Adult phenotype of KCNQ2 encephalopathy Boets, Stephanie; Johannesen, Katrine M; Destree, Anne ...
Journal of medical genetics,
06/2022, Letnik:
59, Številka:
6
Journal Article
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BackgroundPathogenic KCNQ2 variants are a frequent cause of developmental and epileptic encephalopathy.MethodsWe recruited 13 adults (between 18 years and 45 years of age) with KCNQ2 encephalopathy ...and reviewed their clinical, EEG, neuroimaging and treatment history.ResultsWhile most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individuals (46%) remained unable to walk independently, six (46%) had limb spasticity and four (31%) tetraparesis/tetraplegia. Six (46%) remained non-verbal, 10 (77%) had autistic features/autism, 4 (31%) exhibited aggressive behaviour and 4 (31%) destructive behaviour with self-injury. Four patients had visual problems, thought to be related to prematurity in one. Sleep problems were seen in six (46%) individuals.ConclusionSeizure frequency declines over the years and most patients are seizure-free in adulthood. Longer seizure-free periods followed by seizure recurrence are common during childhood and adolescence. Most adult patients have severe ID. Motor, language and behavioural problems are an issue of continuous concern.
Highlights • Reduced mGluR2/3 binding in limbic regions at acute (2 day) and latent periods (7 day) after SE. • Increased mGluR2/3 binding in widely distributed brain areas at late latent phase (14 ...day). • Reduced mGluR2/3 in stratum lacunosum moleculare during chronic epilepsy (42 & 84 day). • mGluR 2/3 binding in CA1 region correlated negatively with cell loss in the hippocampus
Glutamate is the major excitatory neurotransmitter in the brain. The glutamate system plays an important role in the formation of synapses during brain development and synaptic plasticity. ...Dysfunctions in glutamate regulation may lead to hyperexcitatory neuronal networks and neurotoxicity. Glutamate excess is possibly of great importance in the pathophysiology of several neurological and psychiatric disorders such as epilepsy and schizophrenia. Interestingly, cross talk between these disorders has been well documented: psychiatric comorbidities are frequent in epilepsy and temporal lobe epilepsy is one of the highest risk factors for developing psychosis. Therefore, dysfunctions in glutamatergic neurotransmission might constitute a common pathological mechanism. A major negative feedback system is regulated by the presynaptic group II metabotropic glutamate (mGlu) receptors including mGlu2/3 receptors. These receptors are predominantly localised extrasynaptically in basal ganglia and limbic structures. Hence, mGlu2/3 receptors are an interesting target for the treatment of disorders like epilepsy and schizophrenia. A dysfunction in the glutamate system may be associated with alterations in mGlu2/3 receptor expression. In this review, we describe the localization of mGlu2/3 receptors in the healthy brain of mice, rats and humans. Secondly, changes in mGlu2/3 receptor density of the brain regions affected in epilepsy and schizophrenia are summarised. Increased mGlu2/3 receptor density might represent a compensatory mechanism of the brain to regulate elevated glutamate levels, while reduced mGlu2/3 receptor density in some brain regions may further contribute to the aberrant hyperexcitability. Further research considering the mGlu2/3 receptor can contribute significantly to the understanding of the etiological and therapeutic role of group II mGlu receptor in epilepsy, epilepsy with psychosis and schizophrenia.
Intranasal administration of oxytocin is increasingly explored as a new approach to facilitate social development and reduce disability associated with a diagnosis of autism spectrum disorder (ASD). ...The efficacy of multiple-dose oxytocin administration in children with ASD is, however, not well established.
A double-blind, randomized, placebo-controlled trial with parallel design explored the effects of a 4-week intranasal oxytocin administration (12 IU, twice daily) on parent-rated social responsiveness (Social Responsiveness Scale: SRS-2) in pre-pubertal school-aged children (aged 8-12 years, 61 boys, 16 girls). Secondary outcomes included a questionnaire-based assessment of repetitive behaviors, anxiety, and attachment. Effects of oxytocin were assessed immediately after the administration period and at a follow-up, 4 weeks after the last administration. The double-blind phase was followed by a 4-week single-blind phase during which all participants received intranasal oxytocin.
