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Background: Alternating hemiplegia of childhood (AHC) is a rare disorder with both neurologic and cardiac manifestations. The ATP1A3-D801N variant is associated with a pathologically short QT interval and risk of ventricular arrhythmia following bradycardia; however, the mechanism of this remains unknown. We investigated the relationship between heart rate (HR), QT, and QTc, hypothesizing that individuals with ATP1A3-D801N have abnormal, impaired shortening of QT and QTc at lower HR leading to arrhythmia predisposition., Methods: We performed a retrospective observational study of individuals who underwent clinical evaluation, Holter monitoring, and genetic testing for AHC at Duke University Hospitals. We also compiled a group of healthy individuals as a control cohort. A larger, worldwide cohort of individuals with ATP1A3 -related phenotypes was compiled to investigate sinus node dysfunction. Linear regression analysis was then performed., Results: The cohort consisted of 44 individuals with ATP1A3 -related phenotypes with 81 Holter recordings (52.27% female; mean age at first Holter 8.04 years, range 0.58 - 33 years), compared to 36 healthy individuals with 57 Holter recordings (52.78% female; mean age at first Holter 9.84 years, range 0.08 - 38 years). Individuals with ATP1A3-D801N had reduced prolongation of QT at lower HR, manifest as a significantly lower slope for HR vs QT compared to healthy (P<0.0001). This resulted in a significantly higher slope of the relationship for HR vs QTc compared to healthy (P<0.0001). Individuals with ATP1A3 -related phenotypes and baseline QTc <350 milliseconds (ms) had increased shortening of QT and QTc at lower HR compared to those with normal QTc (P=0.003; P=0.001). Among worldwide cases, 3 out of 131 individuals with ATP1A3 -related phenotypes required device implantation and/or had sinus pauses >4 seconds., Conclusions: Individuals with the ATP1A3-D801N variant exhibit paradoxical shortening of QT and QTc at lower HR, which contributes to an increased risk of arrhythmias during bradycardia. This is exacerbated by an underlying risk of sinus node dysfunction., Clinical Perspective: What is Known:Individuals with ATP1A3-D801N have a short baseline QTc.Two individuals with AHC experienced ventricular fibrillation following bradycardia.What the Study Adds:The QT and QTc shorten to a greater extent at lower heart rate in individuals with ATP1A3-D801N than in healthy individuals. Individuals with ATP1A3 -related phenotypes and QTc <350ms show greater impairment of QT and QTc dynamics than those with normal QTc. There is low prevalence of device implantation and significant sinus pauses in individuals with ATP1A3 -related phenotypes, with a relatively greater prevalence in those with ATP1A3-D801N.

Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with any hormone action. They are categorized according to origin and use, such as industrial chemicals like polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs), plastics like bisphenol A (BPA), plasticizers like phthalates, pesticides like dichlorodiphenyltrichloroethane (DDT), fungicides like vinclozolin, and pharmaceuticals like diethylstilbestrol (DES). Natural EDCs, such as phytoestrogens, are present in the diet of both humans and animals. Polyphenols are a large group of natural compounds derived from plants and are found in beverages and food. They are grouped based on their chemical structure into flavonoids and nonflavonoids and are reported to have many beneficial effects on health, including, but not limited to, anticancer, antioxidant, and anti-inflammatory effects. Moreover, polyphenols have both pro- and antioxidant characteristics, and due to their antioxidant and anti-inflammatory potential, they presumably have a protective effect against damage induced by EDCs. However, polyphenols may act as EDCs. In this review, we report that polyphenols regulate the activity of EDCs, having both positive and negative effects. Hence, a better understanding of the associations between EDCs and polyphenols will allow the establishment of improved approaches to protect human health from EDCs.

Copy number variants (CNVs) represent the genetic cause of about 15-20% of neurodevelopmental disorders (NDDs). We identified a ~67 kb de novo intragenic deletion on chromosome 2q22.3 in a female individual showing a developmental encephalopathy characterised by epilepsy, severe intellectual disability, speech delay, microcephaly, and thin corpus callosum with facial dysmorphisms. The microdeletion involved exons 5-6 of GTDC1, encoding a putative glycosyltransferase, whose expression is particularly enriched in the nervous system. In a previous study, a balanced de novo translocation encompassing GTDC1 was reported in a male child with global developmental delay and delayed speech and language development. Based on these premises, we explored the transcriptomic profile of our proband to evaluate the functional consequences of the novel GTDC1 de novo intragenic deletion in relation to the observed neurodevelopmental phenotype. RNA-seq on the proband's lymphoblastoid cell line (LCL) showed expression changes of glycine/serine and cytokine/chemokine signalling pathways, which are related to neurodevelopment and epileptogenesis. Subsequent analysis by ELISA (enzyme-linked immunosorbent assay) and HPLC (high-performance liquid chromatography) revealed increased levels of glycine in the proband's LCL and serum compared to matched controls. Given that an increased level of glycine has been observed in the plasma samples of individuals with Rett syndrome, a condition sharing epilepsy, microcephaly, and intellectual disability with our proband, we proposed that the GTDC1 downregulation is implicated in neurodevelopmental impairment by altering glycine metabolism. Furthermore, our findings expanded the phenotypic spectrum of the novel GTDC1-related condition, including microcephaly and epilepsy among relevant clinical features., (© 2024. The Author(s).)

Background: Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein, essential for cell polarity. Defects in neuronal cell polarity are associated with neurologic disorders. Only three patients with heterozygous MPP5 de novo variants have been reported so far, with global developmental delay, behavioral changes and in only one case epileptic seizures., Objective: To describe a new patient with a novel truncating de novo mutation in MPP5 and to characterize in detail the epileptic phenotype and electroencephalographic features of the encephalopathy., Methods: We identified a novel truncating de novo mutation in MPP5 in a 44 year old patient by exome sequencing (p.Ser498Phefs*15). We retrospectively analyzed his clinical and instrumental data along a thirty-year follow up., Result: Our patient presents with generalized tonic-clonic seizures, myoclonic and clonic seizures, non-epileptic myoclonus, tremor, severe intellectual disability, mild face dysmorphic traits, and psychosis., Discussion and Conclusion: We present a case of a childhood onset developmental encephalopathy with a likely-pathogenic variant in the MPP5 gene.. This represents the first complete description of the epileptic syndrome associated with the MPP5 gene., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2023. Published by Elsevier Ltd.)

