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Atypicalities in connectivity between brain regions have been implicated in a\ud range of neurocognitive disorders. We require metrics to assess stable individual\ud differences in connectivity in the developing brain, while facing the challenge of\ud limited data quality and quantity. Here, we examine how varying core processing\ud parameters can optimise the test-retest reliability of EEG connectivity measures\ud in infants.\ud EEG was recorded twice with a 1-week interval between sessions in 10-\ud month-olds. EEG alpha connectivity was measured across different epoch lengths\ud and numbers, with the phase lag index (PLI) and debiased weighted PLI\ud (dbWPLI), for both whole-head connectivity and graph theory metrics. We\ud calculated intra-class correlations between sessions for infants with sufficient\ud data for both sessions (N’s = 19 – 41, depending on the segmentation method).\ud Reliability for the whole brain dbWPLI was higher across many short\ud epochs, whereas reliability for the whole brain PLI was higher across fewer long\ud epochs. However, the PLI is confounded by the number of available segments.\ud Reliability was higher for whole brain connectivity than graph theory metrics.\ud Thus, segmenting available data into a high number of short epochs and\ud calculating the dbWPLI is most appropriate for characterising connectivity in\ud populations with limited availability of EEG data.

Infants’ socio-cognitive ability develops dramatically during the first year of life. From the perspective of ontogeny, the early development of social behavior allows for parent-child attachment, which in turn enhances survival. Thus, it is theorized that the development of social behavior, driven by social brain networks, forms the core of developmental acquisitions during this period. Further, understanding the maturation within the neural networks during social development is crucial to obtain a better grasp of the development of social developmental disorders. Therefore, we performed a longitudinal study in 854 infants measured at around 5 and 10 months to map the development of functional networks in the brain when infants were processing social and non-social videos. Using EEG, we focused on the frequency bands most commonly connected to social behavior: theta and alpha. We found that alpha networks remained relatively stable over the first year of life and showed no selectivity for social versus non-social stimuli, theta networks, showed strong global reconfigurations. The development of the theta networks progressed from a parietal occipital network in early infancy to a frontoparietal network towards the end of the first year of life. This reconfiguration coincided with selectivity for social versus non-social stimuli, with infants approaching the end of their first year of life showing increased synchronicity of theta communication when watching social videos versus non-social videos. Our findings provide strong evidence for the involvement of a frontoparietal theta network in the development of the social brain.

Understanding the development of attention is key to understanding cognitive maturation. The gap-overlap task can be administered at all ages and is widely used to study the development of overt visual attention. However, studies using the gap-overlap task report different measures and little is known about the tasks’ psychometric properties, especially in infants. We tested the 1-week test–retest reliability of two frequently used gap-overlap measures of attentional disengagement in 10-month-old infants; the gap effect as measured by the difference between the gap and overlap condition and the gap effect as measured by the difference between the gap and baseline condition. Sixty-seven infants performed the gap-overlap task twice, of which 45 infants had sufficient data quality for further analyses. Test–retest reliability of the overlap-gap gap effect was higher (r = .50) than the baseline-gap gap effect (r = .29). Moreover, the shared variance between overlap and baseline saccadic reaction times was moderate to high across sessions. In light of these results and the methodological challenges and limitations of infant research, we consider the overlap-gap gap effect to be a good measure to study the development of attentional disengagement in infants and suggest the exclusion of the baseline condition in future studies.

OBJECTIVE: In the current study, we investigated the role of noradrenaline in directing (bias) and disengagement of visuospatial attention. METHODS: We assessed the effect of clonidine on event-related brain potential (ERP) reflections of bias and disengagement in a double-blind placebo-controlled crossover design. An initial dose of 200-μg clonidine was replaced by 100 μg because of marked side effects. Twenty-one healthy male participants performed the visual-spatial cueing task while an electroencephalogram (EEG) was recorded. The behavioral output is the validity effect (benefit of cueing in terms of reaction time to targets). ERP indices for bias were the cue-related early directing attention negativity and late directing attention positivity, and the target-elicited P1 and N1 modulations by validity ('validity-effect'). The ERP index for disengagement was the target-elicited 'late positive deflection' modulation by validity. Behavioral analyses were performed on 16 participants, electrophysiological analyses on a subset (n=9). RESULTS: Clonidine attenuated the N1 effect, albeit in a subsample. Neither cue-elicited ERPs nor the behavioral validity effect were affected. Clonidine-induced blood pressure reduction was correlated with the reduction of the late positive deflection effect under clonidine. CONCLUSION: Clonidine attenuated the result of bias in a subsample and may have a modulating effect on disengagement.

Understanding the neuropharmacology of inhibition is of importance to fuel optimal treatment for disorders such as Attention Deficit/Hyperactivity Disorder. The aim of the present study was to assess the effect of noradrenergic antagonism by clonidine on behavioral-performance and brain-activity indices of inhibition. A placebo-controlled, double-blind, randomized, crossover design was implemented. Male (N = 21) participants performed in a visual stop signal task while EEG was recorded under clonidine in one session and under placebo in another. We expected that 100 μg clonidine would have a negative effect on EEG indices of inhibition, the Stop N2 and Stop P3. Furthermore, we expected that clonidine would negatively affect the behavioral measure of inhibition, the stop signal reaction time (SSRT). Behavioral analyses were performed on data of 17 participants, EEG analyses on a subset (N = 13). Performance data suggested that clonidine negatively affected attention (response variability, omissions) without affecting inhibition as indexed by SSRT. Electrophysiological data show that clonidine reduced the Stop P3, but not the Stop N2, indicating a partial negative effect on inhibition. Results show that it is unlikely that the Stop P3 reduction was related to the effect of clonidine on lapses of attention and on peripheral cardiovascular functioning. In conclusion, the current dose of clonidine had a negative effect on attention and a partial effect on inhibitory control. This inhibitory effect was restricted to the dorsal region of the prefrontal cortex (presumably the superior frontal gyrus) as opposed to the ventral region of the prefrontal cortex (right inferior frontal gyrus).

