Michael Siniatchkin

ADHD and autism: differential diagnosis or overlapping traits? A selective review

According to DSM-IV TR and ICD-10, a diagnosis of autism or Asperger Syndrome precludes a diagnosis of attention-deficit/hyperactivity disorder (ADHD). However, despite the different conceptualization, population-based twin studies reported symptom overlap, and a recent epidemiologically based study reported a high rate of ADHD in autism and autism spectrum disorders (ASD). In the planned revision of the DSM-IV TR, dsm5 (www.dsm5.org), the diagnoses of autistic disorder and ADHD will not be mutually exclusive any longer. This provides the basis of more differentiated studies on overlap and distinction between both disorders. This review presents data on comorbidity rates and symptom overlap and discusses common and disorder-specific risk factors, including recent proteomic studies. Neuropsychological findings in the areas of attention, reward processing, and social cognition are then compared between both disorders, as these cognitive abilities show overlapping as well as specific impairment for one of both disorders. In addition, selective brain imaging findings are reported. Therapeutic options are summarized, and new approaches are discussed. The review concludes with a prospectus on open questions for research and clinical practice.

Stimulation intensities of transcranial direct current stimulation have to be adjusted in children and adolescents

OBJECTIVE The aim of the present study was to investigate the effect of the transcranial direct current stimulation (tDCS) on motor cortex excitability in healthy children and adolescents. METHODS We applied 1mA anodal or cathodal tDCS for 10min on the left primary motor cortex of 19 healthy children and adolescents (mean age 13.9±0.4years). In order to prove whether the effects of tDCS may be attributed to the stimulation intensity, 10 children and adolescents were studied again using 0.5mA anodal and cathodal tDCS. Sham stimulation was used as a control. RESULTS Compared with sham stimulation, both 1mA anodal and cathodal tDCS resulted in a significant increase of Motor evoked potentials (MEP) amplitudes which remained to be prominent even one hour after the end of stimulation. Interestingly, the 0.5mA cathodal tDCS decreased cortico-spinal excitability whereas the 0.5mA anodal stimulation did not result in any effect. CONCLUSION For the first time, the study demonstrates age-specific influences of tDCS on cortical excitability of the primary motor cortex. SIGNIFICANCE Thus, the stimulation protocols of the tDCS have to be optimized according to age by planning studies in pediatric population.

Structural Alterations of the Social Brain: A Comparison between Schizophrenia and Autism

Autism spectrum disorder and schizophrenia share a substantial number of etiologic and phenotypic characteristics. Still, no direct comparison of both disorders has been performed to identify differences and commonalities in brain structure. In this voxel based morphometry study, 34 patients with autism spectrum disorder, 21 patients with schizophrenia and 26 typically developed control subjects were included to identify global and regional brain volume alterations. No global gray matter or white matter differences were found between groups. In regional data, patients with autism spectrum disorder compared to typically developed control subjects showed smaller gray matter volume in the amygdala, insula, and anterior medial prefrontal cortex. Compared to patients with schizophrenia, patients with autism spectrum disorder displayed smaller gray matter volume in the left insula. Disorder specific positive correlations were found between mentalizing ability and left amygdala volume in autism spectrum disorder, and hallucinatory behavior and insula volume in schizophrenia. Results suggest the involvement of social brain areas in both disorders. Further studies are needed to replicate these findings and to quantify the amount of distinct and overlapping neural correlates in autism spectrum disorder and schizophrenia.

Developmental changes of functional and directed resting-state connectivities associated with neuronal oscillations in EEG.

Several studies demonstrated that resting-state EEG power differs tremendously between school-aged children and adults. Low-frequency oscillations (delta and theta, <7 Hz) are dominant in children but become less prominent in the adult brain, where higher-frequency alpha oscillations (8-12 Hz) dominate the mature brain rhythm. However, this assessment of developmental effects with EEG power mapping is restricted to the scalp level and blind to the information flow between brain regions, thus limiting insights about brain development. In contrast dynamic source synchronization provides a tool to study inter-regional directionality on the cortical and sub-cortical source level. In this study we investigated functional and directed connectivities (information flow) with renormalized partial directed coherence during resting state EEG (eyes open and eyes closed) recordings in 17 school-aged children and 17 young adults. First, we found higher spectral mean source power in children relative to adults, irrespective of the examined frequency band and resting state. We further found that coherence values were stronger in adults compared to children in all frequency bands. The directed within-group coherence analysis indicated information flow from frontal to parietal sources in children, while information flow from parietal to frontal was observed in adults. In addition, significant thalamocortical connectivity was unidirectional (i.e., outflow to cortical regions) in adults, but bidirectional in children. Group comparison confirmed the results of the single subject analyses for both functional and directed connectivities. Our results suggest that both functional and directed connectivities are sensitive to brain maturation as the distribution and directionality of functional connections differ between the developing and adult brains.