Focal adhesion plaques (FAPs) play an important role in the communication between cells and the extracellular matrix (ECM) and in cells' migration. FAPs are macromolecular complexes made by different proteins which also interact with matrix metalloproteinases (MMPs). Because of these fundamental properties, FAPs and MMPs are also involved in cancer cells' invasion and in the metastatic cascade. The most important proteins involved in FAP formation and activity are (i) integrins, (ii) a complex of intracellular proteins and (iii) cytoskeleton proteins. The latter, together with MMPs, are involved in the formation of filopodia and invadopodia needed for cell movement and ECM degradation. Due to their key role in cancer cell migration and invasion, MMPs and components of FAPs are often upregulated in cancer and are thus potential targets for cancer therapy. Polyphenols, a large group of organic compounds found in plant-based food and beverages, are reported to have many beneficial healthy effects, including anticancer and anti-inflammatory effects. In this review, we discuss the growing evidence which demonstrates that polyphenols can interact with the different components of FAPs and MMPs, inhibit various pathways like PI3K/Akt, lower focal adhesion kinase (FAK) phosphorylation and decrease cancer cells' invasiveness, leading to an overall antitumoral effect. Finally, here we highlight that polyphenols could hold potential as adjunctive therapies to conventional cancer treatments due to their ability to target key mechanisms involved in cancer progression.

Background: Previous research suggests that adolescent norms and behaviours may be influenced by peers. The aim of this study was to investigate social clustering of health outcomes among school friendship groups., Methods: Cross-sectional surveys were collected from Oct 26, 2022, to March 30, 2023, in four secondary schools in Scotland's central belt, and all Secondary 2 (12-13 years) and Secondary 4 (14-15 years) students were invited to take part. Schools self-selected into the study, between 6% and 27% had a free school meal registration (Scotland average 25%). The survey asked about health and about friendships in school. The outcomes of interest were binary indicators of: mental health and self-esteem using validated scales, smoking, drinking without parents knowing (DWPK), and trying drugs. Ethics approval for the study was given by the University of Glasgow (200190035) and all participants gave consent via an online form. We used Auto-Logistic Actor Attribute Models (ALAAMs) to model the association between features of individuals' social networks and their health outcomes. We specified a model for each health outcome separately including parameters: indegree, outdegree, and simple contagion, and combined using meta-analysis., Findings: Response rate was 74% (n=1097; 50% boys, 46% girls, 4% other). Based on self-report measures, 40% participants had poor mental health, 15% had low self-esteem, 6% smoked regularly, 4% tried drugs, and 18% were drinking without parents knowing. Preliminary unadjusted analysis found evidence of social contagion for mental health. Odds of poor mental health for each additional friend with poor mental health was 1·15 (95% CI 1·05-1·26). There was no evidence of contagion for self-esteem (1·13, 0·95-1·34), smoking (1·14, 0·46-2·82), DWPK (0·88, 0·71-1·10), and having tried drugs (0·91, 0·38-2·19). Some networks had low or zero prevalence of the outcomes, increasing the uncertainty in the pooled estimate for the contagion parameter., Interpretation: A cross-sectional study cannot differentiate between social contagion and selecting similar friends, and low prevalence and social desirability bias might have masked associations. However, the unique combination of social network data with advanced statistical modelling gives initial findings on the potential communicable nature of mental health and health behaviours in adolescence. Preliminary results indicate preventive approaches in schools could benefit from social network methods., Funding: Medical Research Council (MRC) and Chief Scientist Office (CSO)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Understanding which intrinsic and extrinsic factors dictate decision-making processes such as leaving the natal area or not (migratory vs resident strategy), departure time, and non-breeding destination are key-issues in movement ecology. This is particularly relevant for a partially migratory meta-population in which only some individuals migrate., Methods: We investigated these decision making-processes for 40 juvenile greater flamingos Phoenicopterus roseus fledged in three Mediterranean colonies and equipped with GPS-GSM devices., Results: Contrary to the body size and the dominance hypotheses, juveniles in better body condition were more likely to migrate than those in worse conditions, which opted for a residence strategy. Flamingo probability of departure was not associated with an increase in local wind intensity, but rather with the presence of tailwinds with departure limited to night-time mostly when the wind direction aligned with the migratory destination. Moreover, a positive interaction between tailwind speed and migration distance suggested that juveniles opted for stronger winds when initiating long-distance journeys. In contrast to previous studies, the prevailing seasonal winds were only partially aligned with the migratory destination, suggesting that other factors (e.g., adults experience in mix-aged flocks, availability of suitable foraging areas en route, density-dependence processes) may be responsible for the distribution observed at the end of the first migratory movement. We found potential evidence of sex-biased timing of migration with females departing on average 10 days later and flying ca. 10 km/h faster than males. Female flight speed, but not male one, was positively influenced by tailwinds, a pattern most likely explained by sexual differences in mechanical power requirements for flight (males being ca. 20% larger than females). Furthermore, juveniles considerably reduced their flight speeds after 400 km from departure, highlighting a physiological threshold, potentially linked to mortality risks when performing long-distance non-stop movements., Conclusion: These results suggest that not only intrinsic factors such as individual conditions and sex, but also extrinsic factors like weather, play critical roles in triggering migratory behaviour in a partially migratory metapopulation. Furthermore, social factors, including conspecific experience, should be taken into consideration when evaluating the adaptive processes underlying migration phenology, flight performance, and final destination selection., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Childhood epilepsy can be frequently associated with impaired cognitive functioning. Previous research has suggested an increased risk of cognitive impairment that may be related to the etiology, the electro-clinical pattern and the load of anti-seizure medications (ASMs). The aim of this study was to evaluate the impact of different clinical features on the global intellectual functioning in a cohort of children and adolescents with epilepsy. We studied eighty patients diagnosed and followed in a tertiary care center. These factors were examined: 1. Etiology of epileptic syndrome; 2. Type of seizure; 3. Number of ASMs; 4. Seizure frequency; 5. Age at seizure onset; 6. Total duration of epilepsy; and 7. Active duration of epilepsy. Multiple regression analysis showed that the etiology and the total duration of epilepsy were the best indicators of intellectual functioning. The present data indicate that children with symptomatic epilepsy (SE) have lower IQ scores (M = 63.5), while children with self-limited focal epilepsy and generalized idiopathic epilepsy, i.e. age-related epileptic syndromes (ARES), have a higher IQ (M = 100.0; p < 0.01). Children with epilepsy of unknown etiology (UEE) (M = 75.1; p < 0.05) are positioned at an intermediate level between the SE and the ARES group (p < 0.01). Increased duration of epilepsy was associated with decreased intellectual functioning. In conclusion, knowledge about the risks associated with etiologic factors and the duration of the disease may guide the definition of optimal neuropsychological rehabilitation strategies., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Published by Elsevier Ltd.)

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder that can be associated with intellectual disability (ID) and epilepsy (E). The etiology and the pathogenesis of this disorder is in most cases still to be clarified. Several studies have underlined that the EEG recordings in children with these clinical pictures are abnormal, however the precise frequency of these abnormalities and their relationship with the pathogenic mechanisms and in particular with epileptic seizures are still unknown. We retrospectively reviewed 292 routine polysomnographic EEG tracings of preschool children (age < 6 years) who had received a first multidisciplinary diagnosis of ASD according to DSM-5 clinical criteria. Children (mean age: 34.6 months) were diagnosed at IRCCS E. Medea (Bosisio Parini, Italy). We evaluated: the background activity during wakefulness and sleep, the presence and the characteristics (focal or diffuse) of the slow-waves abnormalities and the interictal epileptiform discharges. In 78.0% of cases the EEG recordings were found to be abnormal, particularly during sleep. Paroxysmal slowing and epileptiform abnormalities were found in the 28.4% of the subjects, confirming the high percentage of abnormal polysomnographic EEG recordings in children with ASD. These alterations seem to be more correlated with the characteristics of the underlying pathology than with intellectual disability and epilepsy. In particular, we underline the possible significance of the prevalence of EEG abnormalities during sleep. Moreover, we analyzed the possibility that EEG data reduces the ASD clinical heterogeneity and suggests the exams to be carried out to clarify the etiology of the disorder.

