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Blockade of Angiotensin type 1 receptor (AT1R) has potential therapeutic utility in the treatment of numerous detrimental consequences of epileptogenesis, including oxidative stress, neuroinflammation, and blood–brain barrier (BBB) dysfunction. We have recently shown that many of these pathological processes play a critical role in seizure onset and propagation in the Scn8a-N1768D mouse model. Here we investigate the efficacy and potential mechanism(s) of action of candesartan (CND), an FDA-approved angiotensin receptor blocker (ARB) indicated for hypertension, in improving outcomes in this model of pediatric epilepsy. We compared length of lifespan, seizure frequency, and BBB permeability in juvenile (D/D) and adult (D/+) mice treated with CND at times after seizure onset. We performed RNAseq on hippocampal tissue to quantify differences in genome-wide patterns of transcript abundance and inferred beneficial and detrimental effects of canonical pathways identified by enrichment methods in untreated and treated mice. Our results demonstrate that treatment with CND gives rise to increased survival, longer periods of seizure freedom, and diminished BBB permeability. CND treatment also partially reversed or ‘normalized’ disease-induced genome-wide gene expression profiles associated with inhibition of NF-κB, TNFα, IL-6, and TGF-β signaling in juvenile and adult mice. Pathway analyses reveal that efficacy of CND is due to its known dual mechanism of action as both an AT1R antagonist and a PPARγ agonist. The robust effectiveness of CND across ages, sexes and mouse strains is a positive indication for its translation to humans and its suitability of use for clinical trials in children with SCN8A epilepsy [ABSTRACT FROM AUTHOR]

Objective Summarize the clinical and genetic characteristics of atypical Rett syndrome and developmental epileptic encephalopathy caused by IQSEC2 gene variation. Methods and Results From May 2020 to April 2022, Anhui Provincial Children's Hospital diagnosed and treated 4 children with atypical Rett syndrome and developmental epileptic encephalopathy caused by IQSEC2 gene variation, including 2 males and 2 females were a pair of identical twins. They all had comprehensive developmental delay before onset. At the age of 2 years, all cases gradually exhibited clinical manifestations of atypical Rett syndrome, such as frequent clapping, biting, sleep disorders (increased sleep or difficulty falling asleep), and grinding teeth, followed by developmental regression and seizures. The initial age of epilepsy was from 2 years and 2 months to 2 years and 10 months. All cases started with generalized tonic-clonic seizure, with epileptic spasm occurring between 2 and 11 months of course. Case 2, Case 3 and Case 4 were also accompanied by focal seizures. Four cases with VEEG background of 4-6 Hz θ wave, the VEEG during the interictal phase was a broad multifocal sharp slow complex wave. In Case 2, Case 3 and Case 4, MRI was abnormal, mainly with increased depth of cerebral hemispheric sulcus and gyrus. The whole exome sequencing suggested pathogenicity and possible pathogenic variations in the IQSEC2 gene, Case 1 and Case 2 were frameshift mutations of c. 608dup (p. Gln204Profs*35), while Case 3 and Case 4 were nonsense mutations of c.2231C>A (p.Ser744Ter) and c.2521C>T (p. Gln841Ter), respectively. The four mutation sites have not been reported domestically or internationally. All cases received treatment with multiple antiepileptic seizure medicine. The last follow-up age was from 4 years and 3 months to 6 years and 3 months. All cases were unable to walk alone and had no active language. There were no seizures in Case 1 for 3 years, occasional seizures in Case 2 and Case 4, and frequent seizures in Case 3. Conclusions IQSEC2 gene variation can manifest as atypical Rett syndrome, which can be accompanied by refractory epileptic spasms. Both males and females have severe phenotypes, and the severity of clinical phenotypes at the same mutation site varies. Our report enriches the variation spectrum and clinical phenotype spectrum of the IQSEC2 gene, expands the genetic spectrum of Rett syndrome and developmental epileptic encephalopathy, and provides value for the clinical diagnosis, treatment and subsequent research of this disease. [ABSTRACT FROM AUTHOR]

Background: Daylength and the rates of changes in daylength have been associated with seasonal fluctuations in psychiatric symptoms and in cognition and mood in healthy adults. However, variations in human brain glucose metabolism in concordance with seasonal changes remain under explored. Methods: In this cross-sectional study, we examined seasonal effects on brain glucose metabolism, which we measured using 18F-fluorodeoxyglucose-PET in 97 healthy participants. To maximize the sensitivity of regional effects, we computed relative metabolic measures by normalizing the regional measures to white matter metabolism. Additionally, we explored the role of rest–activity rhythms/sleep–wake activity measured with actigraphy in the seasonal variations of regional brain metabolic activity. Results: We found that seasonal variations of cerebral glucose metabolism differed across brain regions. Glucose metabolism in prefrontal regions increased with longer daylength and with greater day-to-day increases in daylength. The cuneus and olfactory bulb had the maximum and minimum metabolic values around the summer and winter solstice respectively (positively associated with daylength), whereas the temporal lobe, brainstem, and postcentral cortex showed maximum and minimum metabolic values around the spring and autumn equinoxes, respectively (positively associated with faster daylength gain). Longer daylength was associated with greater amplitude and robustness of diurnal activity rhythms suggesting circadian involvement. Conclusions: The current findings advance our knowledge of seasonal patterns in a key indicator of brain function relevant for mood and cognition. These data could inform treatment interventions for psychiatric symptoms that peak at specific times of the year. [ABSTRACT FROM AUTHOR]

The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain viruses can induce epilepsy by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, epilepsy patients may be more susceptible to viral infections due to factors, such as compromised immune systems, anticonvulsant drugs, or surgical interventions. Neuroinflammation, a common factor in both scenarios, exhibits onset, duration, intensity, and consequence variations. It can modulate epileptogenesis, increase seizure susceptibility, and impact anticonvulsant drug pharmacokinetics, immune system function, and brain physiology. Viral infections significantly impact the clinical management of epilepsy patients, necessitating a multidisciplinary approach encompassing diagnosis, prevention, and treatment of both conditions. We delved into the dual dynamics of viruses inducing epilepsy and epilepsy patients acquiring viruses, examining the unique features of each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms of epilepsy induction, emphasize neuroinflammation's impact, and analyze its effects on anticonvulsant drug pharmacokinetics. Conversely, in epilepsy patients acquiring viruses, we detail the acquired virus, its interaction with existing epilepsy, neuroinflammation effects, and changes in anticonvulsant drug pharmacokinetics. Understanding this interplay advances precision therapies for epilepsy during viral infections, providing mechanistic insights, identifying biomarkers and therapeutic targets, and supporting optimized dosing regimens. However, further studies are crucial to validate tools, discover new biomarkers and therapeutic targets, and evaluate targeted therapy safety and efficacy in diverse epilepsy and viral infection scenarios. [ABSTRACT FROM AUTHOR]

