Intracerebral Dynamics of Sleep Arousals: A Combined Scalp-Intracranial EEG Study.

As an intrinsic component of sleep architecture, sleep arousals represent an intermediate state between sleep and wakefulness and are important for sleep-wake regulation. They are defined in an all-or-none manner, whereas they actually present a wide range of scalp-electroencephalography (EEG) activity patterns. It is poorly understood how these arousals differ in their mechanisms. Stereo-EEG (SEEG) provides the unique opportunity to record intracranial activities in superficial and deep structures in humans. Using combined polysomnography and SEEG, we quantitatively categorized arousals during nonrapid eye movement sleep into slow wave (SW) and non-SW arousals based on whether they co-occurred with a scalp-EEG SW event. We then investigated their intracranial correlates in up to 26 brain regions from 26 patients (12 females). Across both arousal types, intracranial theta, alpha, sigma, and beta activities increased in up to 25 regions (p < 0.05; d = 0.06-0.63), while gamma and high-frequency (HF) activities decreased in up to 18 regions across the five brain lobes (p < 0.05; d = 0.06-0.44). Intracranial delta power widely increased across five lobes during SW arousals (p < 0.05 in 22 regions; d = 0.10-0.39), while it widely decreased during non-SW arousals (p < 0.05 in 19 regions; d = 0.10-0.30). Despite these main patterns, unique activities were observed locally in some regions such as the hippocampus and middle cingulate cortex, indicating spatial heterogeneity of arousal responses. Our results suggest that non-SW arousals correspond to a higher level of brain activation than SW arousals. The decrease in HF activities could potentially explain the absence of awareness and recollection during arousals.

Maternal B cell signaling orchestrates fetal development in mice.

B cell participation in early embryo/fetal development and the underlying molecular pathways have not been explored. To understand whether maternal B cell absence or impaired signaling interferes with placental and fetal growth, we paired CD19-deficient (CD19-/-) mice, females with B cell-specific MyD88 (BMyD88-/-) or IL10 (BIL10-/-) deficiency as well as wild-type and MyD88-/- controls on C57Bl/6 background with BALB/c males. Pregnancies were followed by ultrasound and Doppler measurements. Implantation number was reduced in BMyD88-/- and MyD88-/- mice. Loss of MyD88 or B cell-specific deletion of MyD88 or IL10 resulted in decreased implantation areas at gestational day (gd) 5, gd8 and gd10, accompanied by reduced placental thickness, diameter and areas at gd10. Uterine artery resistance was enhanced in BIL10-/- dams at gd10. Challenge with 0.4 mg lipopolysaccharide/kg bodyweight at gd16 revealed that BMyD88-/-, BIL10-/- and CD19-/- mothers delivered preterm, whereas controls maintained their pregnancy. B cell-specific MyD88 and IL10 expression is essential for appropriate in utero development. IL10+B cells are involved in uterine blood flow regulation during pregnancy. Finally, B cell-specific CD19, MyD88 and IL10 expression influences susceptibility towards preterm birth.

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 compared with other leading interictal biomarkers in a multicentre, international study. We first validated an automated spike ripple detector on intracranial EEG recordings. We then applied this detector to subjects from four centres who subsequently underwent surgical resection with known 1-year outcomes. We evaluated the spike ripple rate in subjects cured after resection [International League Against Epilepsy Class 1 outcome (ILAE 1)] 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. Overall, 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 and P < 0.001, respectively). Among ILAE 1 subjects, the mean spike ripple rate was higher in the resected volume (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 with 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, multicentre cohort, when surgical resection was successful, the majority of spike ripples were removed. Furthermore, automatically detected spike ripples localize the epileptogenic tissue better than spikes, spike-gamma, wideband HFOs, ripples and fast ripples.

High-frequency transcranial alternating current stimulation matching individual frequency of somatosensory evoked high-frequency oscillations can modulate the somatosensory system through thalamocortical pathway.