Nature-based play benefits children's health and development. However, the delivery of this in early learning and childcare centres (ELC) is extremely diverse, and implementation is not well understood. We applied a systems science perspective to understand the factors crucial to implementing nature-based outdoor play in ELC settings. Through Group Model Building workshops with 20 participants in managerial and practitioner roles, crucial factors were appraised using Causal Loops Diagrams. Twelve thematic causal loops emerged. Network analysis was employed to analyse the diagram. Exponential Random graph models explained the diagram construction process. Centrality measures alongside conditional uniform tests identified six leverage factors: use of outdoor space, culture of being outdoors, ELC culture of outdoor play, perceived child safety and enjoyment, educator confidence and educator agency. This research brings novel and practically relevant evidence about the important factors, and interdependencies, involved in the implementation of outdoor play practice within ELC settings., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Descriptions of electroencephalographic (EEG) patterns in Aicardi syndrome (AIC) have to date referred to small cohorts of up to six cases and indicated severe derangement of electrical activity in all cases. The present study was conducted to describe the long-term EEG evolution in a larger AIC cohort, followed for up to 23 years, and identify possible early predictors of the clinical and EEG outcomes., Methods: In a retrospective study, two experienced clinical neurophysiologists systematically reviewed all EEG traces recorded in 12 AIC cases throughout their follow-up, from epilepsy onset to the present. Clinical outcome was assessed with standardized clinical outcome scales., Results: Analysis of the data revealed two distinct AIC phenotypes. In addition to the "classical severe phenotype" already described in the literature, we identified a new "mild phenotype". The two phenotypes show completely different EEG features at onset of epilepsy and during its evolution, which correspond to different clinical outcomes., Conclusions: Data from our long-term EEG and clinical-neuroradiological study allowed us to describe two different phenotypes of AIC, with different imaging severity and, in particular, different EEG at onset, which tend to remain constant over time., Significance: Together, these findings might help to predict long-term clinical outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: We explored the efficacy and safety of lacosamide combined with inhibitors of fast-inactivated sodium channels or with other antiepileptic drugs, in patients with drug refractory focal epilepsy associated with intellectual or psychiatric disability., Methods: Observational study of lacosamide including the monitoring of lacosamide trough plasma levels and of electroencephalograms., Results: We followed up 44 patients from the start of lacosamide therapy for up to 3 years, with a clinical, electroencephalogram (EEG), and pharmacological follow-up. Median patients' age was 32.7 years, median age at epilepsy onset was 3.5 years. Intellectual disability was severe in 55.4% of the cohort and drug refractoriness was diagnosed in 88.6% of patients, who had predominantly focal seizures (80%). The severity of their epilepsy was suggested by the use of combined therapies with non-sodium blockers and sodium blockers in 75% of patients. Lacosamide was added to previous therapies and up-titrated to a median of 300 mg/d. Lacosamide add-on led to simplification of the previous drug regimen with a dose reduction in 87.9% of users of sodium blockers and in 66.7% of users of non-sodium blockers, and to withdrawal of previously administered sodium blockers in 48.5% users and non-sodium blockers in 47.6% users. Lacosamide was prescribed at lower doses in the presence of oxcarbazepine (p = 0.029), lamotrigine (p = 0.015), and topiramate (p < 0.001). Mean lacosamide plasma levels were 6.0 ± 2.4 mg/L; they were in linear correlation with the administered dose (R 2  = 0.38, p < 0.001) and were influenced by the association with lamotrigine (p = 0.008), zonisamide (p = 0.012), and clobazam (p = 0.028). Lacosamide combination regimens led to an average reduction of 42% in baseline seizure frequency, with 50% patients reporting ≥50% seizure frequency reduction. Efficacy was directly correlated with lacosamide dose (R 2  = 0.47, p < 0.001, B = 0.53) and trough plasma levels (R 2  = 0.31, p < 0.001, B = 0.16). Electroencephalogram profiles were improved in 40.9% of patients and EEG improvement was not significantly correlated with seizure frequency reduction. Lacosamide safety was good, with 37 adverse reactions in 30 patients, of which 50% were attributed to lacosamide and led to lacosamide withdrawal in 18% of cases. The retention rate of lacosamide was of 88.6% at 1 year, 86.4% at 2 years, and 72.7% after three years. The severity of intellectual disability was directly correlated with increased possibility of lacosamide retention (OR = 0.46 per severity tier, p = 0.016)., Conclusion: Lacosamide add-on allowed dose reduction of previous therapies and reduced the frequency of seizures, showing good tolerability even at high doses, without exceeding reference plasma levels., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The current study investigated peer relationship and school climate factors associated with adolescent mental health. Cross-sectional data from 2,571 fifteen-year old students in 22 Scottish secondary schools was used. Multilevel models tested for school differences in mental health, and nested linear regression models estimated peer and school effects. Results demonstrated no significant between-school variation in mental health. Peer victimization was the only peer effect associated with mental health. School-belonging, student-teacher relationships, and a perceived inclusive school climate were associated with better mental health, whereas a perceived school climate of exam pressure was associated with worse mental health. The findings highlight multiple aspects of school climate that could be targeted in school-based interventions for adolescent mental health., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Complexity approaches have gained international attention as potentially effective strategies to address population health challenges. In light of this, the Scottish government (Scot. Gov.) set the implementation of these approaches as the recommended practice for its public health sector organizations. This study evaluates the opportunity and feasibility of implementing complexity approaches in public health Scotland employees' everyday routine by employing a qualitative study that involves 20 stakeholders, representative of different organizations and roles. We made use of an assessment framework based on Soft Systems Methodology (SSm) and Normalization Process Theory (NPT) comprised of five phases: Phase One defines the boundaries, aims, and goals of the issue under study; Phase Two consists of data collection, drawing on the e-Health Implementation Toolkit (e-HIT); Phase Three involves short presentations and breakout group activities to provide information on the new policy; Phase Four employs system thinking tasks to structure debate and builds shared understanding among participants; Phase Five applies NPT to appraise the organizational position around complexity based on information from the preceding steps. We found two main obstacles to implementing complexity approaches: (1) a lack of a shared understanding of the key concepts in complexity and their practical implications; (2) stakeholders' fear of significant disruption to work routines and power relationships. We recommend addressing these issues with appropriate training and customization of goals and tools that may enable complexity approaches to succeed within the Scottish public health context. Our assessment framework allows the recognition of key mechanisms to support how Scotland's Public Health body can enhance the implementation of complexity approaches. The appraisal framework could be used to study early-stage policy implementation in other contexts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zucca, Long, Hilton and McCann.)