Objective: To explore the characteristics and mechanisms of working memory impairment in patients with frontal lobe epilepsy (FLE) through a memory game paradigm combined with eye tracking technology. Method: We included 44 patients with FLE and 50 healthy controls (HC). All participants completed a series of neuropsychological scale assessments and a short-term memory game on an automated computer-based memory evaluation platform with an eye tracker. Results: Memory scale scores of FLE patients including digit span (U = 747.50, p = 0.007), visual recognition (U = 766.50, p = 0.010), and logical memory (U = 544.00, p < 0.001) were significantly lower than HC. The patients with FLE took longer to complete the four levels of difficulty of the short-term memory game than healthy controls (level 1: U = 2974.50, p = 0.000; level 2: U = 3060.50, p = 0.000; level 3: U = 2465.00, p = 0.000; level 4: U = 2199.00, p = 0.000). During the memory decoding period, first fixation on the targets took significantly longer for FLE patients for all difficulty levels compared to controls (level 1: U = 3407.00, p = 0.008; level 2: U = 3618.00, p = 0.036; level 3: U = 3345.00, p = 0.006; level 4: U = 2781.00, p = 0.000). The average fixation duration per target among patients with FLE was found to be significantly longer compared to HC (level 1: U = 2994.50, p = 0.000; level 2: U = 3101.00, p = 0.000; level 3: U = 2559.50, p = 0.000; level 4: U = 2184.50, p = 0.000). The total fixation duration on AOI/ total completion time of FLE patients was significantly lower than those of HC for levels 1 to 3 (level 1: U = 1557.00, p = 0.000; level 2: U = 2333.00, p = 0.000; level 3: U = 2757.00, p = 0.000). Furthermore, the eye tracking data during the memory decoding phase were correlated with neuropsychological scale scores (p < 0.05). Conclusion: Patients with FLE exhibited short-term memory impairment probably due to deficits in attentional maintenance, especially during the memory decoding phase. Eye tracking technology provided the possibility to help separate and quantify visual attention from memory processing, contributing to exploring underlying mechanisms of memory impairment in FLE. [ABSTRACT FROM AUTHOR]

Summary: The study objective was to explore associations of fetal and infant weight patterns and preterm birth with sleep and 24‐h activity rhythm parameters at school‐age. In our prospective population‐based study, 1327 children were followed from birth to age 10–15 years. Fetal weight was estimated using ultrasound in the second and third trimester of pregnancy. Birth weight and gestational age were available from midwife registries. Infant weight was measured at 6, 12 and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change of >0.67 standard deviation between the corresponding age intervals. At school‐age, sleep duration, sleep efficiency, wake after sleep onset, social jetlag, inter‐daily stability, and intra‐daily variability were assessed using tri‐axial wrist actigraphy for 9 consecutive nights. We observed that low birth weight (<2500 g) was associated with 0.24 standard deviation (95% confidence interval [CI] 0.04; 0.43) longer sleep duration compared to normal weight. Compared to normal growth, growth deceleration in fetal life and infancy was associated with 0.40 standard deviation (95% CI 0.07; 0.73) longer sleep duration, 0.44 standard deviation (95% CI 0.14; 0.73) higher sleep efficiency, and −0.41 standard deviation (95% CI −0.76; ‐0.07) shorter wake after sleep onset. A pattern of normal fetal growth followed by infant growth acceleration was associated with −0.40 standard deviation (95% CI −0.61; −0.19) lower inter‐daily stability. Preterm birth was not associated with any sleep or 24‐h rhythm parameters. Our findings showed that children with fetal and infant growth restriction had longer and more efficient sleep at school‐age, which may be indicative of an increased need for sleep for maturational processes and development after a difficult start in life. [ABSTRACT FROM AUTHOR]

Objectives To analyse the prevalence of pathogenic variants in DEPDC5, NPRL2 and NPRL3 that encode the GATOR1 (GTPase-activating protein towards the Rags 1) complex, a modulator in the mammalian target of rapamycin (mTOR) pathway, and to define the characteristics of GATOR1-associated epilepsy. Methods Clinical details and whole-exome sequencing data of 170 novel probands with lesional or non-lesional epilepsy were retrieved. Candidate variants in GATOR1 genes were verified by Sanger sequencing, and cosegregate analysis was performed. The pathogenicity of variants and their effect on mTOR signalling were investigated. Results Two novel frameshift variants and one recurrent nonsense variant were detected in DEPDC5, with a prevalence of 1.8% (3 out of 170) in the whole cohort and 3.1% (3 out of 97) in focal epilepsies. These variants cosegregated in pedigrees with epilepsy, respectively. Rare missense variants in NPRL2 and NPRL3 did not segregate with epilepsy in families, respectively. Epileptic phenotypes of 21 patients with DEPDC5 variants showed focal seizures with non-lesional variable foci that were predominantly sleep-related, with a median onset age of 10 years (range 1-30). Seizure outcome was variable. About 24% of patients were drug-resistant, and seizure attacks were absent in 33% of variant carriers. Of 13 patients who experienced seizures, 54% tended to resolve spontaneously. Functional assessments showed that the three variants affected DEPDC5 expression. These loss-of-function (LoF) variants affected the DEPDC5-dependent inhibition of mTOR. Conclusions Patients carrying DEPDC5-LoF variants might show a high prevalence of focal seizures with a dynamic phenotype, indicating reduced penetrance and self-resolving features. The associated epilepsy was caused by loss of inhibition of the mTOR pathway. The pathogenicity of missense variants in GATOR1 genes should be cautiously evaluated. [ABSTRACT FROM AUTHOR]

