L. von Wendt

Association of DISC1 with autism and Asperger syndrome

The DISC1 gene at 1q42 has generated considerable interest in various psychiatric diseases, since a balanced translocation interrupting the gene was found to cosegregate with schizophrenia and related mental illnesses in a large Scottish pedigree. To date, linkage and association findings to this locus have been replicated in several study samples ascertained for psychotic disorders. However, the biological function of DISC1 in neuronal development would suggest a potential role for this gene also in other, early onset neuropsychiatric disorders. Here we have addressed the allelic diversity of the DISC1, DISC2 and TRAX genes, clustered in 1q42, in Finnish families ascertained for infantile autism (97 families, naffected=138) and Asperger syndrome (29 families, naffected=143). We established association between autism and a DISC1 intragenic microsatellite (D1S2709; P=0.004). In addition, evidence for association to Asperger syndrome was observed with an intragenic single nucleotide polymorphism (SNP) of DISC1 (rs1322784; P=0.0058), as well as with a three-SNP haplotype (P=0.0013) overlapping the HEP3 haplotype, that was previously observed to associate with schizophrenia in Finnish families. The strongest associations were obtained with broad diagnostic categories for both disorders and with affected males only, in agreement with the previous sex-dependent effects reported for DISC1. These results would further support the involvement of DISC1 gene also in the etiopathogenesis of early onset neuropsychiatric disorders.

Electrophysiological evidence of enhanced distractibility in ADHD children

Abnormal involuntary attention leading to enhanced distractibility may account for different behavioral and cognitive problems in children with attention deficit hyperactivity disorder (ADHD). This was investigated in the present experiment by recording event-related brain potentials (ERPs) to distracting novel sounds during performance of a visual discrimination task. The overall performance in the visual task was less accurate in the ADHD children than in the control children, and the ADHD children had a higher number of omitted responses following novel sounds. In both groups, the distracting novel sounds elicited a biphasic P3a ERP component and a subsequent frontal Late Negativity (LN). The early phase of P3a (180-240 ms) had significantly smaller amplitudes over the fronto-central left-hemisphere recording sites in the ADHD children than in the control group presumably due to an overlapping enhanced left-hemisphere dominant negative ERP component elicited in the ADHD group. Moreover, the late phase of P3a (300-350 ms) was significantly larger over the left parietal scalp areas in the ADHD children than in the controls. The LN had a smaller amplitude and shorter latency over the frontal scalp in the ADHD group than in the controls. In conclusion, the ERP and behavioral effects caused by the novel sounds reveal deficient control of involuntary attention in ADHD children that may underlie their abnormal distractibility.

Genome-wide scan for loci of Asperger syndrome

Asperger syndrome (AS), characterised by inadequate social interaction, lack of empathy and a dependence of routines and rituals, is classified as belonging to the autism spectrum disorders (DSM-IV and ICD-10). Although the prevalence of AS has been estimated to range from 0.3 up to 48.4 per 10 000, the phenotype still remains relatively unrecognised by clinicians. Several reports, including the original description by Hans Asperger (1944), have suggested that AS has a strong genetic component. Here, we have performed a genome-wide scan on Finnish families ascertained for AS with a strictly defined phenotype. In the initial scan, Zmax>1.5 was observed on nine chromosomal regions, 1q21–22, 3p14–24, 3q25–27, 4p14, 4q32, 6p25, 6q16, 13q31–33 and 18p11. In the fine mapping stage, the highest two-point LOD scores were observed on chromosomes 1q21–22 (D1S484, Zmax dom=3.58), 3p14–24 (D3S2432, Zmax dom=2.50) and 13q31–33 (D13S793, Zmax dom=1.59). The loci on 1q21–22 and 3p14–24 overlap with previously published autism susceptibility loci, and the loci on 1q21–22 and 13q31–33 overlap with the reported schizophrenia susceptibility loci. The present study is the first genome-wide screen in AS and therefore replication data sets are needed to evaluate further the significance of the AS-loci identified here.

Changes in cerebral blood flow in Asperger syndrome during theory of mind tasks presented by the auditory route.

Abstract. Lack of theory of mind (ToM) has been considered to be a key feature in Asperger syndrome (AS). The main aim of the present study was to determine whether an exclusively auditory input of ToM stories activated the same brain areas as demonstrated previously using visual stimuli. Eight righthanded otherwise healthy men with AS and eight healthy righthanded male controls participated in a PET activation study using auditory given ToM stories and stories about physical events for induction. Both subjects with AS and controls showed increased activation in the occipitotemporal area bilaterally and in thalamus during ToM tasks. Both groups also showed activation in the medial frontal area during ToM tests. However, this activation was more intensive and extensive in the control group, especially when a more sensitive analysis method was used. As a group, unrelated to the tasks, the AS subjects showed increased activation of the cerebellum. It was concluded that the activation pattern was mainly in agreement with earlier studies using comparable stimuli administered differently. There was no support for a right hemisphere specific dysfunction.

