Impaired sleep-dependent memory consolidation predicted by reduced sleep spindles in Rolandic epilepsy.

Background and Objectives: Sleep spindles are prominent thalamocortical brain oscillations during sleep that have been mechanistically linked to sleep-dependent memory consolidation in animal models and healthy controls. Sleep spindles are decreased in Rolandic epilepsy and related sleep-activated epileptic encephalopathies. We investigate the relationship between sleep spindle deficits and deficient sleep dependent memory consolidation in children with Rolandic epilepsy. Methods: In this prospective case-control study, children were trained and tested on a validated probe of memory consolidation, the motor sequence task (MST). Sleep spindles were measured from high-density EEG during a 90-minute nap opportunity between MST training and testing using a validated automated detector. Results: Twenty-three children with Rolandic epilepsy (14 with resolved disease), and 19 age- and sex-matched controls were enrolled. Children with active Rolandic epilepsy had decreased memory consolidation compared to control children (p=0.001, mean percentage reduction: 25.7%, 95% CI [10.3, 41.2]%) and compared to children with resolved Rolandic epilepsy (p=0.007, mean percentage reduction: 21.9%, 95% CI [6.2, 37.6]%). Children with active Rolandic epilepsy had decreased sleep spindle rates in the centrotemporal region compared to controls (p=0.008, mean decrease 2.5 spindles/min, 95% CI [0.7, 4.4] spindles/min). Spindle rate positively predicted sleep-dependent memory consolidation (p=0.004, mean MST improvement of 3.9%, 95% CI [1.3, 6.4]%, for each unit increase in spindles per minute). Discussion: Children with Rolandic epilepsy have a sleep spindle deficit during the active period of disease which predicts deficits in sleep dependent memory consolidation. This finding provides a mechanism and noninvasive biomarker to aid diagnosis and therapeutic discovery for cognitive dysfunction in Rolandic epilepsy and related sleep activated epilepsy syndromes.

Assessing quadriceps strength in patellofemoral pain patients: A study on the reliability and validity of a low-cost strain-gauge for clinical practice.

BACKGROUND: Patellofemoral pain (PFP) is a common knee complaint affecting diverse populations both acutely and chronically. Quadriceps muscle weakness is one possible aetiology, but current devices for measuring muscle strength (isokinetic dynamometer [ID] and hand-held dynamometers [HHD]) are frequently too expensive (e.g., ID) or lack reliability (e.g., HHD) for practitioners, especially in under-resourced settings. There is a need to evaluate a low-cost device to manage rehabilitation of people with PFP. METHODS: Isometric quadriceps strength of participants aged 18-35 years (total [n = 33], control group [n = 17] and PFP group [n = 16]) were evaluated on an isokinetic dynamometer and a commercially available strain gauge at baseline and after an 8-week non-standardised intervention. RESULTS: The strain gauge showed high absolute and relative reliability (intraclass correlation coefficient = 0.89-0.99; typical error of measurement = 3.9-10.4%). Clinically meaningful difference scores (12.2-45 Nm) were greater than the typical error of measurement, implying sufficient sensitivity of the strain gauge to measure true changes in isometric quadricep strength. Strong to very strong correlations were evident between the strain gauge and isokinetic dynamometer torque measurements (r = 0.88-0.90, SEE = 0.05-0.07 Nm), but slope values (ß = 0.65-0.77) indicated that torque from the strain gauge was lower than that obtained from the isokinetic dynamometer. An average systematic bias of 16.3-28.8 Nm was evident in favour of the isokinetic dynamometer, with no statistically significant between-group differences apparent between baseline and follow-up testing. CONCLUSION: The present commercially available strain gauge is reliable and sensitive enough to detect clinically meaningful differences in quadriceps strength of both healthy individuals and those with PFP. However, the strain gauge lacks validity and therefore cannot replace isokinetic dynamometry. Given the low cost and excellent reliability, the strain gauge can be a valuable tool to assess quadriceps muscle deficits and track rehabilitation progress in people with PFP.

Thalamic epileptic spikes disrupt sleep spindles in patients with epileptic encephalopathy.