In the double-blind phase, both the oxytocin and placebo group displayed significant pre-to-post-improvements in social responsiveness and secondary questionnaires, but improvements were not specific to the intranasal oxytocin. Notably, in the single-blind phase, participants who were first allocated to intranasal placebo and later changed to intranasal oxytocin displayed a significant improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. Participants receiving oxytocin in the first phase also showed a significant further improvement upon receiving a second course of oxytocin, but only at the 4-week follow-up. Further, exploratory moderator analyses indicated that children who received psychosocial trainings (3 or more sessions per month) along with oxytocin administration displayed a more pronounced improvement in social responsiveness.
Future studies using larger cohorts and more explicitly controlled concurrent psychosocial trainings are warranted to further explore the preliminary moderator effects, also including understudied populations within the autism spectrum, such as children with co-occurring intellectual disabilities.
Four weeks of oxytocin administration did not induce treatment-specific improvements in social responsiveness in school-aged children with ASD. Future studies are warranted to further explore the clinical efficacy of oxytocin administration paired with targeted psychosocial trainings that stimulate socio-communicative behaviors. Trial registration The trial was registered with the European Clinical Trial Registry (EudraCT 2018-000769-35) on June 7th, 2018 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-000769-35/BE ).
Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic administration regimes on endogenous ...oxytocinergic function are largely unknown. Here exploratory biological assessments from a completed randomized, placebo-controlled trial showed that children with autism (n = 79, 16 females) receiving intranasal oxytocin for four weeks (12 IU, twice daily) displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at a four-week follow up session. Regarding salivary oxytocin receptor gene (OXTR) epigenetics (DNA-methylation), oxytocin-induced reductions in OXTR DNA-methylation were observed, suggesting a facilitation of oxytocin receptor expression in the oxytocin compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA-methylation and improved feelings of secure attachment. These findings indicate that four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with autism.
Faces convey an assortment of emotional information via low and high spatial frequencies (LSFs and HSFs). However, there is no consensus on the role of particular spatial frequency (SF) information ...during facial fear processing. Comparison across studies is hampered by the high variability in cut-off values for demarcating the SF spectrum and by differences in task demands. We investigated which SF information is minimally required to rapidly detect briefly presented fearful faces in an implicit and automatic manner, by sweeping through an entire SF range without constraints of predefined cut-offs for LSFs and HSFs. We combined fast periodic visual stimulation with electroencephalography. We presented neutral faces at 6 Hz, periodically interleaved every 5th image with a fearful face, allowing us to quantify an objective neural index of fear discrimination at exactly 1.2 Hz. We started from a stimulus containing either only very low or very high SFs and gradually increased the SF content by adding higher or lower SF information, respectively, to reach the full SF spectrum over the course of 70 s. We found that faces require at least SF information higher than 5.93 cycles per image (cpi) to implicitly differentiate fearful from neutral faces. However, exclusive HSF faces, even in a restricted SF range between 94.82 and 189.63 cpi already carry the critical information to extract the emotional expression of the faces.
Background Categorization and its influence on perceptual discrimination are essential processes to organize information efficiently. Individuals with Autism Spectrum Condition (ASC) are suggested to ...display enhanced discrimination on the one hand, but also to experience difficulties with generalization and ignoring irrelevant differences on the other, which underlie categorization. Studies on categorization and discrimination in ASC have mainly focused on one process at a time, however, and typically only used either behavioral or neural measures in isolation. Here, we aim to investigate the interrelationships between these perceptual processes using novel stimuli sampled from a well-controlled artificial stimulus space. In addition, we complement standard behavioral psychophysical tasks with frequency-tagging EEG (FT-EEG) to obtain a direct, non-task related neural index of discrimination and categorization. Methods The study was completed by 38 adults with ASC and 38 matched neurotypical (NT) individuals. First, we assessed baseline discrimination sensitivity by administering FT-EEG measures and a complementary behavioral task. Second, participants were trained to categorize the stimuli into two groups. Finally, participants again completed the neural and behavioral discrimination sensitivity measures. Results Before training, NT participants immediately revealed a categorical tuning of discrimination, unlike ASC participants who showed largely similar discrimination sensitivity across the stimuli. During training, both autistic and non-autistic participants were able to categorize the stimuli into two groups. However, in the initial training phase, ASC participants were less accurate and showed more variability, as compared to their non-autistic peers. After