Understanding neurodevelopmental trajectories and behavioral profiles in SCN1A-related epilepsy syndromes.

BACKGROUND: A pathogenic variant in SCN1A can result in a spectrum of phenotypes, including Dravet syndrome (DS) and genetic epilepsy with febrile seizures plus (GEFS + ) syndrome. Dravet syndrome (DS) is associated with refractory seizures, developmental delay, intellectual disability (ID), motor impairment, and challenging behavior(1,2). GEFS + is a less severe phenotype in which cognition is often normal and seizures are less severe. Challenging behavior largely affects quality of life of patients and their families. This study describes the profile and course of the behavioral phenotype in patients with SCN1A-related epilepsy syndromes, explores correlations between behavioral difficulties and potential risk factors. METHODS: Data were collected from questionnaires, medical records, and semi-structured interviews. Behavior difficulties were measured using the Adult/Child Behavior Checklist (C/ABCL) and Adult self-report (ASR). Other questionnaires included the Pediatric Quality of Life Inventory (PedsQL), the Functional Mobility Scale (FMS) and the Sleep Behavior Questionnaire by Simonds & Parraga (SQ-SP). To determine differences in behavioral difficulties longitudinally, paired T-tests were used. Pearson correlation and Spearman rank test were used in correlation analyses and multivariable regression analyses were employed to identify potential risk factors. RESULTS: A cohort of 147 participants, including 107 participants with DS and 40 with genetic epilepsy with febrile seizures plus (GEFS + ), was evaluated. Forty-six DS participants (43.0 %) and three GEFS + participants (7.5 %) showed behavioral problems in the clinical range on the A/CBCL total problems scale. The behavioral profile in DS exists out of withdrawn behavior, aggressive behavior, and attention problems. In DS patients, sleep disturbances (ß = 1.15, p < 0.001) and a lower age (ß = -0.21, p = 0.001) were significantly associated with behavioral difficulties. Between 2015 and 2022, behavioral difficulties significantly decreased with age (t = -2.24, CI = -6.10 - -0.15, p = 0.04) in DS participants aging from adolescence into adulthood. A decrease in intellectual functioning (ß = 3.37, p = 0.02) and using less antiseizure medications in 2022 than in 2015, (ß = -1.96, p = 0.04), were identified as possible risk factors for developing (more) behavioral difficulties. CONCLUSIONS: These findings suggest that, in addition to epilepsy, behavioral difficulties are a core feature of the DS phenotype. Behavioral problems require personalized management and treatment strategies. Further research is needed to identify effective interventions.

Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders.

Epilepsy and mental retardation limited to females (EFMR), caused by PCDH19 mutations, has a variable clinical expression that needs further exploration. Onset of epilepsy may be provoked by fever and can resemble Dravet syndrome. Furthermore, transmitting males have no seizures, but are reported to have rigid personalities suggesting possible autism spectrum disorders (ASD). Therefore, this study aimed to determine the phenotypic spectrum associated with PCDH19 mutations in Dravet-like and EFMR female patients and in males with ASD. We screened 120 females suffering from Dravet-like epilepsy, 136 females with EFMR features and 20 males with ASD. Phenotypes and genotypes of the PCDH19 mutation carriers were compared with those of 125 females with EFMR reported in the literature. We report 15 additional patients with a PCDH19 mutation. Review of clinical data of all reported patients showed that the clinical picture of EFMR is heterogeneous, but epilepsy onset in infancy, fever sensitivity and occurrence of seizures in clusters are key features. Seizures remit in the majority of patients during teenage years. Intellectual disability and behavioural disturbances are common. Fifty percent of all mutations are missense mutations, located in the extracellular domains only. Truncating mutations have been identified in all protein domains. One ASD proband carried one missense mutation predicted to have a deleterious effect, suggesting that ASD in males can be associated with PCDH19 mutations.

[Psychoses and epilepsy. A case study]. / Psychosen en epilepsie.

Over the last few decades much research has been done into the raised level of psychiatric comorbidity in epilepsy. On the basis of a case study of a patient suffering from post-ictal psychoses we explain the psychiatric differential diagnosis within the framework of epilepsy and we investigate the frequent psychiatric side-effects of anticonvulsants. It is concluded that the links between epilepsy and psychiatric symptoms are complex and that the neuropsychiatry of epilepsy is concerned with syndromes that are unique and do notfit into modern psychiatric classification systems.