tACS (transcranial alternating current stimulation) is a technique for modulating brain activity through electrical current. Its effects depend on cortical entrainment, which is most effective when transcranial alternating current stimulation matches the brain's natural rhythm. High-frequency oscillations produced by external stimuli are useful for studying the somatosensory pathway. Our study aims to explore transcranial alternating current stimulation's impact on the somatosensory system when synchronized with individual high-frequency oscillation frequencies. We conducted a randomized, sham-controlled study with 14 healthy participants. The study had three phases: Individualized transcranial alternating current stimulation (matching the individual's high-frequency oscillation rhythm), Standard transcranial alternating current stimulation (600 Hz), and sham stimulation. We measured early and late HFO components after median nerve electrical stimulation at three time points: before (T0), immediately after (T1), and 10 min after transcranial alternating current stimulation (T2). Compared to Sham and Standard stimulation Individualized transcranial alternating current stimulation significantly enhanced high-frequency oscillations, especially the early component, immediately after stimulation and for at least 15 min. No other effects were observed for other high-frequency oscillation measures. In summary, our study provides initial evidence that transcranial alternating current stimulation synchronized with an individual's high-frequency oscillation frequency can precisely and time-specifically modulate thalamocortical activity. These insights may pave the way for innovative, personalized neuromodulation methods for the somatosensory system.

Fully learnable deep wavelet transform for unsupervised monitoring of high-frequency time series.

High-frequency (HF) signals are ubiquitous in the industrial world and are of great use for monitoring of industrial assets. Most deep-learning tools are designed for inputs of fixed and/or very limited size and many successful applications of deep learning to the industrial context use as inputs extracted features, which are a manually and often arduously obtained compact representation of the original signal. In this paper, we propose a fully unsupervised deep-learning framework that is able to extract a meaningful and sparse representation of raw HF signals. We embed in our architecture important properties of the fast discrete wavelet transform (FDWT) such as 1) the cascade algorithm; 2) the conjugate quadrature filter property that links together the wavelet, the scaling, and transposed filter functions; and 3) the coefficient denoising. Using deep learning, we make this architecture fully learnable: Both the wavelet bases and the wavelet coefficient denoising become learnable. To achieve this objective, we propose an activation function that performs a learnable hard thresholding of the wavelet coefficients. With our framework, the denoising FDWT becomes a fully learnable unsupervised tool that does not require any type of pre- or postprocessing or any prior knowledge on wavelet transform. We demonstrate the benefits of embedding all these properties on three machine-learning tasks performed on open-source sound datasets. We perform an ablation study of the impact of each property on the performance of the architecture, achieve results well above baseline, and outperform other state-of-the-art methods.

Genetic Transformation of Plasmid DNA into Escherichia coli Using High Frequency Electromagnetic Energy.

We present a novel technique of genetic transformation of bacterial cells mediated by high frequency electromagnetic energy (HF EME). Plasmid DNA, pGLO (5.4 kb), was successfully transformed into Escherichia coli JM109 cells after exposure to 18 GHz irradiation at a power density between 5.6 and 30 kW m-2 for 180 s at temperatures ranging from 30 to 40 °C. Transformed bacteria were identified by the expression of green fluorescent protein (GFP) using confocal scanning microscopy (CLSM) and flow cytometry (FC). Approximately 90.7% of HF EME treated viable E. coli cells exhibited uptake of the pGLO plasmid. The interaction of plasmid DNA with bacteria leading to transformation was confirmed by using cryogenic transmission electron microscopy (cryo-TEM). HF EME-induced plasmid DNA transformation was shown to be unique, highly efficient, and cost-effective. HF EME-induced genetic transformation is performed under physiologically friendly conditions in contrast to existing techniques that generate higher temperatures, leading to altered cellular integrity. This technique allows safe delivery of genetic material into bacterial cells, thus providing excellent prospects for applications in microbiome therapeutics and synthetic biology.

Noninvasive microvascular imaging in newborn rats using high-frequency ultrafast ultrasound.

Ultrasound imaging stands as the predominant modality for neonatal health assessment, with recent advancements in ultrafast Doppler (µDoppler) technology offering significant promise in fields such as neonatal brain imaging. Combining µDoppler with high-frequency ultrasound (HF-µDoppler) presents a potential efficient avenue to enhance in vivo microvascular imaging in small animals, notably newborn rats, a crucial preclinical animal model for neonatal disease and development research. It is necessary to verify the imaging performance of HF-µDoppler in preclinical trials. This study investigates the microvascular imaging capabilities of HF-µDoppler using a 30 MHz high-frequency linear array probe in newborn rats. Results demonstrate the clarity of cerebral microvascular imaging in rats aged 1 to 7 postnatal days, extending to whole-body microvascular imaging, encompassing the central nervous system, including the brain and spinal cord. In conclusion, HF-µDoppler technology emerges as a reliable imaging tool, offering a new perspective for preclinical investigations into neonatal diseases and development.