Background: Conduction velocity of the short segment of the median motor nerve, across wrist (transcarpal motor conduction velocity (TCMCV)), has been used to increase diagnostic yield in carpal tunnel syndrome (CTS). However, repeatability of this parameter has not been studied till date. It has not been used as an indicator of response to treatment. Using surface stimulation techniques, it is difficult to localize the sites of stimulation of transcarpal segment of median nerve in palm. As a result, small errors in measurements of TCMCV can be magnified and variability of TCMCV may occur on successive measurements. Despite this possible variation, TCMCV can be a useful tool for assessing response to therapy, if its repeatability is assessed and a cut-off value determined for a significant change in nerve conduction velocity. Purpose: In this study, it was determined whether TCMCV is repeatable. If found to be repeatable, we show a method to determine the cut-off value of the change in this parameter for it to be considered significant. Methods: Difference between values of TCMCV on successive measurements was obtained in hands of 26 controls. Repeatability of this parameter was determined in this control population following criteria of British Standards Institution. In 19 patients of CTS, treated with intracarpal steroid injection, pre-treatment and post-treatment values of TCMCV, and of symptom severity scale (SSS) and functional status scale (FSS), were obtained at 1, 2, and 3 months after treatment. Results: Repeat measurements of TCMCV were made in each hand of all controls. After applying criteria of British Standards Institution, to such recordings, TCMCV was found to be repeatable and the cut-off value for significant change determined. According to this cut-off value, 4 patients of CTS showed improvement in TCMCV, with consistent improvement in SSS and FSS. Change in TCMCV corroborated qualitatively with changes in SSS and FSS. Conclusion: Repeatability of TCMCV can be assessed by criteria of British Standards Institution and a cut-off value determined to use it as an indicator of response to treatment in CTS. [ABSTRACT FROM AUTHOR]

Circadian regulation causes the activity of biological processes to vary over a 24-h cycle. The pathological effects of this variation are predominantly studied using two different approaches: pre-clinical models or observational clinical studies. Both these approaches have provided useful insights into how underlying circadian mechanisms operate and specifically which are regulated by the molecular oscillator, a key time-keeping mechanism in the body. This review compares and contrasts findings from these two approaches in the context of four common respiratory diseases (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and respiratory infection). Potential methods used to identify and measure human circadian oscillations are also discussed as these will be useful outcome measures in future interventional human trials that target circadian mechanisms. [ABSTRACT FROM AUTHOR]

Copyright of Teacher Development Research is the property of Teacher Development Research and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

FOXG1 syndrome is a rare neurodevelopmental disorder associated with severe cognitive dysfunction, autistic behavior, and early‐onset hyperkinetic movement disorders. Patients have also been reported to experience sleep disturbances. However, these findings are mainly based on subjective caregivers' reports, and limited by small case numbers. Moreover, no studies using objective evaluation tools, such as actigraphy, have been reported. We analyzed the clinical and sleep manifestations of children with FOXG1 syndrome registered in the FOXG1 Research Foundation Patient Registry database. A total of 258 individuals with FOXG1 syndrome were included in this research. 132 (51.16%) had sleep disturbances. The more impaired of language acquisitions (absence of speech, OR: 3.99, 95%CI = 1.69–9.42, p = 0.002), hyperkinetic movement disorders (OR: 2.64, 95%CI = 1.34‐5.20 p = 0.005) and feeding difficulties (OR: 2.81, 95% CI = 1.52–5.19, p = 0.001) were significantly associated with an increase in odds of sleep disturbance after adjusting for age, sex, and antiepileptic drugs. We also performed sleep studies on six individuals with FOXG1 syndrome using The Children's Sleep Habits Questionnaire (CSHQ), the Sleep Disturbance Scale for Children (SDSC), and 7‐day data from Actiwatch. The Pittsburgh Sleep Quality Index (PSQI) and 7‐day data from Actiwatch were also used to evaluate the sleep condition of their parents. The CSHQ scores revealed bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night‐waking, and parasomnia. Sleep–wake transition disorders and disorders of initiating and maintaining sleep were also suggested by the SDSC scores. The children's actigraphy revealed short sleep durations, impaired sleep efficiency, longer wake after sleep onset, and frequent night‐waking. All caregivers reported significantly higher PSQI scores, mildly declined sleep efficiency, and shorter total sleep duration. Sleep disturbances, especially in initiating and maintaining sleep, are common in individuals with FOXG1 syndrome and their caregivers. Sleep disorders in patients with FOXG1 syndrome and their caregivers should be investigated. Lay Summary: FOXG1 syndrome is a rare disorder with several comorbidities, including sleep disorders. However, studies focusing on sleep conditions in FOXG1 syndrome are scarce. Our studies showed that sleep disturbances occur across different genders, ages, and genotypes in FOXG1 syndrome. Hyperkinetic movements, feeding difficulties, and absence of language acquisition significantly increased the probability of sleep disturbance. Our results also demonstrated greater difficulty in initiating and maintaining sleep, as identified in actigraphy studies, and sleep‐disordered breathing symptoms, as revealed by the report questionnaires submitted by the parents of six children with FOXG1 syndrome. Caregivers of children with this condition also tended to have shorter total sleep durations. [ABSTRACT FROM AUTHOR]

Characterized by developmental delay with severe speech delay, dental anomalies, cleft palate, skeletal abnormalities, and behavioral difficulties, SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2. The SAS phenotype range of severity has been documented previously in large series. Using data from the SAS registry, we present the SAS severity score, a comprehensive scoring rubric that encompasses 15 different individual neurodevelopmental and systemic features. Higher (more severe) systemic and total (sum of neurodevelopmental and systemic scores) scores were seen for null variants located after amino acid 350 (the start of the CUT1 domain), the recurrent missense Arg389Cys variant (n = 10), intragenic deletions, and larger chromosomal deletions. The Arg389Cys variant had the highest cognitive, verbal, and sialorrhea severity scores, while large chromosomal deletions had the highest expressive, ambulation, palate, feeding and growth, neurodevelopmental, and total scores. Missense variants not located in the CUT1 or CUT2 domain scored lower in several subcategories. We conclude that the SAS severity score allows quantitative phenotype morbidity description that can be used in routine clinical counseling. Further refinement and validation of the SAS severity score are expected over time. All data from this project can be interactively explored in a new portal. [ABSTRACT FROM AUTHOR]

