FUS-mediated blood-brain barrier disruption for delivering anti-Aß antibodies in 5XFAD Alzheimer's disease mice.

PURPOSE: Amyloid-ß (Aß) peptides, the main component of amyloid plaques found in the Alzheimer's disease (AD) brain, are implicated in its pathogenesis, and are considered a key target in AD therapeutics. We herein propose a reliable strategy for non-invasively delivering a specific anti-Aß antibody in a mouse model of AD by microbubbles-enhanced Focused Ultrasound (FUS)-mediated Blood-brain barrier disruption (BBBD), using a simple single stage MR-compatible positioning device. METHODS: The initial experimental work involved wild-type mice and was devoted to selecting the sonication protocol for efficient and safe BBBD. Pulsed FUS was applied using a single-element FUS transducer of 1 MHz (80 mm radius of curvature and 50 mm diameter). The success and extent of BBBD were assessed by Evans Blue extravasation and brain damage by hematoxylin and eosin staining. 5XFAD mice were divided into different subgroups; control (n = 1), FUS + MBs alone (n = 5), antibody alone (n = 5), and FUS + antibody combined (n = 10). The changes in antibody deposition among groups were determined by immunohistochemistry. RESULTS: It was confirmed that the antibody could not normally enter the brain parenchyma. A single treatment with MBs-enhanced pulsed FUS using the optimized protocol (1 MHz, 0.5 MPa in-situ pressure, 10 ms bursts, 1% duty factor, 100 s duration) transiently disrupted the BBB allowing for non-invasive antibody delivery to amyloid plaques within the sonicated brain regions. This was consistently reproduced in ten mice. CONCLUSION: These preliminary findings should be confirmed by longer-term studies examining the antibody effects on plaque clearance and cognitive benefit to hold promise for developing disease-modifying anti-Aß therapeutics for clinical use.

Corrigendum: Illness perceptions of COVID-19 in Europe: predictors, impacts and temporal evolution.

[This corrects the article DOI: 10.3389/fpsyg.2021.640955.].

The impact of government actions and risk perception on the promotion of self-protective behaviors during the COVID-19 pandemic.

INTRODUCTION: We aim to understand the factors that drive citizens of different countries to adhere to recommended self-protective behaviors during the COVID-19 pandemic. METHODS: Survey data was obtained through the COVID-19 Impact project. We selected countries that presented a sufficiently complete time series and a statistically relevant sample for running the analysis: Cyprus, Germany, Greece, Ireland, Latvia, Spain, Switzerland, the United Kingdom, and the United States of America. To identify country-specific differences in self-protective behaviors, we used previous evidence and change-point detection analysis to establish variations across participating countries whose effect was then assessed by means of interrupted series analysis. RESULTS: A high level of compliance with health and governmental authorities' recommendations were generally observed in all included countries. The level of stress decreased near the period when countries such as Cyprus, Greece or the United Kingdom relaxed their prevention behavior recommendations. However, this relaxation of behaviors did not occur in countries such as Germany, Ireland, or the United States. As observed in the change-point detection analysis, when the daily number of recorded COVID-19 cases decreased, people relaxed their protective behaviors (Cyprus, Greece, Ireland), although the opposite trend was observed in Switzerland. DISCUSSION: COVID-19 self-protective behaviors were heterogeneous across countries examined. Our findings show that there is probably no single winning strategy for exiting future health crises, as similar interventions, aimed to promote self-protective behaviors, may be received differently depending on the specific population groups and on the particular geographical context in which they are implemented.

Predictors of changing patterns of adherence to containment measures during the early stage of COVID-19 pandemic: an international longitudinal study.

