[Internal conflicts in psychoeducation for parents of children with ADHD: discours analysis]. / Tegenstrijdigheden in psycho-educatie voor ouders van kinderen met ADHD: een discoursanalyse.

BACKGROUND: Psychoeducation plays an important role in how people understand their own psychiatric classification. Since children and parents see psychoeducation as a representation of how their story is understood by the therapist, it affects the therapeutic alliance. Moreover, psychoeducation indirectly shapes the way society understands psychological differences. AIM: To understand how the classification ADHD is given meaning through psychoeducation. METHOD: We analyzed the discourse of 41 written psychoeducational materials from four different countries (USA, UK,
the Netherlands and Hungary). RESULTS: We identified five patterns, of which four contained an element of internal conflict. Notably, conflicts were found within a single thematic stance on ADHD as opposed to a conflict between parties with a different vision on ADHD. CONCLUSION: These conflicts cause confusion, misrepresentation and decontextualization of problems. Ultimately, for those diagnosed with ADHD and their parents, this may hamper their ability to understand themselves in the context of their difficulties.

Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project.

An increasing number of large-scale multi-modal research initiatives has been conducted in the typically developing population, e.g. Dev. Cogn. Neur. 32:43-54, 2018; PLoS Med. 12(3):e1001779, 2015; Elam and Van Essen, Enc. Comp. Neur., 2013, as well as in psychiatric cohorts, e.g. Trans. Psych. 10(1):100, 2020; Mol. Psych. 19:659-667, 2014; Mol. Aut. 8:24, 2017; Eur. Child and Adol. Psych. 24(3):265-281, 2015. Missing data is a common problem in such datasets due to the difficulty of assessing multiple measures on a large number of participants. The consequences of missing data accumulate when researchers aim to integrate relationships across multiple measures. Here we aim to evaluate different imputation strategies to fill in missing values in clinical data from a large (total N = 764) and deeply phenotyped (i.e. range of clinical and cognitive instruments administered) sample of N = 453 autistic individuals and N = 311 control individuals recruited as part of the EU-AIMS Longitudinal European Autism Project (LEAP) consortium. In particular, we consider a total of 160 clinical measures divided in 15 overlapping subsets of participants. We use two simple but common univariate strategies-mean and median imputation-as well as a Round Robin regression approach involving four independent multivariate regression models including Bayesian Ridge regression, as well as several non-linear models: Decision Trees (Extra Trees., and Nearest Neighbours regression. We evaluate the models using the traditional mean square error towards removed available data, and also consider the Kullback-Leibler divergence between the observed and the imputed distributions. We show that all of the multivariate approaches tested provide a substantial improvement compared to typical univariate approaches. Further, our analyses reveal that across all 15 data-subsets tested, an Extra Trees regression approach provided the best global results. This not only allows the selection of a unique model to impute missing data for the LEAP project and delivers a fixed set of imputed clinical data to be used by researchers working with the LEAP dataset in the future, but provides more general guidelines for data imputation in large scale epidemiological studies.

Preference for biological motion is reduced in ASD: implications for clinical trials and the search for biomarkers.

BACKGROUND: The neurocognitive mechanisms underlying autism spectrum disorder (ASD) remain unclear. Progress has been largely hampered by small sample sizes, variable age ranges and resulting inconsistent findings. There is a pressing need for large definitive studies to delineate the nature and extent of key case/control differences to direct research towards fruitful areas for future investigation. Here we focus on perception of biological motion, a promising index of social brain function which may be altered in ASD. In a large sample ranging from childhood to adulthood, we assess whether biological motion preference differs in ASD compared to neurotypical participants (NT), how differences are modulated by age and sex and whether they are associated with dimensional variation in concurrent or later symptomatology. METHODS: Eye-tracking data were collected from 486 6-to-30-year-old autistic (N = 282) and non-autistic control (N = 204) participants whilst they viewed 28 trials pairing biological (BM) and control (non-biological, CTRL) motion. Preference for the biological motion stimulus was calculated as (1) proportion looking time difference (BM-CTRL) and (2) peak look duration difference (BM-CTRL). RESULTS: The ASD group showed a present but weaker preference for biological motion than the NT group. The nature of the control stimulus modulated preference for biological motion in both groups. Biological motion preference did not vary with age, gender, or concurrent or prospective social communicative skill within the ASD group, although a lack of clear preference for either stimulus was associated with higher social-communicative symptoms at baseline. LIMITATIONS: The paired visual preference we used may underestimate preference for a stimulus in younger and lower IQ individuals. Our ASD group had a lower average IQ by approximately seven points. 18% of our sample was not analysed for various technical and behavioural reasons. CONCLUSIONS: Biological motion preference elicits small-to-medium-sized case-control effects, but individual differences do not strongly relate to core social autism associated symptomatology. We interpret this as an autistic difference (as opposed to a deficit) likely manifest in social brain regions. The extent to which this is an innate difference present from birth and central to the autistic phenotype, or the consequence of a life lived with ASD, is unclear.