In severe epileptic encephalopathies, epileptic activity contributes to progressive cognitive dysfunction. Epileptic encephalopathies share the trait of spike-wave activation during non-rapid eye movement sleep (EE-SWAS), a sleep stage dominated by sleep spindles, brain oscillations known to coordinate offline memory consolidation. Epileptic activity has been proposed to hijack the circuits driving these thalamocortical oscillations, thereby contributing to cognitive impairment. Using a unique dataset of simultaneous human thalamic and cortical recordings in subjects with and without EE-SWAS, we provide evidence for epileptic spike interference of thalamic sleep spindle production in patients with EE-SWAS. First, we show that epileptic spikes and sleep spindles are both predicted by slow oscillations during stage two sleep (N2), but at different phases of the slow oscillation. Next, we demonstrate that sleep activated cortical epileptic spikes propagate to the thalamus (thalamic spike rate increases after a cortical spike, p≈0). We then show that epileptic spikes in the thalamus increase the thalamic spindle refractory period (p≈0). Finally, we show that in three patients with EE-SWAS, there is a downregulation of sleep spindles for 30 seconds after each thalamic spike (p<0.01). These direct human thalamocortical observations support a proposed mechanism for epileptiform activity to impact cognitive function, wherein epileptic spikes inhibit thalamic sleep spindles in epileptic encephalopathy with spike and wave activation during sleep.

Normative Standards for Isokinetic and Anthropometric Classifications of University-Level Netball Players.

CONTEXT: The purpose of the study was to develop normative ranges and standards for knee and shoulder isokinetic and anthropometric values. These standards can be qualitatively interpreted and allow practitioners to classify isokinetic and anthropometric values more objectively for university-level netball players. DESIGN: Posttest only observational study design. All players were only evaluated once during the in-season to generate normative ranges. METHODS: A total of 51 female players volunteered. Participants were evaluated on an isokinetic dynamometer at 60° per second to obtain knee-extensor and knee-flexor values as well as shoulder-flexor and shoulder-extensor values. A total of 16 anthropometric variables were collected including stature, body mass, 8 skinfolds, and 6 circumferences. Between-group differences were calculated to determine whether playing level was a differentiating factor in data. RESULTS: Normative standards were developed for isokinetic parameters associated with the knee and shoulder joints as well as skinfolds and circumference measures. No statistically significant between-group differences were evident (χ2Kruskal-Wallis[2] = 3.96, P = .140). CONCLUSION: These standards can be used by coaches and practitioners to set attainable goals for individual players or those from secondary leagues, classify individual and team-based performances, and facilitate decision-making processes.

Photothrombosis induced cortical stroke produces electrographic epileptic biomarkers in mice.

Objective: Interictal epileptiform spikes, high-frequency ripple oscillations, and their co-occurrence (spike ripples) in human scalp or intracranial voltage recordings are well-established epileptic biomarkers. While clinically significant, the neural mechanisms generating these electrographic biomarkers remain unclear. To reduce this knowledge gap, we introduce a novel photothrombotic stroke model in mice that reproduces focal interictal electrographic biomarkers observed in human epilepsy. Methods: We induced a stroke in the motor cortex of C57BL/6 mice unilaterally (N=7) using a photothrombotic procedure previously established in rats. We then implanted intracranial electrodes (2 ipsilateral and 2 contralateral) and obtained intermittent local field potential (LFP) recordings over several weeks in awake, behaving mice. We evaluated the LFP for focal slowing and epileptic biomarkers - spikes, ripples, and spike ripples - using both automated and semi-automated procedures. Results: Delta power (1-4 Hz) was higher in the stroke hemisphere than the non-stroke hemisphere in all mice ( p <0.001). Automated detection procedures indicated that compared to the non-stroke hemisphere, the stroke hemisphere had an increased spike ripple ( p =0.006) and spike rates ( p =0.039), but no change in ripple rate ( p =0.98). Expert validation confirmed the observation of elevated spike ripple rates ( p =0.008) and a trend of elevated spike rate ( p =0.055) in the stroke hemisphere. Interestingly, the validated ripple rate in the stroke hemisphere was higher than the non-stroke hemisphere ( p =0.031), highlighting the difficulty of automatically detecting ripples. Finally, using optimal performance thresholds, automatically detected spike ripples classified the stroke hemisphere with the best accuracy (sensitivity 0.94, specificity 0.94). Significance: Cortical photothrombosis-induced stroke in commonly used C57BL/6 mice produces electrographic biomarkers as observed in human epilepsy. This model represents a new translational cortical epilepsy model with a defined irritative zone, which can be broadly applied in transgenic mice for cell type specific analysis of the cellular and circuit mechanisms of pathologic interictal activity. Key Points: Cortical photothrombosis in mice produces stroke with characteristic intermittent focal delta slowing.Cortical photothrombosis stroke in mice produces the epileptic biomarkers spikes, ripples, and spike ripples.All biomarkers share morphological features with the corresponding human correlate.Spike ripples better lateralize to the lesional cortex than spikes or ripples.This cortical model can be applied in transgenic mice for mechanistic studies.