BACKGROUND: Identifying common factors that affect public adherence to COVID-19 containment measures can directly inform the development of official public health communication strategies. The present international longitudinal study aimed to examine whether prosociality, together with other theoretically derived motivating factors (self-efficacy, perceived susceptibility and severity of COVID-19, perceived social support) predict the change in adherence to COVID-19 containment strategies. METHOD: In wave 1 of data collection, adults from eight geographical regions completed online surveys beginning in April 2020, and wave 2 began in June and ended in September 2020. Hypothesized predictors included prosociality, self-efficacy in following COVID-19 containment measures, perceived susceptibility to COVID-19, perceived severity of COVID-19 and perceived social support. Baseline covariates included age, sex, history of COVID-19 infection and geographical regions. Participants who reported adhering to specific containment measures, including physical distancing, avoidance of non-essential travel and hand hygiene, were classified as adherence. The dependent variable was the category of adherence, which was constructed based on changes in adherence across the survey period and included four categories: non-adherence, less adherence, greater adherence and sustained adherence (which was designated as the reference category). RESULTS: In total, 2189 adult participants (82% female, 57.2% aged 31-59 years) from East Asia (217 [9.7%]), West Asia (246 [11.2%]), North and South America (131 [6.0%]), Northern Europe (600 [27.4%]), Western Europe (322 [14.7%]), Southern Europe (433 [19.8%]), Eastern Europe (148 [6.8%]) and other regions (96 [4.4%]) were analyzed. Adjusted multinomial logistic regression analyses showed that prosociality, self-efficacy, perceived susceptibility and severity of COVID-19 were significant factors affecting adherence. Participants with greater self-efficacy at wave 1 were less likely to become non-adherence at wave 2 by 26% (adjusted odds ratio [aOR], 0.74; 95% CI, 0.71 to 0.77; P < .001), while those with greater prosociality at wave 1 were less likely to become less adherence at wave 2 by 23% (aOR, 0.77; 95% CI, 0.75 to 0.79; P = .04). CONCLUSIONS: This study provides evidence that in addition to emphasizing the potential severity of COVID-19 and the potential susceptibility to contact with the virus, fostering self-efficacy in following containment strategies and prosociality appears to be a viable public health education or communication strategy to combat COVID-19.

Glial Gap Junction Pathology in the Spinal Cord of the 5xFAD Mouse Model of Early-Onset Alzheimer's Disease.

Gap junctions (GJs) are specialized transmembrane channels assembled by two hemi-channels of six connexin (Cx) proteins that facilitate neuroglial crosstalk in the central nervous system (CNS). Previous studies confirmed the crucial role of glial GJs in neurodegenerative disorders with dementia or motor dysfunction including Alzheimer's disease (AD). The aim of this study was to examine the alterations in astrocyte and related oligodendrocyte GJs in association with Aß plaques in the spinal cord of the 5xFAD mouse model of AD. Our analysis revealed abundant Aß plaque deposition, activated microglia, and astrogliosis in 12-month-old (12M) 5xFAD mice, with significant impairment of motor performance starting from 3-months (3M) of age. Additionally, 12M 5xFAD mice displayed increased immunoreactivity of astroglial Cx43 and Cx30 surrounding Aß plaques and higher protein levels, indicating upregulated astrocyte-to-astrocyte GJ connectivity. In addition, they demonstrated increased numbers of mature CC1-positive and precursor oligodendrocytes (OPCs) with higher immunoreactivity of Cx47-positive GJs in individual cells. Moreover, total Cx47 protein levels were significantly elevated in 12M 5xFAD, reflecting increased oligodendrocyte-to-oligodendrocyte Cx47-Cx47 GJ connectivity. In contrast, we observed a marked reduction in Cx32 protein levels in 12M 5xFAD spinal cords compared with controls, while qRT-PCR analysis revealed a significant upregulation in Cx32 mRNA levels. Finally, myelin deficits were found focally in the areas occupied by Aß plaques, whereas axons themselves remained preserved. Overall, our data provide novel insights into the altered glial GJ expression in the spinal cord of the 5xFAD model of AD and the implicated role of GJ pathology in neurodegeneration. Further investigation to understand the functional consequences of these extensive alterations in oligodendrocyte-astrocyte (O/A) GJ connectivity is warranted.

Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.

BACKGROUND AND OBJECTIVES: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. METHODS: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. RESULTS: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Mechanisms of change in acceptance and commitment therapy for primary headaches.

