[Show abstract][Hide abstract] ABSTRACT: Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex-and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35-46%) of patients), as well as the deficit in melatonin (51% (45-57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41-54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS-melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS-melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.
Full-text · Article · Oct 2014 · Translational Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Perceiving others in pain generally leads to empathic concern, consisting of both emotional and cognitive processes. Empathy deficits have been considered as an element contributing to social difficulties in individuals with autism spectrum disorders (ASD). Here, we used functional magnetic resonance imaging and short video clips of facial expressions of people experiencing pain to examine the neural substrates underlying the spontaneous empathic response to pain in autism. Thirty-eight adolescents and adults of normal intelligence diagnosed with ASD and 35 matched controls participated in the study. In contrast to general assumptions, we found no significant differences in brain activation between ASD individuals and controls during the perception of pain experienced by others. Both groups showed similar levels of activation in areas associated with pain sharing, evidencing the presence of emotional empathy and emotional contagion in participants with autism as well as in controls. Differences between groups could be observed at a more liberal statistical threshold, and revealed increased activations in areas involved in cognitive reappraisal in ASD participants compared with controls. Scores of emotional empathy were positively correlated with brain activation in areas involved in embodiment of pain in ASD group only. Our findings show that simulation mechanisms involved in emotional empathy are preserved in high-functioning individuals with autism, and suggest that increased reappraisal may have a role in their apparent lack of caring behavior.
Full-text · Article · Jan 2014 · Translational Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Despite the widely-held understanding that the biological changes that lead to autism usually occur during prenatal life, there has been relatively little research into the functional development of the brain during early infancy in individuals later diagnosed with autism spectrum disorder (ASD).
This review explores the studies over the last three years which have investigated differences in various brain regions in individuals with ASD or who later go on to receive a diagnosis of ASD.
We used PRISMA guidelines and selected published articles reporting any neurological abnormalities in very early childhood in individuals with or later diagnosed with ASD.
Various brain regions are discussed including; the amygdala; cerebellum; frontal cortex and lateralised abnormalities of the temporal cortex during language processing. This review discusses studies investigating head circumference, electrophysiological markers and inter-hemispheric synchronisation. All the recent findings from the beginning of 2009 across these different aspects of defining neurological abnormalities are discussed in light of earlier findings.
The studies across these different areas reveal the existence of atypicalities in the first year of life, well before ASD is reliably diagnosed. Cross-disciplinary approaches are essential to elucidate the pathophysiological sequence of events that lead to ASD.
Full-text · Article · Aug 2013 · Behavioural neurology
[Show abstract][Hide abstract] ABSTRACT: This study investigated the utility of adult and infant vocalisation in the prediction of child psychopathology. Families were sampled from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Vocalisation patterns were obtained from 180 videos (60 cases and 120 randomly selected sex-matched controls) of parent-infant interactions when infants were one year old. Cases were infants who had been subsequently diagnosed aged seven years, with at least one psychiatric diagnostic categorisation using the Development and Wellbeing Assessment. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorders, Attention Deficit Hyperactivity Disorder, pervasive development disorder, and emotional disorders. Associations between infant and parent vocalisations and later psychiatric diagnoses were investigated. Low frequencies of maternal vocalisation predicted later development of infant psychopathology. A reduction of five vocalisations per minute predicted a 44% (95%CI: 11-94%; p-value=0.006) increase in the odds of an infant being a case. No association was observed between infant vocalisations and overall case status. In sum, altered vocalisation frequency in mother-infant interactions at one year is a potential risk marker for later diagnosis of a range of child psychopathologies.
Full-text · Article · Jan 2013 · Research in developmental disabilities
[Show abstract][Hide abstract] ABSTRACT: To establish which social interactive behaviours predict later psychiatric diagnosis, we examined 180 videos of a parent-infant interaction when children were aged one year, from within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Sixty of the videos involved infants who were later diagnosed with a psychiatric disorder at seven years, and 120 were a randomly selected sex-matched control group. Interactive behaviours for both the caregiver and the one year old infant were coded from the videos according to eight holistic categories of interpersonal engagement: Well-being, Contingent Responsiveness, Cooperativeness, Involvement, Activity, Playfulness, Fussiness, and Speech. Lower levels of adult activity and speech in interaction at one year significantly predicted overall diagnosis of child psychiatric disorder.
No preview · Article · Oct 2012 · Research in developmental disabilities
[Show abstract][Hide abstract] ABSTRACT: The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the ɛ-N-trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex-ratio disequilibrium.
Full-text · Article · Oct 2012 · Translational Psychiatry
[Show abstract][Hide abstract] ABSTRACT: One of the challenges of developmental psychopathology is to determine whether identifiable pathways to developmental disorders exist in the first months or years of life. Early identification of such disorders poses a similar challenge for clinical services. Using data from a large contemporary birth cohort, we examined whether psychopathology at age seven can be predicted from clinician observation at one year. Two groups of clinical raters observed videos of caregiver-infant interaction. Neither group of raters could reliably identify any precursors of later development of psychopathology in the one-year-old infants in this setting.