Spike ripples localize the epileptogenic zone best: an international intracranial study.

We evaluated whether spike ripples, the combination of epileptiform spikes and ripples, provide a reliable and improved biomarker for the epileptogenic zone (EZ) compared to other leading interictal biomarkers in a multicenter, international study. We first validated an automated spike ripple detector on intracranial EEG recordings. We then applied this detector to subjects from four centers who subsequently underwent surgical resection with known 1-year outcomes. We evaluated the spike ripple rate in subjects cured after resection (ILAE 1 outcome) and those with persistent seizures (ILAE 2-6) across sites and recording types. We also evaluated available interictal biomarkers: spike, spike-gamma, wideband high frequency oscillation (HFO, 80-500 Hz), ripple (80-250 Hz), and fast ripple (250-500 Hz) rates using previously validated automated detectors. The proportion of resected events was computed and compared across subject outcomes and biomarkers. 109 subjects were included. Most spike ripples were removed in subjects with ILAE 1 outcome (P < 0.001), and this was qualitatively observed across all sites and for depth and subdural electrodes (P < 0.001, P < 0.001). Among ILAE 1 subjects, the mean spike ripple rate was higher in the RV (0.66/min) than in the non-removed tissue (0.08/min, P < 0.001). A higher proportion of spike ripples were removed in subjects with ILAE 1 outcomes compared to ILAE 2-6 outcomes (P = 0.06). Among ILAE 1 subjects, the proportion of spike ripples removed was higher than the proportion of spikes (P < 0.001), spike-gamma (P < 0.001), wideband HFOs (P < 0.001), ripples (P = 0.009) and fast ripples (P = 0.009) removed. At the individual level, more subjects with ILAE 1 outcomes had the majority of spike ripples removed (79%, 38/48) than spikes (69%, P = 0.12), spike-gamma (69%, P = 0.12), wideband HFOs (63%, P = 0.03), ripples (45%, P = 0.01), or fast ripples (36%, P < 0.001) removed. Thus, in this large, multicenter cohort, when surgical resection was successful, the majority of spike ripples were removed. Further, automatically detected spike ripples have improved specificity for epileptogenic tissue compared to spikes, spike-gamma, wideband HFOs, ripples, and fast ripples.

Non-Negative Matrix Factorization for Analyzing State Dependent Neuronal Network Dynamics in Calcium Recordings.

Calcium imaging allows recording from hundreds of neurons in vivo with the ability to resolve single cell activity. Evaluating and analyzing neuronal responses, while also considering all dimensions of the data set to make specific conclusions, is extremely difficult. Often, descriptive statistics are used to analyze these forms of data. These analyses, however, remove variance by averaging the responses of single neurons across recording sessions, or across combinations of neurons, to create single quantitative metrics, losing the temporal dynamics of neuronal activity, and their responses relative to each other. Dimensionally Reduction (DR) methods serve as a good foundation for these analyses because they reduce the dimensions of the data into components, while still maintaining the variance. Non-negative Matrix Factorization (NMF) is an especially promising DR analysis method for analyzing activity recorded in calcium imaging because of its mathematical constraints, which include positivity and linearity. We adapt NMF for our analyses and compare its performance to alternative dimensionality reduction methods on both artificial and in vivo data. We find that NMF is well-suited for analyzing calcium imaging recordings, accurately capturing the underlying dynamics of the data, and outperforming alternative methods in common use.