BACKGROUND: Despite the demonstrated effectiveness of behavioural headache interventions, it is not yet known which intervention processes account for treatment responses. Acceptance and commitment therapy (ACT), an emerging behavioural intervention for headaches, proposes psychological flexibility (PF) processes as the mechanisms via which intervention change occurs. This is the first study examining these processes of change variables on headache-related disability and quality of life (treatment outcome). METHODS: Data originated from a Randomized Clinical Trial evaluating the efficacy of ACT for primary headaches. Ninety-four individuals with primary headaches (M = 43 y; 84% females; M headache frequency/month = 9.30) were randomized to either an ACT-based or a Wait-list control group (N = 47 in each). Participants completed questionnaires related to their headache experiences and PF processes at pre- (T1), post-treatment (T2), and 3-month follow-up (T3). RESULTS: Following a bootstrapped cross product of coefficients approach, results demonstrated mediating effects of headache acceptance, cognitive defusion, avoidance of headache, and mindfulness in the ACT group compared to control on parameters of headache-related disability and quality of life at post and 3-month follow-ups. CONCLUSIONS: These findings demonstrate that changes in certain PF processes lower disability and improve quality of life in headache sufferers, supporting that ACT works via its proposed mechanisms of change. Interventions for headache management may be optimized if they target increases in headache acceptance, defusion from thoughts, and mindfulness. SIGNIFICANCE: Psychological flexibility (PF) guides the ACT approach, an emerging behavioral headache intervention that focuses on optimizing head pain adjustment via flexible responses to pain. It targets at increasing daily functioning rather than preventing or controlling headache episodes. Pain acceptance, cognitive defusion, and mindfulness act as processes of functional change in ACT, lowering disability and increasing daily functioning and quality of life. These components can upgrade the established effectiveness of behavioral headache interventions with personalized, modularized therapeutic targets that can help headache sufferers re-establish optimal daily functioning even in fluctuating and persistent headache episodes. TRIAL REGISTRATION: clinical trials.gov registry (NCT02734992).

Mental Health and Adherence to COVID-19 Protective Behaviors among Cancer Patients during the COVID-19 Pandemic: An International, Multinational Cross-Sectional Study.

A population-based cross-sectional study was conducted during the first COVID-19 wave, to examine the impact of COVID-19 on mental health using an anonymous online survey, enrolling 9565 individuals in 78 countries. The current sub-study examined the impact of the pandemic and the associated lockdown measures on the mental health, and protective behaviors of cancer patients in comparison to non-cancer participants. Furthermore, 264 participants from 30 different countries reported being cancer patients. The median age was 51.5 years, 79.9% were female, and 28% had breast cancer. Cancer participants reported higher self-efficacy to follow recommended national guidelines regarding COVID-19 protective behaviors compared to non-cancer participants (p < 0.01). They were less stressed (p < 0.01), more psychologically flexible (p < 0.01), and had higher levels of positive affect compared to non-cancer participants. Amongst cancer participants, the majority (80.3%) reported COVID-19, not their cancer, as their priority during the first wave of the pandemic and females reported higher levels of stress compared to males. In conclusion, cancer participants appeared to have handled the unpredictable nature of the first wave of the pandemic efficiently, with a positive attitude towards an unknown and otherwise frightening situation. Larger, cancer population specific and longitudinal studies are warranted to ensure adequate medical and psychological care for cancer patients.

A Novel CLN6 Variant Associated With Juvenile Neuronal Ceroid Lipofuscinosis in Patients With Absence of Visual Loss as a Presenting Feature.