Temperament profiles and their role in neurodevelopmental assessed preterm children at two years of age.

Abstract The aim of this study was to determine whether preterms (n=80, mean birth weight 1,205 g) differ from full-terms (n=80) in temperament profile at 24 months of age and to explore the relationship between temperament, neurodevelopment, and behavior. Temperament was assessed using the Toddler Temperament Questionnaire, which defines nine temperament dimensions: activity, rhythmicity, approach/withdrawal, adaptability, mood, intensity, distractability, persistence, and sensory threshold. Neurodevelopment was assessed by the Bayley Scales of Infant Development and by neuropediatric examination. Behavior was assessed using the Infant Behavior Record, which is a part of the Bayley Scales. When temperament was considered, the preterms were significantly less active, more adaptive, more positive in mood, less intense, and lower in threshold to respond than the controls. The results on IBR showed that preterms were significantly less goal directed, less attentive, and lower in endurance than the controls. The preterms performed significantly less well than the controls on the Bayley test. Low Bayley scores correlated with temperament scores of high rhythmicity, positive mood, low persistence, and high threshold and with IBR scores of poor social orientation, negative emotional tone, poor co-operation, short attention span, and poor endurance.

Neurological development up to the age of four years of extremely low birthweight infants born in Southern Finland in 1991–94

A total of 142 infants with birthweights of less than 1000 g were examined at the age of 4 y by a child neurologist, by a neuropsychologist and by an occupational therapist in order to establish the rate of neurological disorders. A total of 57 (40%) of the children had normal neurological development, 52 (37%) had minor neurological disorders, 27 (19%) were diagnosed with cerebral palsy, and 6 (4%) were mentally retarded (IQ <71) with no motor disability. The rate of cerebral palsy was identical with the figure at age 2y, but the rate of minor neurological disorders increased from 25% to 37%.

A quantitative controlled MRI study of the brain in 28 persons with Asperger syndrome

Background: As structural brain abnormalities have been reported in infantile autism, the aim of this study was to determine whether such findings also exist in Asperger Syndrome (AS). Methods: The diagnosis of Asperger Syndrome was based on the criteria in ICD-10 and DSM-IV. Brain magnetic resonance imaging (MRI) was performed with a 1.5 T imager. T2-weighted axial and coronal slices and T1- weighted three dimensional sagittal slices were obtained and visual and quantitative analysis were performed. Subjects: There were 28 Asperger individuals, 17 children and adolescents (age 6–19 years, mean 12.4 years), 11 adults (age 20–60 years, mean 37. 9 years) and 28 healthy age and gender matched controls. Results: Mild inconsistent alterations were detected in 13/28 of the individuals with Asperger Syndrome compared to 6/23 in the comparable controls. There were no differences between the right and left hemispheres, nor was there any abnormality in terms of myelination or migration. The anterior-posterior diameters of the mesencephalon were statistically significantly shorter in the Asperger syndrome individuals than in the controls. Conclusions: No consistent focal brain abnormalities for Asperger Syndrome were detected. The reduced diameters of the mesencephalon in the Asperger group support the hypothesis that the mesencephalon may be involved in the pathogenesis of Asperger Syndrome.

Behavioral and electrophysiological indicators of auditory distractibility in children with ADHD and comorbid ODD

Involuntary switching of attention to distracting sounds was studied by measuring effects of these events on auditory discrimination performance and event-related brain potentials (ERPs) in 6-11-year-old boys with Attention Deficit-Hyperactivity Disorder (ADHD) and comorbid Oppositional Defiant Disorder (ODD) and in age-matched controls. The children were instructed to differentiate between two animal calls by pressing one response button, for example, to a dog bark and another button to a cat mew. These task-relevant sounds were presented from one of two loudspeakers in front of the child, and there were occasional task-irrelevant changes in the sound location, that is, the loudspeaker. In addition, novel sounds (e.g., a sound of hammer, rain, or car horn) unrelated to the task were presented from a loudspeaker behind the child. The percentage of correct responses was lower for target sounds preceded by a novel sound than for targets not preceded by such sound in the ADHD group, but not in the control group. In both groups, a biphasic positive P3a response was observed in ERPs to the novel sounds. The later part of the P3a appeared to continue longer over the frontal scalp areas in the ADHD group than in the controls presumably because a reorienting negativity (RON) ERP response following the P3a was smaller in the ADHD group than in the control group. This suggests that the children with ADHD had problems in reorienting their attention to the current task after a distracting novel sound leading to deterioration of performance in this task. The present study also indicates that children with ADHD and comorbid ODD show same kind of distractibility as found in previous studies for children with ADHD without systematic comorbid ODD.