Full-text · Article · Jul 2012 · Research in developmental disabilities
[Show abstract][Hide abstract] ABSTRACT: Disruptive behaviour disorders (DBDs), including attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD) are chronic disorders with significant overlap in aetiology and presentation. An integrative examination of environmental risk factors is lacking. Six literature searches of web-based bibliographic databases were completed to identify literature on DBDs in general and five disorders in particular: CD, ODD, ADHD, deficits of attention, motor control and perception, and reactive attachment disorder. Searches were filtered to focus on studies including diagnostic assessment, focussing on environmental risk and protective factors in the first 4 years of life. The database searches generated 9806 papers of which 47 were reviewed after filters had been applied. The evidence suggests links between a number of early life risk factors and DBDs, including prenatal cigarette smoking and alcohol use, prenatal viral illness, maternal stress and anxiety, low birthweight, peri-partum and early neonatal complications, parental stress and parenting styles in infancy, early deprivation, adoption and separation. Despite the understanding that there is sharing of risk factors between the DBDs, there has been a disproportionate focus on the role of certain risk factors at the expense of others and the field is weakened by difficulties in controlling for all potential confounding variables.
Full-text · Article · Feb 2012 · Child Care Health and Development
[Show abstract][Hide abstract] ABSTRACT: A subgroup of persons with anorexia nervosa (AN) have been proposed to have sociocommunicative problems corresponding to autism spectrum disorders [ASDs, i.e. DSM-IV pervasive developmental disorders (PDDs): autistic disorder, Asperger's disorder, PDD not otherwise specified (NOS)]. Here, clinical problems, personality traits, cognitive test results and outcome are compared across 16 subjects (32%) with teenage-onset AN who meet or have met ASD criteria (AN+ASD), 34 ASD-negative AN subjects and matched controls from a longitudinal Swedish study including four waves of independent assessments from the teens to the early thirties.
The fourth wave included the Structured Clinical Interview for DSM-IV (SCID)-I and the SCID-II (cluster C, i.e. 'anxious' PDs) interviews, the Asperger Syndrome Diagnostic Interview, self-assessments by the Autism Spectrum Quotient and the Temperament and Character Inventory, neurocognitive tests by subscales from the Wechsler scales, continuous performance tests, Tower of London, and Happé's cartoons.
The ASD assessments had substantial inter-rater reliability over time (Cohen's κ between 0.70 and 0.80 with previous assessments), even if only six subjects had been assigned a diagnosis of an ASD in all four waves of the study, including retrospective assessments of pre-AN neurodevelopmental problems. The AN+ASD group had the highest prevalence of personality disorders and the lowest Morgan-Russell scores. The non-ASD AN group also differed significantly from controls on personality traits related to poor interpersonal functioning and on neurocognitive tests.
A subgroup of subjects with AN meet criteria for ASDs. They may represent the extreme of neurocognitive and personality problems to be found more generally in AN.
Full-text · Article · Dec 2011 · Psychological Medicine
[Show abstract][Hide abstract] ABSTRACT: Background Referrals to the Greater Glasgow Community Autism Team (CAT) made before the child's sixth birthday were analysed to obtain an estimation of the proportion of children in Greater Glasgow with childhood autism and investigate whether there were any variations in diagnosis rates, or in age at referral and diagnosis, depending on deprivation or geographical location.
Methods An analysis was made of the database recording referrals to Greater Glasgow CAT, between 2004 and 2007 inclusive, of children referred by age 6 years, comprising 584 cases. Cumulative incidence was calculated for childhood autism. Ages at referral and diagnosis were also analysed.
Results For this subset of children, there were 246 diagnosed cases of childhood autism, a cumulative incidence from 2004 until 2007 of 11.1 per year per 10 000 children aged 0–6 years. Of children with an eventual diagnosis of autism by age 6, 72% were referred by the age of 4 years. Deprivation was found to have an association with referral and diagnostic rates, with higher rates seen in the most deprived. There was geographical variation in the cumulative incidence of autism.
Conclusion Given that the populations were not known to differ in any manner that would lead to a true variation, the geographical variation in the cumulative incidence of autism in children up to 6 years in Greater Glasgow observed in this study is likely to represent differences in the care pathway between areas. Such differences may also explain the observed association with deprivation. Reasons for the variation are being explored.
Preview · Article · Nov 2011 · Child Care Health and Development
[Show abstract][Hide abstract] ABSTRACT: Autistic-like traits (ALTs), that is restrictions in intuitive social interaction, communication and flexibility of interests and behaviors, were studied in two population-based Swedish twin studies, one in children and one in adults: (1) to examine whether the variability in ALTs is a meaningful risk factor for concomitant attention deficit hyperactivity disorder (ADHD), anxiety, conduct problems, depression and substance abuse, and (2) to assess whether common genetic and environmental susceptibilities can help to explain co-existence of ALTs and traits associated with such concomitant problems.
