OBJECTIVE:To develop and prospectively evaluate a method of epileptic seizure detection combining heart rate and movement.METHODS:In this multicenter, in-home, prospective, video-controlled cohort study, nocturnal seizures were detected by heart rate (photoplethysmography) or movement (3-D accelerometry) in persons with epilepsy and intellectual disability. Participants with >1 monthly major seizure wore a bracelet (Nightwatch) on the upper arm at night for 2 to 3 months. Major seizures were tonic-clonic, generalized tonic >30 seconds, hyperkinetic, or others, including clusters (>30 minutes) of short myoclonic/tonic seizures. The video of all events (alarms, nurse diaries) and 10% completely screened nights were reviewed to classify major (needing an alarm), minor (needing no alarm), or no seizure. Reliability was tested by interobserver agreement. We determined device performance, compared it to a bed sensor (Emfit), and evaluated the caregivers' user experience.RESULTS:Twenty-eight of 34 admitted participants (1,826 nights, 809 major seizures) completed the study. Interobserver agreement (major/no major seizures) was 0.77 (95% confidence interval [CI] 0.65-0.89). Median sensitivity per participant amounted to 86% (95% CI 77%-93%); the false-negative alarm rate was 0.03 per night (95% CI 0.01-0.05); and the positive predictive value was 49% (95% CI 33%-64%). The multimodal sensor showed a better sensitivity than the bed sensor (n = 14, median difference 58%, 95% CI 39%-80%, p < 0.001). The caregivers' questionnaire (n = 33) indicated good sensor acceptance and usability according to 28 and 27 participants, respectively.CONCLUSION:Combining heart rate and movement resulted in reliable detection of a broad range of nocturnal seizures.

SummaryObjectiveAutomated seizure detection and alarming could improve quality of life and potentially prevent sudden, unexpected death in patients with severe epilepsy. As currently available systems focus on tonic–clonic seizures, we want to detect a broader range of seizure types, including tonic, hypermotor, and clusters of seizures.MethodsIn this multicenter, prospective cohort study, the nonelectroencephalographic (non‐EEG) signals heart rate and accelerometry were measured during the night in patients undergoing a diagnostic video‐EEG examination. Based on clinical video‐EEG data, seizures were classified and categorized as clinically urgent or not. Seizures included for analysis were tonic, tonic–clonic, hypermotor, and clusters of short myoclonic/tonic seizures. Features reflecting physiological changes in heart rate and movement were extracted. Detection algorithms were developed based on stepwise fulfillment of conditions during increases in either feature. A training set was used for development of algorithms, and an independent test set was used for assessing performance.ResultsNinety‐five patients were included, but due to sensor failures, data from only 43 (of whom 23 patients had 86 seizures, representing 402 h of data) could be used for analysis. The algorithms yield acceptable sensitivities, especially for clinically urgent seizures (sensitivity = 71–87%), but produce high false alarm rates (2.3–5.7 per night, positive predictive value = 25–43%). There was a large variation in the number of false alarms per patient.SignificanceIt seems feasible to develop a detector with high sensitivity, but false alarm rates are too high for use in clinical practice. For further optimization, personalization of algorithms may be necessary.

The respiratory rate is a vital parameter that can provide valuable information about the health condition of a patient. The extraction of respiratory information from photoplethysmographic signal (PPG) was actually encouraged by the reported results, our main goal being to obtain accurate respiratory rate estimation from the PPG signal. We developed a fusion algorithm that identifies the best derived respiratory signals, from which is possible to extract the respiratory rate; based on these, a global respiratory rate is computed using the proposed fusion algorithm. The algorithm is qualitatively tested on real PPG signals recorded by an acquisition system we implemented, using a reflection pulse oximeter sensor. Its performance is also statistically evaluated using benchmark dataset publically available from CapnoBase.Org.

Heart rate is a useful neurophysiological sign when monitoring seizures in patients with epilepsy. In an ambulatory setting, heart rate is measured with ECG involving electrodes on the skin. This method is uncomfortable which is burdensome for patients and is sensitive to motion artifacts, which decrease the usability of measurements. In this study, green light photoplethysmography, an optical technique arising from the fitness industry, was evaluated for usefulness in a medical setting. Simultaneous overnight measurements of HR with a commercially available optical heart rate (OHR) sensor and with ECG (HRECG) were performed in 7 patients with epilepsy. Overall, there was no significant difference between OHR and HRECG in random 10-minute periods during wakefulness (p=0.69) and sleep (p=1.00). The Bland-Altman analysis showed negligible mean differences. Limits of agreement were higher during wakefulness and during the occurrence of two seizures possibly because of less reliable HRECG measurements due to motion artifacts. Optical heart rate seems less sensitive to these motion artifacts, and measurements are more user-friendly. The optical heart rate sensor may fill the gap of systems for ambulatory heart rate monitoring and can be especially useful in the context of seizure detection in patients with epilepsy.