Background and Purpose: Variants in SCN8A, the NaV1.6 channel's coding gene, are characterized by a variety of symptoms, including intractable epileptic seizures, psychomotor delay, progressive cognitive decline, autistic features, ataxia or dystonia. Standard anticonvulsant treatment has a limited impact on the course of disease. Experimental Approach: We investigated the therapeutic potential of eslicarbazepine (S‐licarbazepine; S‐lic), an enhancer of slow inactivation of voltage gated sodium channels, on two variants with biophysical and neuronal gain‐of‐function (G1475R and M1760I) and one variant with biophysical gain‐of‐function but neuronal loss‐of‐function (A1622D) in neuroblastoma cells and in murine primary hippocampal neuron cultures. These three variants cover the broad spectrum of NaV1.6‐associated disease and are linked to representative phenotypes of mild to moderate epilepsy (G1475R), developmental and epileptic encephalopathy (M1760I) and intellectual disability without epilepsy (A1622D). Key Results: Similar to known effects on NaV1.6 wildtype channels, S‐lic predominantly enhances slow inactivation on all tested variants, irrespective of their particular biophysical mechanisms. Beyond that, S‐lic exhibits variant‐specific effects including a partial reversal of pathologically slowed fast inactivation dynamics (A1622D and M1760I) and a trend to reduce enhanced persistent Na+ current by A1622D variant channels. Furthermore, our data in primary transfected neurons reveal that not only variant‐associated hyperexcitability (M1760I and G1475R) but also hypoexcitability (A1622D) can be modulated by S‐lic. Conclusions and Implications: S‐lic has not only substance‐specific effects but also variant‐specific effects. Personalized treatment regimens optimized to achieve such variant‐specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A‐related disease. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disease in clinic. Epilepsy caused by structural causes can be cured by surgery, which has been the focus of attention in the field of epilepsy surgery. With the development of gene sequencing technology, more and more studies have found that structural etiology may be caused by somatic mutations of genes. In this paper, somatic mutation-related pathogenic genes of four common pathological types of epilepsy surgery, including malformation of cortical development (MCD), long-term epilepsy associated tumor (LEAT), hippocampal sclerosis (HS) and hypothalamic hamartoma (HH), were reviewed, and their effects on surgical protocol formulation and prognosis were reviewed, in order to provide a new idea for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Background : Survivors of acute respiratory failure (ARF) experience long-term cognitive impairment and circadian rhythm disturbance after hospital discharge. Although prior studies in aging and neurodegenerative diseases indicate actigraphy-estimated rest-activity circadian rhythm disturbances are risk factors for cognitive impairment, it is unclear if this applies to ARF survivors. This study explored the relationships of actigraphy-estimated rest-activity circadian rhythms with cognitive functioning in ARF survivors at 3 months after discharge. Methods : 13 ARF survivors (mean age 51 years and 69% males) completed actigraphy and sleep diaries for 9 days, followed by at-home neuropsychological assessment. Principal component factor analysis created global cognition and circadian rhythm variables, and these first components were used to examine the global relationships between circadian rhythm and cognitive measure scores. Results : Global circadian function was associated with global cognition function in ARF survivors (r =.70, p =.024) after adjusting for age, education, and premorbid cognition. Also, greater fragmented rest-activity circadian rhythm (estimated by intradaily variability, r =.85, p =.002), and weaker circadian strength (estimated by amplitude, r =.66, p =.039; relative strength, r =.70, p =.024; 24-h lag serial autocorrelation, r =.67, p =.035), were associated with global cognition and individual cognitive tests. Conclusions : These results suggest circadian rhythm disturbance is associated with poorer global cognition in ARF survivors. Future prospective research with larger samples is needed to confirm these results and increase understanding of the relationship between disrupted circadian rhythms and cognitive impairment among ARF survivors. [ABSTRACT FROM AUTHOR]

Summary: Cyclin‐dependent kinase‐like 5 (CDKL5) gene pathogenic variants result in CDKL5 deficiency disorder (CDD). Early onset intractable epilepsy and severe developmental delays are prominent symptoms of CDD. Comorbid sleep disturbances are a major concerning symptom for families. We aimed to explore the relationship between insomnia, daytime sleepiness, sleep medications and quality of life in children with CDD. Caregivers of 129 children with CDD in the International CDKL5 Disorder Database completed the Quality‐of‐Life Inventory‐Disability (QI‐Disability) questionnaire and "Disorders of Maintaining Sleep" (DIMS) and the "Disorders of Excessive Somnolence" (DOES) items of the Sleep Disturbance Scale for Children. Adjusting for covariates, a unit increase in DOES score was associated with reduced quality of life total (coefficient −3.06, 95% confidence interval [CI] 1.35–7.80), physical health (coefficient −7.20, 95% CI −10.64, −3.76) and negative emotions (coefficient −3.90, 95% CI −7.38, −0.42) scores. Adjusting for covariates, a unit increase in DIMS score was associated with reduced negative emotions (coefficient −6.02, 95% CI −10.18, −2.86). Use of sleep medications had small influences on the effect sizes. This study highlights the importance of sleep problems as a determinant of quality of life in children with CDD, consistent with effects observed for other groups of children with intellectual disability. Excessive daytime sleepiness was particularly associated with detrimental effects on quality of life. Further research in optimal behavioural and pharmaceutical management of sleep problems for this population is required. [ABSTRACT FROM AUTHOR]

The teaching and learning of self-study research have received increased attention in recent years, although there is still limited research about the learning of self-study. In this article, we share results from a self-study community of practice that describes how one group of novice teacher-educator-researchers learned self-study in a doctoral seminar on teacher education. The doctoral seminar served as a space through which the students simultaneously learned about and enacted self-study research methods. Data for the study included educational autobiographies and journals between students and the instructor, transcribed audio-recordings of course meetings and coding sessions, and course assignments. Through data analysis, we identified six steps in our particular journey of learning self-study: (1) advancing a willingness to improve; (2) acknowledging the power of reflection, (3) examining practice through collaboration, (4) identifying changes in practice, (5) developing new identities, and (6) sharing with others. We offer our experience of learning self-study to provide readers with one set of signposts, support, encouragement, and direction for the teaching and learning of self-study methods. Findings from this research may provide insights to new self-study researchers, scholars who teach self-study research, and experienced self-study researchers who provide on-going support for self-study colleagues. [ABSTRACT FROM AUTHOR]