Distinct neuropsychological profiles within ADHD: a latent class analysis of cognitive control, reward sensitivity and timing.

BACKGROUND: Multiple pathway models of attention deficit hyperactivity disorder (ADHD) suggest that this disorder is the behavioural expression of dysfunction in one of several separable brain systems. One such model focuses on the brain systems underlying cognitive control, timing and reward sensitivity. It predicts separable subgroups among individuals with ADHD, with performance deficits in only one of these domains. We used latent class analysis (LCA) to identify subgroups of individuals with ADHD based on their overall pattern of neuropsychological performance, rather than grouping them based on cut-off criteria. We hypothesized that we would find separable subgroups with deficits in cognitive control, timing and reward sensitivity respectively. METHOD: Ninety-six subjects with ADHD (of any subtype) and 121 typically developing controls performed a battery assessing cognitive control, timing and reward sensitivity. LCA was used to identify subgroups of individuals with ADHD with a distinct neuropsychological profile. A similar analysis was performed for controls. RESULTS: Three subgroups represented 87% of subjects with ADHD. Two of our three hypothesized subgroups were identified, with poor cognitive control and timing. Two of the ADHD subgroups had similar profiles to control subgroups, whereas one subgroup had no equivalent in controls. CONCLUSIONS: Our findings support multiple pathway models of ADHD, as we were able to define separable subgroups with differing cognitive profiles. Furthermore, we found both quantitative and qualitative differences from controls, suggesting that ADHD may represent both categorical and dimensional differences. These results show that by addressing heterogeneity in ADHD, we can identify more homogeneous subsets of individuals to further investigate.

Functional connectivity during cognitive control in children with autism spectrum disorder: an independent component analysis.

Restrictive and repetitive behavior in autism may be related to deficits in cognitive control. Here, we aimed to assess functional connectivity during a cognitive control task and compare brain network activity and connectivity in children with autism spectrum disorders (ASD) and typically developing children using a multivariate data-driven approach. 19 high-functioning boys with ASD and 19 age-matched typically developing boys were included in this study. Functional magnetic resonance imaging was performed at 3T during the performance of a cognitive control task (go/no-go paradigm). Functional networks were identified using independent component analysis. Network activity and connectivity was compared between groups and correlated with clinical measures of rigid behavior using multivariate analysis of covariance. We found no differences between the groups in task performance or in network activity. Power analysis indicated that, if this were a real difference, it would require nearly 800 subjects to show group differences in network activity using this paradigm. Neither were there correlations between network activity and rigid behavior. Our data do not provide support for the presence of deficits in cognitive control in children with ASD, or the functional networks supporting this ability.

Adolescents at ultra-high risk for psychosis: long-term outcome of individuals who recover from their at-risk state.

