Autism traits: The importance of "co-morbid" problems for impairment and contact with services. Data from the Bergen Child Study.

BACKGROUND: Co-occurring problems are common in individuals with clinical autism spectrum disorder (ASD) but their relevance for impairment and contact with health services in ASD is largely unexplored. AIMS: We investigated the extent of co-occurring problems in children with high ASD traits from a total population sample. We explored the contribution of co-occurring problems to impairment and service contact, and whether there were children without co-occurring problems in this group; as proxy for "ASD only". METHODS AND PROCEDURES: Children screening positive on the Autism Spectrum Screening Questionnaire (ASSQ) were used as proxy for ASD. Attention Deficit/Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder (ODD) were operationalised using symptom counts. A parent or teacher report above the 95th percentile counted as "problem" present for other symptom domains. OUTCOMES AND RESULTS: 92% of ASSQ high-scorers had a minimum of two other problems. Emotional problems, ADHD symptoms and learning problems were the most commonly reported problems, also predicting impairment and contact with services. CONCLUSIONS AND IMPLICATIONS: Co-occurring problems were common in ASD screen positive children and contributed strongly to both impairment and to contact with services. Gender differences indicated that female symptoms were perceived as less impairing by parents and teachers.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

Prevalence and clinical correlates of insomnia in adults with attention-deficit hyperactivity disorder.

OBJECTIVE: To investigate the prevalence of insomnia in adults with Attention-deficit hyperactivity disorder (ADHD) and its association with clinical subtypes, current ADHD symptoms, and stimulant treatment. METHOD: We obtained diagnostic information, symptom rating scales and treatment history from clinically ascertained adult ADHD patients diagnosed according to DSM-IV criteria (n = 268, mean age 38.1 years) and randomly selected population controls (n = 202, mean age 36.5 years). The Bergen Insomnia Scale (BIS) was used to measure insomnia. ADHD symptom domains were self-rated using the Adult ADHD Self-Rating Scale. RESULTS: Insomnia was far more frequent among adults with ADHD (66.8%) than in the population controls (28.8%) (P < 0.001). Insomnia was more common in adults with the combined subtype than in those with the inattentive subtype (79.7% and 55.6%, respectively) (P = 0.003). For self-reported current ADHD symptoms, inattention was strongly correlated to insomnia. Patients currently using stimulant treatment for ADHD reported a lower total insomnia score compared to patients without medication (P < 0.05). CONCLUSION: Insomnia was highly prevalent among adults with ADHD. The lower insomnia score in patients on current stimulant treatment suggests that stimulant treatment is not associated with worsening of insomnia symptoms in adult ADHD patients.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins.

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

The specificity of the Stroop interference score of errors to ADHD in boys.

The Stroop Interference Test is widely used to assess the inhibition function; however, divergent results have emerged from meta-analyses in children with ADHD. This has led to conflicting results as to whether the Stroop test detects the level of inhibition in these children. We hypothesized that the general approach to include interference scores depending on response time causes conflicting results, whereas recordings of errors may prove a superior measure of the inhibition function in children with ADHD. In the present study, 39 children with an ADHD diagnosis, two subgroups with and without another comorbid mental health disorder, were compared with respect to their interference scores of response time and errors with two subgroups of children with no ADHD. The two subgroups comprised 33 children with another mental health disorder other than ADHD and 56 children with no psychiatric disorder. The between-group analyses detected a multivariate, marginal main effect of an ADHD diagnosis on the Stroop interference scores, and a univariate main effect of an ADHD diagnosis on the interference score of errors. Further, only the interference score of errors predicted significantly the parent reported scores on the Inhibit scale from the Behavior Rating Inventory of Executive Function. These findings support that a Stroop interference score of errors is sensitive for inhibition problems in children with ADHD and encourages the use of Stroop versions including error recordings independent of response time.

Emotional development in children with tics: a longitudinal population-based study.

Children with tics often experience accompanying problems that may have more impact on their well being and quality of life than the tics themselves. The present study investigates characteristics and the course of associated problems. In a population-based follow-up study, we investigated the developmental trajectory of children with and without tics when they were 7-9 years old. Parents and teachers completed the strengths and difficulties questionnaire (SDQ) when the children were 7-9 years (wave 1) and 4 years later (wave 2). Using strict criteria, we identified 38 children with tics in the cohort of 4,025 children (0.94% of the total cohort) with a preponderance of boys (78.9%). 22 children (57.9%) in the group with tics had only motor tics, and 16 (42.1%) had both motor and vocal tics. Children with tics had significantly higher parent- and teacher-rated SDQ total difficulty scores and subscale scores in both waves. Children with tics experienced an increase in emotional problems and in peer problems between the first and the second wave. This study in a general population indicates that the presence of tics is associated with a range of internalizing and externalizing difficulties, as well as problems in peer relationships. Moreover, our study indicates that emotional and peer problems tend to increase over time in the group of children with tics.