Multiple Complex Developmental Disorder (MCDD) is a well-defined and validated behavioral subtype of autism with a proposed elevated risk of developing a schizophrenic spectrum disorder. The current study investigated whether children with MCDD show the same deficits in sensory gating that are commonly reported in schizophrenia, or whether they are indistinguishable from children with autism in this respect. P50 suppression and prepulse inhibition (PPI) of the startle reflex were assessed in children with MCDD (n=14) or autism (n=13), and healthy controls (n=12), matched on age and IQ. All subjects showed high levels of PPI and P50 suppression. However, no group differences were found. No abnormalities in sensory filtering could be detected in children with autism or MCDD. Since sensory gating deficits are commonly regarded as possible endophenotypic markers for schizophrenia, the current results do not support a high level of similarity between schizophrenia and MCDD.

Autism is a neurodevelopmental disorder that usually arises on the basis of a complex genetic predisposition. The most significant susceptibility region in the first whole genome screen of multiplex families was on chromosome 7q, although this linkage was evident only in UK IMGSAC families. Subsequently all other genome screens of non-UK families have found some evidence of increased allele sharing in an overlapping 40 cM region of 7q. To further characterize this susceptibility locus, linkage analysis has now been completed on 170 multiplex IMGSAC families. Using a 5 cM marker grid, analysis of 125 sib pairs meeting stringent inclusion criteria resulted in a multipoint maximum LOD score (MLS) of 2.15 at D7S477, whereas analysis of all 153 sib pairs generated an MLS of 3.37. The 71 non-UK sib pairs now contribute to this linkage. Linkage disequilibrium mapping identified two regions of association-one lying under the peak of linkage, the other some 27 cM distal. These results are supported in part by findings in independent German and American singleton families.

Objective:To find out whether the neurodevelopmental disorders autism and childhood-onset schizophrenia have a common developmental pathway and whether the abnormalities detected are ‘disorder-specific’, by reviewing magnetic resonance imaging (MRI) studies.Methods:As a result of a Medline search, we were able to access 28 studies on autism and 12 studies on childhood-onset schizophrenia, which focused on children and adolescents.Results:Larger lateral ventricles were found to be a common abnormality in both disorders. ‘Disorder-specific’ abnormalities in patients with autism were larger brains, a larger thalamic area, and a smaller right cingulate gyrus. Subjects with childhood-onset schizophrenia were found to have smaller brains, a smaller amygdalum and thalamus, and a larger nucleus caudatus. In subjects with childhood-onset schizophrenia, abnormalities appeared to progress over a limited period of time.Conclusions:Because the study designs varied so much, the results should be interpreted cautiously. Before abnormalities found in the disorders can be designated as equal or ‘disorder-specific’, it will be essential to perform large longitudinal and cross-sectional follow-up studies.

Contains fulltext : 98353.pdf (Publisher’s version ) (Open Access) Recent array-based studies have detected a wealth of copy number variations (CNVs) in patients with autism spectrum disorders (ASD). Since CNVs also occur in healthy individuals, their contributions to the patient's phenotype remain largely unclear. In a cohort of children with symptoms of ASD, diagnosis of the index patient using ADOS-G and ADI-R was performed, and the Social Responsiveness Scale (SRS) was administered to the index patients, both parents, and all available siblings. CNVs were identified using SNP arrays and confirmed by FISH or array CGH. To evaluate the clinical significance of CNVs, we analyzed three families with multiple affected children (multiplex) and six families with a single affected child (simplex) in which at least one child carried a CNV with a brain-transcribed gene. CNVs containing genes that participate in pathways previously implicated in ASD, such as the phosphoinositol signaling pathway (PIK3CA, GIRDIN), contactin-based networks of cell communication (CNTN6), and microcephalin (MCPH1) were found not to co-segregate with ASD phenotypes. In one family, a loss of CNTN5 co-segregated with disease. This indicates that most CNVs may by themselves not be sufficient to cause ASD, but still may contribute to the phenotype by additive or epistatic interactions with inherited (transmitted) mutations or non-genetic factors. Our study extends the scope of genome-wide CNV profiling beyond de novo CNVs in sporadic patients and may aid in uncovering missing heritability in genome-wide screening studies of complex psychiatric disorders. 01 november 2011

Background: A detailed visual processing style has been noted in autism spectrum disorder (ASD); this contributes to problems in face processing and has been directly related to abnormal processing of spatial frequencies (SFs). Little is known about the early development of face processing in ASD and the relation with abnormal SF processing. We investigated whether young ASD children show abnormalities in low spatial frequency (LSF, global) and high spatial frequency (HSF, detailed) processing and explored whether these are crucially involved in the early development of face processing.Methods: Three-to 4-year-old children with ASD (n = 22) were compared with developmentally delayed children without ASD (n = 17). Spatial frequency processing was studied by recording visual evoked potentials from visual brain areas while children passively viewed gratings (HSF/LSF). In addition, children watched face stimuli with different expressions, filtered to include only HSF or LSF.Results: Enhanced activity in visual brain areas was found in response to HSF versus LSF information in children with ASD, in contrast to control subjects. Furthermore, facial-expression processing was also primarily driven by detail in ASD.Conclusions: Enhanced visual processing of detailed (HSF) information is present early in ASD and occurs for neutral (gratings), as well as for socially relevant stimuli (facial expressions). These data indicate that there is a general abnormality in visual SF processing in early ASD and are in agreement with suggestions that a fast LSF subcortical face processing route might be affected in ASD. This could suggest that abnormal visual processing is causative in the development of social problems in ASD.