Studies of individuals at ultra-high risk (UHR) for psychosis have mostly reported on long-term outcome of those individuals who develop psychosis compared to those who do not. However, these studies show that a large number of UHR individuals no longer meet criteria for UHR at follow-up. Therefore, this study aimed to investigate functioning at 6-year follow-up in remitted individuals, and to explore the course of their clinical symptoms. Forty-four UHR adolescents completed extensive clinical assessments at baseline and participated in long-term follow-up approximately six years later. UHR adolescents who had either converted to psychosis or who still met UHR criteria (n=26) at follow-up were compared to individuals who had remitted from their UHR status (n=18) on clinical and psychosocial variables. Results show that more than 40% of UHR individuals had fully remitted from their UHR status. At six-year follow-up, remitted individuals had improved clinically on most symptoms. The course of their symptoms showed that the most substantial reduction in positive symptoms occurred within the first two years, while improvements in general, mood and anxiety symptoms occurred at a later stage. Baseline socio-demographic characteristics and clinical symptoms did not distinguish between remitters and non-remitters. Although remitters no longer met criteria for UHR, they did meet diagnostic criteria for a wide range of psychiatric disorders. Our findings suggest that, when related to long-term outcome, UHR criteria capture non-specific psychotic symptoms rather than risk for psychosis per se and relate more to general psychopathology.

Prenatal exposure to cigarette smoke or alcohol and cerebellum volume in attention-deficit/hyperactivity disorder and typical development.

Prenatal exposure to teratogenic substances, such as nicotine or alcohol, increases the risk of developing attention-deficit/hyperactivity disorder (ADHD). To date, studies examining this relationship have used symptom scales as outcome measures to assess the effect of prenatal exposure, and have not investigated the neurobiological pathways involved. This study explores the effect of prenatal exposure to cigarettes or alcohol on brain volume in children with ADHD and typically developing controls. Children with ADHD who had been exposed prenatally to either substance were individually matched to children with and without ADHD who had not been. Controls who had been exposed prenatally were also individually matched to controls who had not been. For prenatal exposure to both smoking and alcohol, we found a pattern where subjects with ADHD who had been exposed had the smallest brain volumes and unexposed controls had the largest, with intermediate volumes for unexposed subjects with ADHD. This effect was most pronounced for cerebellum. A similar reduction fell short of significance for controls who had been exposed to cigarettes, but not alcohol. Our results are consistent with an additive effect of prenatal exposure and ADHD on brain volume, with the effects most pronounced for cerebellum.

Understanding genes, environment and their interaction in attention-deficit hyperactivity disorder: is there a role for neuroimaging?

Attention-deficit hyperactivity disorder (ADHD) has an established heritable component, but identifying the genes involved has proven difficult. To date, the two most investigated risk genes in ADHD are the DRD4 and DAT1-genes. However, individual risk genes have only explained up to 1% of the variance in the phenotype, suggesting that they represent only relatively small risk factors for ADHD. As such, the role of environmental factors, gene-gene and gene-environment interactions are being investigated. However, studies have not always been able to address the neurobiological mechanisms by which environmental factors and interactions with genes exert their effect on the ADHD-phenotype. Neuroimaging is being used as a tool to investigate the neurobiological effects of individual risk genes. We suggest it could also be applied to investigate the mechanisms involved in environmental effects and interactions between genetic and environmental factors.

MRI-based morphometry in children with multiple complex developmental disorder, a phenotypically defined subtype of pervasive developmental disorder not otherwise specified.

BACKGROUND: The DSM-IV-R classification Pervasive Developmental Disorder - Not otherwise Specified (PDD-NOS) is based on the symptoms for autism and includes a wide variety of phenotypes that do not meet full criteria for autism. As such, PDD-NOS is a broad and poorly defined residual category of the autism spectrum disorders. In order to address the heterogeneity in this residual category it may be helpful to define clinical and neurobiological subtypes. Multiple complex developmental disorder (MCDD) may constitute such a subtype. In order to study the neurobiological specificity of MCDD in comparison with other autism spectrum disorders, we investigated brain morphology in children (age 7-15 years) with MCDD compared to children with autism and typically developing controls. METHOD: Structural MRI measures were compared between 22 high-functioning subjects with MCDD and 21 high-functioning subjects with autism, and 21 matched controls. RESULTS: Subjects with MCDD showed an enlarged cerebellum and a trend towards larger grey-matter volume compared to control subjects. Compared to subjects with autism, subjects with MCDD had smaller intracranial volume. CONCLUSIONS: We report a pattern of volumetric changes in the brains of subjects with MCDD, similar to that seen in autism. However, no enlargement in head size was found. This suggests that although some of the neurobiological changes associated with MCDD overlap with those in autism, others do not. These neurobiological changes may reflect differences in the developmental trajectories associated with these two subtypes of autism spectrum disorders.