Background: Purified cannabidiol (CBD) was administered to highly refractory patients with Dravet (DS) or Lennox-Gastaut (LGS) syndromes in an ongoing expanded access program (EAP). Herein, we report interim results on CBD safety and seizure outcomes in patients treated for a 12-month period. Material and Methods: Thirty centers were enrolled from December 2018 to December 2019 within the open-label prospective EAP up to a maximum of 25 mg/kg per day. Adverse effects and liver function tests were assessed after 2 weeks; 1, 3, and 6 months of treatment; and periodically thereafter. Seizure endpoints were the percentage of patients with ≥50 and 100% reduction in seizures compared to baseline. Results: A total of 93 patients were enrolled and included in the safety analysis. Eighty-two patients [27 (32.9%) DS, 55 (67.1%) LGS] with at least 3 months of treatment have been included in the effectiveness analysis; median previously failed antiseizure medications was eight. Pediatric and adult patients were uniformly represented in the cohort. At 3-month follow-up, compared to the 28-day baseline period, the percentage of patients with at least a 50% reduction in seizure frequency was 40.2% (plus 1.2% seizure-free). Retention rate was similar according to diagnosis, while we found an increased number of patients remaining under treatment in the adult group. CBD was mostly coadministered with valproic acid (62.2%) and clobazam (41.5%). In the safety dataset, 29 (31.2%) dropped out: reasons were lack of efficacy [16 (17.2%)] and adverse events (AEs) [12 (12.9%)], and one met withdrawal criteria (1.1%). Most reported AEs were somnolence (22.6%) and diarrhea (11.9%), followed by transaminase elevation and loss of appetite. Conclusions: CBD is associated with improved seizure control also in a considerable proportion of highly refractory patients with DS and LGS independently from clobazam use. Overall, CBD safety and effectiveness are not dose-related in this cohort., Competing Interests: FB has participated in clinical trials for GW Pharmaceuticals; received research grants, speaker fees or participated to advisory boards for Eisai, Cyberonics, UCB Pharma and Bial. MPC Canevini has participated advisory boards and/or received research fundings from UCB Pharma, Eisai, Italfarmaco, Cyberonics, Novartis, and the European Union. AC has received speaker fees by Eisai. CB has received speaker fees from Eisai, UCB Pharma, FB Health and Sandoz. Gd'O has served on the advisory board of Eisai. CG has received research grants and/or speaker fees from UCB Pharma, Eisai and Bial. TG received a speaker fee from GW Pharmaceuticals. RG has received consulting fees and speaker honoraria from Zogenix, Biomarin, UCB, Eisai, Novartis, GW Pharma, and Biocodex. OM has received consulting fees and speaker honoraria by Bial, Eisai, GW Pharmaceuticals and UCB Pharma. AL has received speaker's or consultancy fees from Eisai, Mylan, Sanofi, Bial, GW Pharmaceuticals and UCB Pharma. PP received speaker's fees from Eisai and UCB Pharma. AR received consulting fees from GW Pharmaceuticals. ER has received speaker fees and/or fundings and has participated in advisory boards for Eisai, Pfizer, GW Pharmaceuticals, UCB Pharma, Arvelle Therapeutics. NS has received grant support and fees for advisory board participation from GW Pharmaceuticals. PS developed within the framework of the DINOGMI Department of Excellence of MIUR 2018-2022 (legge 232 del 2016) and received speaker fees and participated at advisory boards for Biomarin, Zogenyx, GW Pharmaceuticals, Neuraxpharma; he also received research funding by ENECTA BV, GW Pharmaceuticals, Kolfarma srl., Eisai. ET has received speaker's fees from Eisai and Sandoz. AV received speaker's fees from Eisai, Italfarmaco, and GW Pharmaceuticals. MV received speaker's fees from Eisai and GW Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Iannone, Arena, Battaglia, Bisulli, Bonanni, Boni, Canevini, Cantalupo, Cesaroni, Contin, Coppola, Cordelli, Cricchiuti, De Giorgis, De Leva, De Rinaldis, d'Orsi, Elia, Galimberti, Morano, Granata, Guerrini, Lodi, La Neve, Marchese, Masnada, Michelucci, Nosadini, Pilolli, Pruna, Ragona, Rosati, Santucci, Spalice, Pietrafusa, Striano, Tartara, Tassi, Papa, Zucca, Russo, Mecarelli and The CBD LICE Italy Study Group.)

Objective: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay., Methods: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature., Results: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy., Conclusions: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory., Competing Interests: Declaration of competing interest None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To define the risks and consequences of cardiac abnormalities in ATP1A3 -related syndromes., Methods: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl +/- ) to determine the sequence of events in seizure-related cardiac death., Results: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death., Conclusions: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3 -related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3 -related disease. ATP1A3 -related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Introduction: Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4 years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12 months of RFM therapy., Methods: This was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58 years (mean = 22 ± 16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100 mg/week increments up to a dose of 300-2400 mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12 months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered., Results: After 12 months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL., Conclusion: Adjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1 year of follow-up., Competing Interests: Declaration of competing interest P.S. has received speaker fees and participated at advisory boards for BioMarin, Zogenyx, GW Pharmaceuticals, and has received research funding by ENECTA BV, GW Pharmaceuticals, Kolfarmasrl., Eisai. M.E. participated at advisory boards for GW Pharmaceuticals and Eisai. G.C. participated at advisory boards and scientific meetings for Eisai. F.F.O and G.M.G.P. participated at advisory boards for Eisai., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The Inverse First Passage time problem seeks to determine the boundary corresponding to a given stochastic process and a fixed first passage time distribution. Here, we determine the numerical solution of this problem in the case of a two dimensional Gauss-Markov diffusion process. We investigate the boundary shape corresponding to Inverse Gaussian or Gamma first passage time distributions for different choices of the parameters, including heavy and light tails instances. Applications in neuroscience framework are illustrated.

Mutations in tubulin genes are responsible for a large spectrum of brain malformations secondary to abnormal neuronal migration, organization, differentiation and axon guidance and maintenance. Motor impairment, intellectual disability and epilepsy are the main clinical symptoms. In the present study 15 patients from a personal cohort and 75 from 21 published studies carrying mutations in TUBA1A , TUBB2B and TUBB3 tubulin genes were evaluated with the aim to define a clinical and electrophysiological associated pattern. Epilepsy shows a wide range of severity without a specific pattern. Mutations in TUBA1A (60%) and TUBB2B (74%) and TUBB3 (25%) genes are associated with epilepsy. The accurate analysis of the Electroencephalogram (EEG) pattern in wakefulness and sleep in our series allows us to detect significant abnormalities of the background activity in 100% of patients. The involvement of white matter and of the inter-hemispheric connection structures typically observed in tubulinopathies is evidenced by the high percentage of asynchronisms in the organization of sleep activity recorded. In addition to asymmetries of the background activity, excess of slowing, low amplitude and Magnetic Resonance (MR) imaging confirm the presence of extensive brain malformations involving subcortical and midline structures. In conclusion, epilepsy in tubulinopathies when present has a favorable evolution over time suggesting a not particularly aggressive therapeutic approach.