Two nationwide twin cohorts from Sweden (consisting of 11 222 children and 18 349 adults) were assessed by DSM-based symptom algorithms for autism. The twins were divided into six groups based on their degree of ALTs and the risk for concomitant mental health problems was calculated for each group. Genetic and environmental susceptibilities common to ALTs and the other problem types were examined using bivariate twin modeling.
In both cohorts, even the lowest degree of ALTs increased the risk for all other types of mental health problems, and these risk estimates increased monotonically with the number of ALTs. For all conditions, common genetic and environmental factors could be discerned. Overall, the phenotypic correlation between ALTs and the traits examined were less pronounced in adulthood than in childhood and less affected by genetic compared with environmental factors.
Even low-grade ALTs are relevant to clinical psychiatry as they increase the risk for several heterotypical mental health problems. The association is influenced partly by common genetic and environmental susceptibilities. Attention to co-existing ALTs is warranted in research on a wide range of mental disorders.
Full-text · Article · Mar 2011 · Psychological Medicine
[Show abstract][Hide abstract] ABSTRACT: Autism was long considered to be a very rare disorder, the best defined in child psychiatry (Rutter & Schopler, 1992), and one that occurred in isolation, often with no comorbidity (except, possibly, mental retardation) and presumably with one etiology. It is now clear that autism in its classic variant is but part of a broader spectrum of disorders that include not only “autistic disorder” (as defined by DSM-IV) but also a number of conditions, including Asperger disorder and so-called pervasive developmental disorders not otherwise specified (PDDNOS)/atypical autism (Wing & Potter, 2002). It has also become generally accepted that these “autism spectrum disorders” (ASDs, including autistic disorder) are much more common than previously assumed, with overall childhood prevalence usually reported at just under 1% (Gillberg et al., 2006). To complicate things, genetic studies have shown that ASDs extend into “lesser variants” and “broader phenotypes” with some characteristic autism features but with little or no clinical impairment. Population studies suggest that such lesser variants or features of autism occur in several percent of children (Briskman, Happé, & Frith, 2001; Constantino & Todd, 2003; Posserud et al., 2006). The comorbidity issue in autism has not been resolved, and authorities in the field still argue about whether autism can be associated with other disorders, including ADHD. Both the DSM-IV and ICD-10 include a section of the diagnostic criteria that is difficult to interpret but that would tend to make researchers and clinicians loathe to diagnose coexisting/comorbid ADHD in ASD. Conversely, ADHD has long been agreed to be a common type of childhood behavior disorder and one that does blend into normality.
[Show abstract][Hide abstract] ABSTRACT: To explore attachment narratives in children diagnosed with reactive attachment disorder (RAD).
We compared attachment narratives, as measured by the Manchester Child Attachment Story Task, in a group of 33 children with a diagnosis of RAD and 37 comparison children.
The relative risk (RR) for children with RAD having an insecure attachment pattern was 2.4 (1.4-4.2) but 30% were rated as securely attached. Within the RAD group, children with a clear history of maltreatment were more likely to be Insecure-Disorganised than children without a clear history of maltreatment.
Reactive attachment disorder is not the same as attachment insecurity, and questions remain about how attachment research informs clinical research on attachment disorders.
Full-text · Article · May 2009 · Journal of Child Psychology and Psychiatry
[Show abstract][Hide abstract] ABSTRACT: Life-course persistent conduct disorder is a major public health problem with implications for individual health and for society at large. Recent evidence has shown that treatment can be cost-effective, and early symptom detection is improving. We weigh the evidence for and against the introduction of population screening for conduct disorder in early childhood using Wilson and Jungner's criteria.
No preview · Article · May 2009 · Archives of Disease in Childhood
[Show abstract][Hide abstract] ABSTRACT: Prevalence rates for child psychopathology in Denmark are unknown; and efficient screening and non-respondent analyses are essential for epidemiological purposes.
A multi-method strategy involving a two-step design: first screening of 621 children between the ages of 8-9 years attending mainstream education using the Child Behaviour Checklist (CBCL). Second, screen-positive probands and a sample of screen-negative probands were given in-depth child-psychiatric assessment. In cases of non-respondents, children were assessed by teachers.
CBCL screening results were compared with case status in clinical assessment. A positive predictive value of 0.25 and a correct classification rate (CCR) of 0.72 were obtained. The teacher interviews, used in cases of non-respondents, had a CCR of 0.87. According to DSM-IV criteria, the prevalence rate of psychiatric disorders was 10.l% [95% CI; 7.0-13.2].
The CBCL proved an effective screening tool. The brief interview with teachers is a valid assessment of psychiatric disorders among non-respondents.
No preview · Article · Feb 2005 · Acta Psychiatrica Scandinavica