Mouse model of focal cortical dysplasia type II generates a wide spectrum of high-frequency activities.

High-frequency oscillations (HFOs) represent an electrographic biomarker of endogenous epileptogenicity and seizure-generating tissue that proved clinically useful in presurgical planning and delineating the resection area. In the neocortex, the clinical observations on HFOs are not sufficiently supported by experimental studies stemming from a lack of realistic neocortical epilepsy models that could provide an explanation of the pathophysiological substrates of neocortical HFOs. In this study, we explored pathological epileptiform network phenomena, particularly HFOs, in a highly realistic murine model of neocortical epilepsy due to focal cortical dysplasia (FCD) type II. FCD was induced in mice by the expression of the human pathogenic mTOR gene mutation during embryonic stages of brain development. Electrographic recordings from multiple cortical regions in freely moving animals with FCD and epilepsy demonstrated that the FCD lesion generates HFOs from all frequency ranges, i.e., gamma, ripples, and fast ripples up to 800 Hz. Gamma-ripples were recorded almost exclusively in FCD animals, while fast ripples occurred in controls as well, although at a lower rate. Gamma-ripple activity is particularly valuable for localizing the FCD lesion, surpassing the utility of fast ripples that were also observed in control animals, although at significantly lower rates. Propagating HFOs occurred outside the FCD, and the contralateral cortex also generated HFOs independently of the FCD, pointing to a wider FCD network dysfunction. Optogenetic activation of neurons carrying mTOR mutation and expressing Channelrhodopsin-2 evoked fast ripple oscillations that displayed spectral and morphological profiles analogous to spontaneous oscillations. This study brings experimental evidence that FCD type II generates pathological HFOs across all frequency bands and provides information about the spatiotemporal properties of each HFO subtype in FCD. The study shows that mutated neurons represent a functionally interconnected and active component of the FCD network, as they can induce interictal epileptiform phenomena and HFOs.

Accelerated Evolution Analysis Uncovers PKNOX2 as a Key Transcription Factor in the Mammalian Cochlea.

The genetic bases underlying the evolution of morphological and functional innovations of the mammalian inner ear are poorly understood. Gene regulatory regions are thought to play an important role in the evolution of form and function. To uncover crucial hearing genes whose regulatory machinery evolved specifically in mammalian lineages, we mapped accelerated noncoding elements (ANCEs) in inner ear transcription factor (TF) genes and found that PKNOX2 harbors the largest number of ANCEs within its transcriptional unit. Using reporter gene expression assays in transgenic zebrafish, we determined that four PKNOX2-ANCEs drive differential expression patterns when compared with ortholog sequences from close outgroup species. Because the functional role of PKNOX2 in cochlear hair cells has not been previously investigated, we decided to study Pknox2 null mice generated by CRISPR/Cas9 technology. We found that Pknox2-/- mice exhibit reduced distortion product otoacoustic emissions (DPOAEs) and auditory brainstem response (ABR) thresholds at high frequencies together with an increase in peak 1 amplitude, consistent with a higher number of inner hair cells (IHCs)-auditory nerve synapsis observed at the cochlear basal region. A comparative cochlear transcriptomic analysis of Pknox2-/- and Pknox2+/+ mice revealed that key auditory genes are under Pknox2 control. Hence, we report that PKNOX2 plays a critical role in cochlear sensitivity at higher frequencies and that its transcriptional regulation underwent lineage-specific evolution in mammals. Our results provide novel insights about the contribution of PKNOX2 to normal auditory function and to the evolution of high-frequency hearing in mammals.

Aging suppresses subthalamic neuronal activity in patients with Parkinson's disease.

Age is a primary risk factor for Parkinson's disease (PD); however, the effects of aging on the Parkinsonian brain remain poorly understood, particularly for deep brain structures. We investigated intraoperative micro-electrode recordings from the subthalamic nucleus (STN) of PD patients aged between 42 and 76 years. Age was associated with decreased oscillatory beta power and non-oscillatory high-frequency power, independent of PD-related variables. Single unit firing and burst rates were also reduced, whereas the coefficient of variation and the structure of burst activity were unchanged. Phase synchronization (debiased weighed phase lag index [dWPLI]) between sites was pronounced in the beta band between electrodes in the superficial STN but was unaffected by age. Our results show that aging is associated with reduced neuronal activity without changes to its temporal structure. We speculate that the loss of activity in the STN may mediate the relationship between PD and age.

Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

Parvalbumin-positive (PV+ ) fast-spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV+ interneurons imposes high-energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single-cell transcriptomic data for the mouse cortex, we identified a metabolism-associated gene with highly restricted expression to PV+ interneurons: Cox6a2, which codes for an isoform of a cytochrome c oxidase subunit. Cox6a2 deletion in mice disrupts perineuronal nets and enhances oxidative stress in PV+ interneurons, which in turn impairs the maturation of their morphological and functional properties. Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons. Energy disbalance and aberrant maturation likely hinder the integration of PV+ interneurons into cortical neuronal circuits, leading to behavioral alterations in mice. Additionally, in a human patient bearing mutations in COX6A2, we found a potential association of the mutations with mental/neurological abnormalities.

Identification of congenital aortic valve malformations in juvenile natriuretic peptide receptor 2-deficient mice using high-frequency ultrasound.

Mouse models of congenital aortic valve malformations are useful for studying disease pathobiology, but most models have incomplete penetrance [e.g., ∼2 to 77% prevalence of bicuspid aortic valves (BAVs) across multiple models]. For longitudinal studies of pathologies associated with BAVs and other congenital valve malformations, which manifest over months in mice, it is operationally inefficient, economically burdensome, and ethically challenging to enroll large numbers of mice in studies without first identifying those with valvular abnormalities. To address this need, we established and validated a novel in vivo high-frequency (30 MHz) ultrasound imaging protocol capable of detecting aortic valvular malformations in juvenile mice. Fifty natriuretic peptide receptor 2 heterozygous mice on a low-density lipoprotein receptor-deficient background (Npr2+/-;Ldlr-/-; 32 males and 18 females) were imaged at 4 and 8 wk of age. Fourteen percent of the Npr2+/-;Ldlr-/- mice exhibited features associated with aortic valve malformations, including 1) abnormal transaortic flow patterns on color Doppler (recirculation and regurgitation), 2) peak systolic flow velocities distal to the aortic valves reaching or surpassing ∼1,250 mm/s by pulsed-wave Doppler, and 3) putative fusion of cusps along commissures and abnormal movement elucidated by two-dimensional (2-D) imaging with ultrahigh temporal resolution. Valves with these features were confirmed by ex vivo gross anatomy and histological visualization to have thickened cusps, partial fusions, or Sievers type-0 bicuspid valves. This ultrasound imaging protocol will enable efficient, cost effective, and humane implementation of studies of congenital aortic valvular abnormalities and associated pathologies in a wide range of mouse models.NEW & NOTEWORTHY We developed a high-frequency ultrasound imaging protocol for diagnosing congenital aortic valve structural abnormalities in 4-wk-old mice. Our protocol defines specific criteria to distinguish mice with abnormal aortic valves from those with normal tricuspid valves using color Doppler, pulsed-wave Doppler, and two-dimensional (2-D) imaging with ultrahigh temporal resolution. This approach enables early identification of valvular abnormalities for efficient and ethical experimental design of longitudinal studies of congenital valve diseases and associated pathologies in mice.

Impact of weight adjusted high frequency low tidal volume ventilation and atrial pacing in lesion metrics in high-power short-duration ablation: Results of a pilot study.

