i.e., their past and trauma) and to older adults with a NL-PDW (i.e., their loss and bereavement). The heterogeneity of both groups and the diverse nature of their death wish indicate that careful assessment of the death wish, its background, and underlying needs is required to provide personalized help and support to older adults with a death wish.

Low-grade inflammation as mediator between diet and behavioral disinhibition: A UK Biobank study.

BACKGROUND: Dietary patterns have been associated with variations in behavior. However, evidence has been limited and mixed, and the underlying mechanism remains unclear. OBJECTIVE: Extend a previous study reporting significant associations between food patterns and behavioral disinhibition and explore whether low-grade inflammation is linked to behaviors and mediates the association between diet and behavioral disinhibition. DESIGN: Among participants of the UK Biobank (UKB) we extracted a single behavioral disinhibition principal component using the UKB touchscreen questionnaire, Mental Health Questionnaire (MHQ), and registered diagnoses. We identified four dietary patterns (prudent diet, elimination of wheat/dairy/eggs, meat-based diet, full-cream dairy consumption) by using the Food Frequency Questionnaire (FFQ). Immune biomarkers and an aggregated inflammation score (INFLA-score) were used to characterize low-grade inflammation. Associations between dietary patterns and immune biomarkers, between immune biomarkers and disinhibition were assessed, with adjustment for demographics, lifestyle factors, and somatic health conditions. Next, mediation analyses were run to examine whether the association between dietary patterns and disinhibition was partially explained by inflammatory levels. We also conducted subgroup analyses to explore whether associations and the mediation effect differed by sex, age, ethnicity/race, body-mass-index (BMI), and socioeconomic status (SES). RESULTS: The prudent diet was negatively, and the meat-based diet was positively associated with several pro-inflammatory biomarkers. Most immune biomarkers were positively associated with disinhibition (numbers of lymphocytes (ßstandardized = 0.082, p < 0.001), monocytes (ßstandardized = 0.043, p < 0.001), neutrophils (ßstandardized = 0.071, p < 0.001), platelets (ßstandardized = 0.022, p < 0.001), leukocytes (ßstandardized = 0.093, p < 0.001), C-reactive protein (ßstandardized = 0.051, p < 0.001), and for INFLA-score (ßstandardized = 0.074, p < 0.001). In the mediation model, the INFLA-score mediated the association between prudent diet and meat-based diet and disinhibition score, with a significant indirect effect of low-grade inflammation for the prudent diet-disinhibition association (ßstandardized = -0.007, p < 0.001) and for meat-disinhibition association (ßstandardized = 0.001, p < 0.001)). Although all effects were small, covariates and interaction term adjustments did not attenuate the effects, and neither did most subgroup-only analyses. CONCLUSIONS: The prudent diet was associated with a lower disinhibition score and this effect was partially mediated by the lower inflammation. Reversely, the meat-based diet was linked to more inflammation, which was associated with more disinhibition. Our findings suggest mediating effects of immune function in the relationship between diet and behavioral disinhibition. However further alternative designs such as interventional trials are needed to establish causal effects.

Socioeconomic differences in major depressive disorder onset among adults are partially explained by lifestyle factors: A longitudinal analysis of the Lifelines Cohort Study.

BACKGROUND: Major depressive disorder (MDD) onset varies by socioeconomic position (SEP), this could be explained by lifestyle factors, but little is known about this pathway. Our study aims to disentangle the interplay between SEP measures (i.e., education, income and occupational prestige) and MDD onset and to examine to what extent these associations are mediated by lifestyle (i.e., occupational- and leisure time physical activity, smoking, alcohol intake, diet quality, sleep and central adiposity). METHODS: A subsample (n = 76,045) of the Lifelines Cohort Study without MDD at baseline was included. MDD onset was measured after a median follow-up time of 3.8 years with the Mini International Neuropsychiatric Interview (MINI). Direct associations between SEP, lifestyle and MDD onset were estimated using logistic regression analyses. Mediating percentages were estimated using the Karlson-Holm-Breen method. RESULTS: 1864 participants (2.5 %) showed MDD at follow-up. SEP was inversely associated with MDD onset, with education showing the strongest association. Educational, income and occupational differences in MDD onset were for 18.7 %, 5.9 % and 21.7 % explained by lifestyle factors (mainly smoking, alcohol intake and central adiposity). LIMITATIONS: SEP and lifestyle factors were measured simultaneously at baseline. MDD status (only based on a screening tool) was only measured at baseline and 3.8 years later. CONCLUSIONS: Compared to their lower SEP counterparts, higher SEP individuals had a lower risk of MDD onset. This was partially explained by a healthier lifestyle (mainly less smoking, alcohol intake and central adiposity) of the higher SEP individuals.