SATB2‐associated syndrome (SAS) is a rare disorder characterized by developmental delay, behavioral problems, and craniofacial anomalies in particular dental and palatal abnormalities. We describe the clinical course, genetic and autopsy findings in a Chinese boy with global developmental delay, hypotonia, epilepsy, recurrent fractures and osteopenia. Brain magnetic resonance imaging showed pachygyria, white matter hypoplasia and hypogenesis of the corpus callosum. Whole‐exome sequencing identified a novel heterozygous missense variant c.1555G>A p.(Glu519Lys) in the SATB2 gene. Unfortunately, he died at 26 months of bronchiolitis and pneumonia. Autopsy revealed pachygyria which was more severe anteriorly, dilated lateral and third ventricles and partial agenesis of the corpus callosum. Histology showed features compatible with two‐layered lissencephaly. The bone showed disordered lamination and bone matrix. Although SATB2 has been shown to be involved in the regulation of neuronal migration in the developing brain, lissencephaly has not been reported so far. This could represent a more severe phenotype of SAS. [ABSTRACT FROM AUTHOR]

Autistic children and adults often have sleep disturbances, which may affect their and their family's quality of life. Yet, the relationship between sleep–wake patterns and autism spectrum traits is understudied. Identifying such relationships could lead to future research elucidating common mechanistic underpinnings. Thus, we aimed to determine whether sleep–wake patterns, specifically related to sleep, physical activity, and the daily sleep–wake rhythm (i.e., circadian rhythm), are associated with autism spectrum‐related traits. Accelerometer‐derived sleep–wake parameters were estimated in individuals with autistic spectrum traits and their family members (N = 267). We evaluated autism spectrum traits using the Social Responsiveness Scale (SRS) to assess the presence and severity of social impairment and the Behavior Rating Inventory of Executive Function (BRIEF) to assess executive function. The linear multivariate regression analysis (using SOLAR‐Eclipse) showed that in adults, increased core autism spectrum traits and executive dysfunction were associated with disruption of several sleep–wake parameters, particularly related to the daily sleep–wake rhythm, and that executive dysfunction was associated with disrupted sleep quality and level of physical activity. We highlight the interplay between daytime function and disrupted sleep–wake patterns, specifically related to the daily sleep–wake rhythm, that could guide future research into common mechanisms. Lay Summary: Autistic children and adults often report sleep disturbances. To dissect the relationship between a range of autism spectrum traits and sleep–wake patterns, we assessed social interaction and executive function in participants who also wore actimetry watches on their wrists to assess their sleep–wake patterns. We found that increased impairments in social and executive function occurred with increased sleep–wake disturbances, particularly those related to the circadian rhythm, suggesting that these perturbations/disruptions in the sleep–wake cycle could be connected to autism spectrum traits. [ABSTRACT FROM AUTHOR]

The identification of geriatric depression and anxiety is important because such conditions are the most common comorbid mood problems that occur in older adults. The goal of this study was to build a machine learning framework that identifies geriatric mood disorders of depression and anxiety using low-cost activity trackers and minimal geriatric assessment scales. We collected activity tracking data from 352 mild cognitive impairment patients, from 60 to 90 in age, by having them wear activity trackers on their wrist for more than a month. We then extracted the features of 24-h activity rhythms and sleep patterns from the time-series activity tracking data. To increase the accuracy, we designed a novel method to incorporate additional features from questionnaire-based assessments of the geriatric depression scale and geriatric anxiety inventory into the activity tracking features. In the multi-label classification, we applied the binary relevance method to develop two single-label classifiers for depression and anxiety. The best hyper-parameters of classification algorithms for each label were selected by comparing the classification performance. We finally selected the combination of classifiers for depression and anxiety with the lowest Hamming loss as a multi-label classifier. This study successfully demonstrated the possibility of identifying geriatric depression and anxiety using low-cost activity trackers and minimal geriatric assessment scales for use in the real fields. [ABSTRACT FROM AUTHOR]

Copyright of Journal on Developmental Disabilities is the property of Ontario Association on Developmental Disabilities and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Working memory is a multicomponent system that is supported by overlapping specialized networks in the brain. Baddeley's working memory model includes four components: the phonological loop, visuo-spatial sketchpad, the central executive, and episodic buffer. The aim of this review was to establish the gravity and pattern of working memory deficits in pediatric epilepsy. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guided electronic searches. Sixty-five studies were included in the review. Meta-analyses revealed significant impairments across each working memory component: phonological loop (g = 0.739), visuo-spatial sketchpad (g = 0.521), and central executive (g = 0.560) in children with epilepsy compared to controls. The episodic buffer was not examined. The pattern of impairments, however, differed according to the site and side of seizure focus. This suggests that working memory components are differentially vulnerable to the location of seizure focus in the developing brain. [ABSTRACT FROM AUTHOR]

CDKL5 deficiency disorder (CDD) results in early-onset seizures and severe developmental impairments. A CDD clinical severity assessment (CCSA) was previously developed with clinician and parent-report items to capture information on a range of domains. Consistent with US Food and Drug Administration (FDA) guidelines, content validation is the first step in evaluating the psychometric properties of an outcome measure. The aim of this study was to validate the content of the clinician-reported items in the CCSA (CCSA-Clinician). Eight neurologists leading the USA CDD Center of Excellence clinics were interviewed using the "think aloud" technique to critique 26 clinician-reported items. Common themes were aggregated, and a literature search of related assessments informed item modifications. The clinicians then participated in 2 consensus meetings to review themes and finalize the items. A consensus was achieved for the content of the CCSA-Clinician. Eight of the original items were omitted, 11 items were added, and the remaining 18 items were revised. The final 29 items were classified into 2 domains: functioning and neurologic impairments. This study enabled refinement of the CCSA-Clinician and provided evidence for its content validity. This preliminary validation is essential before field testing and further validation, in order to advance the instrument toward clinical trial readiness. [ABSTRACT FROM AUTHOR]

Focal cortical dysplasia is a malformation of cortical development in which there are abnormalities with cortical lamination, neuronal maturation, and neuronal differentiation. It is the most common cause of medically refractory epilepsy in the pediatric population and the second/third most common etiology of medically intractable seizures in adults. Herein, we present the case of 23-years-old female patient, presenting with loss of consciousness, and convulsions. A MRI revealed a 5mm cortical thickening on either side of the posterior aspect of the right superior temporal gyrus without transmantle extension towards ventricle. This abnormal area is measured about 24x16mm and there was no evidence for mesial temporal sclerosis. Both hippocampi are normal is size, morphology and signal. These features are consistent with cortical dysplasia type 1. This case report emphasizes the importance of MRI in the detection of FCD. MRI can show no abnormalities in type 1 FCD, but when the changes are apparent, they are on the temporal lobe, and seizures presents most commonly in adults. [ABSTRACT FROM AUTHOR]