There is converging evidence for the presence of a fast subcortical face-processing route that operates on global face characteristics in the mature brain. Until now, little has been known about the development of such a route, which is surprising given suggestions that this fast subcortical face-processing route might be affected in neurodevelopmental disorders such as autism. To address this, early visual event-related potentials to pictures of fearful and neutral faces containing detailed or global information in 3- to 4-year-old (n = 20), 5- to 6-year-old (n = 25), and 7- to 8-year-old (n = 25) children were compared. In children, emotional processing was driven by detailed information. Developmental effects are discussed in terms of maturation of the fast subcortical face-processing route as well as an increase in experience with facial expressions with age.

Obsessive-compulsive disorder (OCD) is associated with deficits in inhibition mechanisms. This is reflected in reports showing impaired sensorimotor and sensory gating in OCD patients, as measured with prepulse inhibition (PPI) of the startle reflex and P50 suppression paradigms. However, most of the patients in these studies used medication and the results were not controlled for menstrual cycle phase in women. In this study PPI and P50 suppression were tested in 25 medication-free OCD patients and 25 healthy controls, using auditory stimuli and controlling for menstrual cycle effects. Subgroups were established, based on clinical variables (e.g. 'washers' and 'checkers'). No impairments in PPI or P50 suppression were found in the OCD group when compared with healthy controls. However, a subgroup of OCD patients ('checkers', n=12) showed increased P50 suppression. It was concluded that sensorimotor and sensory gating is not impaired in drug-free OCD patients, taking into account the menstrual cycle effects in women. These results do not support hypotheses linking deficits in these inhibition paradigms and the pathogenesis of OCD. The finding of an increased P50 suppression in the subgroup of 'checkers' deserves further investigation and underlines the value of studying subgroups of OCD.

Many genetic studies in autism have been performed, resulting in the identification of multiple linkage regions and cytogenetic aberrations, but little unequivocal evidence for the involvement of specific genes exists. By identifying novel symptoms in these patients, enhanced phenotyping of autistic individuals not only improves understanding and diagnosis but also helps to define biologically more homogeneous groups of patients, improving the potential to detect causative genes. Supported by recent copy number variation findings in autism, we hypothesized that for some susceptibility loci, autism resembles a contiguous gene syndrome, caused by aberrations within multiple (contiguous) genes, which jointly increases autism susceptibility. This would result in various different clinical manifestations that might be rather atypical, but that also co-occur with autism. To test this hypothesis, 13 susceptibility loci, identified through genetic linkage and cytogenetic analyses, were systematically analyzed. The Online Mendelian Inheritance in Man database was used to identify syndromes caused by mutations in the genes residing in each of these loci. Subsequent analysis of the symptoms expressed within these disorders allowed us to identify 33 symptoms (significantly more than expected, P = 0.037) that were over-represented in previous reports mapping to these loci. Some of these symptoms, including seizures and craniofacial abnormalities, support our hypothesis as they are already known to co-occur with autism. These symptoms, together with ones that have not previously been described to co-occur with autism, might be considered for use as inclusion or exclusion criteria toward defining etiologically more homogeneous groups for molecular genetic studies of autism European Journal of Human Genetics (2010) 18, 588-595; doi:10.1038/ejhg.2009.206; published online 25 November 2009

Autism spectrum disorders (ASD) and schizophrenia are both neurodevelopmental disorders that have extensively been associated with impairments in functional brain connectivity. Using a cross-sensory P50 suppression paradigm, this study investigated low-level audiovisual interactions on cortical EEG activation, which provides crucial information about functional integrity of connections between brain areas involved in cross-sensory processing in both disorders. Thirteen high functioning adult males with ASD, 13 high functioning adult males with schizophrenia, and 16 healthy adult males participated in the study. No differences in neither auditory nor cross-sensory P50 suppression were found between healthy controls and individuals with ASD. In schizophrenia, attenuated P50 responses to the first auditory stimulus indicated early auditory processing deficits. These results are in accordance with the notion that filtering deficits may be secondary to earlier sensory dysfunction. Also, atypical cross-sensory suppression was found, which implies that the cognitive impairments seen in schizophrenia may be due to deficits in the integrity of connections between brain areas involved in low-level cross-sensory processing. (C) 2009 Elsevier Ltd. All rights reserved.

The association between the 22q11.2 deletion syndrome (22q11DS) and psychiatric disorders, particularly psychosis, suggests a causal relationship between 22q11DS genes and abnormal brain function. The genes catechol-O-methyl-transferase (COMT) and proline dehydrogenase both reside within the commonly deleted region of 22q11.2. COMT activity and proline levels may therefore be altered in 22q11DS individuals. Associations of both COMT(158) genotype and elevated serum proline levels with abnormal brain function have been reported. Fifty-six 22q11DS children and 75 healthy controls were assessed on physiological measures of brain function, including prepulse inhibition (PPI) of startle, P50 auditory sensory gating and smooth pursuit eye movements (SPEM). COMT(158) genotype and plasma proline levels were determined in the 22q11DS children. We hypothesized an interaction between the COMT(158) genotype and proline, predicting the strongest negative effect of high proline on brain function to occur in 22q11DS children who are carriers of the COMT(met) allele. Of the three physiological measures, only SPEM and PPI were abnormal in the patient sample. With regard to the SPEM performance, there was a significant interaction between the COMT(158) genotype and proline level with significantly decreased SPEM performance in children with high plasma proline levels and the low activity COMT(met) allele. A similar interaction effect was not observed with regard to PPI. These findings are consistent with a model in which elevated proline negatively affects brain function by an increase in dopamine in the prefrontal cortex. 22q11DS patients with low dopamine catabolic capacity are therefore especially vulnerable to this functional disruption.