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive lysosomal storage disorders that are characterized by neurodegeneration, progressive cognitive decline, motor impairment, ataxia, loss of vision, seizures, and premature death. To date, pathogenic variants in more than 13 genes have been associated with NCLs. CLN6 encodes an endoplasmic reticulum non-glycosylated transmembrane protein, which is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile juvenile NCL (JNCL) adult-onset NCL, and Kufs disease. Members from two available families with JNCL were clinically evaluated, and samples were collected from consenting individuals. The molecular investigation was performed by whole-exome sequencing, Sanger sequencing, and family segregation analysis. Furthermore, in silico prediction analysis and structural modeling of the identified CLN6 variants were performed. We report clinical and genetic findings of three patients from two Greek-Cypriot families (families 915 and 926) with JNCL. All patients were males, and the first symptoms appeared at the age of 6 years. The proband of family 926 presented with loss of motor abilities, ataxia, spasticity, seizure, and epilepsy. The proband of family 915 had ataxia, spasticity, dysarthria, dystonia, and intellectual disability. Both probands did not show initial signs of vision and/or hearing loss. Molecular analysis of family 926 revealed two CLN6 biallelic variants: the novel, de novo p.Tyr295Cys and the known p.Arg136His variants. In family 915, both patients were homozygous for the p.Arg136His CLN6 variant. Prediction analysis of the two CLN6 variants characterized them as probably damaging and disease-causing. Structural modeling of the variants predicted that they probably cause protein structural differentiation. In conclusion, we describe two unrelated Cypriot families with JNCL. Both families had variants in the CLN6 gene; however, they presented with slightly different symptoms, and notably none of the patients has loss of vision. In silico prediction and structural analyses indicate that both variants are most likely pathogenic.

Pathogenic and Low-Frequency Variants in Children With Central Precocious Puberty.

Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1, and KISS1R genes were investigated in patients with CPP. Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative (n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed. Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP. Conclusion: The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.

The Neurocognitive Study for the Aging: Longitudinal Analysis on the Contribution of Sex, Age, Education and APOE ɛ4 on Cognitive Performance.

Objective: The effects of normal cognitive aging on executive functions (EF), Verbal Episodic Memory (VEM) and the contribution of age, sex, education, and APOΕ Îµ4 in a group of old Greek Cypriots across a five-year period were investigated. Design: NEUROAGE, the first project on cognitive aging in Cyprus, is a prospective longitudinal study with a rolling admission process. Participants are assessed at baseline and retested every 24-30 months. Subjects: 170 participants completed all three testing cycles; 86 men and 84 women with ages ranging between 60 and 88 years (mean = 73.21, SD = 5.84); education, 2-20 years (mean = 9.07, SD = 4.27). Results: Α Repeated Measures Multivariate Analysis of Covariance was conducted with one between-subject factor: sex; two covariates: age and education, while Time (time 1, time 2, time 3) served as a within - subject factor. Time did not have an effect on mini mental status examination in Greek (MMSE), EF or VEM. Also, sex had no effect on MMSE, EF and VEM. There was no time by sex interaction. Age and Education significantly predicted the EF performance, F(1, 168) = 11.23, p < 0.05; F(1, 158) = 90.03, p < 0.001 and VEM performance, F(1, 171) = 17.22, p < 0.001; F(1, 171) = 61.25, p < 0.001. Furthermore, there was a significant interaction effect between time and education, for EF, F(2, 167) = 7.02, p < 0.001. Performance of the APOE ε4 carriers did not differ on any of the above measures as compared to performance of non-carriers in this older adult group. Conclusion: Cognitively healthy adults maintained overall cognitive performance across the five-year period. Male and female participants performed similarly and the pattern of change over time was similar across the two sexes. Education was predictive of VEM and EF performance across time. Furthermore, those with higher education maintained higher levels of EF performance. APOE results did not differentiate performance at baseline. Implications of findings are discussed.

Illness Perceptions of COVID-19 in Europe: Predictors, Impacts and Temporal Evolution.