A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q.

A genome scan was performed on 164 Dutch affected sib pairs (ASPs) with attention-deficit/hyperactivity disorder (ADHD). All subjects were white and of Dutch descent and were phenotyped according to criteria set out in the Diagnostic and Statistical Manual Of Mental Disorders, 4th edition. Initially, a narrow phenotype was defined, in which all the sib pairs met the full ADHD criteria (117 ASPs). In a broad phenotype, additional sib pairs were included, in which one child had an autistic-spectrum disorder but also met the full ADHD criteria (164 ASPs). A set of 402 polymorphic microsatellite markers with an average intermarker distance of 10 cM was genotyped and analyzed using the Mapmaker/sibs program. Regions with multipoint maximum likelihood scores (MLSs) >1.5 in both phenotypes were fine mapped with additional markers. This genome scan indicated several regions of interest, two of which showed suggestive evidence for linkage. The most promising chromosome region was located at 15q, with an MLS of 3.54 under the broad phenotype definition. This region was previously implicated in reading disability and autism. In addition, MLSs of 3.04 and 2.05 were found for chromosome regions 7p and 9q in the narrow phenotype. Except for a region on chromosome 5, no overlap was found with regions mentioned in the only other independent genome scan in ADHD reported to date.

Effects of dose, sex, and long-term abstention from use on toxic effects of MDMA (ecstasy) on brain serotonin neurons.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug that has been shown to damage brain serotonin neurons in high doses. However, effects of moderate MDMA use on serotonin neurons have not been studied, and sex differences and the long-term effects of MDMA use on serotonin neurons have not been identified. We investigated the effects of moderate and heavy MDMA use, sex differences, and long-term effects of MDMA use on serotonin neurons in different brain regions. METHODS: By means of flyers posted in "rave" venues in Amsterdam, the Netherlands, we recruited 15 moderate MDMA users, 23 heavy MDMA users, 16 ex-MDMA users who had stopped using MDMA for more than 1 year, and 15 controls who claimed never to have used MDMA. We studied the effects of MDMA on brain serotonin neurons using 123iodine-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane ([123I]beta-CIT)-a radioligand that binds with high affinity to serotonin transporters. Density of binding (expressed as a ratio of region-of-interest binding over binding in the cerebellum) was calculated by single-photon-emission computed tomography (SPECT). FINDINGS: We saw significant effects of group and group by sex (p=0.041 and p=0.022, respectively) on overall [123I]beta-CIT binding ratios. In heavy MDMA users, significant decreases in overall binding ratios were seen in women (p<0.01) but not men (p=0.587). In female ex-MDMA users, overall densities of serotonin transporters were significantly higher than in heavy MDMA users (p=0.004), but not higher than in controls (p=0.524). INTERPRETATION: Our results indicate that heavy use of MDMA is associated with neurotoxic effects on serotonin neurons, that women might be more susceptible than men, and that MDMA-induced neurotoxic changes in several brain regions of female ex-MDMA users are reversible.

Addition of a 5-HT receptor agonist to methylphenidate potentiates the reduction of [123I]FP-CIT binding to dopamine transporters in rat frontal cortex and hippocampus.

The neurotoxic potential of amphetamine and related drugs is well documented. However, methylphenidate, an amphetamine derivative used in the treatment of attention deficit hyperactivity disorder, and known to increase synaptic dopamine (DA) levels, seems to lack neurotoxic potential. It is hypothesized that both dopaminergic and serotonergic systems are involved in the neurotoxicity of amphetamine derivatives. The purpose of the present study was to evaluate the neurotoxic potential of methylphenidate and to test whether stimulation of the serotonergic system may confer neurotoxic properties to methylphenidate for DA or serotonin (5-HT) neurons. In addition, the present study was undertaken to evaluate the necessity to perform future SPECT studies in individuals using both methylphenidate and 5-HT-acting agents. We therefore measured monoaminergic transporters in rat brain using radioligands suitable for SPECT imaging ([123I]beta-CIT and [123I]FP-CIT). Groups of rats were treated with methylphenidate or saline for 4 days. Additional groups were treated with the selective 5-HT(2) receptor agonist quipazine or the selective 5-HT reuptake blocker fluoxetine, alone or in combination with methylphenidate. Binding studies were performed 5 days after the last treatment. In a second experiment, methylphenidate in combination with quipazine, along with a control group, was retested. In this experiment, monoaminergic terminal density was estimated 2 weeks (rather than 5 days) after drug treatment. Five days, but not 2 weeks, after treatment a significant reduction in specific [123I]FP-CIT binding was observed in the frontal cortex and hippocampus of rats treated with methylphenidate in combination with quipazine. These changes probably do not reflect neurotoxic changes of frontal cortex and hippocampal DA terminal markers, but a compensatory downregulation of DA transporters. These findings suggest potential harmful effects of concomitant use of drugs directly activating 5-HT2 receptors in patients using methylphenidate.

