Working Memory-Related Functional Brain Patterns in Never Medicated Children with ADHD

Attention Deficit/Hyperactivity Disorder (ADHD) is a pervasive neurodevelopmental disorder characterized by 3 clusters of age-inappropriate cardinal symptoms: inattention, hyperactivity and impulsivity. These clinical/behavioural symptoms are assumed to result from disturbances within brain systems supporting executive functions including working memory (WM), which refers to the ability to transiently store and flexibly manipulate task-relevant information. Ongoing or past medications, co-morbidity and differences in task performance are potential, independent confounds in assessing the integrity of cerebral patterns in ADHD. In the present study, we recorded WM-related cerebral activity during a memory updating N-back task using functional Magnetic Resonance Imaging (fMRI) in control children and never medicated, prepubescent children with ADHD but without comorbid symptoms. Despite similar updating performance than controls, children with ADHD exhibited decreased, below baseline WM-related activation levels in a widespread cortico-subcortical network encompassing bilateral occipital and inferior parietal areas, caudate nucleus, cerebellum and functionally connected brainstem nuclei. Distinctive functional connectivity patterns were also found in the ADHD in these regions, with a tighter coupling in the updating than in the control condition with a distributed WM-related cerebral network. Especially, cerebellum showed tighter coupling with activity in an area compatible with the brainstem red nucleus. These results in children with clinical core symptoms of ADHD but without comorbid affections and never treated with medication yield evidence for a core functional neuroanatomical network subtending WM-related processes in ADHD, which may participate to the pathophysiology and expression of clinical symptoms.     

A Multi-Methodological MR Resting State Network Analysis to Assess the Changes in Brain Physiology of Children with ADHD

The purpose of this work was to highlight the neurological differences between the MR resting state networks of a group of children with ADHD (pre-treatment) and an age-matched healthy group. Results were obtained using different image analysis techniques. A sample of n = 46 children with ages between 6 and 12 years were included in this study (23 per cohort). Resting state image analysis was performed using ReHo, ALFF and ICA techniques. ReHo and ICA represent connectivity analyses calculated with different mathematical approaches. ALFF represents an indirect measurement of brain activity. The ReHo and ICA analyses suggested differences between the two groups, while the ALFF analysis did not. The ReHo and ALFF analyses presented differences with respect to the results previously reported in the literature. ICA analysis showed that the same resting state networks that appear in healthy volunteers of adult age were obtained for both groups. In contrast, these networks were not identical when comparing the healthy and ADHD groups. These differences affected areas for all the networks except the Right Memory Function network. All techniques employed in this study were used to monitor different cerebral regions which participate in the phenomenological characterization of ADHD patients when compared to healthy controls. Results from our three analyses indicated that the cerebellum and mid-frontal lobe bilaterally for ReHo, the executive function regions in ICA, and the precuneus, cuneus and the clacarine fissure for ALFF, were the “hubs” in which the main inter-group differences were found. These results do not just help to explain the physiology underlying the disorder but open the door to future uses of these methodologies to monitor and evaluate patients with ADHD.     

Ethanol Alters Brain Phospholipid Levels Which Correlate with Altered Brain Morphology

The effects of embryonic exposure on brain phospholipid levels were studied by injecting various concentrations of ethanol into fertile chicken eggs at 0 days of development. At 18 days of development, the levels of total phospholipids and various phospholipid classes were assayed in brain tissue and correlated to neuron densities within the cerebral hemispheres and the optic lobes. Although ethanol concentrations ranging from 0 to 3700 μm/Kg egg wt. failed to influence either total brain weight or total brain phospholipid levels, ethanol-induced changes in the levels of individual phospholipid classes were observed. When injected with 7 μm of ethanol/Kg egg wt., a 2- to 3-fold increase in brain phosphatidylethanolamine (PE) levels were observed with reduced levels of brain phosphatidylcholine (PC) and brain sphingomyelin (SP). When injected with 74 μm of ethanol/Kg egg wt., ethanol-induced increases in brain phosphatidylserine (PS) and PE were observed with ethanol-induced decreases in brain PC and SP. Cell fractionation studies demonstrated ethanol-induced increases in brain PE and PS and ethanol-induced decreases in brain PC and SP in nuclear, mitochondrial, and microsomal membranes. These ethanol-induced alterations in brain phospholipid profiles correlated with ethanol-induced reductions in neuron densities within the cerebral hemispheres and optic lobes.     