The gut microbiome as mediator between diet and its impact on immune function.

Dietary habits may affect inflammatory status in humans. Here we explore this interaction as well as the potential mediating role of the gut microbiome (GM), given that the GM is both involved in processing of dietary components and influences the immune system. A cross-sectional analysis of a sample of 482 healthy participants (207 males and 275 females) was performed. Dietary intake was assessed by a semiquantitative food questionnaire. Adipokines and soluble inflammatory mediators were assayed with multiple immunoassays and ELISA. Microbial DNA was extracted from frozen stool samples of 471 participants. Polychoric correlation analysis was used to establish dietary patterns, and joint multivariate associations between these dietary patterns and immune biomarkers were studied using regression analyses with adjustment for sex, age, BMI, smoking, education levels and physical exercise and other dietary patterns. Non-parametric entropy mediation was applied to investigate whether diet-immune relationships are mediated by abundance of microbial species. In this cohort, we identified three dietary patterns, characterized as "high-meat" (meat and sweetened drink), "prudent diet" (fish, fruit, legumes and vegetables) and "high alcohol" (higher alcohol consumption). Higher adherence to prudent diet was associated with a higher adiponectin level. The high alcohol pattern was associated with high concentrations of circulating concentrations of pro-inflammatory markers (CRP, IL-6, VEGF). Dialister invisus was found to mediate the relationship between a prudent dietary pattern and adiponectin, AAT, CRP, IL-6, and VEGF. In conclusion, a meat-based diet and a diet with high alcohol consumption were associated with high concentrations of biomarkers of chronic low-grade inflammation, and conversely, a prudent diet was associated with anti-inflammatory biomarkers. Diet-inflammation regulation may differ between sexes. Mediation analyses revealed that the association between prudent diet and immune function was partially mediated by the GM. The study adds to our understanding of the associations between diet, the immune system and the GM in a healthy population.

Association of sweetened carbonated beverage consumption during pregnancy and ADHD symptoms in the offspring: a study from the Norwegian Mother, Father and Child Cohort Study (MoBa).

PURPOSE: Intrauterine exposures influence offspring health and development. Here we investigated maternal intake of sweetened carbonated beverages (SCB) during pregnancy and its association with ADHD symptoms in the offspring. METHODS: This study was based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. Maternal diet mid-pregnancy was assessed using a food frequency questionnaire (FFQ). All mothers who responded to the FFQ and a questionnaire when their child was 8 years of age were included (n = 39,870). The exposure was defined as maternal intake (daily servings) of SCB, using no daily intake as reference. Outcome was offspring ADHD symptoms, evaluated as a continuous standardized ADHD score and as a binary outcome of six or more ADHD symptoms vs. five symptoms or less. Associations were analysed using log-binomial regression and linear mixed regression models with adjustment for covariates. RESULTS: The adjusted regression coefficients for the standardized ADHD offspring symptom score were 0.31 [95% confidence intervals (0.001, 0.62)] and 0.46 (0.15, 0.77) for maternal daily intake of ≥ 1 glasses of SCB, when the models included adjustments for total energy intake or energy intake from other sources than SCBs and sweet drinks, respectively. The corresponding adjusted relative risks were 1.16 (1.004, 1.34) and 1.21. (1.05, 1.39) for drinking ≥ 1 glasses daily. CONCLUSION: In a large pregnancy cohort with offspring followed until 8 years of age, we found an association between maternal daily intake of SCB and offspring ADHD symptoms. These results suggest a weak positive relationship between prenatal exposure to SCB and offspring ADHD.

Cortical and Subcortical Brain Volumes Partially Mediate the Association between Dietary Composition and Behavioral Disinhibition: A UK Biobank Study.