Simultaneous EEG and fMRI recordings (EEG-fMRI) in children with epilepsy.

By combining electroencephalography (EEG) with functional magnetic resonance imaging (fMRI) it is possible to describe blood oxygenation level–dependent (BOLD) signal changes related to EEG patterns. This way, EEG‐pattern–associated networks of hemodynamic changes can be detected anywhere in the brain with good spatial resolution. This review summarizes EEG‐fMRI studies that have been performed in children with epilepsy. EEG‐fMRI studies in focal epilepsy (structural and nonlesional cases, benign epilepsy with centrotemporal spikes), generalized epilepsy (especially absence epilepsy), and epileptic encephalopathies (West syndrome, Lennox‐Gastaut syndrome, continuous spike and waves during slow sleep, and Dravet syndrome) are presented. Although EEG‐fMRI was applied mainly to localize the region presumably generating focal interictal discharges in focal epilepsies, EEG‐fMRI identified underlying networks in patients with generalized epilepsies and thereby contributed to a better understanding of these epilepsies. In epileptic encephalopathies a specific fingerprint of hemodynamic changes associated with the particular syndrome was detected. The value of the EEG‐fMRI technique for diagnosis and investigation of pathogenetic mechanisms of different forms of epilepsy is discussed.

Visual event-related potentials to biological motion stimuli in autism spectrum disorders

Atypical visual processing of biological motion contributes to social impairments in autism spectrum disorders (ASD). However, the exact temporal sequence of deficits of cortical biological motion processing in ASD has not been studied to date. We used 64-channel electroencephalography to study event-related potentials associated with human motion perception in 17 children and adolescents with ASD and 21 typical controls. A spatio-temporal source analysis was performed to assess the brain structures involved in these processes. We expected altered activity already during early stimulus processing and reduced activity during subsequent biological motion specific processes in ASD. In response to both, random and biological motion, the P100 amplitude was decreased suggesting unspecific deficits in visual processing, and the occipito-temporal N200 showed atypical lateralization in ASD suggesting altered hemispheric specialization. A slow positive deflection after 400 ms, reflecting top-down processes, and human motion-specific dipole activation differed slightly between groups, with reduced and more diffuse activation in the ASD-group. The latter could be an indicator of a disrupted neuronal network for biological motion processing in ADS. Furthermore, early visual processing (P100) seems to be correlated to biological motion-specific activation. This emphasizes the relevance of early sensory processing for higher order processing deficits in ASD.

Behavioural Treatment Increases Activity in the Cognitive Neuronal Networks in Children with Attention Deficit/Hyperactivity Disorder

Response cost and token approach (RCT) within the scope of a summer camp training is an effective treatment program for attention deficit hyperactivity disorder (ADHD). It is likely that intensive RCT training influences networks responsible for ADHD symptoms. Functional magnetic resonance imaging (fMRI) was carried out in 12 children with ADHD before and after the RCT program and in 12 healthy control children twice. For fMRI, a Go/No-go paradigm was used to investigate the influence of RCT training on attention and impulsivity. The No-go condition revealed only weak activation in the dorsal part of the anterior cingulate cortex (ACC), parietal and dorsolateral prefrontal cortex (DLPFC) before the training in children with ADHD compared to healthy children. However, this activation in these brain regions was significantly more pronounced after the training. This increase in hemodynamic response cannot be attributed merely to repetition of the measurement since the effect was not observed in healthy children. The increase in hemodynamic response in the ACC and right DLPFC was significantly associated with a reduction in response time variability and clinical symptoms in ADHD patients. After the RCT training, the children with ADHD demonstrated more pronounced activation of cortical structures which are typically related to response monitoring and self-control. It seems likely that children with ADHD learned more cognitive control in a continuous performance task as was revealed by both neuropsychological outcome and fMRI.