The assessment of alcohol expectancies in school children: measurement or modification?

AIMS: Earlier research has suggested that measuring children's positive alcohol-related expectancies could have the undesirable side effect of increasing them. This has been reported for an instrument that only measured positive expectancies and used a puppet-reference. The present study investigated whether this increase was still found using an unbiased instrument. Further, it was tested whether the assessment method with puppets influenced children's expectancies. DESIGN: Children were assigned randomly to respond on an unbiased expectancy questionnaire in one of two assessment conditions: with reference to a puppet (P) or without reference to a puppet (Q). One month later, children were again administered one of the two assessment conditions, resulting in four assessment orders (PP, PQ, QP, QQ). SETTING AND PARTICIPANTS: Three hundred and ninety-five second- to fifth-graders were administered one of the two methods in their schools and 260 children were measured a second time, 1 month later. MEASUREMENTS: A questionnaire measuring children's positive and negative expectancies was developed that could be administered with or without a puppet-reference. FINDINGS: A large direct response-effect was found: in the puppet condition, children scored higher on positive but not on negative expectancies. A smaller indirect measurement-effect was found at borderline significance: children who had used the puppet method 1 month earlier had significantly stronger positive expectancies than children who had used the questionnaire earlier. CONCLUSIONS: The present results confirm earlier indications that measuring children's positive expectancies may have the undesirable side effect of increasing them. This can be avoided by measuring children's expectancies with an unbiased questionnaire without a puppet-reference.

A confirmatory analysis of the hierarchical structure of positive and negative dose-related alcohol expectancies in alcoholics and the associations with family history of alcoholism.

OBJECTIVE: The usefulness of measuring four types of alcohol-outcome expectancies in alcoholics was investigated. METHOD: The investigation was conducted in three steps. First, a measurement model previously fitted in a general population sample was fitted in the present sample of alcoholics, using confirmative factor analysis. In the hierarchical model tested, four types of expectancies are represented as four second-order factors: positive and negative expectancies for a low and for a high dose of alcohol. The model was compared with competing models. Second, a common measurement model was tested for subgroups of alcoholics categorized by gender and family history of alcoholism. Third, using path analysis, the associations were investigated for the four types of expectancies with variables of potential relevance for treatment. A sample of 451 male and female clinically referred alcoholics volunteered to complete a series of questionnaires, including the expectancy questionnaire. RESULTS: Following minor modifications, the measurement model was found to fit adequately in the present sample of alcoholics and across the subsamples. Family history of alcoholism was positively associated with positive expectancies, especially for a high dose of alcohol. This association was mediated by cluster-B personality disorders. CONCLUSIONS: Even though the expectancy questionnaire used here should be refined in several respects, the results demonstrate the usefulness of measuring four types of expectancies in alcoholics.

Platelet adenylyl cyclase activity as a biochemical trait marker for predisposition to alcoholism.

Previous studies demonstrated a reduced Gs-protein stimulated adenylyl cyclase activity in the brain and blood cells of alcoholics. We investigated this phenomenon in platelets of children of alcoholics (COA), i.e., of children at high risk for the acquisition of alcoholism and (as yet) not regularly consuming alcohol. Gs-protein mediated stimulation of adenylyl cyclase by 30 mM NaF and 50 microM forskolin stimulated adenylyl cyclase activity were assessed in platelet membranes of 23 (male and female) COA and 20 control children. Gs-protein stimulated cAMP production by NaF, unlike that induced by direct stimulation of adenylyl cyclase with forskolin, in platelet membranes of COA was profoundly lower than in platelet membranes of control children. Moreover, such a reduced Gs-protein functioning was only observed in platelet membranes of COA with a multigenerational family history of alcoholism. A reduction of Gs-protein stimulated adenylyl cyclase activity in platelets may represent a sensitive and gender-independent trait marker for predisposition to alcoholism, rather than a state marker for alcoholism.