Bright light treatment is an effective way to influence circadian rhythms in healthy adults, but previous research with dementia patients has yielded mixed results. The present study presents a primary outcome of the DEM.LIGHT trial, a 24-week randomized controlled trial conducted at nursing homes in Bergen, Norway, investigating the effects of a bright light intervention. The intervention consisted of ceiling-mounted LED panels providing varying illuminance and correlated color temperature throughout the day, with a peak of 1000 lx, 6000 K between 10 a.m. and 3 p.m. Activity was recorded using actigraphs at baseline and after 8, 16, and 24 weeks. Non-parametric indicators and extended cosine models were used to investigate rest-activity rhythms, and outcomes were analyzed with multi-level regression models. Sixty-one patients with severe dementia (median MMSE = 4) were included. After 16 weeks, the acrophase was advanced from baseline in the intervention group compared to the control group (B = -1.02, 95%; CI = -2.00, -0.05). There was no significant difference between the groups on any other rest-activity measures. When comparing parametric and non-parametric indicators of rest-activity rhythms, 25 out of 35 comparisons were significantly correlated. The present results indicate that ambient bright light treatment did not improve rest-activity rhythms for people with dementia. [ABSTRACT FROM AUTHOR]

As children with epilepsy may have a number of learning and behavioral problems, it is important that insight into the underlying neurocognitive differences in these children, which may underlie these areas of challenge is gained. Executive function (EF) problems particularly are associated with specific learning abilities as well as behavioral problems. We aim to review systematically the current status of empirical studies on the association between EF problems and behavior and socioemotional problems in children with epilepsy. After search, 26 empirical studies were identified, most of them of moderate quality. Overall, attention problems were the most reported cognitive deficit in test assessment and the most reported problem by parents. In 54% of the studies, children with epilepsy scored below average compared to controls/normative samples on different aspects of EF. Most studies reported behavior problems, which ranged from mild to severe. Forty-two percent of the studies specifically reported relationships between EF deficits and behavioral problems. In the remaining studies, below average neuropsychological functioning seemed to be accompanied by above average reported behavioral problems. The association was most pronounced for cognitive control and attention in relation to externalizing behavior problems. This cognitive control is also associated with social functioning. Relevant epilepsy variables in this relationship were early age at onset and high seizure frequency. Future research should distinguish specific aspects of EF and take age into account, as this provides more insight on the association between EF and behavior in pediatric epilepsy, which makes it possible to develop appropriate and early intervention. [ABSTRACT FROM AUTHOR]

Epileptic encephalopathy is a condition resulting from extreme forms of intractable childhood epilepsy. The disease can cause severe delays in cognitive, sensory, and motor function development, in addition to being fatal in some cases. Missense mutations of SCN8A, which encodes Nav1.6, one of the main voltage-gated sodium channel subunits in neurons and muscles, have been linked to early infantile SCN8A encephalopathy. Herein, we report the case of a 5-month-old girl with SCN8A encephalopathy with a novel missense mutation. Apart from intractable seizures and autistic phenotypes, the results of blood and biochemical tests, electroencephalogram (EEG) results, and brain magnetic resonance imaging (MRI) results were all normal. As the phenotypes caused by these mutations cannot be identified by any clinical, neuroimaging, or electrophysiological features, genetic sequencing should be considered to identify the underlying genetic causes. Although phenytoin is recommended as a last-resort treatment for SCN8A encephalopathy, the administration of the oxcarbazepine, instead of phenytoin, mitigated this patient's intractable seizures. [ABSTRACT FROM AUTHOR]

Mutations in the X‐linked CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition mainly characterized by infantile epileptic encephalopathy, intellectual disability, and autistic features. The molecular mechanisms underlying the clinical symptoms remain largely unknown and the identification of reliable biomarkers in animal models will certainly contribute to increase our comprehension of CDD as well as to assess the efficacy of therapeutic strategies. Here, we used different Magnetic Resonance (MR) methods to disclose structural, functional, or metabolic signatures of Cdkl5 deficiency in the brain of adult mice. We found that loss of Cdkl5 does not cause cerebral atrophy but affects distinct brain areas, particularly the hippocampus. By in vivo proton‐MR spectroscopy (MRS), we revealed in the Cdkl5 null brain a metabolic dysregulation indicative of mitochondrial dysfunctions. Accordingly, we unveiled a significant reduction in ATP levels and a decrease in the expression of complex IV of mitochondrial electron transport chain. Conversely, the number of mitochondria appeared preserved. Importantly, we reported a significant defect in the activation of one of the major regulators of cellular energy balance, the adenosine monophosphate‐activated protein kinase (AMPK), that might contribute to the observed metabolic impairment and become an interesting therapeutic target for future preclinical trials. In conclusion, MRS revealed in the Cdkl5 null brain the presence of a metabolic dysregulation suggestive of a mitochondrial dysfunction that permitted to foster our comprehension of Cdkl5 deficiency and brought our interest towards targeting mitochondria as therapeutic strategy for CDD. [ABSTRACT FROM AUTHOR]

We investigated synaptic mechanisms in the hippocampus that could explain how loss of circadian timing leads to impairments in spatial and recognition memory. Experiments were performed in hippocampal slices from Siberian hamsters (Phodopus sungorus) because, unlike mice and rats, their circadian rhythms are easily eliminated without modifications to their genome and without surgical manipulations, thereby leaving neuronal circuits intact. Recordings of excitatory postsynaptic field potentials and population spikes in area CA1 and dentate gyrus granule cells revealed no effect of circadian arrhythmia on basic functions of synaptic circuitry, including long‐term potentiation. However, dentate granule cells from circadian‐arrhythmic animals maintained a more depolarized resting membrane potential than cells from circadian‐intact animals; a significantly greater proportion of these cells depolarized in response to the cholinergic agonist carbachol (10 μM), and did so by increasing their membrane potential three‐fold greater than cells from the control (entrained) group. Dentate granule cells from arrhythmic animals also exhibited higher levels of tonic inhibition, as measured by the frequency of spontaneous inhibitory postsynaptic potentials. Carbachol also decreased stimulus‐evoked synaptic excitation in dentate granule cells from both intact and arrhythmic animals as expected, but reduced stimulus‐evoked synaptic inhibition only in cells from control hamsters. These findings show that loss of circadian timing is accompanied by greater tonic inhibition, and increased synaptic inhibition in response to muscarinic receptor activation in dentate granule cells. Increased inhibition would likely attenuate excitation in dentate‐CA3 microcircuits, which in turn might explain the spatial memory deficits previously observed in circadian‐arrhythmic hamsters. [ABSTRACT FROM AUTHOR]

