Relevance of continuous EEG versus routine EEG for outcome prediction after traumatic brain injury.

INTRODUCTION: In a cohort of adult patients with disturbance of consciousness after TBI, we aimed to explore the relationship of continuous video-EEG (cEEG) and routine EEG (rEEG) with mortality and functional outcome. METHODS: Post-hoc analysis of data from a randomized controlled trial (CERTA study), in which adults with disorder of consciousness and needing EEG were randomized 1:1 to cEEG or two rEEG. In TBI patients, correlation between EEG duration and mortality and modified Rankin score (mRs, good 0-2) at 6 months was assessed. RESULTS: Among 364 patients, 44 patients presenting with consciousness impairment after TBI were included; 29 randomized to cEEG and 15 to rEEG. Mortality (p=0.88) and functional outcome (p=0.58) at 6 months were similar between groups. There was a nonsignificant tendency toward more seizure/status epilepticus detection with cEEG (p=0.08). In multivariable regression, cEEG was not related to functional outcome (OR 0.75 [0.13-4.24], p=0.745) or mortality (OR 7.11 [0.51-99.32], p=0.145). CONCLUSION: Despite allowing increased seizure detections in TBI patients, cEEG does not seem to be not associated with better functional clinical outcome or mortality over rEEG. Pending larger trials, repeated rEEG might be acceptable in post TBI disorder of consciousness, especially in resource-limited environments.

The critical dynamics of hippocampal seizures.

Epilepsy is defined by the abrupt emergence of harmful seizures, but the nature of these regime shifts remains enigmatic. From the perspective of dynamical systems theory, such critical transitions occur upon inconspicuous perturbations in highly interconnected systems and can be modeled as mathematical bifurcations between alternative regimes. The predictability of critical transitions represents a major challenge, but the theory predicts the appearance of subtle dynamical signatures on the verge of instability. Whether such dynamical signatures can be measured before impending seizures remains uncertain. Here, we verified that predictions on bifurcations applied to the onset of hippocampal seizures, providing concordant results from in silico modeling, optogenetics experiments in male mice and intracranial EEG recordings in human patients with epilepsy. Leveraging pharmacological control over neural excitability, we showed that the boundary between physiological excitability and seizures can be inferred from dynamical signatures passively recorded or actively probed in hippocampal circuits. Of importance for the design of future neurotechnologies, active probing surpassed passive recording to decode underlying levels of neural excitability, notably when assessed from a network of propagating neural responses. Our findings provide a promising approach for predicting and preventing seizures, based on a sound understanding of their dynamics.

Ultra-Long-Term-EEG Monitoring (ULTEEM) Systems: Towards User-Friendly Out-of-Hospital Recordings of Electrical Brain Signals in Epilepsy.

Epilepsy is characterized by the occurrence of epileptic events, ranging from brief bursts of interictal epileptiform brain activity to their most dramatic manifestation as clinically overt bilateral tonic-clonic seizures. Epileptic events are often modulated in a patient-specific way, for example by sleep. But they also reveal temporal patterns not only on ultra- and circadian, but also on multidien scales. Thus, to accurately track the dynamics of epilepsy and to thereby enable and improve personalized diagnostics and therapies, user-friendly systems for long-term out-of-hospital recordings of electrical brain signals are needed. Here, we present two wearable devices, namely ULTEEM and ULTEEMNite, to address this unmet need. We demonstrate how the usability concerns of the patients and the signal quality requirements of the clinicians have been incorporated in the design. Upon testbench verification of the devices, ULTEEM was successfully benchmarked against a reference EEG device in a pilot clinical study. ULTEEMNite was shown to record typical macro- and micro-sleep EEG characteristics in a proof-of-concept study. We conclude by discussing how these devices can be further improved and become particularly useful for a better understanding of the relationships between sleep, epilepsy, and neurodegeneration.

Development of an Open-source and Lightweight Sensor Recording Software System for Conducting Biomedical Research: Technical Report.