Objective: Illness perceptions (IP) are important predictors of emotional and behavioral responses in many diseases. The current study aims to investigate the COVID-19-related IP throughout Europe. The specific goals are to understand the temporal development, identify predictors (within demographics and contact with COVID-19) and examine the impacts of IP on perceived stress and preventive behaviors. Methods: This was a time-series-cross-section study of 7,032 participants from 16 European countries using multilevel modeling from April to June 2020. IP were measured with the Brief Illness Perception Questionnaire. Temporal patterns were observed considering the date of participation and the date recoded to account the epidemiological evolution of each country. The outcomes considered were perceived stress and COVID-19 preventive behaviors. Results: There were significant trends, over time, for several IP, suggesting a small decrease in negativity in the perception of COVID-19 in the community. Age, gender, and education level related to some, but not all, IP. Considering the self-regulation model, perceptions consistently predicted general stress and were less consistently related to preventive behaviors. Country showed no effect in the predictive model, suggesting that national differences may have little relevance for IP, in this context. Conclusion: The present study provides a comprehensive picture of COVID-19 IP in Europe in an early stage of the pandemic. The results shed light on the process of IP formation with implications for health-related outcomes and their evolution.

Patterns of Psychological Responses among the Public during the Early Phase of COVID-19: A Cross-Regional Analysis.

This study aimed to compare the mediation of psychological flexibility, prosociality and coping in the impacts of illness perceptions toward COVID-19 on mental health among seven regions. Convenience sampled online survey was conducted between April and June 2020 from 9130 citizens in 21 countries. Illness perceptions toward COVID-19, psychological flexibility, prosociality, coping and mental health, socio-demographics, lockdown-related variables and COVID-19 status were assessed. Results showed that psychological flexibility was the only significant mediator in the relationship between illness perceptions toward COVID-19 and mental health across all regions (all ps = 0.001-0.021). Seeking social support was the significant mediator across subgroups (all ps range = <0.001-0.005) except from the Hong Kong sample (p = 0.06) and the North and South American sample (p = 0.53). No mediation was found for problem-solving (except from the Northern European sample, p = 0.009). Prosociality was the significant mediator in the Hong Kong sample (p = 0.016) and the Eastern European sample (p = 0.008). These findings indicate that fostering psychological flexibility may help to mitigate the adverse mental impacts of COVID-19 across regions. Roles of seeking social support, problem-solving and prosociality vary across regions.

To Help or Not to Help? Prosocial Behavior, Its Association With Well-Being, and Predictors of Prosocial Behavior During the Coronavirus Disease Pandemic.

The coronavirus disease (COVID-19) pandemic fundamentally disrupted humans' social life and behavior. Public health measures may have inadvertently impacted how people care for each other. This study investigated prosocial behavior, its association well-being, and predictors of prosocial behavior during the first COVID-19 pandemic lockdown and sought to understand whether region-specific differences exist. Participants (N = 9,496) from eight regions clustering multiple countries around the world responded to a cross-sectional online-survey investigating the psychological consequences of the first upsurge of lockdowns in spring 2020. Prosocial behavior was reported to occur frequently. Multiple regression analyses showed that prosocial behavior was associated with better well-being consistently across regions. With regard to predictors of prosocial behavior, high levels of perceived social support were most strongly associated with prosocial behavior, followed by high levels of perceived stress, positive affect and psychological flexibility. Sociodemographic and psychosocial predictors of prosocial behavior were similar across regions.

Acceptance and Commitment Therapy for Primary Headache Sufferers: A Randomized Controlled Trial of Efficacy.

Prevention of headaches via avoidance of triggers remains the main behavioral treatment suggestion for headache management despite trigger avoidance resulting in increases in potency, lifestyle restrictions, internal locus of control decreases, pain exacerbation and maintenance. New approaches, such as Acceptance and Commitment Therapy (ACT), instead emphasize acceptance and valued living as alternatives to avoidance. Though ACT is an empirically supported treatment for chronic pain, there is limited evidence for headache management while preliminary outcome studies are afflicted with methodological limitations. This study compared an ACT-based group headache-specific intervention to wait-list control, in a randomized clinical trial, on disability, distress, medical utilization, functioning, and quality of life. Ninety-four individuals with primary headache (84% women; Mage = 43 years; 87.35% migraine diagnosis) were randomized into 2 groups (47 in each). Assessments occurred: before, immediately after, and at 3 months following treatment end. Only the ACT group was additionally assessed at 6- and 12-month follow-up. Results (intent to treat analyses corroborated by linear mixed model analyses) showed substantial improvements in favor of ACT compared to control, on disability, quality of life, functional status, and depression at 3-, 6-, and 12-month follow-up. Improvements were maintained in the ACT group at 6- and 12-month follow-up. At 3-month follow-up, clinical improvement occurred in headache-related disability (63%) and 65% in quality of life in ACT versus 37% and 35% in control. These findings offer new evidence for the utility and efficacy of ACT in localized pain conditions and yields evidence for both statistical and clinical improvements over a years' period. PERSPECTIVE: An Acceptance and Commitment Therapy approach focusing on acceptance and values-based activities was found to improve disability, functioning, and quality of life among patients with primary headaches.