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Disrupted sleep is common among nursing home patients and is associated with cognitive decline and reduced well-being. Sleep disruptions may in part be a result of insufficient daytime light exposure. This pilot study examined the effects of dynamic "circadian" lighting and individual light exposure on sleep, cognitive performance, and well-being in a sample of 14 senior home residents. The study was conducted as a within-subject study design over five weeks of circadian lighting and five weeks of conventional lighting, in a counterbalanced order. Participants wore wrist accelerometers to track rest-activity and light profiles and completed cognitive batteries (National Institute of Health (NIH) toolbox) and questionnaires (depression, fatigue, sleep quality, lighting appraisal) in each condition. We found no significant differences in outcome variables between the two lighting conditions. Individual differences in overall (indoors and outdoors) light exposure levels varied greatly between participants but did not differ between lighting conditions, except at night (22:00-6:00), with maximum light exposure being greater in the conventional lighting condition. Pooled data from both conditions showed that participants with higher overall morning light exposure (6:00-12:00) had less fragmented and more stable rest-activity rhythms with higher relative amplitude. Rest-activity rhythm fragmentation and long sleep duration both uniquely predicted lower cognitive performance. [ABSTRACT FROM AUTHOR]

Rett syndrome (RTT, MIM * 312750) is an X‐linked neurodevelopmental disorder caused by pathogenic variants at the Xq28 region involving the gene methyl‐CpG‐binding protein 2 (MECP2, MIM * 300005). The spectrum of MECP2‐related phenotypes is wide and it ranges from asymptomatic female carriers to severe neonatal‐onset encephalopathy in males. Abnormal breathing represents one of the leading features, but today little is known about polysomnographic features in RTT females; no data are available about males. We report the case of a male of Moroccan origins with a MECP2 pathogenic variant and a history of encephalopathy and severe breathing disturbances in the absence of dysmorphic features. For the first time we describe in detail the polysomnographic characteristics of a MECP2‐mutated male and we show the relevance of severe central apneas, which may represent a new clinical clue to suggest the diagnosis. Moreover, we want to highlight the importance to maintain a high index of suspicion for MECP2‐related disorders in the presence of severe hypotonia, apneic crises, and respiratory insufficiency in males to permit an earlier diagnosis and the consequent definition of recurrence risk of the family and to avoid other useless and invasive exams. [ABSTRACT FROM AUTHOR]

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Background The genetic architecture of non-acquired focal epilepsies (NAFEs) becomes increasingly unravelled using genome-wide sequencing datasets. However, it remains to be determined how this emerging knowledge can be translated into a diagnostic setting. To bridge this gap, we assessed the diagnostic outcomes of exome sequencing (ES) in NAFE. Methods 112 deeply phenotyped patients with NAFE were included in the study. Diagnostic ES was performed, followed by a screen to detect variants of uncertain significance (VUSs) in 15 well-established focal epilepsy genes. Explorative gene prioritisation was used to identify possible novel candidate aetiologies with so far limited evidence for NAFE. Results ES identified pathogenic or likely pathogenic (ie, diagnostic) variants in 13/112 patients (12%) in the genes DEPDC5, NPRL3, GABRG2, SCN1A, PCDH19 and STX1B. Two pathogenic variants were microdeletions involving NPRL3 and PCDH19. Nine of the 13 diagnostic variants (69%) were found in genes of the GATOR1 complex, a potentially druggable target involved in the mammalian target of rapamycin (mTOR) signalling pathway. In addition, 17 VUSs in focal epilepsy genes and 6 rare variants in candidate genes (MTOR, KCNA2, RBFOX1 and SCN3A) were detected. Five patients with reported variants had double hits in different genes, suggesting a possible (oligogenic) role of multiple rare variants. Conclusion This study underscores the molecular heterogeneity of NAFE with GATOR1 complex genes representing the by far most relevant genetic aetiology known to date. Although the diagnostic yield is lower compared with severe early-onset epilepsies, the high rate of VUSs and candidate variants suggests a further increase in future years. [ABSTRACT FROM AUTHOR]

Epilepsy is a disease characterized by abnormal brain activity and a predisposition to generate epileptic seizures, leading to neurobiological, cognitive, psychological, social, and economic impacts for the patient. There are several known causes for epilepsy; one of them is the malfunction of ion channels, resulting from mutations. Voltage-gated sodium channels (NaV) play an essential role in the generation and propagation of action potential, and malfunction caused by mutations can induce irregular neuronal activity. That said, several genetic variations in NaV channels have been described and associated with epilepsy. These mutations can affect channel kinetics, modifying channel activation, inactivation, recovery from inactivation, and/or the current window. Among the NaV subtypes related to epilepsy, NaV1.1 is doubtless the most relevant, with more than 1500 mutations described. Truncation and missense mutations are the most observed alterations. In addition, several studies have already related mutated NaV channels with the electrophysiological functioning of the channel, aiming to correlate with the epilepsy phenotype. The present review provides an overview of studies on epilepsy-associated mutated human NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7. [ABSTRACT FROM AUTHOR]

Background: Cognitive impairments in temporal lobe epilepsy (TLE) patients has been described as a chronically progressive feature of the disease. However, how severe recurrent seizures modify neuronal circuits in the human brain and subsequently degrade cognitive function, remains largely unknown. Here, we aimed to investigate longitudinal alterations by functional magnetic resonance imaging (fMRI) in TLE patients and to assess how those alterations are related to cognitive function performance. Methods: Sixteen TLE patients and 20 normal controls (NCs) were recruited for a study to observe longitudinal alterations in resting-state functional connectivity (FC) and to estimate alertness, orientation, and executive function both at baseline and at a follow-up time ~3 years later. Results: TLE patients, compared with NCs, showed impaired executive function, intrinsic alertness, and phasic alertness and exhibited lengthened reaction time (RT) in the spatial cue and center cue conditions at baseline. The orienting function of TLE patients was declined at follow-up compared to the baseline. Cross-sectional analysis demonstrated that TLE patients displayed significantly greater positive correlation than NCs between the right dorsolateral prefrontal cortex (DLPFC) and the right inferior parietal lobule (IPL) and right superior frontal gyrus (SFG). Furthermore, among TLE patients, the longitudinal study revealed a decrease in correlation between the right DLPFC and the right SFG compared to the baseline. In addition, there was a significant negative correlation between the longitudinal change in FC and the change in orienting function in TLE subjects. Conclusions: Abnormal connectivity between the DLPFC and the SFG suggests the potential of longitudinal resting-state fMRI to delineate regions relevant to cognitive dysfunction for disease progression. [ABSTRACT FROM AUTHOR]