training, ASC participants showed significantly enhanced neural and behavioral discrimination sensitivity across the category boundary. Behavioral indices of a reduced categorical processing and perception were related to the presence of more severe autistic traits. Bayesian analyses confirmed overall results. Limitations Data-collection occurred during the COVID-19 pandemic. Conclusions Our behavioral and neural findings indicate that adults with and without ASC are able to categorize highly similar stimuli. However, while categorical tuning of discrimination sensitivity was spontaneously present in the NT group, it only emerged in the autistic group after explicit categorization training. Additionally, during training, adults with autism were slower at category learning. Finally, this multi-level approach sheds light on the mechanisms underlying sensory and information processing issues in ASC. Keywords: Frequency-tagging electroencephalography, Category learning, Discrimination sensitivity, Visual perception, Autism
We objectively quantified the neural sensitivity of school-aged boys with and without autism spectrum disorder (ASD) to detect briefly presented fearful expressions by combining fast periodic visual ...stimulation with frequency-tagging electroencephalography. Images of neutral faces were presented at 6 Hz, periodically interleaved with fearful expressions at 1.2 Hz oddball rate. While both groups equally display the face inversion effect and mainly rely on information from the mouth to detect fearful expressions, boys with ASD generally show reduced neural responses to rapid changes in expression. At an individual level, fear discrimination responses predict clinical status with an 83% accuracy. This implicit and straightforward approach identifies subtle deficits that remain concealed in behavioral tasks, thereby opening new perspectives for clinical diagnosis.
The neuropeptide oxytocin (OXT) is suggested to exert an important role in human social behaviors by modulating the salience of social cues. To date, however, there is mixed evidence whether a single ...dose of OXT can improve the behavioral and neural sensitivity for emotional face processing. To overcome difficulties encountered with classic event‐related potential studies assessing stimulus‐saliency, we applied frequency‐tagging EEG to implicitly assess the effect of a single dose of OXT (24 IU) on the neural sensitivity for positive and negative facial emotions. Neutral faces with different identities were presented at 6 Hz, periodically interleaved with an expressive face (angry, fearful, and happy, in separate sequences) every fifth image (i.e., 1.2 Hz oddball frequency). These distinctive frequency tags for neutral and expressive stimuli allowed direct and objective quantification of the neural expression‐categorization responses. The study involved a double‐blind, placebo‐controlled, cross‐over trial with 31 healthy adult men. Contrary to our expectations, we did not find an effect of OXT on facial emotion processing, neither at the neural, nor at the behavioral level. A single dose of OXT did not evoke social enhancement in general, nor did it affect social approach‐avoidance tendencies. Possibly ceiling performances in facial emotion processing might have hampered further improvement.
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To surmount difficulties encountered when assessing stimulus‐saliency with classic EEG, we applied frequency‐tagging EEG to implicitly measure the effect of oxytocin on the neural sensitivity to positive and negative facial emotions, as this technique allows to objectively quantify neural expression‐categorization responses. The absence of an oxytocin‐induced effect on facial emotion processing at the neural level argues against a strong account of the social salience hypothesis. Neither do our results align with the social approach/withdrawal hypothesis.
Categorization is an essential cognitive and perceptual process, which happens spontaneously. However, earlier research often neglected the spontaneous nature of this process by mainly adopting ...explicit tasks in behavioral or neuroimaging paradigms. Here, we use frequency-tagging (FT) during electroencephalography (EEG) in 22 healthy human participants (both male and female) as a direct approach to pinpoint spontaneous visual categorical processing. Starting from schematic natural visual stimuli, we created morph sequences comprising 11 equal steps. Mirroring a behavioral categorical perception discrimination paradigm, we administered a FT-EEG oddball paradigm, assessing neural sensitivity for equally sized differences within and between stimulus categories. Likewise, mirroring a behavioral category classification paradigm, we administered a sweep FT-EEG oddball paradigm, sweeping from one end of the morph sequence to the other, thereby allowing us to objectively pinpoint the neural category boundary. We found that FT-EEG can implicitly measure categorical processing and discrimination. More specifically, we could derive an objective neural index of the required level to differentiate between the two categories, and this neural index showed the typical marker of categorical perception (i.e., stronger discrimination across as compared with within categories). The neural findings of the implicit paradigms were also validated using an explicit behavioral task. These results provide evidence that FT-EEG can be used as an objective tool to measure discrimination and categorization and that the human brain inherently and spontaneously (without any conscious or decisional processes) uses higher-level meaningful categorization information to interpret ambiguous (morph) shapes.
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