The aim of this study is to assess the ability of EEG-based indices in providing relevant information about cognitive engagement level during the execution of a clinical sustained attention (SA) test in healthy volunteers and DAI (diffused axonal injury)-affected patients. We computed three continuous power-based engagement indices (P β /P α , 1/P α , and P β / (P α + P θ )) from EEG recordings in a control group (n = 7) and seven DAI-affected patients executing a 10-min Conners' "not-X" continuous performance test (CPT). A correlation analysis was performed in order to investigate the existence of relations between the EEG metrics and behavioral parameters in both the populations. P β /P α and 1/P α indices were found to be correlated with reaction times in both groups while P β / (P α + P θ ) and P β /P α also correlated with the errors rate for DAI patients. In line with previous studies, time course fluctuations revealed a first strong decrease of attention after 2 min from the beginning of the test and a final fading at the end. Our results provide evidence that EEG-derived indices extraction and evaluation during SA tasks are helpful in the assessment of attention level in healthy subjects and DAI patients, offering motivations for including EEG monitoring in cognitive rehabilitation practice. Graphical abstract Three EEG-derived indices were computed from four electrodes montages in a population of seven healthy volunteers and a group of seven DAI-affected patients. Results show a significant correlation between the time course of the indices and behavioral parameters, thus demonstrating their usefulness in monitoring mental engagement level during a sustained attention task.

Introduction: Phelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS., Methods: Following the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with SHANK3 deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism., Results: WGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microhomology-mediated insertion of partial Alu- elements at one breakpoint junction disrupted the topological associating domain joining NFAM1 to the transcriptional coregulator TCF20 . WES failed to detect BPP-associated variants., Conclusions: Although we were unable to highlight the molecular basis of BPP, our data suggest that SHANK3 haploinsufficiency and TCF20 misregulation, both associated with intellectual disability, contributed to the patient's NDD, while NFAM1 interruption likely caused her skin rashes, as previously reported. We provide the first example of chromoanasynthesis in a constitutional ring chromosome and reinforce the growing evidence that chromosomal rearrangements may be more complex than estimated by conventional diagnostic approaches and affect the phenotype by global alteration of the topological chromatin organisation rather than simply by deletion or duplication of dosage-sensitive genes., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aim: Mowat-Wilson Syndrome (MWS) is a genetic rare disease. Epilepsy is present in 70-75% of Patients and an age-dependent electroclinical pattern has been described. Up to date, there are studies with overnight sleep EEGs, probably because of the severe intellectual disability (ID) and hyperactivity of these Patients. Our purpose was to verify the hypothesis that MWS Patients might have electrical status epilepticus in slow wave sleep (ESES pattern)., Methods: A retrospective analysis of anamnestic and electrographic data was performed on 7 consecutive MWS Patients followed between 2007 and 2016. Only Patients with at least one overnight sleep EEG were included in the study., Results: Five out of 7 Patients had overnight sleep EEG studies and were included in this study. All of them had an anterior ESES pattern with spike-and-wave index>85%. The architecture of sleep was abnormal. An ESES related regression of cognitive and motor functions with impact on daily activities (ESES-related syndrome) was demonstrated in 3 out of 5 (60%) Patients. In two Patients marked improvement of cognitive and motor performances was observed when the epileptiform activity during sleep was successfully controlled or it was spontaneously reduced., Conclusions: The clinical significance of the ESES pattern is hard to assess in MWS Patients due to severe ID, but changing in behaviour or in motor and cognitive functions should mandate sleep EEG investigation and, if ESES is present, an appropriate treatment should be tried. Furthermore, overnight sleep EEG recordings, if regularly performed in the follow up, might help to understand if ESES pattern hampers the cognitive and communicative profile in MWS., (Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Standard treatment provided by mental health services, mainly based on drug therapy and individual sessions, does not help patients to enhance their capacity to prevent and manage crises., Aim: This paper aims at examining the effectiveness of four group-based rehabilitative interventions carried out in the Acute Psychiatric Inpatient Ward and in the Department of Mental Health of Viterbo, Italy., Methods: The effectiveness of the four group-based interventions on patients and their relatives was evaluated in both inpatient and outpatient settings in terms of clinical efficacy, disease awareness, quality of life, and ability to cope with stress. A set of specific assessment tools was used for the purpose., Results: Group-based interventions showed high level of effectiveness in improving patients' insight, clinical stability, quality of life and satisfaction in using the services, and in enhancing family members' ability to manage stress., Conclusions: Group-based rehabilitative interventions enable mental health services to provide users with additional treatment options complementary to drug therapy, improving the quality of life of patients and their families in a recovery-oriented perspective.

Restoration efforts in the Mediterranean Basin have been changing from a silvicultural to an ecological restoration approach. Yet, to what extent the projects are guided by ecological restoration principles remains largely unknown. To analyse this issue, we built an on-line survey addressed to restoration practitioners. We analysed 36 restoration projects, mostly from drylands (86%). The projects used mainly soil from local sources. The need to comply with legislation was more important as a restoration motive for European Union (EU) than for non-EU countries, while public opinion and health had a greater importance in the latter. Non-EU countries relied more on non-native plant species than EU countries, thus deviating from ecological restoration guidelines. Nursery-grown plants used were mostly of local or regional provenance, whilst seeds were mostly of national provenance. Unexpected restoration results (e.g. inadequate biodiversity) were reported for 50% of the projects and restoration success was never evaluated in 22%. Long term evaluation (>6years) was only performed in 31% of cases, and based primarily on plant diversity and cover. The use of non-native species and species of exogenous provenances may: i) entail the loss of local genetic and functional trait diversity, critical to cope with drought, particularly under the predicted climate change scenarios, and ii) lead to unexpected competition with native species and/or negatively impact local biotic interactions. Absent or inappropriate monitoring may prevent the understanding of restoration trajectories, precluding adaptive management strategies, often crucial to create functional ecosystems able to provide ecosystem services. The overview of ecological restoration projects in the Mediterranean Basin revealed high variability among practices and highlighted the need for improved scientific assistance and information exchange, greater use of native species of local provenance, and more long-term monitoring and evaluation, including functional and ecosystem services' indicators, to improve and spread the practice of ecological restoration., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

We report on a child, aged 4 7/12 years, with borderline intelligence quotient, normal brain magnetic resonance imaging, and focal epilepsy. The polysomnographic electroencephalogram recording revealed asynchronous central spikes at both brain hemispheres resembling the features observed in focal idiopathic epileptic syndromes. Array comparative genomic hybridization analysis revealed a 32-kb partial deletion of the DEP domain-containing protein 5 ( DEPDC5 ) gene, involved in a wide spectrum of inherited focal epileptic syndromes. The parental origin of the deletion could not be fully ascertained because the pregnancy had been achieved through anonymous egg donation and insemination by intracytoplasmic sperm injection. However, we demonstrate that the deletion, shared by all alternatively spliced isoforms of DEPDC5 , produces a transcript presumably generating a DEPDC5 protein missing the entire DEP domain. Our findings suggest that partial deletion of DEPDC5 may be sufficient to cause the focal epilepsy in our patient, highlighting the importance of the DEP domain in DEPDC5 function. This study expands the phenotypic spectrum of DEPDC5 to sporadic forms of focal idiopathic epilepsy and underscores the fact that partial deletions, albeit probably very rare, are part of the genetic spectrum of DEPDC5 mutations.