BACKGROUND: Digital sensing devices have become an increasingly important component of modern biomedical research, as they help provide objective insights into individuals' everyday behavior in terms of changes in motor and nonmotor symptoms. However, there are significant barriers to the adoption of sensor-enhanced biomedical solutions in terms of both technical expertise and associated costs. The currently available solutions neither allow easy integration of custom sensing devices nor offer a practicable methodology in cases of limited resources. This has become particularly relevant, given the need for real-time sensor data that could help lower health care costs by reducing the frequency of clinical assessments performed by specialists and improve access to health assessments (eg, for people living in remote areas or older adults living at home). OBJECTIVE: The objective of this paper is to detail the end-to-end development of a novel sensor recording software system that supports the integration of heterogeneous sensor technologies, runs as an on-demand service on consumer-grade hardware to build sensor systems, and can be easily used to reliably record longitudinal sensor measurements in research settings. METHODS: The proposed software system is based on a server-client architecture, consisting of multiple self-contained microservices that communicated with each other (eg, the web server transfers data to a database instance) and were implemented as Docker containers. The design of the software is based on state-of-the-art open-source technologies (eg, Node.js or MongoDB), which fulfill nonfunctional requirements and reduce associated costs. A series of programs to facilitate the use of the software were documented. To demonstrate performance, the software was tested in 3 studies (2 gait studies and 1 behavioral study assessing activities of daily living) that ran between 2 and 225 days, with a total of 114 participants. We used descriptive statistics to evaluate longitudinal measurements for reliability, error rates, throughput rates, latency, and usability (with the System Usability Scale [SUS] and the Post-Study System Usability Questionnaire [PSSUQ]). RESULTS: Three qualitative features (event annotation program, sample delay analysis program, and monitoring dashboard) were elaborated and realized as integrated programs. Our quantitative findings demonstrate that the system operates reliably on consumer-grade hardware, even across multiple months (>420 days), providing high throughput (2000 requests per second) with a low latency and error rate (<0.002%). In addition, the results of the usability tests indicate that the system is effective, efficient, and satisfactory to use (mean usability ratings for the SUS and PSSUQ were 89.5 and 1.62, respectively). CONCLUSIONS: Overall, this sensor recording software could be leveraged to test sensor devices, as well as to develop and validate algorithms that are able to extract digital measures (eg, gait parameters or actigraphy). The proposed software could help significantly reduce barriers related to sensor-enhanced biomedical research and allow researchers to focus on the research questions at hand rather than on developing recording technologies.

On the relationships between epilepsy, sleep, and Alzheimer's disease: A narrative review.

Epilepsy, sleep, and Alzheimer's disease (AD) are tightly and potentially causally interconnected. The aim of our review was to investigate current research directions on these relationships. Our hope is that they may indicate preventive measures and new treatment options for early neurodegeneration. We included articles that assessed all three topics and were published during the last ten years. We found that this literature corroborates connections on various pathophysiological levels, including sleep-stage-related epileptiform activity in AD, the negative consequences of different sleep disorders on epilepsy and cognition, common biochemical pathways as well as network dysfunctions. Here we provide a detailed overview of these topics and we discuss promising diagnostic and therapeutic consequences.

An Instrumented Apartment to Monitor Human Behavior: A Pilot Case Study in the NeuroTec Loft.

For patients suffering from neurodegenerative disorders, the behavior and activities of daily living are an indicator of a change in health status, and home-monitoring over a prolonged period of time by unobtrusive sensors is a promising technology to foster independent living and maintain quality of life. The aim of this pilot case study was the development of a multi-sensor system in an apartment to unobtrusively monitor patients at home during the day and night. The developed system is based on unobtrusive sensors using basic technologies and gold-standard medical devices measuring physiological (e.g., mobile electrocardiogram), movement (e.g., motion tracking system), and environmental parameters (e.g., temperature). The system was evaluated during one session by a healthy 32-year-old male, and results showed that the sensor system measured accurately during the participant's stay. Furthermore, the participant did not report any negative experiences. Overall, the multi-sensor system has great potential to bridge the gap between laboratories and older adults' homes and thus for a deep and novel understanding of human behavioral and neurological disorders. Finally, this new understanding could be utilized to develop new algorithms and sensor systems to address problems and increase the quality of life of our aging society and patients with neurological disorders.

A Primer on Hyperdimensional Computing for iEEG Seizure Detection.