Background Schizophrenia is a highly heritable and complex disorder. Multiple genes are likely to be involved, complicating genetic research into the etiology of this disorder. Intermediate phenotypes or endophenotypes may facilitate genetic research if they display a simpler mode of transmission than schizophrenia itself, i.e., if they reflect more closely the underlying genetic effects. Methods Twenty-five multigenerational families with multiple members affected with schizophrenia (180 subjects) were administered an extensive neuropsychological, psychophysiological, and personality test battery. Familial correlations were calculated to select heritable traits. Subsequent heritability analysis followed by commingling and segregation analysis were performed to unravel the pattern of transmission and to estimate heritability. Results Five traits, including sensorimotor gating, openness, verbal fluency, early visual perception, and spatial working memory, showed moderate familial correlations. Heritability estimates for these traits ranged from 37% to 54%. A major gene model resembling dominant transmission was found for both sensorimotor gating and openness. Verbal fluency, early visual perception, and spatial working memory may be accounted for by polygenic, multifactorial, or environmental effects. Conclusions Only 2 of 13 candidate endophenotypes showed a simple mode of transmission useful for successful application in molecular genetic research: sensorimotor gating and openness. To our knowledge, this is the first study to investigate the pattern of transmission for these traits.

This study investigated self-monitoring in children with autism spectrum disorder (ASD) with event-related potentials looking at both the error-related negativity (ERN) and error-related positivity (Pe). The ERN is related to early error/conflict detection, and the Pe has been associated with conscious error evaluation or attention allocation. In addition, post-error slowing in reaction times (RTs) was measured. Children with ASD and age- and IQ- matched controls were administered an easy and a hard version of an auditory decision task. Results showed that the ERN was smaller in children with ASD but localized in the anterior cingulate cortex (ACC) in both groups. In addition we found a negativity on correct trials (CRN) that did not differ between the groups. Furthermore, a reduced Pe and a lack of post-error slowing in RTs were found in children with ASD. The reduced ERN in children with ASD, in the presence of an intact CRN, might suggest a specific insensitivity to detect situations in which the chance of making errors is enhanced. This might in turn lead to reduced error awareness/attention allocation to the erroneous event (reduced Pe) and eventually in a failure in change of strategy to deal with a situation, as becomes evident from the lack of post-error slowing in the ASD group. This relates well to the perseverative behaviour that is seen in children with ASD. We discuss these results in terms of a general deficit in self-monitoring, underlying social disturbance in ASD and the involvement of the ACC.

An important characteristic of autism spectrum disorder (ASD) is increased visual detail perception. Yet, there is no standing neurobiological explanation for this aspect of the disorder. We show evidence from EEG data, from 31 control subjects (three females) and 13 subjects (two females) aged 16-28 years, for a specific impairment in object boundary detection in ASD, which is present as early as 120 ms after stimulus presentation. In line with a neural network model explicating the role of feedforward, horizontal and recurrent processing in visual perception, we can attribute this deficit to a dysfunction of horizontal connections within early visual areas. Interestingly, ASD subjects showed an increase in subsequent activity at lateral occipital sites (225 ms), which might reflect a compensational mechanism. In contrast, recurrent processing between higher and lower visual areas (around 260 ms), associated with the segregation between figure and background, was normal. Our results show specific neural abnormalities in ASD related to low-level visual processing. In addition, given the reconciliation between our findings and previous neuropathology and neurochemistry research, we suggest that atypical horizontal interactions might reflect a more general neural abnormality in this disorder.

Background: Integration of information from multiple sensory sources is an important prerequisite for successful social behavior, especially during face-to-face conversation. It has been suggested that communicative impairments among individuals with pervasive developmental disorders (PDD) might be caused by an inability to integrate synchronously presented visual and auditory cues. Method: We investigated audiovisual integration of speech stimuli among a group of high-functioning adult PDD individuals and age- and IQ-matched controls using electroencephalography, measuring both early pre-phonological, as well as late phonologically driven integration. Results: Pre-phonological AV interactions are intact, while AV interactions corresponding to more complex phonological processes are impaired in individuals with PDD. Conclusions: The present findings argue for a pattern of impairments on tasks related to complex audiovisual integration combined with relative sparing of low-level integrational abilities. This combination may very well contribute to the communicative disabilities which are typical for the disorder.

Objective: Response inhibition and attention processing in 5- to 7-year-old children with or without symptoms of attention-deficit hyperactivity disorder (ADHD) were examined.Methods: Twelve children with ADHD symptoms and 15 control children performed a CPT-AX task. Behavioral Measures of inattention and impulsivity and ERP measures of conflict monitoring and inhibition (Nogo-N2 and Nogo-P3), cue-orientation and prestimulus target expectation (CUe-P2 and P3) and response preparation (CNV) were collected.Results: ADHD children detected fewer targets and had higher Inattention scores accompanied by reduced centro-parietal Cue- and Go-P3 activity. Occipital CNV amplitude was larger in ADHD children. At fronto-central leads, strong and comparable fronto-parietal Nogo-N2 effects were found in both groups, whereas the Nogo-P3 was only marginally significant in both groups.Conclusions: The attenuated Cue- and Go-P3 effects in the ADHD-symptom group are interpreted as early signs of delayed attention development, resulting in less preparation and less alertness to detect significant events. Whereas the Nogo-N2 effects were interpreted as signs of comparable levels of conflict processing in both groups, the small Nogo-P3 suggests that inhibitory processing is still immature at this age.Significance: The present Study shows that specific attention problems can already be detected in the behavior and brain activity of 5- to 7-year-old children with symptoms of ADHD performing a CPT-AX task, and might be better indicators for the risk of developing ADHD than impulsivity measures. (c) 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All Fights reserved.