Statistical properties of spike trains as well as other neurophysiological data suggest a number of mathematical models of neurons. These models range from entirely descriptive ones to those deduced from the properties of the real neurons. One of them, the diffusion leaky integrate-and-fire neuronal model, which is based on the Ornstein-Uhlenbeck (OU) stochastic process that is restricted by an absorbing barrier, can describe a wide range of neuronal activity in terms of its parameters. These parameters are readily associated with known physiological mechanisms. The other model is descriptive, Gamma renewal process, and its parameters only reflect the observed experimental data or assumed theoretical properties. Both of these commonly used models are related here. We show under which conditions the Gamma model is an output from the diffusion OU model. In some cases, we can see that the Gamma distribution is unrealistic to be achieved for the employed parameters of the OU process.

Although the occurrence of concomitant positive BOLD responses (PBRs) and negative BOLD responses (NBRs) to visual stimuli is increasingly investigated in neuroscience, it still lacks a definite explanation. Multimodal imaging represents a powerful tool to study the determinants of negative BOLD responses: the integration of functional Magnetic Resonance Imaging (fMRI) and electroencephalographic (EEG) recordings is especially useful, since it can give information on the neurovascular coupling underlying this complex phenomenon. In the present study, the brain response to intermittent photic stimulation (IPS) was investigated in a group of healthy subjects using simultaneous EEG-fMRI, with the main objective to study the electrophysiological mechanisms associated with the intense NBRs elicited by IPS in extra-striate visual cortex. The EEG analysis showed that IPS induced a desynchronization of the basal rhythm, followed by the instauration of a novel rhythm driven by the visual stimulation. The most interesting results emerged from the EEG-informed fMRI analysis, which suggested a relationship between the neuronal rhythms at 10 and 12 Hz and the BOLD dynamics in extra-striate visual cortex. These findings support the hypothesis that NBRs to visual stimuli may be neuronal in origin rather than reflecting pure vascular phenomena. Hum Brain Mapp 37:2247-2262, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: After traumatic brain injury, epilepsy affects up to 20 % of children. It is a risk factor, for both clinical recovery and cognitive performance; therefore pharmacological therapy is advisable. Current guidelines recommend prophylaxis to be initiated as soon as possible and tapered 1 week after trauma. However, no guideline exists for paediatric patients and the clinical practice is heterogeneous., Objective: In our institute, prophylaxis was routinely tapered 6 months after trauma. Therefore we investigated whether this prophylaxis or its tapering influenced the development of post-traumatic epilepsy, together with several clinical-demographic factors., Methods: The study population comprised all patients with post-traumatic brain injury referred to this institute between 2002 and 2009 who consented to participate. Clinical, epileptological and pharmacological data were collected. The role of prophylaxis and several other predictors on occurrence of post-traumatic epilepsy was analysed through logistic regressions., Results: Two hundred and three patients (145 paediatric) were followed for 57 months on average. Risk factors for epilepsy were past neurosurgery [odds ratio (OR) = 2.61, 95 % confidence interval (CI) 1.15-5.96], presence of epileptiform anomalies (OR = 6.92, 95 % CI 3.02-15.86) and the presence of prophylaxis (OR = 2.49, 95 % CI 1.12-5.52), while higher intelligence quotient (IQ) was protective (OR = 0.96, 95 % CI 0.95-0.98). While evaluating possible different effects within and after 6 months (tapering, for those under prophylaxis), we found that epileptiform anomalies (OR = 7.61, 95 % CI 2.33-24.93, and OR = 8.21, 95 % CI 3.00-22.44) and IQ (OR = 0.96, 95 % CI 0.94-0.98, and OR = 0.97, 95 % CI 0.95-0.98) were always significant predictors of epilepsy, while neurosurgery (OR = 4.38, 95 % CI 1.10-17.45) was significant only within 6 months from trauma, and prophylaxis (OR = 3.98, 95 % CI 1.62-9.75) only afterwards., Conclusions: These results suggest that prophylaxis was irrelevant when present; furthermore its tapering increased the risk of epilepsy. Since the presence of epileptiform anomalies was the main predictor of post-traumatic epilepsy, such anomalies may be useful to better direct the choice of prophylaxis.

Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.)

This paper investigates the relation between mental engagement level and sustained attention in 9 healthy adults performing a Conners' "not-X" continuous performance test (CPT), while their electroencephalographic (EEG) activity was simultaneously acquired. Spectral powers were estimated and extracted in the classical EEG frequency bands. The engagement index (β/α) was calculated employing four different cortical montages suggested by the literature. Results show the efficacy of the estimated measures in detecting changes in mental state and its correlation with subject reaction times throughout the test. Moreover, the influence of the recording sites was proved underling the role of frontal cortex in maintaining a constant sustained attention level.