Background: To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A‐related developmental epileptic encephalopathy (DEE). Methods: We enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole‐cell patch‐clamp recording. Results: The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast‐inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature. Conclusion: These findings provided the insights into the phenotype–genotype–funotype relationships of SCN2A‐related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the cyclin‐dependent kinase‐like 5 (CDKL5) gene cause the neurodevelopmental disorder, the CDKL5 deficiency disorder. Reports of individuals with pathogenic variants in CDKL5 without seizures are exceedingly rare, and in‐depth analyses of their variants have been lacking. Whole‐genome sequencing was performed on a 29‐year‐old female with mild intellectual disability who, in the absence of overt seizures, presented with multiple episodes of altered mental status over a 24‐year period. Clinical history was supplemented by a parent completed questionnaire from the International CDKL5 Disorder Database. We identified a de novo heterozygous variant in CDKL5 (NM_003159.2:c.645T>A;p.Ser215Arg). In‐depth computational analysis performed to predict the impact of the variant on protein structure and function demonstrated that the variant was likely pathogenic. In this light, cell‐based studies showed that the S215R substitution causes a marked reduction in CDKL5 kinase activity. Similarities between our case and one previously reported case are striking. These cases, both without seizures but with apparent behavioral symptomatology, together question whether seizures are mandatory in this neurodevelopmental disorder. [ABSTRACT FROM AUTHOR]

A hallmark feature of Alzheimer's disease (AD) and other Tauopathies, like Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17), is the accumulation of neurofibrillary tangles composed of the microtubule-associated protein Tau. As in AD, symptoms of FTDP-17 include cognitive decline, neuronal degeneration, and disruptions of sleep patterns. However, mechanisms by which Tau may lead to these disturbances in sleep and activity patterns are unknown. To identify such mechanisms, we have generated novel Drosophila Tauopathy models by replacing endogenous fly dTau with normal human Tau (hTau) or the FTDP-17 causing hTauV337M mutation. This mutation is localized in one of the microtubule-binding domains of hTau and has a dominant effect. Analyzing heterozygous flies, we found that aged hTauV337M flies show neuronal degeneration and locomotion deficits when compared to wild type or hTauWT flies. Furthermore, hTauV337M flies are hyperactive and they show a fragmented sleep pattern. These changes in the sleep/activity pattern are accompanied by morphological changes in the projection pattern of the central pacemaker neurons. These neurons show daily fluctuations in their connectivity, whereby synapses are increased during the day and reduced during sleep. Synapse formation requires cytoskeletal changes that can be detected by the accumulation of the end-binding protein 1 (EB1) at the site of synapse formation. Whereas, hTauWT flies show the normal day/night changes in EB1 accumulation, hTauV337M flies do not show this fluctuation. This suggests that hTauV337M disrupts sleep patterns by interfering with the cytoskeletal changes that are required for the synaptic homeostasis of central pacemaker neurons. [ABSTRACT FROM AUTHOR]

Wrist actigraphy has been used to assess sleep in older adult populations for nearly half a century. Over the years, the continuous raw activity data derived from actigraphy has been used for the characterization of factors beyond sleep/wake such as physical activity patterns and circadian rhythms. Behavioral activity rhythms (BAR) are useful to describe individual daily behavioral patterns beyond sleep and wake, which represent important and meaningful clinical outcomes. This paper reviews common rhythmometric approaches and summarizes the available data from the use of these different approaches in older adult populations. We further consider a new approach developed in our laboratory designed to provide graphical characterization of BAR for the observed behavioral phenomenon of activity patterns across time. We illustrate the application of this new approach using actigraphy data collected from a well-characterized sample of older adults (age 60+) with osteoarthritis (OA) pain and insomnia. Generalized additive models (GAM) were implemented to fit smoothed nonlinear curves to log-transformed aggregated actigraphy-derived activity measurements. This approach demonstrated an overall strong model fit (R2 = 0.82, SD = 0.09) and was able to provide meaningful outcome measures allowing for graphical and parameterized characterization of the observed activity patterns within this sample. [ABSTRACT FROM AUTHOR]

Circadian rhythm disorders have been classically associated with disorders of abnormal timing of the sleep–wake cycle, however circadian dysfunction can play a role in a wide range of pathology, ranging from the increased risk for cardiometabolic disease and malignancy in shift workers, prompting the need for a new field focused on the larger concept of circadian medicine. The relationship between circadian disruption and human health is bidirectional, with changes in circadian amplitude often preceding the classical symptoms of neurodegenerative disorders. As our understanding of the importance of circadian dysfunction in disease grows, we need to develop better clinical techniques for identifying circadian rhythms and also develop circadian based strategies for disease management. Overall this review highlights the need to bring the concept of time to all aspects of medicine, emphasizing circadian medicine as a prime example of both personalized and precision medicine. [ABSTRACT FROM AUTHOR]

The circadian system regulates physiology and behavior. Acute challenges to the system, such as those experienced when traveling across time zones, will eventually result in re‐synchronization to local environmental time cues, but this re‐synchronization is oftentimes accompanied by adverse short‐term consequences. When such challenges are experienced chronically, adaptation may not be achieved, as for example in the case of rotating night shift workers. The transient and chronic disturbance of the circadian system is most frequently referred to as "circadian disruption", but many other terms have been proposed and used to refer to similar situations. It is now beyond doubt that the circadian system contributes to health and disease, emphasizing the need for clear terminology when describing challenges to the circadian system and their consequences. The goal of this review is to provide an overview of the terms used to describe disruption of the circadian system, discuss proposed quantifications of disruption in experimental and observational settings with a focus on human research, and highlight limitations and challenges of currently available tools. For circadian research to advance as a translational science, clear, operationalizable, and scalable quantifications of circadian disruption are key, as they will enable improved assessment and reproducibility of results, ideally ranging from mechanistic settings, including animal research, to large‐scale randomized clinical trials. [ABSTRACT FROM AUTHOR]