INTRODUCTION: Lesion size index (LSI) was introduced with the use of Tacticath™ and as a surrogate of lesion quality. The metric used to achieve the predetermined values involves combined information of contact force (CF), power and radiofrequency time. Rapid atrial pacing (RAP) and high-frequency low-tidal volume ventilation (HFLTV) independently or in combination improve catheter stability and CF and quality of lesions. Data of the impact of body weight adjusted HFLTV ventilation strategy associated with RAP in the lesion metrics still lacking. The study aimed to compare the results of high-power short-duration (HPSD) atrial fibrillation ablation using simultaneous weight adjusted HFLTV and RAP and standard ventilation (SV) protocol. METHODS: Prospective, nonrandomized study with 136 patients undergoing de novo ablation divided into two groups; 70 in RAP (100 ppm) + HFLTV with 4 mL/kg of tidal volume and 25 breaths/min (group A) and 66 patients with SV in intrinsic sinus rhythm (group B). Ablation using 50 W, CF of 5-10 g/10-20 g and 40 mL/minute flow rate on the posterior and anterior left atrial wall, respectively. RESULTS: No procedure-related complications. Group A: Mean LSI points 70 ± 16.5, mean total lower LSI 3.4 ± 0.5, mean total higher LSI 8.2 ± 0.4 and mean total LSI 5.6 ± 0.6. Anterior and posterior wall mean total LSI was 6.0 ± 0.4 and 4.2 ± 0.3, respectively. Mean local impedance drop (LID) points were 118.8 ± 28.4, mean LID index (%) 12.9 ± 1.5, and mean LID < 12% points 55.9 ± 23.8. Anterior and posterior wall mean total LID index were 13.6 ± 2.0 and 11.9 ± 1.7, respectively. Recurrence in 11 (15.7%) patients. Group B: Mean LSI points 56 ± 2.7, mean total lower LSI 2.9 ± 0.7, mean total higher LSI 6.9 ± 0.9, and mean total LSI 4.8 ± 0.8. Anterior and posterior wall mean total LSI was 5.1 ± 0.3 and 3.5 ± 0.5, respectively. Mean LID points were 111.4 ± 21.5, mean LID index (%) 11.4 ± 1.2, and mean LID < 12% points 54.9 ± 25.2. Anterior and posterior wall mean total LID index were 11.8 ± 1.9 and 10.3 ± 1.7, respectively. Recurrence in 14 (21.2%) patients. Mean follow up was 15.2 ± 4.4 months. CONCLUSION: Weight adjusted HFLTV ventilation with RAP HPSD ablation produced lower recurrence rate and better LSI and LID parameters in comparison to SV and intrinsic sinus rhythm.

Predictors of first pass isolation of the pulmonary veins in real world ablations: An analysis of 2671 patients from the REAL-AF registry.

INTRODUCTION: During atrial fibrillation ablation (AFA), achievement of first pass isolation (FPI) reflects effective lesion formation and predicts long-term freedom from arrhythmia recurrence. We aim to determine the clinical and procedural predictors of pulmonary vein FPI. METHODS: We reviewed AFA procedures in a multicenter prospective registry of AFA (REAL-AF). A multivariate ordinal logistic regression, weighted by inverse proceduralist volume, was used to determine predictors of FPI. RESULTS: A total of 2671 patients were included with 1806 achieving FPI in both vein sides, 702 achieving FPI in one, and 163 having no FPI. Individually, age, left atrial (LA) scar, higher power usage (50 W), greater posterior contact force, ablation index >350 posteriorly, Vizigo™ sheath utilization, nonstandard ventilation, and high operator volume (>6 monthly cases) were all related to improved odds of FPI. Conversely sleep apnea, elevated body mass index (BMI), diabetes mellitus, LA enlargement, antiarrhythmic drug use, and center's higher fluoroscopy use were related to reduced odds of FPI. Multivariate analysis showed that BMI > 30 (OR 0.78 [0.64-0.96]) and LA volume (OR per mL increase = 1.00 [0.99-1.00]) predicted lower odds of achieving FPI, whereas significant left atrial scarring (>20%) was related to higher rates of FPI. Procedurally, the use of high power (50 W) (OR 1.32 [1.05-1.65]), increasing force posteriorly (OR 2.03 [1.19-3.46]), and nonstandard ventilation (OR 1.26 [1.00-1.59]) predicted higher FPI rates. At a site level, high procedural volume (OR 1.89 [1.48-2.41]) and low fluoroscopy centers (OR 0.72 [0.61-0.84]) had higher rates of FPI. CONCLUSION: FPI rates are affected by operator experience, patient comorbidities, and procedural strategies. These factors may be postulated to impact acute lesion formation.