Potency of quality indicators in Dutch and international diabetes registries.

BACKGROUND: Diabetes mellitus forms a slow pandemic. Cardiovascular risk and quality of diabetes care are strongly associated. Quality indicators improve diabetes management and reduce mortality and costs. Various national diabetes registries render national quality indicators. We describe diabetes care indicators for Dutch children and adults with diabetes, and compare them with indicators established by registries worldwide. METHODS: Indicator scores were derived from the Dutch Pediatric and Adult Registry of Diabetes Indicator sets of other national diabetes registries were collected and juxtaposed with global and continental initiatives for indicator sets. RESULTS: This observational cohort study included 3738 patients representative of the Dutch diabetic outpatient population. The Dutch Pediatric and Adult Registry of Diabetes harbors ten quality indicators comprising treatment volumes, HbA1c control, foot examination, insulin pump therapy, and real-time continuous glucose monitoring. Worldwide, nine national registries record quality indicators, with great variety between registries. HbA1c control is recorded most frequently, and no indicator is reported among all registries. CONCLUSIONS: Wide variety among quality indicators recorded by national diabetes registries hinders international comparison and interpretation of quality of diabetes care. The potential of quality evaluation will be greatly enhanced when diabetes care indicators are aligned in an international standard set with variation across countries taken into consideration.

The autism spectrum disorder risk gene NEXMIF over-synchronizes hippocampal CA1 network and alters neuronal coding.

Mutations in autism spectrum disorder (ASD) risk genes disrupt neural network dynamics that ultimately lead to abnormal behavior. To understand how ASD-risk genes influence neural circuit computation during behavior, we analyzed the hippocampal network by performing large-scale cellular calcium imaging from hundreds of individual CA1 neurons simultaneously in transgenic mice with total knockout of the X-linked ASD-risk gene NEXMIF (neurite extension and migration factor). As NEXMIF knockout in mice led to profound learning and memory deficits, we examined the CA1 network during voluntary locomotion, a fundamental component of spatial memory. We found that NEXMIF knockout does not alter the overall excitability of individual neurons but exaggerates movement-related neuronal responses. To quantify network functional connectivity changes, we applied closeness centrality analysis from graph theory to our large-scale calcium imaging datasets, in addition to using the conventional pairwise correlation analysis. Closeness centrality analysis considers both the number of connections and the connection strength between neurons within a network. We found that in wild-type mice the CA1 network desynchronizes during locomotion, consistent with increased network information coding during active behavior. Upon NEXMIF knockout, CA1 network is over-synchronized regardless of behavioral state and fails to desynchronize during locomotion, highlighting how perturbations in ASD-implicated genes create abnormal network synchronization that could contribute to ASD-related behaviors.

Different Methods to Estimate the Phase of Neural Rhythms Agree But Only During Times of Low Uncertainty.

Rhythms are a common feature of brain activity. Across different types of rhythms, the phase has been proposed to have functional consequences, thus requiring its accurate specification from noisy data. Phase is conventionally specified using techniques that presume a frequency band-limited rhythm. However, in practice, observed brain rhythms are typically nonsinusoidal and amplitude modulated. How these features impact methods to estimate phase remains unclear. To address this, we consider three phase estimation methods, each with different underlying assumptions about the rhythm. We apply these methods to rhythms simulated with different generative mechanisms and demonstrate inconsistency in phase estimates across the different methods. We propose two improvements to the practice of phase estimation: (1) estimating confidence in the phase estimate, and (2) examining the consistency of phase estimates between two (or more) methods.

Effects of COVID-19 on diabetes care among dutch diabetes outpatients.