A central challenge in today's care of epilepsy patients is that the disease dynamics are severely under-sampled in the currently typical setting with appointment-based clinical and electroencephalographic examinations. Implantable devices to monitor electrical brain signals and to detect epileptic seizures may significantly improve this situation and may inform personalized treatment on an unprecedented scale. These implantable devices should be optimized for energy efficiency and compact design. Energy efficiency will ease their maintenance by reducing the time of recharging, or by increasing the lifetime of their batteries. Biological nervous systems use an extremely small amount of energy for information processing. In recent years, a number of methods, often collectively referred to as brain-inspired computing, have also been developed to improve computation in non-biological hardware. Here, we give an overview of one of these methods, which has in particular been inspired by the very size of brains' circuits and termed hyperdimensional computing. Using a tutorial style, we set out to explain the key concepts of hyperdimensional computing including very high-dimensional binary vectors, the operations used to combine and manipulate these vectors, and the crucial characteristics of the mathematical space they inhabit. We then demonstrate step-by-step how hyperdimensional computing can be used to detect epileptic seizures from intracranial electroencephalogram (EEG) recordings with high energy efficiency, high specificity, and high sensitivity. We conclude by describing potential future clinical applications of hyperdimensional computing for the analysis of EEG and non-EEG digital biomarkers.

Stroke causes a transient imbalance of interhemispheric information flow in EEG during non-REM sleep.

OBJECTIVE: Large-scale connectivity, especially interhemispheric connections, plays a crucial role for recovery after stroke. Here we used methods from information theory to characterize interhemispheric information flow in wake- and sleep-EEG after cerebral ischemia. METHODS: 34 patients with unilateral ischemic stroke were included. Symbolic Transfer Entropy (STE) was applied between bipolar EEG signals on the left and the right cerebral hemisphere during polysomnographic recordings in the acute phase and 3 months after stroke. RESULTS: In the acute phase, we found a sleep stage-dependent preferred interhemispheric asymmetry: during non-REM sleep the information flow was predominantly directed from the contralesional toward the ipsilesional hemisphere. This effect was greatly reduced in a follow-up recording 3 months after stroke onset. CONCLUSION: Our findings are consistent with functional imaging studies showing a transient hyperactivity of contralesional areas after stroke. We conclude that STE is a robust method for detecting post-stroke connectivity reorganizations, and that sleep stages have to be taken into account when assessing functional connectivity. SIGNIFICANCE: EEG is more widely available than functional MRI. Future studies will have to confirm whether EEG derived STE can be useful in a clinical setting during rehabilitation after stroke.

Giardia in a selected population of dogs and cats in Germany - diagnostics, coinfections and assemblages.

Infections with the zoonotic endoparasite Giardia duodenalis are widely spread among dogs and cats worldwide. Since the question whether the infection might be transmitted from domestic animals to their owners is still an important topic, a reliable detection of patent Giardia infections and the determination of the associated Giardia assemblages is of major concern. The objectives of the present study were to determine the prevalence of Giardia infections in dogs and cats living in Germany using different diagnostic tests and to identify the Giardia assemblages of infected animals. Furthermore, a possible correlation of coinfections with other endoparasites was analysed. All samples were investigated by enzyme-linked immunosorbent assay (ELISA), merthiolate-iodine-formalin concentration technique (MIFC) and zinc chloride flotation. ELISA-positive samples were additionally screened with a direct immunofluorescence assay (IFA). Faecal DNA was extracted from all Giardia cyst-positive samples and used for multilocus sequence typing with nested PCRs targeting the following gene loci: SSU rRNA (SSU), glutamate dehydrogenase (gdh) and triosephosphate isomerase (tpi). Samples from dogs and cats tested positive for Giardia coproantigen (ELISA) in 30.6% and 17.9%, respectively. The MIFC technique revealed Giardia cysts in 33.9% of canine and in 34.6% of feline ELISA-positive samples, while using IFA, cysts were present in 90.4% of canine and in 76.9% of feline ELISA-positive samples. Coinfections with other endoparasites besides Giardia were found in both dogs and cats, yet a statistically significant correlation could solely be drawn for the canine samples. The success rate of the different PCR protocols varied between 23.1% (tpi) and 91.3% (SSU) for dogs and between 25.0% (gdh) and 90.0% (SSU) for cats. Dog-specific Giardia assemblages C and D were detected in 42 and 55 canine isolates, respectively. The cat-specific Giardia assemblage F was detected in 14 feline isolates. Two canine and two feline samples harboured the zoonotic assemblage A. According to the results of the study, Giardia is a common endoparasite in dogs and cats from Germany. The exclusive application of MIFC is insufficient for a reliable identification of patent Giardia infections since the IFA revealed a higher sensitivity for the detection of Giardia cysts in feline and canine faecal samples. Even though the majority of investigated animals harboured the species-specific Giardia assemblages C, D and F, a zoonotic potential arising from assemblage A could not be excluded.