The looking behavior of children with pervasive developmental disorder (PDD) and age- and IQ-matched normal control children was studied using infrared oculography. Stimuli varying in complexity and topic were presented to test whether children with PDD have specific abnormalities in looking behavior to complex stimuli and/or to faces. All children showed more and longer fixations on the complex objects than on the simple objects, especially the complex nonsense figure, but group differences were not found. The results show no evidence for specific abnormalities in looking behavior to either faces or to complex stimuli in high functioning children with PDD.

ResumenPropósitoEl efecto del metilfenidato (MF) sobre el control inhibitorio evaluado por la tarea de parada (stop task) en niños con trastorno por déficit de atención e hiperactividad (TDAH) podría estar influido por la dificultad de la tarea y puede estar mediado por la atención.Sujetos y métodosQuince niños con TDAH realizaron la tarea de parada y la de cambio después de placebo, 0,5 y 1,0 mg/kg de MF en un diseño intrasujeto.ResultadosEl análisis de tendencia lineal mostró un efecto similar del MF en ambas tareas y un efecto más fuerte para el control inhibitorio que para la atención. Además, se encontró una correlación entre los metabolitos en el suero sanguíneo de la norepinefrina y la dopamina para las medidas de atención y las de control inhibitorio, respectivamente.Discusión y conclusiónEn niños con TDAH, el MF podría actuar primariamente sobre el control inhibitorio y no está influido por la dificultad de la tarea. Además, la atención y el control inhibitorio podrían tener perfiles farmacológicos diferenciales.

Observing facial expressions automatically prompts imitation, as can be seen with facial electromyography. To investigate whether this reaction is driven by automatic mimicry or by recognition of the emotion displayed we recorded electromyograph responses to presentations of facial expressions, face-voice combinations and bodily expressions, which resulted from happy and fearful stimuli. We observed emotion-specific facial muscle activity (zygomaticus for happiness, corrugator for fear) for all three stimulus categories. This indicates that spontaneous facial expression is more akin to an emotional reaction than to facial mimicry and imitation of the seen face stimulus. We suggest that seeing a facial expression, an emotional body expression or hearing an emotional tone of voice all activate the affect program corresponding to the emotion displayed.

Objective Basic abnormalities in visual information processing could be associated with the local visual bias often found in subjects with PDD. Therefore, the present study investigated the existence of deficits in spatial frequency processing at an early sensory level in children with PDD. Methods Visual evoked potentials (VEPs) and VEP dipole sources elicited by high and low spatial frequency gratings were analyzed in high-functioning children with PDD and matched controls. Results Around 80ms (N80-latency) children with PDD did not show the same robust differences between high and low spatial frequencies in VEP amplitude and VEP brain sources as controls, because of atypical processing of high frequencies. Analyses at the P1-latency (130ms) revealed that, although similar inferior–medial brain sources were activated for the processing of both spatial frequencies in the PDD and control group, source strength in response to both frequencies was weaker in the PDD compared to control group. Moreover, additional superior–lateral brain sources were activated during the processing of both frequencies in the PDD group. Conclusions Decreased specialized processing of high and low spatial frequencies might be a robust characteristic of PDD. Early in processing abnormalities in high spatial frequency processing seem to occur in PDD. At a later phase in processing there seems to be both atypical high and low spatial frequency processing. Considering that the processing of specific spatial frequencies plays an important role in the processing of global and local aspects of hierarchical stimuli and faces and of emotions, present data suggest that peculiarities in PDD subjects with respect to these stimuli might be related to an abnormality in more fundamental visual processes. Significance A basic abnormality in visual frequency processing is established in children with PDD.

Children with ADHD make more errors than control children in response-conflict tasks. To explore whether this is mediated by enhanced sensitivity to conflict or reduced error-processing, task-related brain activity (N2, Ne/ERN, Pe) was compared between 8- to 12-year-old children with ADHD and healthy controls during performance of a flanker task. Furthermore, effects of methylphenidate were investigated in ADHD children in a second study. ADHD children made more errors, especially in high-response-conflict conditions, without showing post-error slowing. N2 amplitudes were enhanced on trials resulting in an error response, Ne/ERN amplitude was unaffected and Pe amplitude was reduced in the ADHD group. Methylphenidate reduced errors in both low- and high-conflict conditions and normalized Pe amplitudes in children with ADHD. It was concluded that the inaccurate behaviour of ADHD children in conflict tasks might be related to reduced error-awareness and higher sensitivity to response conflict. Methylphenidate's ameliorating effects might be established through its influence on brain networks including posterior (parietal) cortex, enabling children with ADHD to allocate more attention to significant events.

Objective: The aim of the present study was to investigate whether similar neural sources are involved in generating Nogo-N2 scalp topography in children and adults. Methods: Source analysis was performed on the Nogo-N2 data from two groups of children (sixteen 6/7 year-olds and seventeen 9/10 year-olds) and seventeen young adults (aged 19-23 years) that were obtained in a prior study by Jonkman LM. The development of preparation, conflict monitoring and inhibition from early childhood to young adulthood; a go/nogo ERP study. Brain Res 2006;1097:181-93. Results: In both children and adults a bilateral source pair in the medial frontal cortex (near ACC) was involved in the generation of Nogo-N2 activity. However, children needed an additional, posteriorly located source pair to adequately explain the Nogo-N2 distribution. In 6/7 year-olds this posterior source was localized in occipito-temporal areas, whereas in 9/10 year-olds the posterior sources shifted to parietal locations. Conclusions: Although children recruit similar frontal regions as adults in the Nogo-N2 time window, the additional activation of posterior sources might indicate that early executive control performance is less automatic or requires more effortful control in children. This in turn might cause them to rely on more basic stimulus processing or to activate additional attention-related areas. Significance: Results from the present study show that in children, a more diffuse brain network is involved in executive control processing (conflict monitoring) in the Nogo-N2 time window than in adults.