Revealing a Brain Network Endophenotype in Families with Idiopathic Generalised Epilepsy

Idiopathic generalised epilepsy (IGE) has a genetic basis. The mechanism of seizure expression is not fully known, but is assumed to involve large-scale brain networks. We hypothesised that abnormal brain network properties would be detected using EEG in patients with IGE, and would be manifest as a familial endophenotype in their unaffected first-degree relatives. We studied 117 participants: 35 patients with IGE, 42 unaffected first-degree relatives, and 40 normal controls, using scalp EEG. Graph theory was used to describe brain network topology in five frequency bands for each subject. Frequency bands were chosen based on a published Spectral Factor Analysis study which demonstrated these bands to be optimally robust and independent. Groups were compared, using Bonferroni correction to account for nonindependent measures and multiple groups. Degree distribution variance was greater in patients and relatives than controls in the 6–9 Hz band (p = 0.0005, p = 0.0009 respectively). Mean degree was greater in patients than healthy controls in the 6–9 Hz band (p = 0.0064). Clustering coefficient was higher in patients and relatives than controls in the 6–9 Hz band (p = 0.0025, p = 0.0013). Characteristic path length did not differ between groups. No differences were found between patients and unaffected relatives. These findings suggest brain network topology differs between patients with IGE and normal controls, and that some of these network measures show similar deviations in patients and in unaffected relatives who do not have epilepsy. This suggests brain network topology may be an inherited endophenotype of IGE, present in unaffected relatives who do not have epilepsy, as well as in affected patients. We propose that abnormal brain network topology may be an endophenotype of IGE, though not in itself sufficient to cause epilepsy.     

儿童癫痫的围产期高危因素分析

目的：研究儿童癫痫相关的国产期高危因素。方法：随访16986例新生儿后期癫痫的患病情况,分为儿童癫痫组与非癞痫组,比较两组各项围产期高危因素,进行单因素与多因素统计分析。结果：随访期内儿童癫痫的发病例数为118例（6．95‰）,癫痫的发病率在1岁以下的儿童最高（27．12％）。儿童癫痫的发生与孕周、高龄产妇、低出生体重、流产史、宫内窘迫、喂养方式、孕期感染、子痫、胎盘早剥、新生儿惊厥都有相关性,并且孕周、子痫和新生儿惊厥是儿童癫痫发生的独立危险因素。结论：儿童癫痫的发生与围产期高危因素密切相关,这对临床儿童癫痫的诊疗可能有提示作用。     

儿童癫痫的围产期高危因素分析

目的:研究儿童癫痫相关的围产期高危因素。方法:随访16986例新生儿后期癫痫的患病情况,分为儿童癫痫组与非癫痫组,比较两组各项围产期高危因素,进行单因素与多因素统计分析。结果:随访期内儿童癫痫的发病例数为118例(6.95‰),癫痫的发病率在1岁以下的儿童最高(27.12%)。儿童癫痫的发生与孕周、高龄产妇、低出生体重、流产史、宫内窘迫、喂养方式、孕期感染、子痫、胎盘早剥、新生儿惊厥都有相关性,并且孕周、子痫和新生儿惊厥是儿童癫痫发生的独立危险因素。结论:儿童癫痫的发生与围产期高危因素密切相关,这对临床儿童癫痫的诊疗可能有提示作用。     

Clinical Characteristics of Children with Autism Spectrum Disorder and Co-Occurring Epilepsy

Objectives

To estimate the prevalence of epilepsy in children with Autism Spectrum Disorder (ASD) and to determine the demographic and clinical characteristics of children with ASD and epilepsy in a large patient population.

Methods

Cross-sectional study using four samples of children with ASD for a total of 5,815 participants with ASD. The prevalence of epilepsy was estimated from a population-based sample. Children with and without epilepsy were compared on demographic and clinical characteristics. Multivariate logistic regression was used to examine the association between demographic and clinical characteristics and epilepsy.