Detection of Strongylus vulgaris in equine faecal samples by real-time PCR and larval culture - method comparison and occurrence assessment.

BACKGROUND: Strongylus vulgaris has become a rare parasite in Germany during the past 50 years due to the practice of frequent prophylactic anthelmintic therapy. To date, the emerging development of resistance in Cyathostominae and Parascaris spp. to numerous equine anthelmintics has changed deworming management and the frequency of anthelmintic usage. In this regard, reliable detection of parasitic infections, especially of the highly pathogenic S. vulgaris is essential. In the current study, two diagnostic methods for the detection of infections with S. vulgaris were compared and information on the occurrence of this parasite in German horses was gained. For this purpose, faecal samples of 501 horses were screened for S. vulgaris with real-time PCR and an additional larval culture was performed in samples of 278 horses. A subset of 26 horses underwent multiple follow-up examinations with both methods in order to evaluate both the persistence of S. vulgaris infections and the reproducibility of each diagnostic method. RESULTS: The real-time PCR revealed S. vulgaris-DNA in ten of 501 investigated equine samples (1.9%). The larval culture demonstrated larvae of S. vulgaris in three of the 278 samples (1.1%). A direct comparison of the two methods was possible in 321 samples including 43 follow-up examinations with the result of 11 S. vulgaris-positive samples by real-time PCR and 4 S. vulgaris-positive samples by larval culture. The McNemar's test (p-value = 0.016) revealed a significant difference and the kappa values (0.525) showed a moderate agreement between real-time PCR and larval culture. CONCLUSIONS: The real-time PCR detected a significantly higher proportion of positives of S. vulgaris compared to larval culture and should thus be considered as a routine diagnostic method for the detection of S. vulgaris in equine samples.

Prognostic and diagnostic value of EEG signal coupling measures in coma.

OBJECTIVE: Our aim was to assess the diagnostic and predictive value of several quantitative EEG (qEEG) analysis methods in comatose patients. METHODS: In 79 patients, coupling between EEG signals on the left-right (inter-hemispheric) axis and on the anterior-posterior (intra-hemispheric) axis was measured with four synchronization measures: relative delta power asymmetry, cross-correlation, symbolic mutual information and transfer entropy directionality. Results were compared with etiology of coma and clinical outcome. Using cross-validation, the predictive value of measure combinations was assessed with a Bayes classifier with mixture of Gaussians. RESULTS: Five of eight measures showed a statistically significant difference between patients grouped according to outcome; one measure revealed differences in patients grouped according to the etiology. Interestingly, a high level of synchrony between the left and right hemisphere was associated with mortality on intensive care unit, whereas higher synchrony between anterior and posterior brain regions was associated with survival. The combination with the best predictive value reached an area-under the curve of 0.875 (for patients with post anoxic encephalopathy: 0.946). CONCLUSIONS: EEG synchronization measures can contribute to clinical assessment, and provide new approaches for understanding the pathophysiology of coma. SIGNIFICANCE: Prognostication in coma remains a challenging task. qEEG could improve current multi-modal approaches.

Nanosized IrO(x)-Ir Catalyst with Relevant Activity for Anodes of Proton Exchange Membrane Electrolysis Produced by a Cost-Effective Procedure.