Enhanced visual detail processing in subjects with pervasive developmental disorder (PDD) has been related to impairments in feature integration. The functional integrity of two types of neuronal connections involved in visual feature integration, namely horizontal and feedbackward connections, were tested. Sixteen children with PDD and 17 age- and IQ-matched control children (mean age 13.3 years) were included. In a texture segregation task the difference in ERP response to homogeneous and checkered visual stimuli was determined. Additionally, in a contour integration task subjects had to point out a contour consisting of colinearly aligned Gabor signals in backgrounds increasing in noise. Children with PDD showed a normal performance on the contour integration task, suggesting that neurons in the primary visual cortex of children with PDD can effectively integrate the activity of local detectors that process different aspects of the same object information by making use of long-range lateral connections. The amplitude of ERP activity related to texture segregation was also not different between the PDD and control groups, indicating functional visual feedback mechanisms between V I and higher order areas in subjects with PDD. However, a difference in latency of texture-segmentation related activity between the groups was noted. This effect did not reach significance, which could be due to the small N of the study. Therefore, the data need replication in a study with larger samples before more definitive conclusions can be drawn.

PurposeThe effect of methylphenidate (MPH) on inhibitory control as assessed by the stop task in children with attention-deficit/hyperactivity disorder (ADHD) could be influenced by task difficulty and may be mediated by attention.Subjects and methodsFifteen children with ADHD performed the stop and the change task after placebo, 0.5 and 1.0 mg/kg MPH in a within-subject design.ResultsLinear-trend analysis showed a similar effect of MPH in both tasks and a stronger effect for inhibitory control than for attention. Furthermore, a correlation was found between blood serum metabolites of norepinephrine and dopamine for attentional measures and inhibitory control measures, respectively.Discussion and conclusionIn children with ADHD MPH could act primarily on inhibitory control, and is not influenced by task difficulty. Also, attention and inhibitory control could have differential pharmacological profiles.

Background: Children with pervasive developmental disorder (PDD) show behavioral abnormalities in gaze and face processing, but recent studies have indicated that normal activation of face-specific brain areas in response to faces is possible in this group. It is not clear whether the brain activity related to gaze processing is also normal in children with PDD. Methods: Event-related brain potentials (ERPs) were measured during two spatial attention tasks in which a centrally presented stimulus served as cue for the location of a forthcoming target. In one task faces were used as cues, and in the other arrows. Seventeen children with PDD and 18 age- and IQ-matched control children were tested. Results: Face stimuli elicited the same specific ERP activity in both groups. Also, both children with PDD and controls showed shorter reaction times as well as larger amplitudes and shorter latency times of several ERP peaks to congruently cued targets than to incongruently cued targets in both tasks. However, children with PDD showed abnormally small occipital ERPs in response to both face and arrow stimuli. Conclusion: The results provide evidence for the capability of normal processing of face and gaze change in children with PDD. The smaller occipital activity might be related to more general abnormalities in perception.

This paper studied whether abnormal P3 amplitudes in PDD are a corollary of abnormalities in ERP components related to selective attention in visual and auditory tasks. Furthermore, this study sought to clarify possible age differences in such abnormalities. Children with PDD showed smaller P3 amplitudes than controls, but no abnormalities in selective attention. Adolescents with PDD showed abnormal selective attention, as reflected by larger auditory Processing Negativity (PN) and visual N2b, but no P3 abnormalities. Dipole localizations revealed that the locations of PN generators in subjects with PDD differed from controls. It was concluded that the abnormalities in selective attention in adolescents with PDD have a normalizing effect on P3, and possibly act as a compensatory process.

We assessed the disembedding performance on the Embedded Figures Test (EFT) of high-functioning subjects with autism or autism spectrum disorders from multi-incidence families and the performance of their parents. The individuals with autism spectrum disorders were significantly faster than matched controls in locating the shape, but their parents were not faster than a control group of parents. However, both the individuals with autism spectrum disorders and their fathers made significantly fewer incorrect attempts before finding the right shape than matched controls. These results suggest that the number of incorrect attempts is a more subtle measure than accuracy or response time for assessing superior disembedding skills and therefore may be useful in the assessment of individuals with autism spectrum disorders.

Background. Autism is a neurodevelopmental disorder with an estimated genetic origin of 90%. Previous studies have reported an increase in brain volume of approximately 5% in autistic subjects, especially in children. If this increase in brain volume is genetically determined, biological parents of autistic probands might be expected to show brain enlargement, or at least intracranial enlargement, as well. Identifying structural brain abnormalities under genetic control is of particular importance as these could represent endophenotypes of autism.Method. Using quantitative anatomic brain magnetic resonance imaging, volumes of intracranial, total brain, frontal, parietal, temporal and occipital lobe, cerebral and cortical gray and white matter, cerebellum, lateral ventricle, and third ventricle were measured in biological, non-affected parents of autistic probands (19 couples) and in healthy, closely matched control subjects (20 couples).Results. No significant differences were found between the parents of the autistic probands and healthy control couples in any of the brain volumes. Adding gender as a factor in a second analysis did not reveal a significant interaction effect of gender by group.Conclusions. The present sample of biological, non-affected parents of autistic probands did not show brain enlargements. As the intracranium is not enlarged, it is unlikely that the brain volumes of the parents of autistic probands have originally been enlarged and have been normalized. Thus, increased brain volume in autism might be caused by the interaction of paternal and maternal genes, possibly with an additional effect of environmental factors, or increased brain volumes might reflect phenotypes of autism.