Despite negative blood oxygenation level dependent (BOLD) responses to visual stimuli have recently gained considerable interest, the explanation for their underlying neuronal and vascular mechanisms is still controversial. In the present study, a multimodal experimental approach is presented to shed light on the negative BOLD phenomenon in the human brain. In particular, information from functional magnetic resonance imaging (fMRI) and near infrared spectroscopy (NIRS) was integrated to confirm and gain insight into the phenomenon of negative BOLD responses (NBRs) to unpatterned intermittent photic stimulation (IPS) in healthy subjects. Eight healthy subjects participated in the study. Consistent findings emerged from the activation analysis of fMRI and NIRS data and the comparison of BOLD and hemoglobin responses at the single channel level showed that NBRs are related to a decrease in oxyhemoglobin (HbO) combined with a lower increase in deoxyhemoglobin (HHb), corresponding to a decrease in total hemoglobin (THb) and estimated cerebral blood volume (CBV). The HbO and HHb variations were significant in at least one channel in six subjects out of eight (p<0.05). The NIRS technique allowed obtaining valuable information on the vascular determinants of the NBRs, since the discrimination between HbO, HHb and THb information provided a more comprehensive view of the negative BOLD phenomenon. The within and between subject heterogeneous BOLD-Hb temporal relations pave the way to further investigations into the neurovascular properties of NBRs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To provide an estimate of the occurrence of misdiagnosis in paroxysmal events in institutionalized children with severe disabilities and refractory epilepsy. A multi-step diagnostic survey, from observational to long-term video-EEG monitoring was performed in 46 severe disabled children. Multirater Kappa statistic was used to assess agreement between investigators and to individualize children who remained with dubious events. Subsequently, prolonged EEG-video monitoring analysis was performed in selected children to define phenomena due to seizures. A total of 128 video records were performed, 64 routine video-EEG and 27 long-monitoring video-EEG data were screened for detailed analysis. Thirty (21 female, 9 male) children (65%) with dubious seizures were identified by video records (concordance K=0.63). Of these, in 18 children (39%) seizures were excluded by routine video-EEG monitoring (K=0.86). Twelve children (26%) required accurate investigations with long-term video-EEG. In 5 children (11%), 3 symptomatic and 2 cryptogenic, very short and subtle seizures were confirmed by investigators concordance (K=0.83). Distinguishing paroxysmal phenomena is a challenge in children with severe disabilities; its most remarkable consequence is inappropriate pharmacological treatment and social costs. Our data suggest that the frequency of misdiagnosis could have been underestimated. The clinicians who manage children with severe disabilities and refractory epilepsy must remain alert to risk of an incorrect treatment., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Functional Magnetic Resonance Imaging (fMRI) is used for exploring brain functionality, and recently it was applied for mapping the brain connection patterns. To give a meaningful neurobiological interpretation to the connectivity network, it is fundamental to properly define the network framework. In particular, the choice of the network nodes may affect the final connectivity results and the consequent interpretation., New Method: We introduce a novel method for the intra subject topological characterization of the nodes of fMRI brain networks, based on a whole brain parcellation scheme. The proposed whole brain parcellation algorithm divides the brain into clusters that are homogeneous from the anatomical and functional point of view, each of which constitutes a node. The functional parcellation described is based on the Tononi's cluster index, which measures instantaneous correlation in terms of intrinsic and extrinsic statistical dependencies., Results: The method performance and reliability were first tested on simulated data, then on a real fMRI dataset acquired on healthy subjects during visual stimulation. Finally, the proposed algorithm was applied to epileptic patients' fMRI data recorded during seizures, to verify its usefulness as preparatory step for effective connectivity analysis. For each patient, the nodes of the network involved in ictal activity were defined according to the proposed parcellation scheme and Granger Causality Analysis (GCA) was applied to infer effective connectivity., Conclusions: We showed that the algorithm 1) performed well on simulated data, 2) was able to produce reliable inter subjects results and 3) led to a detailed definition of the effective connectivity pattern., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been recently described in Ohtahara syndrome, or early infantile epileptic encephalopathy with suppression-burst pattern, and in other early-onset epileptic encephalopathies. A 3-year-old boy affected by epileptic encephalopathy started at 8 months of age is described. Focal epilepsy was characterized by drug resistance seizures with multifocal interictal and ictal electroencephalographic (EEG) features and variable EEG focus. Direct sequencing of the STXBP1 gene showed a novel de novo mutation (c.751G>A), leading to a p.Ala251Thr substitution. Based on reported data, treatment with vigabatrin was attempted and patient became immediately seizure free for 4 months. The present case further expands the clinical spectrum of "STXBP1-related encephalopathy" suggesting molecular analysis of STXBP1 in early onset epileptic encephalopathies of unknown etiology (with onset within the first year of life). In addition, the case provides valuable suggestions on seizures treatment in STXBP1 mutated subjects.

Motivated by a neuronal modeling problem, a bivariate Wiener process with two independent components is considered. Each component evolves independently until one of them reaches a threshold value. If the first component crosses the threshold value, it is reset while the dynamics of the other component remains unchanged. But, if this happens to the second component, the first one has a jump of constant amplitude; the second component is then reset to its starting value and its evolution restarts. Both processes evolve once again until one of them reaches again its boundary. In this work, the coupling of the first exit times of the two connected processes is studied., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Functional Magnetic Resonance Imaging (fMRI) in combination with Near Infrared Spectroscopy (NIRS) is finding widespread use in the analysis of brain function. While most of the studies deal with the detection of positive responses, here we focus on negative responses to visual stimulation. In a group fMRI study on Intermittent Photic Stimulation (IPS) we detected a sustained Negative BOLD Response (NBR) in the extrastriate visual cortex. To confirm and better characterize NBR, we repeated the same protocol during NIRS recordings. In this paper we show fMRI results and demonstrate the NBR on the basis of NIRS findings.

Purpose: Duplications encompassing the MECP2 gene on the Xq28 region have been described in male patients with moderate to severe mental retardation, absent speech, neonatal hypotonia, progressive spasticity and/or ataxia, recurrent severe respiratory infections, gastrointestinal problems, mild facial dysmorphisms (midface hypoplasia, depressed nasal bridge, large ears) and epilepsy. Epilepsy can occur in >50% of cases, but the types of seizures and the electroclinical findings in affected male individuals have been poorly investigated up to the present. Herein we describe eight patients with MECP2 duplication syndrome and a specific clinical and electroencephalographic pattern., Methods: Array CGH of genomic DNA from the probands was performed, and an Xq28 duplication ranging from 209 kb to 6.36 Mb was found in each patient. Electroencephalography studies and clinical and seizure features of all the patients were analyzed., Key Findings: We found that epilepsy tended to occur between late childhood and adolescence. Episodes of loss of tone of the head and/or the trunk were the most represented seizure types. Generalized tonic-clonic seizures were rarely observed. The typical interictal EEG pattern showed abnormal background activity, with generalized slow spike and wave asynchronous discharge with frontotemporal predominance. Sleep electroencephalography studies also demonstrated abnormal background activity; spindles and K complex were often abnormal in morphology and amplitude. Response to therapy was generally poor and drug resistance was a significant feature., Significance: Although these cases and a review of the literature indicate that epilepsy associated with MECP2 duplication syndrome cannot be considered a useful marker for early diagnosis, epilepsy is present in >90% of adolescent patients and shows a peculiar electroclinical pattern. Consequently, it should be considered a significant sign of the syndrome, and an EEG follow-up of these patients should be encouraged from early childhood. Moreover, the definition of a more specific epileptic phenotype could be useful in order to suspect MECP2 duplication syndrome in older undiagnosed patients., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Ethical, legal, and social issues related to the collection, storage, and use of biospecimens and data derived from children raise critical concerns in the international debate. So far, a number of studies have considered a variety of the individual issues crucial to pediatric biobanking such as decision making, privacy protection, minor recontact, and research withdrawal by focusing on theoretical or empirical perspectives. Our research attempted to analyze such issues in a comprehensive manner by exploring practices, rules, and researcher opinions regarding proxy consent, minor assent, specimens and data handling, and return of results as faced in 10 European countries. Because of the lack of comparative analyses of these topics, a pilot study was designed. Following a qualitative methodology, a questionnaire draft mostly including open-ended queries was developed, tested, and sent by e-mail to a selected group of researchers dealing with pediatric biobanking (n=57). Returned questionnaires (n=31) highlighted that the collection, storage, distribution, and use of biospecimens and data from children were widely practiced in the contacted laboratories. In most cases, pediatric biobanking was subjected to national or local regulations covering adult biobanks (n=26). Informed consent was generally given by parents or legal representatives (n=17). Children's opinions were frequently sought and taken into account (n=16). However, minors were usually not recontacted at the age of maturity to express their own choices (n=26). Based on the collected data, dedicated recommendations are needed to govern unique ethical and regulatory issues surrounding pediatric biobanking.