Do young children of alcoholics hold more positive or negative alcohol-related expectancies than controls?

Alcohol-related expectancies and alcohol use were examined in 185 children of alcoholics (COAs) and controls, aged 7 to 18 years. Concerning the expectancies of young COAs, two contrasting hypotheses have been proposed: COAs should hold more negative expectancies than controls due to aversive learning, or hold more positive expectancies due to either social learning or a more favorable response to alcohol. We propose that COAs of elementary school age hold more negative expectancies due to aversive learning, whereas older COAs hold more positive expectancies due to a more favorable response to alcohol. The critical variable with respect to the change from more negative to more positive expectancies is proposed to be the child's own initiation of alcohol use. The results of the present cross-sectional study provide suggestive evidence in favor of this hypothesis. First, elementary school-aged COAs had stronger negative expectancies than controls. Second, the hypothesized interaction between family history and own experience with alcohol was confirmed in the adolescent subsample. The proposed model should be critically tested with longitudinal data. If confirmed, the model may be of importance for prevention of alcohol-related problems in high-risk populations.

P3 scalp topography to target and novel visual stimuli in children of alcoholics.

The P3 event-related potential (ERP) component was recorded from 7- to 18-year-old children of alcoholics (COAs, n = 50) and age- and sex-matched control children (n = 50) using a visual oddball paradigm, involving nontarget (76%), target (12%), and novel (12%) stimuli. Topographic maps of P3 and associated scalp current density were obtained to supplement a topographic profile analysis. COAs manifested a smaller amplitude P3 to target stimuli over the centroparietal, parietal, and occipital scalp locations than controls. Also, COAs exhibited a smaller amplitude P3 to novel stimuli over the occipital scalp than controls. There were no significant differences between COAs and controls in the P3 scalp topography, indicating that differences in intracranial source strength rather than in source configuration were responsible for the between-group amplitude differences. Also, no significant group differences were observed in the P3 peak latency or in behavioral performance. These results support the notion that the visual P3 may provide a vulnerability marker of alcoholism.

Is a mild deficit in executive functions in boys related to childhood ADHD or to parental multigenerational alcoholism?

A mild deficit in executive functions has been hypothesized to be associated with attention deficit hyperactivity disorder (ADHD), with externalizing problem behaviors such as conduct disorder (CD) and with the vulnerability to alcoholism in sons of multi-generational alcoholics (SOMGAs). These three categories overlap, which raises concerns about the specificity of the hypothesized associations. In the present study, measures of executive functions (EFs) were tested in seventy-six 7- to 11-year-old boys: boys with ADHD but without a family history of addiction, SOMGAs, and controls. Specific deficits in EFs were found for boys with ADHD but not for SOMGAs. The association between a deficit in EFs and attention problems remained after controlling for externalizing problem behaviors, but not for the reverse. These results suggest that a mild deficit in EFs is specifically related to ADHD and that the deficits reported in boys with CD and in SOMGAs are due to relatively high attentional problems in these groups or due to other factors such as motivation.

Event-related potentials during visual selective attention in children of alcoholics.

Event-related potentials were recorded from 7- to 18-year-old children of alcoholics (COAs, n = 50) and age- and sex-matched control children (n = 50) while they performed a visual selective attention task. The task was to attend selectively to stimuli with a specified color (red or blue) in an attempt to detect the occurrence of target stimuli. COAs manifested a smaller P3b amplitude to attended-target stimuli over the parietal and occipital scalp than did the controls. A more specific analysis indicated that both the attentional relevance and the target properties of the eliciting stimulus determined the observed P3b amplitude differences between COAs and controls. In contrast, no significant group differences were observed in attention-related earlier occurring event-related potential components, referred to as frontal selection positivity, selection negativity, and N2b. These results represent neurophysiological evidence that COAs suffer from deficits at a late (semantic) level of visual selective information processing that are unlikely a consequence of deficits at earlier (sensory) levels of selective processing. The findings support the notion that a reduced visual P3b amplitude in COAs represents a high-level processing dysfunction indicating their increased vulnerability to alcoholism.