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls.

Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior.

Parametric manipulation of conflict and response competition using rapid mixed-trial event-related fMRI.

In the current study we examined the influence of preceding context on attentional conflict and response competition using a flanker paradigm. Nine healthy right-handed adults participated in a rapid mixed trial event-related functional magnetic resonance imaging (fMRI) study, in which increasing numbers of either compatible or incompatible trials preceded an incompatible trial. Behaviorally, reaction times on incompatible trials increased as a function of the number of preceding compatible trials. Several brain regions showed monotonic changes to the preceding context manipulation. The most common pattern was observed in anterior cingulate, dorsolateral prefrontal, and superior parietal regions. These areas showed an increase in activity for incompatible trials as the number of preceding compatible trials increased and a decrease in activity for incompatible trials as the number of preceding incompatible trials increased. Post hoc analysis showed that while the MR signal in the anterior cingulate and dorsolateral prefrontal regions peaked before the superior parietal region, the dorsolateral prefrontal MR signal peaked early and remained at this level. These findings are consistent with the conflict monitoring theory that postulates that the anterior cingulate cortex detects or monitors conflict, while PFC is involved in control adjustments that may then lead to modulation of superior parietal cortex in top-down biasing of attention.

Brain morphology in antipsychotic-naïve schizophrenia: a study of multiple brain structures.

BACKGROUND: Although brain volume changes are found in schizophrenia, only a limited number of structural magnetic resonance imaging studies have exclusively examined antipsychotic-naïve patients. AIMS: To comprehensively investigate multiple brain structures in a single sample of patients who were antipsychotic-naïve. METHOD: Twenty antipsychotic-naïve patients with first-episode schizophrenia and 20 healthy comparison subjects were included. Intracranial, total brain, frontal lobe, grey and white matter, cerebellar, hippocampal, parahippocampal, thalamic, caudate nucleus and lateral and third ventricular volumes were measured. Repeated-measures analyses of (co)variance were conducted with intracranial volume as covariate. RESULTS: Third ventricle volume enlargement was found in patients compared with the healthy subjects. No differences were found in other brain regions. CONCLUSIONS: These findings suggest that some brain abnormalities are present in the early stages of schizophrenia. Moreover, it suggests that brain abnormalities reported in patients with chronic schizophrenia develop in a later stage of the disease and/or are medication induced.

The effect of preceding context on inhibition: an event-related fMRI study.

In this study we combined event-related fMRI with a parametric manipulation of the go nogo paradigm to examine the effect of preceding context on inhibitory processes. Nogo trials were preceded by either 1, 3, or 5 go trials and then compared to one another. Two distinct patterns of activation were associated with behavioral inhibition: First, the ventral prefrontal cortex, cingulate gyrus, and superior parietal regions showed a context effect with an increase in MR signal to nogo trials with increasing number of preceding go trials. Second, anterior regions in the supplementary and premotor cortex showed an increase in MR signal on the nogo condition after 5 preceding go trials, but not after only 1 or 3. A model using the BOLD response in our data was used to verify that the effect of context was not an artifact of the randomization scheme used in the design.

Anatomical MRI of the developing human brain: what have we learned?

OBJECTIVE: To critically review and integrate the existing literature on magnetic resonance imaging (MRI) studies of the normally developing brain in childhood and adolescence and discuss the implications for clinical MRI studies. METHOD: Changes in regional brain volume with age and differences between the sexes are summarized from reports in refereed journal articles pertaining to MRI of the developing human brain. RESULTS: White matter volume increases with age. Gray matter volumes increase during childhood and then decrease before adulthood. On average, boys have larger brains than girls; after correction for overall brain volume the caudate is relatively larger in girls, and the amygdala is relatively larger in boys. Differences are of clinical interest given gender-related differences in the age of onset, symptomatology, and prevalence noted for nearly all childhood-onset psychiatric disorders. Attention-deficit/hyperactivity disorder is frequently used as an example to demonstrate these points. CONCLUSIONS: Understanding the developmental trajectories of normal brain development and differences between the sexes is important for the interpretation of clinical imaging studies.