We have developed a highly active nanostructured iridium catalyst for anodes of proton exchange membrane (PEM) electrolysis. Clusters of nanosized crystallites are obtained by reducing surfactant-stabilized IrCl3 in water-free conditions. The catalyst shows a five-fold higher activity towards oxygen evolution reaction (OER) than commercial Ir-black. The improved kinetics of the catalyst are reflected in the high performance of the PEM electrolyzer (1 mg(Ir) cm(-2)), showing an unparalleled low overpotential and negligible degradation. Our results demonstrate that this enhancement cannot be only attributed to increased surface area, but rather to the ligand effect and low coordinate sites resulting in a high turnover frequency (TOF). The catalyst developed herein sets a benchmark and a strategy for the development of ultra-low loading catalyst layers for PEM electrolysis.

Seizure termination.

A better understanding of the mechanisms by which most focal epileptic seizures stop spontaneously within a few minutes would be of highest importance, because they could potentially help to improve existing and develop novel therapeutic measures for seizure control. Studies devoted to unraveling mechanisms of seizure termination often take one of the two following approaches. The first approach focuses on metabolic mechanisms such as ionic concentrations, acidity, or neuromodulator release, studying how they are dependent on, and in turn affect changes of neuronal activity. The second approach uses quantitative tools to derive functional networks from electrophysiological recordings and analyzes these networks with mathematical methods, without focusing on actual details of cell biology. In this chapter, we summarize key results obtained by both of these approaches and attempt to show that they are complementary and equally necessary in our aim to gain a better understanding of seizure termination.

Variable-pitch rectangular cross-section radiofrequency coils for the nitrogen-14 nuclear quadrupole resonance investigation of sealed medicines packets.

The performance of rectangular radio frequency (RF) coils capable of being used to detect nuclear quadrupole resonance (NQR) signals from blister packs of medicines has been compared. The performance of a fixed-pitch RF coil was compared with that from two variable-pitch coils, one based on a design in the literature and the other optimized to obtain the most homogeneous RF field over the whole volume of the coil. It has been shown from (14)N NQR measurements with two medicines, the antibiotic ampicillin (as trihydrate) and the analgesic medicine Paracetamol, that the latter design gives NQR signal intensities almost independent of the distribution of the capsules or pills within the RF coil and is therefore more suitable for quantitative analysis.

Evolving functional network properties and synchronizability during human epileptic seizures.

We assess electrical brain dynamics before, during, and after 100 human epileptic seizures with different anatomical onset locations by statistical and spectral properties of functionally defined networks. We observe a concave-like temporal evolution of characteristic path length and cluster coefficient indicative of a movement from a more random toward a more regular and then back toward a more random functional topology. Surprisingly, synchronizability was significantly decreased during the seizure state but increased already prior to seizure end. Our findings underline the high relevance of studying complex systems from the viewpoint of complex networks, which may help to gain deeper insights into the complicated dynamics underlying epileptic seizures.

Fast oscillations trigger bursts of action potentials in neocortical neurons in vitro: a quasi-white-noise analysis study.

PURPOSE: Recent evidence supports the importance of action potential bursts in physiological neural coding, as well as in pathological epileptogenesis. To better understand the temporal dynamics of neuronal input currents that trigger burst firing, we characterized spectral patterns of stimulation current that generate bursts of action potentials from regularly spiking neocortical neurons in vitro. METHODS: Sharp microelectrodes were used for intracellular recording and stimulation of cortical neurons in rat brain slices. Quasi-white-noise (0-2 kHz) and "chirp" sine wave currents of decreasing wavelength were applied to represent a broad spectrum of stimulation frequencies. Action potential-related averaging of the stimulation current variations preceding bursting was used to characterize stimulation current patterns more likely to result in a burst rather than a single-spike response. RESULTS: Bursts of action potentials were most reliably generated by a preceding series of > or = 2 positive current transients at 164+/-37 Hz of the quasi-white-noise, and to sine wave currents with frequencies greater than 90 Hz. The intraburst action potential rate was linearly related to the frequency of the input sine wave current. CONCLUSIONS: This study demonstrates that regularly spiking cortical neurons in vitro burst in response to fast oscillations of input currents. In the presence of positive cortical feedback loops, encoding input frequency in the intraburst action potential rate may be safer than producing a high-frequency regular output spike train. This leads to the experimentally testable and therapeutically important hypothesis that burst firing could be an antiepileptogenic and/or anti-ictogenic mechanism.

A role of the mitochondrial apoptosis-inducing factor in granulysin-induced apoptosis.