Impact of COVID-19 pandemic on mental health: An international study.

BACKGROUND: The COVID-19 pandemic triggered vast governmental lockdowns. The impact of these lockdowns on mental health is inadequately understood. On the one hand such drastic changes in daily routines could be detrimental to mental health. On the other hand, it might not be experienced negatively, especially because the entire population was affected. METHODS: The aim of this study was to determine mental health outcomes during pandemic induced lockdowns and to examine known predictors of mental health outcomes. We therefore surveyed n = 9,565 people from 78 countries and 18 languages. Outcomes assessed were stress, depression, affect, and wellbeing. Predictors included country, sociodemographic factors, lockdown characteristics, social factors, and psychological factors. RESULTS: Results indicated that on average about 10% of the sample was languishing from low levels of mental health and about 50% had only moderate mental health. Importantly, three consistent predictors of mental health emerged: social support, education level, and psychologically flexible (vs. rigid) responding. Poorer outcomes were most strongly predicted by a worsening of finances and not having access to basic supplies. CONCLUSIONS: These results suggest that on whole, respondents were moderately mentally healthy at the time of a population-wide lockdown. The highest level of mental health difficulties were found in approximately 10% of the population. Findings suggest that public health initiatives should target people without social support and those whose finances worsen as a result of the lockdown. Interventions that promote psychological flexibility may mitigate the impact of the pandemic.

Altered Expression of Glial Gap Junction Proteins Cx43, Cx30, and Cx47 in the 5XFAD Model of Alzheimer's Disease.

Glial gap junction proteins, called connexins (Cxs), form gap junctions in the central nervous system (CNS) to allow the bidirectional cytosolic exchange of molecules between adjacent cells. Their involvement in inheritable diseases and the use of experimental animal models that closely mimic such diseases revealed the critical role of glial GJs in myelination and homeostasis. Cxs are also implicated in acquired demyelinating disorders, such as Multiple Sclerosis (MS) and Alzheimer's disease (AD). Animal and human studies have revealed a role of the astrocytic Cx43 in the progression of AD but the role of Cx47, which is the main partner of Cx43 in the astrocyte-oligodendrocyte GJs is still unknown. The aim of this study was to investigate the astrocytic connexins, Cx43 and Cx30 in relation to oligodendrocytic Cx47 in the cortex and thalamus of the 5XFAD mouse model of AD. The model was characterized by increased Aß deposition, gliosis, neuronal loss, and memory impairment. Compared to wild-type mice, Cx43 and Cx30 showed increased immunoreactivity in older 5XFAD mice, reflecting astrogliosis, while Cx47 immunoreactivity was reduced. Moreover, Cx47 GJ plaques showed reduced colocalization with Cx43 plaques. Oligodendrocyte precursor cells (OPCs) and mature oligodendrocyte populations were also depleted, and myelin deficits were observed. Our findings indicate reduced astrocyte-oligodendrocyte gap junction connectivity and possibly a shift in Cx43 expression toward astrocyte-astrocyte gap junctions and/or hemichannels, that could impair oligodendrocyte homeostasis and myelination. However, other factors, such as Aß toxicity, could directly affect oligodendrocyte survival in AD. Our study provides evidence that Cxs might have implications in the progression of AD, although the role of oligodendrocyte Cxs in AD requires further investigation.