Behavioral disinhibition is observed to be an important characteristic of many neurodevelopmental and psychiatric disorders. Recent studies have linked dietary quality to levels of behavioral inhibition. However, it is currently unclear whether brain factors might mediate this. The current study investigates whether cortical and subcortical brain volumes mediate part of the association between dietary composition and behavioral disinhibition. A total of 15,258 subjects from the UK Biobank project were included in the current study. Dietary composition and behavioral disinhibition were based on Principle Component Analyses of self-reported dietary composition). As a further data reduction step, cortical and subcortical volume segmentations were input into an Independent Component Analysis. The resulting four components were used as mediator variables in the main mediation analyses, where behavioral disinhibition served as the outcome variable and dietary components as predictors. Our results show: (1) significant associations between all dietary components and brain volume components; (2) brain volumes are associated with behavioral disinhibition; (3) the mediation models show that part of the variance in behavioral disinhibition explained by dietary components (for healthy diet, restricted diet, and high-fat dairy diet) is mediated through the frontal-temporal/parietal brain volume component. These results are in part confirming our hypotheses and offer a first insight into the underlying mechanisms linking dietary composition, frontal-parietal brain volume, and behavioral disinhibition in the general adult population.

Diet, Physical Activity, and Disinhibition in Middle-Aged and Older Adults: A UK Biobank Study.

Disinhibition is a prominent feature of multiple psychiatric disorders, and has been associated with poor long-term somatic outcomes. Modifiable lifestyle factors including diet and moderate-to-vigorous physical activity (MVPA) may be associated with disinhibition, but their contributions have not previously been quantified among middle-aged/older adults. Here, among N = 157,354 UK Biobank participants aged 40-69, we extracted a single disinhibition principal component and four dietary components (prudent diet, elimination of wheat/dairy/eggs, meat consumption, full-cream dairy consumption). In addition, latent profile analysis assigned participants to one of five empirical dietary groups: prudent-moderate, unhealthy, restricted, meat-avoiding, low-fat dairy. Disinhibition was regressed on the four dietary components, the dietary grouping variable, and self-reported MVPA. In men and women, disinhibition was negatively associated with prudent diet, and positively associated with wheat/dairy/eggs elimination. In men, disinhibition was also associated with consumption of meat and full-cream dairy products. Comparing groups, disinhibition was lower in the prudent-moderate diet (reference) group compared to all other groups. Absolute ßs ranged from 0.02-0.13, indicating very weak effects. Disinhibition was not associated with MVPA. In conclusion, disinhibition is associated with multiple features of diet among middle-aged/older adults. Our findings foster specific hypotheses (e.g., early malnutrition, elevated immune-response) to be tested in alternative study designs.

Investigating whether a combination of higher CRP and depression is differentially associated with worse executive functioning in a cohort of 43,896 adults.

Many depressed individuals experience difficulties in executive functioning that contribute substantially to functional impairment. It is unknown whether a subtype of depression characterized by chronic inflammation is differentially associated with worse executive functioning. This study examined whether the combination of depression and higher C reactive protein (CRP) is differentially associated with worse executive functioning and whether this association is stronger in older adults. This cross-sectional study analyzed data collected from a population-representative sample of 43,896 adults aged 44.13 years (SD = 13.52) who participated in the baseline assessment of the Lifelines cohort study. Multivariate regression models tested whether depressed individuals (established via structured interview) exhibiting higher levels of inflammation (indexed via high-sensitivity CRP assay following an overnight fast) performed worse on a behavioral test of executive functioning. Depression (B = -3.66, 95% CI: -4.82, -2.49, p < .001) and higher log-transformed CRP (B = -0.67, 95% CI: -0.87,-0.47, p < .001) were associated with worse executive functioning, after adjustment for age, sex, educational attainment, body mass index, smoking status, exposure to stressful life events and chronic stressors, sedentary behavior, and number of chronic medical conditions. Depressed individuals with higher log-transformed CRP exhibited differentially poorer executive functioning (B = -1.09, 95% CI: -2.07,-0.11, p < .001). This association did not differ based on age (B = 0.01, 95% CI: -0.08, 0.10, p = .82). Executive functioning is poorer in depressed individuals with higher CRP, even in early adulthood. Interventions that reduce inflammation may improve cognitive functioning in depression.

Diet quality, stress and common mental health problems: A cohort study of 121,008 adults.