AIMS: The COVID-19 pandemic impacted diabetes care by reducing diabetes outpatient visits and diabetes-related screening due to allocation of healthcare resources. Yet the impact of COVID-19 on diabetes outpatients has not been extensively evaluated. This study aimed to assess the effect of the COVID-19 pandemic on diagnostics and intermediate outcomes of outpatient diabetes care pre- and during COVID. METHODS: This observational cohort study included 8,442 diabetes patients in the Dutch Pediatric and Adult Registry of Diabetes (DPARD) visiting diabetes outpatient clinics in 2019 and 2021. A mixed-effects regression analysis was used to examine differences in target achievement of HbA1c, BMI, blood pressure, LDL-cholesterol, eGFR, and the difference in mean HbA1c between 2019 and 2020 among n = 1,426 outpatients who visited in both years. Analyses were adjusted for age, sex, and BMI. RESULTS: A 22.7% (21.6-23.8%, p < 0.001) decline in outpatient volume was observed during the pandemic (2020). BMI, lipid spectrum, kidney function, and HbA1c were assessed less frequently in 2020 than in 2019. In 2020, compared to 2019, the median HbA1c level increased by 2.2% (1.0 mmol/mol, p = 0.035) and the percentages of patients with known HbA1C meeting targets below 10, 8, 7% (86, 64, and 53 mmol/mol) decreased by 0.5%, 1.7% and 1.4%, respectively. Target blood pressure ≤ 130/80 mmHg was achieved more often in 2020 (15.0% versus 18.3%, p = 0.018), while HbA1c ≤ 86 mmol/mol was achieved less (89.3% versus 87.1%, p = 0.001), among diabetes outpatients seen in both 2019 and 2020. In patients visiting both years, HbA1c was 2.3% (1.9 mmol/l, 95% CI 1.2-2.5, p < 0.001) lower during the pandemic than in the prepandemic (2019). CONCLUSIONS: The COVID pandemic was associated with a marked reduction in patient volume in diabetes outpatient care among five hospitals. Among patients who received outpatient care both before and during the pandemic period, HbA1c control and blood pressure control enhanced during the pandemic. Re-evaluation of current diabetes outpatient care organization is warranted to ensure optimal diabetes care in future times.

The Acute Effects of Schoolbag Loading on Posture and Gait Mechanics in 10- to 13-Year-Old Children: A Cohort from the North West Province.

Most schoolchildren carry schoolbags, of which a substantial proportion carry loads that exceed 15% of their body mass. Although the effects of loading have been investigated to varying degrees, the status of schoolbag loading and the acute affects thereof on gait and posture have not been thoroughly investigated within the South African context. A total of 60 participants in the 10-13-year age range volunteered for the present study. Significant differences were evident for relative load carriage (χ2(3) = 14.54, p < 0.001), forefoot and heel forces (Mdiff = 17.05-34.86 N, p < 0.001), force ratios (Mdiff = 0.02, p = 0.029), and gait speed (Mdiff = -0.18 km/hr, p = 0.016), but not for any postural angles (Mdiff = -3.37-6.08 deg, all p > 0.052). Those who exceeded 15% BM were ~9 times more likely to report pain than those below 15% BM. The children in the current study carried significantly heavier relative loads (p < 0.001) compared to similarly aged children from other countries. Loading leads to acute changes in posture and gait that are likely not meaningful. However, excessive loading (>15% BM) leads to significantly higher perceptions and reporting of pain in 10-13-year-old children.

Different methods to estimate the phase of neural rhythms agree, but only during times of low uncertainty.

Rhythms are a common feature of brain activity. Across different types of rhythms, the phase has been proposed to have functional consequences, thus requiring its accurate specification from noisy data. Phase is conventionally specified using techniques that presume a frequency band-limited rhythm. However, in practice, observed brain rhythms are typically non-sinusoidal and amplitude modulated. How these features impact methods to estimate phase remains unclear. To address this, we consider three phase estimation methods, each with different underlying assumptions about the rhythm. We apply these methods to rhythms simulated with different generative mechanisms and demonstrate inconsistency in phase estimates across the different methods. We propose two improvements to the practice of phase estimation: (1) estimating confidence in the phase estimate, and (2) examining the consistency of phase estimates between two (or more) methods.