Abnormal vascular thickness and stiffness in young adults with type 1 diabetes: new insights from cutting-edge ultrasound modalities.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with Type 1 Diabetes (T1D). Early markers of CVD include increased carotid intima-media thickness (CIMT) and pulse wave velocity (PWV), but these existing ultrasound technologies show limited spatial and temporal resolution in young adults. The purpose of this study is to evaluate the utility of high-resolution ultrasound modalities, including high frequency ultrasound CIMT (hfCIMT) and ultrafast ultrasound PWV (ufPWV), in young adults with Type 1 Diabetes. METHODS: This is a prospective single-center observational cohort study including 39 participants with T1D and 25 age and sex matched controls. All participants underwent hfCIMT and ufPWV measurements. hfCIMT and ufPWV measures of T1D were compared with controls and associations with age, sex, BMI, A1c, blood pressure, and lipids were studied. RESULTS: Mean age was 24.1 years old in both groups. T1D had a greater body mass index (27.7 [5.7] vs 23.1 [3.2] kg/m2), LDL Cholesterol, and estimated GFR, and had a mean A1c of 7.4 [1.0] % (57 mmol/mol) and diabetes duration of 16.1 [3.7] years with 56% using insulin pumps. In T1D, hfCIMT was significantly increased as compared to controls (0.435 ± 0.06 mm vs 0.379 ± 0.06 mm respectively, p < 0.01). ufPWV measures were significantly increased in T1D (systolic foot PWV: 5.29 ± 0.23 m/s vs 5.50 ± 0.37 m/s, p < 0.01; dicrotic notch PWV = 7.54 ± 0.46 m/s vs 7.92 ± 0.41 m/s, p < 0.01). Further, there was an impact of A1c-measured glycemia on hfCIMT, but this relationship was not seen with ufPWV. No significant statistical correlations between hfCIMT and ufPWV measures in either T1D or healthy controls were observed. CONCLUSION: Young adults with T1D present with differences in arterial thickness and stiffness when compared with controls. Use of novel high-resolution ultrasound measures describe important relationships between early structural and vascular pathophysiologic changes and are promising tools to evaluate pre-clinical CVD risk in youth with T1D. TRIAL REGISTRATION: ISRCTN91419926.

Cognitive Effects Following Offline High-Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) in Healthy Populations: A Systematic Review and Meta-Analysis.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is a commonly used form of rTMS to treat neuropsychiatric disorders. Emerging evidence suggests that 'offline' HF-rTMS may have cognitive enhancing effects, although the magnitude and moderators of these effects remain unclear. We conducted a systematic review and meta-analysis to clarify the cognitive effects of offline HF-rTMS in healthy individuals. A literature search for randomised controlled trials with cognitive outcomes for pre and post offline HF-rTMS was performed across five databases up until March 2022. This study was registered on the PROSPERO international prospective protocol for systematic reviews (PROSPERO 2020 CRD 42,020,191,269). The Risk of Bias 2 tool was used to assess the risk of bias in randomised trials. Separate analyses examined the cognitive effects of excitatory and inhibitory forms of offline HF-rTMS on accuracy and reaction times across six cognitive domains. Fifty-three studies (N = 1507) met inclusion criteria. Excitatory offline HF-rTMS showed significant small sized effects for improving accuracy (k = 46, g = 0.12) and reaction time (k = 44, g = -0.13) across all cognitive domains collapsed. Excitatory offline HF-rTMS demonstrated a relatively greater effect for executive functioning in accuracy (k = 24, g = 0.14). Reaction times were also improved for the executive function (k = 21, g = -0.11) and motor (k = 3, g = -0.22) domains following excitatory offline HF-rTMS. The current review was restricted to healthy individuals and future research is required to examine cognitive enhancement from offline HF-rTMS in clinical cohorts.

Oscillometry for personalizing continuous distending pressure maneuvers: an observational study in extremely preterm infants.

RATIONALE: Lung recruitment and continuous distending pressure (CDP) titration are critical for assuring the efficacy of high-frequency ventilation (HFOV) in preterm infants. The limitation of oxygenation (peripheral oxygen saturation, SpO2) in optimizing CDP calls for evaluating other non-invasive bedside measurements. Respiratory reactance (Xrs) at 10 Hz measured by oscillometry reflects lung volume recruitment and tissue strain. In particular, lung volume recruitment and decreased tissue strain result in increased Xrs values. OBJECTIVES: In extremely preterm infants treated with HFOV as first intention, we aimed to measure the relationship between CDP and Xrs during SpO2-driven CDP optimization. METHODS: In this prospective observational study, extremely preterm infants born before 28 weeks of gestation undergoing SpO2-guided lung recruitment maneuvers were included in the study. SpO2 and Xrs were recorded at each CDP step. The optimal CDP identified by oxygenation (CDPOpt_SpO2) was compared to the CDP providing maximal Xrs on the deflation limb of the recruitment maneuver (CDPXrs). RESULTS: We studied 40 infants (gestational age at birth = 22+ 6-27+ 5 wk; postnatal age = 1-23 days). Measurements were well tolerated and provided reliable results in 96% of cases. On average, Xrs decreased during the inflation limb and increased during the deflation limb. Xrs changes were heterogeneous among the infants for the amount of decrease with increasing CDP, the decrease at the lowest CDP of the deflation limb, and the hysteresis of the Xrs vs. CDP curve. In all but five infants, the hysteresis of the Xrs vs. CDP curve suggested effective lung recruitment. CDPOpt_SpO2 and CDPXrs were highly correlated (ρ = 0.71, p < 0.001) and not statistically different (median difference [range] = -1 [-3; 9] cmH2O). However, CDPXrs were equal to CDPOpt_SpO2 in only 6 infants, greater than CDPOpt_SpO2 in 10, and lower in 24 infants. CONCLUSIONS: The Xrs changes described provide complementary information to oxygenation. Further investigation is warranted to refine recruitment maneuvers and CPD settings in preterm infants.