Neurophysiological and Genetic Findings in Patients With Juvenile Myoclonic Epilepsy.

OBJECTIVE: Transcranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia. METHODS: 20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10-15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied. RESULTS: We identified increased polyphasia in patients (85%) and relatives (70%) compared to controls (47%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; p < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in SYT14 (Synaptotagmin 14), in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia. CONCLUSION: Polyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives.

A European questionnaire survey on epilepsy monitoring units' current practice for postoperative psychogenic nonepileptic seizures' detection.

BACKGROUND: In cases undergoing epilepsy surgery, postoperative psychogenic nonepileptic seizures (PNES) may be underdiagnosed complicating the assessment of postsurgical seizures' outcome and the clinical management. We conducted a survey to investigate the current practices in the European epilepsy monitoring units (EMUs) and the data that EMUs could provide to retrospectively detect cases with postoperative PNES and to assess the feasibility of a subsequent postoperative PNES research project for cases with postoperative PNES. METHODS: We developed and distributed a questionnaire survey to 57 EMUs. Questions addressed the number of patients undergoing epilepsy surgery, the performance of systematic preoperative and postoperative psychiatric evaluation, the recording of sexual or other abuse, the follow-up period of patients undergoing epilepsy surgery, the performance of video-electroencephalogram (EEG) and postoperative psychiatric assessment in suspected postoperative cases with PNES, the existence of electronic databases to allow extraction of cases with postoperative PNES, the data that these bases could provide, and EMUs' interest to participate in a retrospective postoperative PNES project. RESULTS: Twenty EMUs completed the questionnaire sheet. The number of patients operated every year/per center is 26.7 ( ±â€¯19.1), and systematic preoperative and postoperative psychiatric evaluation is performed in 75% and 50% of the EMUs accordingly. Sexual or other abuse is systematically recorded in one-third of the centers, and the mean follow-up period after epilepsy surgery is 10.5 ±â€¯7.5 years. In suspected postoperative PNES, video-EEG is performed in 85% and psychiatric assessment in 95% of the centers. An electronic database to allow extraction of patients with PNES after epilepsy surgery is used in 75% of the EMUs, and all EMUs that sent the sheet completed expressed their interest to participate in a retrospective postoperative PNES project. CONCLUSION: Postoperative PNES is an underestimated and not well-studied entity. This is a European survey to assess the type of data that the EMUs surgical cohorts could provide to retrospectively detect postoperative PNES. In cases with suspected PNES, most EMUs perform video-EEG and psychiatric assessment, and most EMUs use an electronic database to allow extraction of patients developing PNES.

Functional brain networks of patients with epilepsy exhibit pronounced multiscale periodicities, which correlate with seizure onset.

Epileptic seizure detection and prediction by using noninvasive measurements such as scalp EEG signals or invasive, intracranial recordings, has been at the heart of epilepsy studies for at least three decades. To this end, the most common approach has been to consider short-length recordings (several seconds to a few minutes) around a seizure, aiming to identify significant changes that occur before or during seizures. An inherent assumption in this approach is the presence of a relatively constant EEG activity in the interictal period, which is interrupted by seizure occurrence. Here, we examine this assumption by using long-duration scalp EEG data (21-94 hr) in nine patients with epilepsy, based on which we construct functional brain networks. Our results reveal that these networks vary over time in a periodic fashion, exhibiting multiple peaks at periods ranging between 1 and 24 hr. The effects of seizure onset on the functional brain network properties were found to be considerably smaller in magnitude compared to the changes due to these inherent periodic cycles. Importantly, the properties of the identified network periodic components (instantaneous phase) were found to be strongly correlated to seizure onset, especially for the periodicities around 3 and 5 hr. These correlations were found to be largely absent between EEG signal periodicities and seizure onset, suggesting that higher specificity may be achieved by using network-based metrics. In turn, this implies that more robust seizure detection and prediction can be achieved if longer term underlying functional brain network periodic variations are taken into account.