Results

The average prevalence of epilepsy in children with ASD 2–17 years was 12.5%; among children aged 13 years and older, 26% had epilepsy. Epilepsy was associated with older age, lower cognitive ability, poorer adaptive and language functioning, a history of developmental regression and more severe ASD symptoms. The association between epilepsy and the majority of these characteristics appears to be driven by the lower IQ of participants with epilepsy. In a multivariate regression model, only age and cognitive ability were independently associated with epilepsy. Children age 10 or older had 2.35 times the odds of being diagnosed with epilepsy (p<.001) and for a one standard deviation increase in IQ, the odds of having epilepsy decreased by 47% (p<.001).

Conclusion

This is among the largest studies to date of patients with ASD and co-occurring epilepsy. Based on a representative sample of children with ASD, the average prevalence of epilepsy is approximately 12% and reaches 26% by adolescence. Independent associations were found between epilepsy and older age and lower cognitive ability. Other risk factors, such as poor language and developmental regression, are not associated with epilepsy after controlling for IQ. These findings can help guide prognosis and alert clinicians to patients with ASD who are at increased risk for epilepsy.     

Premarket Safety and Efficacy Studies for ADHD Medications in Children

Background

Attention-deficit hyperactivity disorder (ADHD) is a chronic condition and pharmacotherapy is the mainstay of treatment, with a variety of ADHD medications available to patients. However, it is unclear to what extent the long-term safety and efficacy of ADHD drugs have been evaluated prior to their market authorization. We aimed to quantify the number of participants studied and their length of exposure in ADHD drug trials prior to marketing.

Methods

We identified all ADHD medications approved by the Food and Drug Administration (FDA) and extracted data on clinical trials performed by the sponsor and used by the FDA to evaluate the drug’s clinical efficacy and safety. For each ADHD medication, we measured the total number of participants studied and the length of participant exposure and identified any FDA requests for post-marketing trials.

Results

A total of 32 clinical trials were conducted for the approval of 20 ADHD drugs. The median number of participants studied per drug was 75 (IQR 0, 419). Eleven drugs (55%) were approved after <100 participants were studied and 14 (70%) after <300 participants. The median trial length prior to approval was 4 weeks (IQR 2, 9), with 5 (38%) drugs approved after participants were studied <4 weeks and 10 (77%) after <6 months. Six drugs were approved with requests for specific additional post-marketing trials, of which 2 were performed.

Conclusions

Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy. While post-marketing studies can fill in some of the gaps, better assurance is needed that the proper trials are conducted either before or after a new medication is approved.     

托吡酯与苯巴比妥对小儿癫痫患儿发作次数及痫样放电的影响对比

目的:研究托吡酯(topiramate,TPM)与苯巴比妥(phenobarbital,PB)对小儿癫痫(Epilepsy)患儿发作次数及痫样放电的影响。方法:将我院2010年8月至2013年8月入院接受诊治的200例癫痫患儿作为观察对象,随机分成两组。观察组采用TPM治疗,对照组采用PB治疗。对比两组患儿治疗前以及治疗后3个月癫痫发作次数、疗效以及不良反应情况。结果:观察组部分性发作减少次数、全身性发作减少次数及总发作减少次数,均显著高于对照组;观察组治愈率、愈显率、总有效率,均显著高于对照组;观察组不良反应情况显著少于对照组;差异均具有统计学意义(均P0.05)。结论:与PB相比,TPM治疗小儿癫痫疗效更佳,且不良反应更少,值得临床推荐。     

Anticipatory Electrodermal Response as a Differentiating Somatic Marker Between Children with ADHD and Controls

Six children with Attention Deficit Hyperactivity Disorder (ADHD) and five control children between the ages of 9 and 11 years were administered an adapted version of the Iowa Gambling Task while measuring anticipatory electrodermal response (EDR). Anticipatory EDR measures were compared between groups. Results indicate that the ADHD group exhibited significantly lower autonomic reactivity to anticipated consequences, evidencing a neuropsychological profile similar to patients with lesions in the ventromedial prefrontal cortex.     