Interaction of interictal epileptiform activity with sleep spindles is associated with cognitive deficits and adverse surgical outcome in pediatric focal epilepsy.

OBJECTIVE: Temporal coordination between oscillations enables intercortical communication and is implicated in cognition. Focal epileptic activity can affect distributed neural networks and interfere with these interactions. Refractory pediatric epilepsies are often accompanied by substantial cognitive comorbidity, but mechanisms and predictors remain mostly unknown. Here, we investigate oscillatory coupling across large-scale networks in the developing brain. METHODS: We analyzed large-scale intracranial electroencephalographic recordings in children with medically refractory epilepsy undergoing presurgical workup (n = 25, aged 3-21 years). Interictal epileptiform discharges (IEDs), pathologic high-frequency oscillations (HFOs), and sleep spindles were detected. Spatiotemporal metrics of oscillatory coupling were determined and correlated with age, cognitive function, and postsurgical outcome. RESULTS: Children with epilepsy demonstrated significant temporal coupling of both IEDs and HFOs to sleep spindles in discrete brain regions. HFOs were associated with stronger coupling patterns than IEDs. These interactions involved tissue beyond the clinically identified epileptogenic zone and were ubiquitous across cortical regions. Increased spatial extent of coupling was most prominent in older children. Poor neurocognitive function was significantly correlated with high IED-spindle coupling strength and spatial extent; children with strong pathologic interactions additionally had decreased likelihood of postoperative seizure freedom. SIGNIFICANCE: Our findings identify pathologic large-scale oscillatory coupling patterns in the immature brain. These results suggest that such intercortical interactions could predict risk for adverse neurocognitive and surgical outcomes, with the potential to serve as novel therapeutic targets to restore physiologic development.

Pathological neurons generate ripples at the UP-DOWN transition disrupting information transfer.

OBJECTIVE: To confirm and investigate why pathological high-frequency oscillations (pHFOs), including ripples (80-200 Hz) and fast ripples (200-600 Hz), are generated during the UP-DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure-onset zone (SOZ). METHODS: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross-correlograms. RESULTS: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p < < .001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p < < .001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d = .11-.83) and fast ripples (d = .36-.90) at the UP-DOWN transition (p < .05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d = .14-.30) and 8.5% (d = .33-.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non-SOZ (N = 3). SIGNIFICANCE: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation.

Effects of midazolam on high-frequency oscillations in amygdala and hippocampus of epilepsy patients.

High-frequency oscillations (HFOs) are associated with normal brain function, but are also increasingly recognized as potential biomarkers of epileptogenic tissue. Considering the important role of interneuron activity in physiological HFO generation, we studied their modulation by midazolam (MDZ), an agonist of γ-aminobutyric acid type A (GABAA)-benzodiazepine receptors. Here, we analyzed 80 intracranial electrode contacts in amygdala and hippocampus of 13 patients with drug-refractory focal epilepsy who had received MDZ for seizure termination during presurgical monitoring. Ripples (80-250 Hz) and fast ripples (FRs; 250-400 Hz) were compared before and after seizures with MDZ application, and according to their origin either within or outside the individual seizure onset zone (SOZ). We found that MDZ distinctly suppressed all HFOs (ripples and FRs), whereas the reduction of ripples was significantly less pronounced inside the SOZ compared to non-SOZ contacts. The rate of FRs inside the SOZ was less affected, especially in hippocampal contacts. In a few cases, even a marked increase of FRs following MDZ administration was seen. Our results demonstrate, for the first time, a significant HFO modulation in amygdala and hippocampus by MDZ, thus giving insights into the malfunction of GABA-mediated inhibition within epileptogenic areas and its role in HFO generation.