A vascular approach to mild amnestic cognitive impairment: a pilot study.

OBJECTIVE: Mild cognitive impairment (MCI) is a subtle memory disorder not matching criteria for dementia. There is evidence for vascular comorbidity in several types of dementia. We hypothesized that neurovascular workup would detect a high degree of vascular disease in patients with MCI. MATERIALS AND METHODS: In cooperation with our memory clinic, patients with amnestic MCI were referred to our department for neurovascular investigation. The workup encompassed ultrasound examination with carotid duplex including Intima-Media-Thickness (IMT) measurement, and transcranial Doppler (TCD) including one-hour microemboli monitoring, cerebrovascular reactivity measurement and Bubble test. Cerebral MRI for the evaluation of vascular and white-matter lesions, brain atrophy, hippocampal volumes, and amyloid angiopathy was performed. RESULTS: Ten patients were included. Vascular risk factors were present in six patients. Four patients had atherosclerotic lesions, three classified as mild, and one as moderate carotid stenosis. IMT > 1 mm was found in two patients, with a maximum IMT of 1.11 mm. None of the patients with acceptable bone window had intracranial stenosis in TCD. Vasoreactivity was pathologically low in one patient. Permanent right-left shunt was found in three patients, of which one showed spontaneous cerebral microembolism. Hippocampal volume reduction and cortical atrophy were found in four patients. Chronic ischemic changes in MRI were present in one patient, and three patients had subcortical infarctions. Cortical infarctions, microbleeds, or amyloid angiopathy were not found. CONCLUSIONS: Pure amnestic MCI is probably less associated with cerebrovascular disease and may be more consistent with evolving Alzheimer's disease. However, vascular risk factors are common in these patients.

Representative Factor Generation for the Interactive Visual Analysis of High-Dimensional Data.

Datasets with a large number of dimensions per data item (hundreds or more) are challenging both for computational and visual analysis. Moreover, these dimensions have different characteristics and relations that result in sub-groups and/or hierarchies over the set of dimensions. Such structures lead to heterogeneity within the dimensions. Although the consideration of these structures is crucial for the analysis, most of the available analysis methods discard the heterogeneous relations among the dimensions. In this paper, we introduce the construction and utilization of representative factors for the interactive visual analysis of structures in high-dimensional datasets. First, we present a selection of methods to investigate the sub-groups in the dimension set and associate representative factors with those groups of dimensions. Second, we introduce how these factors are included in the interactive visual analysis cycle together with the original dimensions. We then provide the steps of an analytical procedure that iteratively analyzes the datasets through the use of representative factors. We discuss how our methods improve the reliability and interpretability of the analysis process by enabling more informed selections of computational tools. Finally, we demonstrate our techniques on the analysis of brain imaging study results that are performed over a large group of subjects.

Genome-wide association studies establish that human intelligence is highly heritable and polygenic.

General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549,692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted ∼1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence.

Emotional and behavioural problems in subgroups of children with chronic illness: results from a large-scale population study.

BACKGROUND: Children with chronic illness are known to have an increased risk of emotional and behavioural problems. In the present population-based study children with asthma, neurological disorders and other chronic illnesses were compared with children without chronic illnesses to assess differences in psychological presentation across illness groups. METHODS: A total of 537 children with parent-reported chronic illness in the Bergen Child Study were categorized into three groups: asthma, neurological disorders and other chronic illnesses. Emotional and behavioural problems were assessed by the Strengths and Difficulties Questionnaire. RESULTS: All three illness groups had an increased rate of emotional and behavioural problems, as well as increased probability of a psychiatric disorder compared with children without a chronic illness. Most children with asthma and other chronic illnesses did not have emotional and behavioural problems, and effect sizes were small in both groups. In children with neurological disorders the effect sizes ranged from moderate to large, with emotional problems, inattention hyperactivity and peer problems being the most frequent problems. CONCLUSIONS: The increased rate of emotional and behavioural problems in children with chronic illness, especially neurological disorders, emphasizes the importance of early detection of mental health problems in these children.

Association between catechol O-methyltransferase (COMT) haplotypes and severity of hyperactivity symptoms in adults.