Dynamic Imaging of Coherent Sources Reveals Different Network Connectivity Underlying the Generation and Perpetuation of Epileptic Seizures

The concept of focal epilepsies includes a seizure origin in brain regions with hyper synchronous activity (epileptogenic zone and seizure onset zone) and a complex epileptic network of different brain areas involved in the generation, propagation, and modulation of seizures. The purpose of this work was to study functional and effective connectivity between regions involved in networks of epileptic seizures. The beginning and middle part of focal seizures from ictal surface EEG data were analyzed using dynamic imaging of coherent sources (DICS), an inverse solution in the frequency domain which describes neuronal networks and coherences of oscillatory brain activities. The information flow (effective connectivity) between coherent sources was investigated using the renormalized partial directed coherence (RPDC) method. In 8/11 patients, the first and second source of epileptic activity as found by DICS were concordant with the operative resection site; these patients became seizure free after epilepsy surgery. In the remaining 3 patients, the results of DICS / RPDC calculations and the resection site were discordant; these patients had a poorer post-operative outcome. The first sources as found by DICS were located predominantly in cortical structures; subsequent sources included some subcortical structures: thalamus, Nucl. Subthalamicus and cerebellum. DICS seems to be a powerful tool to define the seizure onset zone and the epileptic networks involved. Seizure generation seems to be related to the propagation of epileptic activity from the primary source in the seizure onset zone, and maintenance of seizures is attributed to the perpetuation of epileptic activity between nodes in the epileptic network. Despite of these promising results, this proof of principle study needs further confirmation prior to the use of the described methods in the clinical praxis.

EEG‐fMRI in atypical benign partial epilepsy

Atypical benign partial epilepsy (ABPE) is a subgroup among the idiopathic focal epilepsies of childhood. Aim of this study was to investigate neuronal networks underlying ABPE and compare the results with previous electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) studies of related epilepsy syndromes. Ten patients with ABPE underwent simultaneous EEG‐fMRI recording. In all 10 patients several types of interictal epileptiform discharges (IEDs) were recorded. Individual IED‐associated blood oxygen level–dependent (BOLD) signal changes were analyzed in a single subject analysis for each IED type (33 studies). A group analysis was also performed to determine common BOLD signal changes across the patients. IED‐associated BOLD signal changes were found in 31 studies. Focal BOLD signal changes concordant with the spike field (21 studies) and distant cortical and subcortical BOLD signal changes (31 studies) were detected. The group analysis revealed a thalamic activation. This study demonstrated that ABPE is characterized by patterns similar to studies in rolandic epilepsy (focal BOLD signal changes in the spike field) as well as patterns observed in continuous spikes and waves during slow sleep (CSWS) (distant BOLD signal changes in cortical and subcortical structures), thereby underscoring that idiopathic focal epilepsies of childhood form a spectrum of overlapping syndromes.

Ten minutes of 1 mA transcranial direct current stimulation was well tolerated by children and adolescents: Self-reports and resting state EEG analysis

Transcranial direct current stimulation (tDCS) is a promising and well-tolerated method of non-invasive brain stimulation, by which cortical excitability can be modulated. However, the effects of tDCS on the developing brain are still unknown, and knowledge about its tolerability in children and adolescents is still lacking. Safety and tolerability of tDCS was assessed in children and adolescents by self-reports and spectral characteristics of electroencephalogram (EEG) recordings. Nineteen typically developing children and adolescents aged 11-16 years participated in the study. Anodal and cathodal tDCS as well as sham stimulation were applied for a duration of 10 min over the left primary motor cortex (M1), each with an intensity of 1 mA. Subjects were unable to identify whether they had received active or sham stimulation, and all participants tolerated the stimulation well with a low rate of adverse events in both groups and no serious adverse events. No pathological oscillations, in particular, no markers of epileptiform activity after 1mA tDCS were detected in any of the EEG analyses. In summary, our study demonstrates that tDCS with 1mA intensity over 10 min is well tolerated, and thus may be used as an experimental and treatment method in the pediatric population.