The dynamics of a neuron are influenced by the connections with the network where it lies. Recorded spike trains exhibit patterns due to the interactions between neurons. However, the structure of the network is not known. A challenging task is to investigate it from the analysis of simultaneously recorded spike trains. We develop a non-parametric method based on copulas, that we apply to simulated data according to different bivariate Leaky Integrate and Fire models. The method discerns dependencies determined by the surrounding network, from those determined by direct interactions between the two neurons. Furthermore, the method recognizes the presence of delays in the spike propagation. This article is part of a Special Issue entitled "Neural Coding"., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of this study was to describe in detail the neurological features of nine patients carrying the recently reported microduplication at Xp11.22-11.23. Clinical and neurological examination, brain magnetic resonance imaging (except for two patients), electroencephalography and a neuropsychological assessment specific for language disturbances were performed in nine patients with microduplication at Xp11.22-11.23, disclosed by comparative genomic hybridisation array. Six patients were familial cases belonging to three unrelated pedigrees and three were sporadic cases. The patients had the following characteristics: mild dysmorphic facial features (except for two patients), mental retardation with moderate to severe global language deterioration, electroencephalographic epileptiform discharges during wakefulness and especially during sleep or electrical status epilepticus during slow sleep in younger cases, and negative brain magnetic resonance imaging. The main clinical features of this new microduplication syndrome were mild facial dysmorphisms, from increased electroencephalogram abnormalities during sleep to electrical status epilepticus during slow sleep, and mental retardation mainly involving language function in the absence of detectable brain lesions. In the absence of detectable brain lesions, speech delay may be associated with electrical status epilepticus during slow sleep or, alternatively, related to abnormal brain expression of a dosage-sensitive gene contained within the duplication region.

In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS., Competing Interests: The authors have declared that no competing interests exist.

A splice site variation (c.603-91G>A or rs3812718) in the SCN1A gene has been claimed to influence efficacy and dose requirements of carbamazepine and phenytoin. We investigated the relationship between c.603-91G>A polymorphism and response to antiepileptic drugs (AEDs) in 482 patients with drug-resistant and 401 patients with drug-responsive focal epilepsy. Most commonly used AEDs were carbamazepine and oxcarbazepine. The distribution of c.603-91G>A genotypes was similar among drug-resistant and drug-responsive subjects, both in the entire population and in the groups treated with carbamazepine or oxcarbazepine. There was no association between the c.603-91G>A genotype and dosages of carbamazepine or oxcarbazepine. These findings rule out a major role of the SCN1A polymorphism as a determinant of AED response., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

We describe the detailed clinical and molecular characterization of three patients (aged 7, 8(4/12) and 31 years) with overlapping microdeletions in 19p13.12, extending to 19p13.13 in two cases. The patients share the following clinical features with a recently reported 10-year-old girl with a 19p13.12 microdeletion: mental retardation (MR), psychomotor and language delay, hearing impairment, brachycephaly, anteverted nares and ear malformations. All patients share a 359-kb deleted region in 19p13.12 harboring six genes (LPHN1, DDX39, CD97, PKN1, PTGER1 and GIPC1), several of which may be MR candidates because of their function and expression pattern. LPHN1 and PKN1 are the most appealing; LPHN1 for its interaction with Shank family proteins, and PKN1 because it is involved in a variety of functions in neurons, including cytoskeletal organization. Haploinsufficiency of GIPC1 may contribute to hearing impairment for its interaction with myosin VI. A behavioral phenotype was observed in all three patients; it was characterized by overactive disorder associated with MR and stereotyped movements (ICD10) in one patient and hyperactivity in the other two. As Ptger1-null mice show behavioral inhibition and impulsive aggression with defective social interaction, PTGER1 haploinsufficiency may be responsible for the behavioral traits observed in these patients.

Purpose: To study neuropsychological functions in children with idiopathic epilepsy at onset of treatment and after 1 year of therapy and to identify factors associated with cognitive impairment., Methods: 43 Subjects aged 5.2-16.9 years with newly diagnosed idiopathic epilepsy were enrolled and started treatment with valproate or carbamazepine. At admission and after 12 months, all patients underwent clinical examinations, the Child Behavioural Checklist, EEG and a neuropsychological test battery. The results of each test were correlated to demographic, clinical, electrophysiological and therapeutic variables., Results: Except for attention, all neuropsychological functions were normal at admission and after 12 months. An improvement with time was noted for memory (p<0.05) and logical-executive functions (p<0.01). Attentive deficit was worse at 12 months (53.5% vs. 32.6%). Low socio-economic level and emotional and behavioural disturbances were the only factors negatively correlated to intelligence, memory and attention. Compared to valproate, carbamazepine was most commonly implicated., Discussion: Idiopathic epilepsy can affect attention, even before starting treatment. Emotional and behavioural difficulties and a low socio-economical status are associated with cognitive impairment., (Copyright © 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Mutations in the calcium channel voltage dependent P/Q-type alpha-1A subunit (CACNA1A) can cause different neurological disorders which share a wide range of symptoms, including episodic ataxia type 2 (EA2), familial hemiplegic migraine (FHM1) and progressive spinocerebellar ataxia (SCA6)., Objective: To describe a three generations family in which a spectrum of different phenotypes, ranging from SCA6 (proband), to EA2 (proband's mother) to FHM1 (proband's mother and proband's aunt) was found. All of the family members carried a novel CACNA1A missense mutation., Patients and Methods: A clinical, molecular, neuroradiological and neurophysiological study was carried out in all subjects., Results: A single heterozygous base change in exon 9, c1213G-->A, leading to the amino acid substitution pAla405Thr was found to segregate within the family. Brain MRI showed cerebellar and cerebral atrophy signs in all but one mutation carriers. Neurophysiological findings (electroencephalography and evoked potentials) confirmed possible cerebral cortex and white matter involvement regardless of the clinical symptoms displayed., Conclusions: This novel CACNA1A mutation adds to the number of mutations associated with a heterogeneous clinical picture in family members. This mutation might affect the interaction between the intracellular loops and the beta subunit, leading to a relatively rapid cell death. In order to explain the wide phenotypic variability observed in this family, it is hypothesised that additional genetic and environmental (hormonal) factors play a role in the pathophysiology of the disease.