No electrocortical evidence of automatic mismatch dysfunction in children of alcoholics.

The mismatch negativity (MMN) event-related potential (ERP) component is an automatic, attention-independent brain response to auditory stimulus change, which has been reported to be smaller in alcoholics relative to nonalcoholic controls. To determine whether MMN decrements might be a trait marker of alcoholism that is also present in nonalcoholic individuals at high risk for developing alcoholism, we investigated MMN in 9- to 18-year-old children of alcoholics (n = 20) and control children (n = 20) in three different stimulus conditions using a passive auditory oddball paradigm. There were no statistically significant between-group differences observed in amplitude, scalp topography, and peak latency of MMN. These findings, if replicated, suggest that reported MMN decrements in alcoholics most likely represent a state marker, and not a trait marker, of alcoholism. Also, inasmuch as another ERP component, the P300, is attention-dependent and reported to be smaller in children of alcoholics, the present results implicate that deviations in attentive, but not in automatic, information processing are associated with alcoholism vulnerability.

Changing a response set in normal development and in ADHD children with and without tics.

The current study was designed to provide a rigorous investigation of the locus of task-inappropriate (impulsive) responding in ADHD children with and without tics. For this purpose we used a variant of Sternberg's (1969) response bias task. The task measures a set of mental operations, namely, preparing a planned response, carrying out or stopping a planned response, and preparing to execute an alternative response. In the first study, we determined the effect of age in a normal sample. As expected, task performance improved as a function of age. Younger children had problems changing a response set. In the second experiment, we compared ADHD children with and without tics with normal children. Unexpectedly, the noticeable task inefficiency of the patient groups was not related to (a) a hasty scan of the display, (b) an inability to change response set, or (c) a speed-accuracy trade-off. Implications for and a discussion about the response inhibition hypothesis in ADHD are discussed.

Adenylate cyclase, a biochemical marker of alcoholism?

A possible biochemical vulnerability (trait) marker is examined in a cross-sectional study to determine the biochemical factors associated with the development of alcoholism in a population of non-adult children of alcoholics. The activity of adenylate cyclase, an enzyme that plays a role in the signal transduction pathway of several hormones and neurotransmitters, is assessed in blood platelets. This activity was reported to be lower in blood cells of alcoholics and abstinent alcoholics compared with that in controls. In addition, dysregulation of adenylate cyclase in the CNS of animals seems to be involved in drug-seeking behaviour. The relation between these biochemical findings and psychopathology is currently being investigated in a project by the Amsterdam Institute for Addiction Research.

Children of alcoholics: attention, information processing and event-related brain potentials.

Recent studies on biological markers and risk factors for alcoholism have distinguished between nonalcoholic individuals with a family history of alcoholism and those without such a family history on measures of event-related brain potentials. The main finding of these "high-risk" studies is a smaller amplitude of the P300 component in males with a history of paternal alcoholism. This relationship between P300 amplitude and a family history of paternal alcoholism has been observed in adults and children. Consequently, several authors have suggested that a reduced P300 amplitude could serve as a vulnerability marker for alcoholism. We address several conceptual and methodological issues involved in the study of event-related potentials in children at high risk for alcoholism. Subsequently, the ongoing high-risk study of the Amsterdam Institute for Addiction Research is described briefly.

Children of alcoholics. Predictors for psychopathology and addiction.

Children of alcoholics have a higher risk of psychopathology and alcoholism. Therefore, in 1993 the Amsterdam Institute for Addiction Research initiated a study on vulnerability markers and risk factors in children of alcoholics, aimed at identifying predictors for the development of psychopathology and addiction in children of alcoholics. This article provides a summary of the background, rationales and aims of the study. With more specific and sensitive biological vulnerability markers that indicate risk status, more effective preventive interventions might become available. The biochemical part of the study aims at answering the question whether adenylate cyclase is a vulnerability marker for alcoholism. The psychophysiological part is directed at event-related potentials during task performance to clarify the nature of the brain and cognitive functions that may underlie or relate to vulnerability to alcoholism. The third part, the psychological component, aims at possible psychological mechanisms of enhanced risk of addition in children of alcoholics as well as the relationship with childhood psychopathology.