Granulysin is a cytolytic molecule released by CTL via granule-mediated exocytosis. In a previous study we showed that granulysin induced apoptosis using both caspase- and ceramide-dependent and -independent pathways. In the present study we further characterize the biochemical mechanism for granulysin-induced apoptosis of tumor cells. Granulysin-induced death is significantly inhibited by Bcl-2 overexpression and is associated with a rapid (1-5 h) loss of mitochondrial membrane potential, which is not mediated by ceramide generation and is not inhibited by the general caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Ceramide generation induced by granulysin is a slow event, only observable at longer incubation times (12 h). Apoptosis induced by exogenous natural (C(18)) ceramide is truly associated with mitochondrial membrane potential loss, but contrary to granulysin, this event is inhibited by benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone. Ceramide-induced apoptosis is also completely prevented by Bcl-2 overexpression. The nuclear morphology of cells dying after granulysin treatment in the presence of caspase inhibitors suggested the involvement of mitochondrial apoptosis-inducing factor (AIF) in granulysin-induced cell death. We demonstrate using confocal microscopy that AIF is translocated from mitochondria to the nucleus during granulysin-induced apoptosis. The majority of Bcl-2 transfectants are protected from granulysin-induced cell death, mitochondrial membrane potential loss, and AIF translocation, while a small percentage are not protected. In this small percentage the typical nuclear apoptotic morphology is delayed, being of the AIF type at 5 h time, while at longer times (12 h) the normal apoptotic morphology is predominant. These and previous results support a key role for the mitochondrial pathway of apoptosis, and especially for AIF, during granulysin-induced tumoral cell death.

Granulysin blocks replication of varicella-zoster virus and triggers apoptosis of infected cells.

Granulysin, a lytic protein present in cytolytic granules of human natural killer and cytotoxic T cells, entered cells infected with varicella-zoster virus (VZV). Exposure to granulysin accelerated death of infected cells as assessed by apoptosis markers. The functional domain of granulysin that mediated its antiviral effects was amino acid 23-51; this domain also mediates the additional antitumor cell effects of granulysin. Because granulysin is a product of natural killer cells and T lymphocytes, it is possible that its antiviral activity may act as a mediator of innate and adaptive immune mechanisms.

A distinct pathway of cell-mediated apoptosis initiated by granulysin.

Granulysin is an antimicrobial and tumoricidal molecule expressed in granules of CTL and NK cells. In this study, we show that granulysin damages cell membranes based upon negative charge, disrupts the transmembrane potential (Deltapsi) in mitochondria, and causes release of cytochrome c. Granulysin-induced apoptosis is blocked in cells overexpressing Bcl-2. Despite the release of cytochrome c, procaspase 9 is not processed. Nevertheless, activation of caspase 3 is observed in granulysin-treated cells, suggesting that granulysin activates a novel pathway of CTL- and NK cell-mediated death distinct from granzyme- and death receptor-induced apoptosis.

Bactericidal and tumoricidal activities of synthetic peptides derived from granulysin.

Granulysin, a 9-kDa protein localized to human CTL and NK cell granules, is cytolytic against tumor cells and microbes. Molecular modeling predicts that granulysin is composed of five alpha-helices separated by short loop regions. In this report, synthetic peptides corresponding to the linear granulysin sequence were characterized for lytic activity. Peptides corresponding to the central region of granulysin lyse bacteria, human cells, and synthetic liposomes, while peptides corresponding to the amino or carboxyl regions are not lytic. Peptides corresponding to either helix 2 or helix 3 lyse bacteria, while lysis of human cells and liposomes is dependent on the helix 3 sequence. Peptides in which positively charged arginine residues are substituted with neutral glutamine exhibit reduced lysis of all three targets. While reduction of recombinant 9-kDa granulysin increases lysis of Jurkat cells, reduction of cysteine-containing granulysin peptides decreases lysis of Jurkat cells. In contrast, lysis of bacteria by recombinant granulysin or by cysteine-containing granulysin peptides is unaffected by reducing conditions. Jurkat cells transfected with either CrmA or Bcl-2 are protected from lysis by recombinant granulysin or the peptides. Differential activity of granulysin peptides against tumor cells and bacteria may be exploited to develop specific antibiotics without toxicity for mammalian cells.