The processing of global and local elements and of low- and high-spatial frequencies are thought to be interrelated. Evidence for this stems from findings showing that brain localizations for global/local elements and for low/high spatial frequencies seem to overlap. the present study aimed to provide direct evidence that topographical differences between the processing of. global and local visual elements can directly be explained by their spatial frequency content, and to study at which point in time this relation is present. This was done by studying the event-related potentials (ERPs) and source models elicited by unfiltered, low- or high-pass filtered hierarchical stimuli. Results showed that performance for global and local targets was affected by removing low and high spatial frequencies, respectively. ERP data indicated that at 250 ins, there was an interaction between the processing of global/local targets and of spatial frequencies because at this time-point removal of low spatial frequencies decreased activity associated with the processing of global targets. When localizing this effect, we found evidence implying that spatial frequency content indeed affected the brain region in which local/ global targets were processed. Results implicated that the processing of global information depended on its low spatial frequency content, which was processed more laterally. Instead, processing of local information seemed to depend on its high spatial frequency content, which was processed more medially. Thereby, present results extend former results showing that global and local processing is dependent on spatial frequency and mapped retinotopically in the visual cortex.

Schizophrenic patients show a loss of sensory gating, which is reflected in a reduced P50 suppression. Because most of the symptoms inschizophrenia can be reduced by antagonists of the dopaminergic (D2) system, the loss in sensory gating might be related to an increased dopaminergic activity. Therefore, in the present study, the effects of increased dopaminergic neurotransmisson on sensory gating in healthy volunteers were investigated. In a double-blind, balanced, placebo-controlled design, healthy male volunteers were challenged in twoseparate studies with either 300 mg L-dopa (precursor of dopamine) or placebo ( n = 16) and 1.25 mg bromocriptine (D2 agonist) or placebo ( n = 17). Subsequently, they were tested for their sensory gating (P50 suppression). P50 suppression values in the placebo condition werecomparable to those found in literature. Although both L-dopa and bromocriptine reduced P50 amplitude, they did so in an equal ratio for both the response to the conditioning (C) and the testing (T) stimuli, therefore not resulting in a reduction of the P50 suppression ratio (T/C). In the present study, neither L-dopa nor bromocriptine reduced sensory gating in healthy volunteers. This suggests that an increased dopaminergic activity in humans is not responsible for the reduction in sensory gating as seen, for example, in schizophrenia.

Genetic studies of autism would benefit from the identification of (neurophysiological) markers of the disease. Reports that subjects with autism suffer from abnormalities of visual motor processing, indicate that abnormalities in smooth pursuit eye movements (SPEM) may be a marker of the disorder. Sixteen high-functioning school-aged children with pervasive developmental disorder (PDD) were compared with a matched group of eighteen normally developing controls on performance of a SPEM task and a task which tested the integrity of visually guided saccadic eye movements. Both groups of children had normal eye movements during performance of these tasks. Thus abnormalities in SPEM would appear not to be a marker of PDD. The earlier reported abnormalities in visual motion processing might need to be reinterpreted.

Objective: This study was aimed at investigating whether attention-deficit hyperactivity disorder (ADHD) children suffer from specific early selective attention deficits in the visual modality with the aid of event-related brain potentials (ERPs). Furthermore, brain source localization was applied to identify brain areas underlying possible deficits in selective visual processing in ADHD children. Methods: A two-channel visual color selection task was administered to 18 ADHD and 18 control subjects in the age range of 7-13 years and ERP activity was derived from 30 electrodes. Results: ADHD children exhibited lower perceptual sensitivity scores resulting in poorer target selection. The ERP data suggested an early selective-attention deficit as manifested in smaller frontal positive activity (frontal selection positivity; FSP) in ADHD children around 200 ms whereas later occipital and fronto-central negative activity (OSN and N2b; 200-400 ms latency) appeared to be unaffected. Source localization explained the FSP by posterior-medial equivalent dipoles in control subjects, which may reflect the contribution of numerous surrounding areas. Conclusions: ADHD children have problems with selective visual processing that might be caused by a specific early filtering deficit (absent FSP) occurring around 200 ms. The neural sources underlying these problems have to be further identified. Source localization also suggested abnormalities in the 200-400 ms time range, pertaining to the distribution of attention-modulated activity in lateral frontal areas.

In schizophrenia both an involvement of a reduced prefrontal dopaminergic activity and an enhanced noradrenergic activity have been suggested. In addition, patients suffering from schizophrenia show reduced sensorimotor gating and reduced habituation. If there is a causality between these neurotransmitters and these processes, then either a reduction in dopaminergic activity or an enhanced noradrenergic activity in healthy volunteers would result in reduced sensorimotor gating and reduced habituation. In the present study, a group of 12 healthy male volunteers was tested four times in a prepulse inhibition (PPI) paradigm 2.5 h following administration of placebo/placebo, placebo/desipramine (50 mg), placebo/haloperidol (2 mg) and desipramine (50 mg)/haloperidol (2 mg). A significant reduction of percentage PPI was found in all active treatments compared with placebo/placebo, while no treatment effects on habituation were found. Furthermore, a significant increase in heart rate was found in both desipramine treatments, from 120 min following oral intake onwards. Both desipramine and haloperidol reduced PPI, which suggests that an enhanced noradrenergic activity and a reduced dopaminergic activity lead to a reduction in sensorimotor gating. Since reduced sensorimotor gating is found in schizophrenia, these results supply further evidence for a reduced prefrontal dopaminergic activity and an enhanced noradrenergic activity in schizophrenia. Furthermore, the combination of haloperidol and desipramine did not have a synergistic effect on PPI, which indicates an interaction between the compounds. The site for this interaction is most likely located in the prefrontal cortex, since evidence is accumulating that extracellular dopamine concentration is regulated by noradrenergic terminals, particularly in the frontal areas of the brain. Since no effects on habituation were found, this suggests that neither enhanced noradrenergic nor decreased dopaminergic activity is involved in this process.