BACKGROUND & AIMS: Overall diet quality may partially mediate the detrimental effects of stress and neuroticism on common mental health problems: stressed and/or neurotic individuals may be more prone to unhealthy dietary habits, which in turn may contribute to depression and anxiety. Lifestyle interventions for depressed, anxious or at-risk individuals hinge on this idea, but evidence to support such pathway is missing. Here, we aim to prospectively evaluate the role of overall diet quality in common pathways to developing depression and anxiety. METHODS: At baseline, N = 121,008 individuals from the general population (age 18-93) completed an extensive food frequency questionnaire, based on which overall diet quality was estimated. Participants also reported on two established risk factors for mental health problems, i.e. past-year stress exposure (long-term difficulties, stressful life-events) and four neuroticism traits (anger-hostility, self-consciousness, impulsivity, vulnerability). Depression and anxiety were assessed at baseline and follow-up (n = 65,342, +3.6 years). Overall diet quality was modeled as a mediator in logistic regression models predicting the development of depression and anxiety from common risk factors. RESULTS: High stress and high neuroticism scores were - albeit weakly - associated with poorer diet quality. Poor diet quality, in turn, did not predict mental health problems. Overall diet quality did not mediate the relationship between stress/neuroticism and common mental health problems: effects of stress, neuroticism and stress-by-neuroticism interactions on mental health problems at follow-up consisted entirely of direct effects (98.6%-100%). CONCLUSIONS: Diet quality plays no mediating role in two established pathways to common mental health problems. As overall diet quality was reduced in stressed and neurotic individuals, these groups may benefit from dietary interventions. However, such interventions are unlikely to prevent the onset or recurrence of depression and anxiety.

Trajectories of depression symptom change during and following treatment in adolescents with unipolar major depression.

OBJECTIVE: To classify a cohort of depressed adolescents recruited to the UK IMPACT trial, according to trajectories of symptom change. We examined for predictors and compared the data-driven categories of patients with a priori operational definitions of treatment response. METHOD: Secondary data analysis using growth mixture modelling (GMM). Missing data were imputed. Trajectories of self-reported depressive symptoms were plotted using scores taken at six nominal time points over 86 weeks from randomisation in all 465 patients. RESULTS: A piecewise GMM categorised patients into two classes with initially similar and subsequently distinct trajectories. Both groups had a significant decline in depressive symptoms over the first 18 weeks. Eighty-four per cent (84.1%, n = 391) of patients were classed as 'continued-improvers' with symptoms reducing over the duration of the study. A further class of 15.9% (n = 74) of patients were termed 'halted-improvers' with higher baseline depression scores, faster early recovery but no further improvement after 18 weeks. Presence of baseline comorbidity somewhat increased membership to the halted-improvers class (OR = 1.40, CI: 1.00-1.96). By end of study, compared with classes, a clinical remission cut-off score (≤27) and a symptom reduction score (≥50%) indexing treatment response misclassified 15% and 31% of cases, respectively. CONCLUSIONS: A fast reduction in depressive symptoms in the first few weeks of treatment may not indicate a good prognosis. Halted improvement is only seen after 18 weeks of treatment. Longitudinal modelling may improve the precision of revealing differential responses to treatment. Improvement in depressive symptoms may be somewhat better in the year after treatment than previously considered.

Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples.

OBJECTIVE: Neuroimaging studies show structural alterations of various brain regions in children and adults with attention deficit hyperactivity disorder (ADHD), although nonreplications are frequent. The authors sought to identify cortical characteristics related to ADHD using large-scale studies. METHODS: Cortical thickness and surface area (based on the Desikan-Killiany atlas) were compared between case subjects with ADHD (N=2,246) and control subjects (N=1,934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, case subjects, unaffected siblings, and control subjects in the NeuroIMAGE study (N=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, N=2,707). RESULTS: In the ENIGMA-ADHD sample, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest significant effect was for total surface area (Cohen's d=-0.21). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescent or adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in the Generation-R sample. CONCLUSIONS: Subtle differences in cortical surface area are widespread in children but not adolescents and adults with ADHD, confirming involvement of the frontal cortex and highlighting regions deserving further attention. Notably, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to nonsignificant findings in adolescent and adult groups despite the presence of an ADHD diagnosis.