It has been suggested that symptoms of attention-deficit/hyperactivity disorder (ADHD) is related to low dopamine levels in the prefrontal cortex. The enzyme catechol O-methyltransferase (COMT), which degrades dopamine and other catecholamines, is important for monoamine signaling in this brain-region, but genetic studies of the functional Val158Met (rs4680) polymorphism in ADHD have been inconsistent. However, recently it was shown that also common synonymous COMT variants modulate total COMT enzymatic activity by affecting the expression of the gene [Nackley et al. (2006); Science 314(5807):1930-1933]. We therefore hypothesized that analysis of haplotypes could reveal more about the association between COMT and ADHD symptoms than the Val158Met polymorphism alone. SNPs rs6269, rs4633, rs4818, and rs4680, tagging the common putative functional COMT haplotypes, were genotyped in 435 adult subjects with a clinical diagnosis of ADHD and 383 controls and analyzed for association with ADHD and the hyperactivity/impulsivity and inattention dimensions from the Adult ADHD Self-Report Scale (ASRS). All markers showed a trend for association with the hyperactivity/impulsivity scale, peaking at marker rs6269 (P = 0.007). Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in our sample (P = 0.01). Our results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, we suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies.

Behaviour-emotional characteristics of primary-school children rated as having language problems.

BACKGROUND: Primary-school teachers are expected to detect problems related to language function, but the teachers' evaluations may be heavily influenced by gender and classroom behaviour. AIM: To investigate the relationship between language problems (LPs) and behaviour-emotional problems as rated by primary-school teachers. METHODS: All participants participated in a population-based study, the Bergen Child Study (BCS). Teachers of 9,072 children and parents of 6,234 children completed forms containing questions pertaining to language function and the strengths and difficulties questionnaire (SDQ) to screen for behaviour-emotional problems. LP was defined as a score above the 95th percentile on the sum score of five language items. Children achieving a total SDQ score above the 90th percentile were defined as high scorers, indicating a high risk for behavioural-emotional problems. RESULTS: Based on teacher reports, 540 children were defined as having LP, more boys (N=366) than girls. Children defined as having LP were reported to have significantly higher scores on all SDQ subscales, and a higher total difficulty score than children without language problems (NLP). More LP boys than LP girls were defined as high scorers on the SDQ, with the highest effect size on the hyperactivity-inattention subscore. The agreement between teachers and parents was moderate to low, with the highest consensus of behaviour-emotional problems in children with LP. CONCLUSIONS: Primary-school children defined as having LP according to their teachers are frequently characterized by behavioural-emotional problems. Further assessment is warranted for primary-school children defined as having LP by their teachers.

Intellectual function in children with teacher reported language problems.

We predicted that teacher reported language problems are associated with low IQ, even when gender and behavior-emotional disorders are controlled for. All subjects were participants in a population based study. In stage 1, teachers completed a questionnaire containing four items pertaining to language function. A case-control sample (n= 294) was assessed using WISC-III and Kiddie-SADS-PL. A child was defined with "language problems" (LP) if s/he obtained a score indicating severe problems on at least one item. Teacher reported LP was found in 9.9% of the population sample and 20.7% of the case-control sample, with a three-fold higher risk for boys than girls. The LP group obtained significantly lower scores on all WISC-III factors compared with the non-LP group. The differences were not accounted for by the presence of behavioral-emotional disorders. When primary school teachers report LP, further assessment of the child's cognitive function is warranted.

Genetic analyses of dopamine related genes in adult ADHD patients suggest an association with the DRD5-microsatellite repeat, but not with DRD4 or SLC6A3 VNTRs.

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable psychiatric disorder in children and adults. Recent meta-analyses have indicated an association between genes involved in dopaminergic signaling and childhood ADHD, but little is known about their possible role in adult ADHD. In this study of adults with ADHD, we evaluated the three most commonly studied ADHD candidate genetic polymorphisms; the dopamine receptor D4 (DRD4) exon 3 VNTR repeat, a microsatellite repeat 18.5 kb upstream of the DRD5 locus and the 3'UTR dopamine transporter SLC6A3 (DAT 1) VNTR. We examined 358 clinically diagnosed adult Norwegian ADHD patients (51% males) and 340 ethnically matched controls. We found a nominally significant overall association with adult ADHD for the DRD5 microsatellite marker (P = 0.04), and a trend toward increased risk associated with the 148-bp allele consistent with recent meta-analyses. The strongest overall association (P = 0.02) and increased risk for the 148-bp allele [odds ratio (OR) = 1.27 (95% CI: 1.00-1.61)] were seen in the inattentive and combined inattentive/hyperactive group as previously reported for childhood ADHD. No association was found for the DRD4 or SLC6A3 polymorphisms in this patient sample. In conclusion, our results among adults with a clinical diagnosis of ADHD support an association between ADHD and the DRD5 locus, but not the DRD4 or SLC6A3 loci. It is possible that the latter polymorphisms are associated with a transient form of ADHD with better long-term clinical outcome.

General psychopathology is more important for executive functioning than diagnosis.