In-Season Resisted-Jump Training Enables Power, Agility, and Jump-Ability Maintenance in University-Level Male Rugby Players.

PURPOSE: To determine the effects and transferability of a resisted-jump training program on strength, speed, power, and agility maintenance during the in-season phase of rugby training. METHODS: Thirty high-level male rugby players (age: 21.78 [1.86] y; height: 1.83 [0.10] m; mass: 95.17 [10.45] kg) participated in a crossover, within-subject study design. Participants were randomly assigned to treatment groups (resistance band [VertiMax, VM] or control [Con]) and evaluated on jumping, sprinting, agility, and strength over a 4-week period. A 10-week wash-out period was initiated, followed by a crossover that incorporated randomization of the treatment sequence (ie, receiving VM during the first or second phase of the testing period). Within- and between-groups differences for each variable of interest were evaluated using a linear mixed-effects model. RESULTS: No significant treatment (VM vs Con) or time (pre vs postintervention) effects were evident across all variables (all P > .197), although the order or treatment allocation may play a role for strength (P = .037) and jumping (P = .003). Power, agility, and countermovement-jump height were statistically equivalent for the intervention period. Following the VM treatment, changes in strength seem to transfer favorably to changes in agility (r = -.54, P < .05) but no other variables, and no significant associations were evident for the Con treatment. CONCLUSION: Regardless of treatment, power, agility, and jump height were conserved throughout the treatment period. Although changes in mean sprint and strength were not significantly different from zero, it was not possible to conclude whether performance decrements could be eliminated.

Decreased thalamocortical connectivity in resolved Rolandic epilepsy.

OBJECTIVE: Median nerve somatosensory evoked fields (SEFs) conduction times reflect the integrity of neural transmission across the thalamocortical circuit. We hypothesized median nerve SEF conduction time would be abnormal in children with Rolandic epilepsy (RE). METHODS: 22 children with RE (10 active; 12 resolved) and 13 age-matched controls underwent structural and diffusion MRI and median nerve and visual stimulation during magnetoencephalography (MEG). N20 SEF responses were identified in contralateral somatosensory cortices. P100 were identified in contralateral occipital cortices as controls. Conduction times were compared between groups in linear models controlling for height. N20 conduction time was also compared to thalamic volume and Rolandic thalamocortical structural connectivity inferred using probabilistic tractography. RESULTS: The RE group had slower N20 conduction compared to controls (p = 0.042, effect size 0.6 ms) and this difference was driven by the resolved RE group (p = 0.046). There was no difference in P100 conduction time between groups (p = 0.83). Ventral thalamic volume positively correlated with N20 conduction time (p = 0.014). CONCLUSIONS: Children with resolved RE have focally decreased Rolandic thalamocortical connectivity. SIGNIFICANCE: These results identify a persistent focal thalamocortical circuit abnormality in resolved RE and suggest that decreased Rolandic thalamocortical connectivity may support symptom resolution in this self-limited epilepsy.

Distinguishing between different percolation regimes in noisy dynamic networks with an application to epileptic seizures.

In clinical neuroscience, epileptic seizures have been associated with the sudden emergence of coupled activity across the brain. The resulting functional networks-in which edges indicate strong enough coupling between brain regions-are consistent with the notion of percolation, which is a phenomenon in complex networks corresponding to the sudden emergence of a giant connected component. Traditionally, work has concentrated on noise-free percolation with a monotonic process of network growth, but real-world networks are more complex. We develop a class of random graph hidden Markov models (RG-HMMs) for characterizing percolation regimes in noisy, dynamically evolving networks in the presence of edge birth and edge death. This class is used to understand the type of phase transitions undergone in a seizure, and in particular, distinguishing between different percolation regimes in epileptic seizures. We develop a hypothesis testing framework for inferring putative percolation mechanisms. As a necessary precursor, we present an EM algorithm for estimating parameters from a sequence of noisy networks only observed at a longitudinal subsampling of time points. Our results suggest that different types of percolation can occur in human seizures. The type inferred may suggest tailored treatment strategies and provide new insights into the fundamental science of epilepsy.