Overweight in family members of probands with ADHD.

The widely reported association between ADHD and overweight may be attributable to genetic and environmental factors also present in unaffected family members. Therefore, the purpose of this study was to examine the association between ADHD and overweight within families. A cohort was used of families with at least one member with ADHD, recruited as part of the Dutch node of the International Multicenter ADHD Genetics (IMAGE) study, with assessments taking place between 2003 and 2006, 2009 and 2012, and 2013 and 2015. The three assessment waves yielded N = 1828 youth assessments and N = 998 parent assessments from N = 447 unique families. Overweight was defined as a body mass index (BMI) ≥ 85th percentile for youth of the same age and sex; overweight in adults as a BMI ≥ 25. Effects of age, gender, and medication use (psychostimulants, antipsychotics, and melatonin) were taken into account. Generalized estimation equations were used to correct for within-family and within-subject correlations. There was no difference in risk between ADHD-affected youth and their unaffected siblings (OR 0.92, 95% CI 0.78-1.09). However, compared to population prevalence data, all ADHD family members alike were at increased risk for being overweight: ADHD-affected youth (OR 1.33, 95% CI 1.13-1.59), unaffected siblings (OR 1.73, 95% CI 1.45-2.08), mothers (OR 1.74, 95% CI 1.40-2.17) and fathers (OR 1.78, 95% CI 1.46-2.15). Parental overweight-but not parental ADHD-was predictive of offspring overweight (mothers OR 1.40; 95% CI 1.14-1.73, fathers OR 1.83; 95% CI 1.41-2.36). Being overweight runs in ADHD families, yet is not specifically linked to ADHD within families. Shared unhealthy lifestyle factors (including nutrition, sleep, exercise, stress) as well as genetic factors shared by family members likely explain the findings.

Stimulant treatment profiles predicting co-occurring substance use disorders in individuals with attention-deficit/hyperactivity disorder.

Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence (ND). It remains unclear whether and how stimulant treatment may affect this risk. We aimed to investigate how stimulant use profiles influence the risk of SUDs and ND, using a novel data-driven community detection analysis to construct different stimulant use profiles. Comprehensive lifetime stimulant prescription data and data on SUDs and ND were available for 303 subjects with ADHD and 219 controls, with a mean age 16.3 years. Community detection was used to define subgroups based on multiple indicators of treatment history, start age, treatment duration, total dose, maximum dose, variability, stop age. In stimulant-treated participants, three subgroups with distinct medication trajectories were distinguished (late-and-moderately dosed, n = 91; early-and-moderately dosed, n = 51; early-and-intensely dosed, n = 103). Compared to stimulant-naïve participants (n = 58), the early-and-intense treatment group had a significantly lower risk of SUDs and ND (HR = 0.28, and HR = 0.29, respectively), while the early-and-moderate group had a significantly lower risk of ND only (HR = 0.30). The late-and-moderate group was at a significantly higher risk of ND compared to the other two treatment groups (HR = 2.66 for early-and-moderate, HR = 2.78 for early-and-intense). Our findings show that in stimulant-treated adolescents with ADHD, long-term outcomes are associated with treatment characteristics, something that is often ignored when treated individuals are compared to untreated individuals.

Long-term effects of stimulant treatment on ADHD symptoms, social-emotional functioning, and cognition.

BACKGROUND: Methodological and ethical constraints have hampered studies into long-term lasting outcomes of stimulant treatment in individuals with attention-deficit/hyperactivity disorder (ADHD). Lasting effects may be beneficial (i.e. improved functioning even when treatment is temporarily ceased) or detrimental (i.e. worse functioning while off medication), but both hypotheses currently lack empirical support. Here we investigate whether stimulant treatment history predicts long-term development of ADHD symptoms, social-emotional functioning or cognition, measured after medication wash-out. METHODS: ADHD symptoms, social-emotional functioning and cognitive test performance were measured twice, 6 years apart, in two ADHD groups (stimulant-treated versus not stimulant-treated between baseline and follow-up). Groups were closely matched on baseline clinical and demographic variables (n = 148, 58% male, age = 11.1). A matched healthy control group was included for reference. RESULTS: All but two outcome measures (emotional problems and prosocial behaviour) improved between baseline and follow-up. Improvement over time in the stimulant-treated group did not differ from improvement in the not stimulant-treated group on any outcome measure. CONCLUSIONS: Stimulant treatment is not associated with the long-term developmental course of ADHD symptoms, social-emotional functioning, motor control, timing or verbal working memory. Adolescence is characterised by clinical improvement regardless of stimulant treatment during that time. These findings are an important source to inform the scientific and public debate.