This study sought to investigate whether the abnormally small P3 amplitudes observed in pervasive developmental disorder (PDD) are related to differences in processing capacity. PDD children and adolescents and their control groups participated in the study. Visual probe stimuli were presented during an auditory task with two levels of difficulty. Event-related potentials (ERP) were measured from 62 electrodes during task performance. All groups showed amplitude increases to auditory stimuli with increasing task load. Controls showed expected smaller P3 amplitudes to visual probes, whereas PDD subjects did not. The results suggest that autistic subjects show abnormal capacity allocation. Some of these abnormalities may dissolve over time, while others remain into adolescence.

The objective of this study was to investigate the effects of methylphenidate (MPH) on attention and inhibition in children with Attention Deficit Hyperactivity Disorder (ADHD) and to establish what the relative contributions of the noradrenergic and dopaminergic systems to this effect were. In addition to MPH, two other drugs were administered in order to affect both transmitter systems more selectively, L-dopa (dopamine (DA) agonist) and desipramine (DMI) (noradrenaline (NA) re-uptake inhibitor). Sixteen children with ADHD performed a stop-task, a laboratory task that measures the ability to inhibit an ongoing action, in a double-blind randomized within-subjects design. Each child received an acute clinical dose of MPH, DMI, L-dopa, and placebo; measures of performance and plasma were determined. The results indicated that inhibition performance was improved under DMI but not under MPH or L-dopa. The response-time to the stop-signal was marginally shortened after intake of DMI. MPH decreased omission and choice-errors and caused faster reaction times to the trials without the stop-tone. No effects of L-dopa whatsoever were noted. Prolactin levels were increased and 5-HIAA levels were lowered under DMI relative to placebo. It is suggested that the effects of MPH on attention are due to a combination of noradrenergic and dopaminergic mechanisms. The improved inhibition under DMI could be serotonergically mediated.

Background An important characteristic of children with autism is their unusual reaction to stimuli, which may be related to problems in the filtering of sensory input. For this reason, sensory filtering was measured in children with autism using the P50 gating paradigm. Method Twelve non-mentally retarded children with autism (i.e., having a DSM-IV diagnosis of either autistic disorder or pervasive developmental disorder not otherwise specified) and 11 healthy control children were tested for their ability to suppress P50, measured at the Cz electrode. Results No differences were found between the children with autism and the control children with regard to absolute P50 amplitudes and P50 suppression. Conclusion The excitability of the neuronal substrate that causes P50 is normal in children with autism, as are the early, inhibitory processes related to P50 gating. These results distinguish between subjects with autism and subjects with schizophrenia, in whom sensory gating is abnormal.

Background: The abnormal gaze behavior of autistic children toward human faces, as observed in daily-life situations, are investigated in two fixation time studies. It has been argued that faces are a special kind of stimuli for normal individuals and that this might not be the case for autistic children. Methods: A group of high-functioning autistic children (including a group of sub-threshold PDD-NOS children) was compared with a group of normal children, with respect to their fixation behavior for photographs of human faces. Using an infrared eye-tracking device, fixation times for the whole face and for the facial elements of faces were compared between the two groups. The first study dealt with faces having an emotional expression. The second study dealt with neutral faces presented either upright or upside-down. Results: Results of the two studies showed that autistic children have the same fixation behavior as normal children for upright faces, with or without an emotional expression. Furthermore, results of the second study showed that normal children spent less time looking at upside-down faces, but that the fixation times of autistic children were not influenced by the orientation of the faces. Conclusions: These results plead against the notion that the abnormal gaze behavior in everyday life is due to the presence of facial stimuli per se. Furthermore, the absence of a face orientation effect in autistic children might be a reflection of a lack of holistic processing of human faces in autism.

Based on clinical observations of abnormal gaze behavior of autistic children, it has been suggested that autistic children have a problem in processing social information. Several studies on eye movements have indeed found indications that children with autism show particularly abnormal gaze behavior in relation to social stimuli. However, the methodology used in such investigations did not allow for precise gaze analysis. In the present study, the looking behavior of autistic children toward cartoon-like scenes that included a human figure was measured quantitatively using an infrared eye-tracking device. Fixation behavior of autistic children was similar to that of their age- and IQ-matched normal peers. These results do not support the notion that autistic children have a specific problem in processing socially loaded visual stimuli. Also, there is no indication for an abnormality in gaze behavior in relation to neutral objects. It is suggested that the often-reported abnormal use of gaze in everyday life is not related to the nature of the visual stimuli but that other factors, like social interaction, may play a decisive role.

Item does not contain fulltext The effects of olanzapine on the symptomatology of children with pervasive developmental disorder with emphasis on problems of communication and the safety of the drug were investigated in a 3-month open-label, open-dosage study. Participating in the study were 25 children age 6 to 16 years with a diagnosis of either autistic disorder or pervasive developmental disorder not otherwise specified. Psychometric measures included the Clinical Global Impression of Severity/Improvement, the Aberrant Behavior Checklist, and the TARGET (a checklist of five target symptoms). Communication skills were assessed during behavioral analysis of a playroom session. Safety measures included clinical chemistry variables, electrocardiography, the SimpsonAngus Neurological Rating Scale, the Barnes Akathisia Scale, and vital signs. Twenty-three children completed the study and showed significant improvement on three subscales of the Aberrant Behavior Checklist (Irritability, Hyperactivity, and Excessive Speech) and the TARGET. The final mean dose was 10.7 mg/day. Several aspects of communication were also improved after olanzapine treatment. However, only three children were considered responders in terms of the Clinical Global Impression of Severity/Improvement scores. The most important adverse events were weight gain, increased appetite, and loss of strength. Three children showed extrapyramidal symptoms that disappeared after the dose was lowered. Thus, while olanzapine was a relatively safe medication in children, its clinical relevance in children with pervasive developmental disorder may be limited.