Preliminary evidence of a relationship between sleep spindles and treatment response in epileptic encephalopathy.

OBJECTIVE: Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) is a challenging neurodevelopmental disease characterized by abundant epileptiform spikes during non-rapid eye movement (NREM) sleep accompanied by cognitive dysfunction. The mechanism of cognitive dysfunction is unknown, but treatment with high-dose diazepam may improve symptoms. Spike rate does not predict treatment response, but spikes may disrupt sleep spindles. We hypothesized that in patients with EE-SWAS: (1) spikes and spindles would be anti-correlated, (2) high-dose diazepam would increase spindles and decrease spikes, and (3) spindle response would be greater in those with cognitive improvement. METHODS: Consecutive EE-SWAS patients treated with high-dose diazepam that met the criteria were included. Using a validated automated spindle detector, spindle rate, duration, and percentage were computed in pre- and post-treatment NREM sleep. Spikes were quantified using a validated automated spike detector. The cognitive response was determined from a chart review. RESULTS: Spindle rate was anti-correlated with the spike rate in the channel with the maximal spike rate (p = 0.002) and averaged across all channels (p = 0.0005). Spindle rate, duration, and percentage each increased, and spike rate decreased, after high-dose diazepam treatment (p ≤ 2e-5, all tests). Spindle rate, duration, and percentage (p ≤ 0.004, all tests) were increased in patients with cognitive improvement after treatment, but not those without. Changes in spindle rate but not changes in spike rate distinguished between groups. INTERPRETATION: These findings confirm thalamocortical disruption in EE-SWAS, identify a mechanism through which benzodiazepines may support cognitive recovery, and introduce sleep spindles as a promising mechanistic biomarker to detect treatment response in severe epileptic encephalopathies.

Preliminary evidence of a relationship between sleep spindles and treatment response in epileptic encephalopathy.

Objective: Epileptic encephalopathy with spike wave activation in sleep (EE-SWAS) is a challenging neurodevelopmental disease characterized by abundant epileptiform spikes during non-rapid eye movement (NREM) sleep accompanied by cognitive dysfunction. The mechanism of cognitive dysfunction is unknown, but treatment with high-dose diazepam may improve symptoms. Spike rate does not predict treatment response, but spikes may disrupt sleep spindles. We hypothesized that in patients with EE-SWAS: 1) spikes and spindles would be anticorrelated, 2) high-dose diazepam would increase spindles and decrease spikes, and 3) spindle response would be greater in those with cognitive improvement. Methods: Consecutive EE-SWAS patients treated with high-dose diazepam that met criteria were included. Using a validated automated spindle detector, spindle rate, duration, and percentage were computed in pre- and post-treatment NREM sleep. Spikes were quantified using a validated automated spike detector. Cognitive response was determined from chart review. Results: Spindle rate was anticorrelated with spike rate in the channel with the maximal spike rate ( p =0.002) and averaged across all channels ( p =0.0005). Spindle rate, duration, and percentage each increased, and spike rate decreased, after high-dose diazepam treatment ( p≤ 2e-5, all tests). Spindle rate, duration, and percentage ( p ≤0.004, all tests) were increased in patients with cognitive improvement after treatment, but not those without. Changes in spike rate did not distinguish between groups. Interpretation: These findings confirm thalamocortical disruption in EE-SWAS, identify a mechanism through which benzodiazepines may support cognitive recovery, and introduce sleep spindles as a promising mechanistic biomarker to detect treatment response in severe epileptic encephalopathies.

The 1/f-like behavior of neural field spectra are a natural consequence of noise driven brain dynamics.

Consistent observations across recording modalities, experiments, and neural systems find neural field spectra with 1/f-like scaling, eliciting many alternative theories to explain this universal phenomenon. We show that a general dynamical system with stochastic drive and minimal assumptions generates 1/f-like spectra consistent with the range of values observed in vivo, without requiring a specific biological mechanism or collective critical behavior.