Volumes of brain structures in twins discordant for schizophrenia.

BACKGROUND: The study was designed to examine the relative contributions of genetic and nongenetic factors to structural brain abnormalities in schizophrenia and subjects at risk to develop the disorder. METHODS: The brains of 15 monozygotic and 14 same-sex dizygotic twins discordant for schizophrenia (patients) and 29 healthy twins pair-wise matched for zygosity, sex, age, and birth order were studied using high-resolution magnetic resonance imaging scans. RESULTS: Intracranial and whole-brain corrected frontal lobe volumes were smaller (4.6% and 2.7%, respectively) in discordant monozygotic twins as compared with healthy monozygotic twins. Irrespective of zygosity, discordant twins had smaller whole-brain (2%), parahippocampal (9%), and hippocampal (8%) volumes than healthy twins. Moreover, patients had smaller whole-brain volumes (2. 2%) than their nonschizophrenic cotwins, who in turn had smaller brains (1%) than healthy twins. Lateral and third-ventricle volumes were increased in discordant dizygotic twins as compared with healthy dizygotic twins (60.6% and 56.6%, respectively). Finally, within discordant twins, lateral ventricles were larger (14.4%) in patients than in their nonschizophrenic cotwins. CONCLUSIONS: Smaller intracranial volumes in the monozygotic patients and their cotwins suggest that increased genetic risk to develop schizophrenia is related to reduced brain growth early in life. The additional reduction in whole-brain volume found in the patients suggests that the manifestation of the disorder is related to (neurodegenerative) processes that are most likely nongenetic in origin.

Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients.

PURPOSE: [corrected] Capecitabine (Xeloda) is a novel fluoropyrimidine carbamate rationally designed to generate 5-fluorouracil (5-FU) preferentially in tumors. The purpose of this study was to demonstrate the preferential activation of capecitabine, after oral administration, in tumor in colorectal cancer patients, by the comparison of 5-FU concentrations in tumor tissues, healthy tissues and plasma. METHODS: Nineteen patients requiring surgical resection of primary tumor and/or liver metastases received 1,255 mg/m2 of capecitabine twice daily p.o. for 5-7 days prior to surgery. On the day of surgery, samples of tumor tissue, adjacent healthy tissue and blood samples were collected simultaneously from each patient, 2 to 12 h after the last dose of capecitabine had been administered. Concentrations of 5-FU in various tissues and plasma were determined by HPLC. The activities of the enzymes (CD, TP and DPD) involved in the formation and catabolism of 5-FU were measured in tissue homogenates, by catabolic assays. RESULTS: The ratio of 5-FU concentrations in tumor to adjacent healthy tissue (T/H) was used as the primary marker for the preferential activation of capecitabine in tumor. In primary colorectal tumors, the concentration of 5-FU was on average 3.2 times higher than in adjacent healthy tissue (P = 0.002). The mean liver metastasis/healthy tissue 5-FU concentration ratio was 1.4 (P = 0.49, not statistically different). The mean tissue/plasma 5-FU concentration ratios exceeded 20 for colorectal tumor and ranged from 8 to 10 for other tissues. CONCLUSIONS: The results demonstrated the preferential activation of capecitabine to 5-FU in colorectal tumor, after oral administration to patients. This is explained to a great extent by the activity of TP in colorectal tumor tissue, (the enzyme responsible for the conversion of 5'-DFUR to 5-FU), which is approximately four times that in adjacent healthy tissue. In the liver, TP activity is approximately equal in metastatic and healthy tissue, which explains the lack of preferential activation of capecitabine in these tissues.

Cartilage protective agent (CPA) Ro 32-3555, a new matrix metalloproteinase inhibitor for the treatment of rheumatoid arthritis.

CPA was well tolerated at all dose levels (10-150 mg) following single oral dose administration to healthy male volunteers. There was no relationship between the intensity, duration and number of adverse events reported and the dose of CPA. There was a dose-related increase in exposure as measured by AUC0-infinity and Cmax. Administration of 10 mg CPA following food resulted in a delayed tmax, and a significant decrease in Cmax but not AUC0-infinity.