Stimulant Treatment Trajectories Are Associated With Neural Reward Processing in Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: The past decades have seen a surge in stimulant prescriptions for the treatment of attention-deficit/hyperactivity disorder (ADHD). Stimulants acutely alleviate symptoms and cognitive deficits associated with ADHD by modulating striatal dopamine neurotransmission and induce therapeutic changes in brain activation patterns. Long-term functional changes after treatment are unknown, as long-term studies are scarce and have focused on brain structure. In this observational study (2009-2012), we investigated associations between lifetime stimulant treatment history and neural activity during reward processing. METHODS: Participants fulfilling DSM-5 criteria for ADHD (N = 269) were classified according to stimulant treatment trajectory. Of those, 124 performed a monetary incentive delay task during magnetic resonance imaging, all in their nonmedicated state (nEARLY&INTENSE = 51; nLATE&MODERATE = 49; nEARLY&MODERATE = 9; nNAIVE = 15; mean age = 17.4 years; range, 10-26 years). Whole-brain analyses were performed with additional focus on the striatum, concentrating on the 2 largest treatment groups. RESULTS: Compared to the late-and-moderate treatment group, the early-and-intense treatment group showed more activation in the supplementary motor area and dorsal anterior cingulate cortex (SMA/dACC) during reward outcome (cluster size = 8,696 mm³; PCLUSTER < .001). SMA/dACC activation of the control group fell in between the 2 treatment groups. Treatment history was not associated with striatal activation during reward processing. CONCLUSIONS: Our findings are compatible with previous reports of acute increases of SMA/dACC activity in individuals with ADHD after stimulant administration. Higher SMA/dACC activity may indicate that patients with a history of intensive stimulant treatment, but currently off medication, recruit brain regions for cognitive control and/or decision-making upon being rewarded. No striatal or structural changes were found.

Healthy cortical development through adolescence and early adulthood.

Adolescence is a period of significant brain changes; however, the effects of age and sex on cortical development are yet to be fully characterized. Here, we utilized innovative intrinsic curvature (IC) analysis, along with the traditional cortical measures [cortical thickness (CT), local gyrification index (LGI), and surface area (SA)], to investigate how these indices (1) relate to each other and (2) depend on age and sex in adolescent cortical development. T1-weighted magnetic resonance images from 218 healthy volunteers (age range 8.3-29.2 years, M[SD] = 16.5[3.4]) were collected at two sites and processed with FreeSurfer and Caret software packages. Surface indices were extracted per cortex area (frontal, parietal, occipital, temporal, insula, and cingulate). Correlation analyses between the surface indices were conducted and age curves were modelled using generalized additive mixed-effect models. IC showed region-specific associations with LGI, SA, and CT, as did CT with LGI. SA was positively associated with LGI in all regions and CT in none. CT and LGI, but not SA, were inversely associated with age in all regions. IC was inversely associated with age in all but the occipital region. For all regions, males had larger cortical SA than females. Males also had larger LGI in all regions and larger IC of the frontal area; however, these effects were accounted for by sex differences in SA. There were no age-by-sex interactions. The study of IC adds a semi-independent, sensitive measure of cortical morphology that relates to the underlying cytoarchitecture and may aid understanding of normal brain development and deviations from it.

An update on the safety of psychostimulants for the treatment of attention-deficit/hyperactivity disorder.

INTRODUCTION: Methylphenidate is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). Although methylphenidate has a well-established evidence base for treating ADHD, its long-term benefits are unclear. Areas covered: Physical adverse effects, psychiatric adverse events and brain development Expert opinion: Some physical adverse events have been described (e.g. sleep disturbances, growth reduction, loss of appetite), although most are of transient nature. Psychiatric adverse events seem more related to the diagnosis ADHD itself, and not stimulant treatment. Concluding, short-to-mid-term use (i.e., up to 2 years) stimulants are relatively safe, but much less is known about longer-term efficacy and safety of these drugs.