OBJECTIVE: Impaired executive functioning (EF) has often been reported in patients with major depression or schizophrenia. We hypothesize that the variance in EF is more affected by level of general psychopathology than by diagnosis. METHOD: Forty-three patients with major depression and 47 with schizophrenia were included. EF was measured with Wisconsin Card Sorting Test, Stroop Colour Word Test, Paced Auditory Serial Addition Test, Digits Backwards and Controlled Oral Word Association Test. The level of general psychopathology was measured with Brief Psychiatric Rating Scale - Expanded and Positive and Negative Syndrome Scale, the General psychopathology subscale. RESULTS: The level of general psychopathology predicted more of the variance in EF than diagnosis. In multivariate analyses, the effect of general psychopathology on EF was more robust for adjustment for diagnosis than vice versa. CONCLUSION: Future research on cognitive functioning in psychiatric patients should include level of general psychopathology to avoid overemphasising effects of diagnoses.

Dichotic memory: paradoxical effect of removing a left frontal gyrus: a case study.

A 27-year-old right-handed woman was operated with resection of an epileptogenic lesion, a nonmalignant tumor, in the left frontal lobe. The surrounding cortical and subcortical tissue in the tumor-containing gyrus was also resected. Care was taken during the operation not to interfere with motor or language related cortical areas. Pre- and postoperatively, she was tested with a dichotic memory test. In the preoperative test, she showed a marked Left Ear Advantage. In the corresponding tests on the second and fourth postoperative days and at follow-up, her performance had changed to a Right Ear Advantage. A possible explanation of this result is that neighboring cortical areas involved in hemispheric specialization for lateralized, verbal cognitive functions are suppressed by a focal epiletogeneic activity caused by the tumor. The subsequent removal of this influence allowed these cortical areas to function normally.

Dichotic-listening performance and intracarotid injections of amobarbital in children and adolescents. Preoperative and postoperative comparisons.

BACKGROUND: Dichotic listening (DL) to consonant-vowel syllables is frequently used in clinical and experimental studies of brain laterality. However, the paradigm of consonant-vowel syllables has not been thoroughly validated through a comparison with injections of amobarbital sodium (Amytal). OBJECTIVE: To validate the DL test for hemisphere dominance preoperatively vs postoperatively with the results from intracarotid injections of amobarbital (i.e., the Wada test) in epileptic children and adolescents. DESIGN AND MAIN OUTCOME MEASURES: Patients were tested with DL preoperatively and at 6-month follow-up. Correct reports in the DL tests were entered in a stepwise discriminant analysis for calculation of correct classification of hemisphere dominance with the results from the injections of amobarbital as the grouping variable. Correct reports from the right and left ears on the consonant-vowel DL test were compared preoperatively and postoperatively, separated for the subjects with regard to language dominance in the left and right hemispheres. SETTING: The Department of Pediatrics, Ostra Hospital, University of Göteborg, Göteborg, Sweden. PATIENTS: Thirteen children and adolescents between the ages of 10 and 19 years, who were surgically treated for resistant epilepsy, were included in the study. The operated area corresponded with morphological changes and functional dysfunctions according to findings from computed tomography, magnetic resonance imaging, single photon emission computed tomography, and electroencephalography. RESULTS: The results of the Wada tests revealed that 10 subjects had left hemisphere language dominance, with 3 subjects having right hemisphere language dominance. All 3 subjects with right hemisphere language dominance showed a left ear advantage on the DL test preoperatively and postoperatively, with 8 and 7 of the 10 subjects with left hemisphere dominance showing a right ear advantage, preoperatively and postoperatively, respectively. However, according to discriminant analysis, knowledge of the DL performance led to a correct classification according to the Wada test results in 12 (92%) of the 13 subjects. CONCLUSIONS: A quantitative classification procedure like discriminant analysis may be more sensitive when predicting hemisphere speech dominance from DL data than a qualitative procedure based on the ear advantage dichotomy. The ear advantage dichotomy may actually introduce arbitrary left-right categories that do not correspond to the actual clustering of the data.

Variability in cognitive function among persons at high genetic risk of Huntington's disease.

The present study explores cognitive variability and specificity of cognitive decline in persons at high genetic risk (AR+ persons) of Huntington's disease (HD). Risk status was determined by RFLP markers. Three subgroups were defined according to neuropsychological test performance. One subgroup showed a typical HD pattern of impairment, a second group selectively impaired verbal memory function, and a third group was more heterogeneous. Verbal memory function was frequently impaired among AR+ persons. The specificity of verbal memory dysfunction was evaluated by using a multivariate statistical clustering procedure. While 60% of the AR+ persons were allocated to clusters typical of "subcortical dementia", most AR- persons were allocated to a "normal" cluster. However, the variability was wide within both the AR+ and AR- group. The heterogeneity among AR+ persons was consistent with findings in genetic, neuroimaging, and neuropathological studies of HD. Multidisciplinary studies should be performed to better understand biological determinants of cognitive variability, and to facilitate clinical diagnosis and councelling in individual AR+ persons.