Functional Brain Dysfunction in Patients with Benign Childhood Epilepsy as Revealed by Graph Theory

There is growing evidence that brain networks are altered in epileptic subjects. In this study, we investigated the functional connectivity and brain network properties of benign childhood epilepsy with centrotemporal spikes using graph theory. Benign childhood epilepsy with centrotemporal spikes is the most common form of idiopathic epilepsy in young children under the age of 16 years. High-density EEG data were recorded from patients and controls in resting state with eyes closed. Data were preprocessed and spike and spike-free segments were selected for analysis. Phase locking value was calculated for all paired combinations of channels and for five frequency bands (δ, θ, α, β₁ and β₂). We computed the degree and small-world parameters—clustering coefficient (C) and path length (L)—and compared the two patient conditions to controls. A higher degree at epileptic zones during interictal epileptic spikes (IES) was observed in all frequency bands. Both patient conditions reduced connection at the occipital and right frontal regions close to the epileptic zone in the α band. The “small-world” features (high C and short L) were deviated in patients compared to controls. A changed from an ordered network in the δ band to a more randomly organized network in the α band was observed in patients compared to healthy controls. These findings show that the benign epileptic brain network is disrupted not only at the epileptic zone, but also in other brain regions especially frontal regions.     

Effects of Neurofeedback Training on Performing Bimanual Coordination In-phase and Anti-phase Patterns in Children with ADHD

It is generally accepted that children with attention-deficit/hyperactivity disorder (ADHD) have poor motor control, especially in bimanual coordination tasks. Such children characteristically have impaired fine motor ability, problems with force control, and poor motor coordination. They are at particular risk of loss of motor control and reduced bimanual coordination. We tested whether, compared to a control condition, neurofeedback training (NFT) could improve bimanual coordination among children with ADHD. 20 Children with ADHD (mean age 7.9 years; SD 2.11) were randomly assigned either to NFT or to a control condition. All participants completed a bimanual coordination test at the following time points: baseline, assessment 1, assessment 2, assessment 3, and again 12 session later at posttest. NFT consisted of Sensory Motor Rhythm (SMR) training to achieve increased SMR in C3 and C4, while participants in the control condition were under mock NFT conditions. Bimanual coordination accuracy and consistency improved from baseline to completion of the intervention (significant Time effect), but in the NFT condition (significant time?×?group interaction). Compared to the control condition, the NFT group had fewer errors in both patterns of bimanual coordination (significant Group effect). Among children with ADHD, SMR neurofeedback training (NFT) led to significant improvements in a bimanual coordination task. The SMR NFT thus appears to have the potential to improve and enhance the motor control of ADHD patients.     

Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities

Objective

Epilepsy and intellectual/developmental disabilities (ID/DD) have a high rate of co-occurrence. Here, we investigated gene mutations in Chinese children with unexplained epilepsy and ID/DD.

Methods

We used targeted next-generation sequencing to detect mutations within 300 genes related to epilepsy and ID/DD in 253 Chinese children with unexplained epilepsy and ID/DD. A series of filtering criteria was used to find the possible pathogenic variations. Validation and parental origin analyses were performed by Sanger sequencing. We reviewed the phenotypes of patients with each mutated gene.

Results

We identified 32 novel and 16 reported mutations within 24 genes in 46 patients. The detection rate was 18% (46/253) in the whole group and 26% (17/65) in the early-onset (before three months after birth) epilepsy group. To our knowledge, we are the first to report KCNAB1 is a disease-causing gene of epilepsy by identifying a novel de novo mutation (c.1062dupCA p.Leu355HisfsTer5) within this gene in one patient with early infantile epileptic encephalopathy (EIEE). Patients with an SCN1A mutation accounted for the largest proportion, 17% (8/46). A total of 38% (9/24) of the mutated genes re-occurred at least 2 times and 63% (15/24) occurred only one time. Ion channel genes are the most common (8/24) and genes related to synapse are the next most common to occur (5/24).

Significance

We have established genetic diagnosis for 46 patients of our cohort. Early-onset epilepsy had the highest detection rate. KCNAB1 mutation was first identified in EIEE patient. We expanded the phenotype and mutation spectrum of the genes we identified. The mutated genes in this cohort are mostly isolated. This suggests that epilepsy and ID/DD phenotypes occur as a consequence of brain dysfunction caused by a highly diverse population of mutated genes. Ion channel genes and genes related to synapse were more common mutated in this patient cohort.