For people suffering from nocturnal epileptic seizures it is crucial to have a system that can detect such seizures in real-time. In this paper, we present a preclinical demonstrator for real-time detection of nocturnal seizures based on the heart rate. The system is built on the VITRUVIUS body sensor platform, which consists of a body hub (a smart phone) and sensors communicating via Bluetooth. The seizure detection application running on the body hub has an online classifier that is triggered by an adaptable cumulative sum (CUSUM) algorithm. In case of an event, an alarm message can be sent to the seizure monitoring application or to the caregiver's phone. We present the architecture of the system with emphasis on the detection algorithm and the applications. The off-line evaluation of the system on five patients achieved a sensitivity of 95% and a positive predictive value of 85%. The preliminary results are encouraging and the system will be implemented in a clinical trial at Kempenhaeghe epilepsy clinic in the Netherlands.

For people who are suffering from epilepsy (both diurnal and nocturnal) it is essential to have a system that can detect and alarm seizures in real-time. In this paper, we present a preclinical demonstrator for real-time detection of seizures based on heart rate. The system consists of a body hub (a smart phone having Bluetooth Low Energy and Android Operating System) and a MIO Alpha Watch which are connected via Bluetooth. The seizure detection application running on the body hub is using the output value of the heart rate to classify the data from the MIO Alpha. It can generate a local alarm followed by sending an SMS message when a seizure has been detected. The user has the possibility to set the alarm threshold for the absolute level of the heart rate, the temporal variation in the heart rate and to choose where to send the SMS. In addition, the application detects when the system is disconnected or when the sensor is not in contact with the skin. The preliminary results are encouraging and the application is available for the public.

Currently, gold nanorods can be synthesized in a wide range of sizes. However, for the intended biological applications gold nanorods with approximate dimensions 50 nm × 15 nm are used. We investigate by computer simulation the effect of particle dimensions on the optical and thermal properties in the context of the specific applications of photoacoustic imaging. In addition we discuss the influence of particle size in overcoming the following biophysical barriers when administrated in vivo: extravasation, avoidance of uptake by organs of the reticuloendothelial system, penetration through the interstitium, binding capability and uptake by the target cells. Although more complex biological influences can be introduced in future analysis, the present work illustrates that larger gold nanorods, designated by us as 'nanobig rods', may perform better at meeting the requirements for successful in vivo applications compared to their smaller counterparts, which are conventionally used.

Gold nanorods (AuNR) can be tailored to possess an intense and narrow longitudinal plasmon (LP) absorption peak in the far-red to near-infrared wavelength region, where tissue is relatively transparent to light. This makes AuNRs excellent candidates as contrast agents for photoacoustic imaging, and as photothermal therapeutic agents. The favorable optical properties of AuNR which depend on the physical parameters of shape, size and plasmonic coupling effects, are required to be stable during use. We investigate the changes that are likely to occur in these physical parameters in the setting of photothermal therapeutics, and the influence that these changes have on the optical properties and the capacity to achieve target cell death. To this end we study 3 sets of interactions: pulsed light with AuNR, AuNR with cells, and pulsed light with cells incubated with AuNR. In the first situation we ascertain the threshold value of fluence required for photothermal melting or reshaping of AuNR to shorter AuNR or nanospheres, which results in drastic changes in optical properties. In the second situation when cells are exposed to antibody-conjugated AuNR, we observe using transmission electron microscopy (TEM) that the particles are closely packed and clustered inside vesicles in the cells. Using dark-field microscopy we show that plasmonic interactions between AuNRs in this situation causes blue-shifting of the LP absorption peak. As a consequence, no direct lethal damage to cells can be inflicted by laser irradiation at the LP peak. On the other hand, using irradiation at the transverse peak (TP) wavelength in the green, at comparative fluences, extensive cell death can be achieved. We attribute this behavior on the one hand to the photoreshaping of AuNR into spheres and on the other hand to clustering of AuNR inside cells. Both effects create sufficiently high optical absorption at 532 nm, which otherwise would have been present at the LP peak. We discuss implications of these finding on the application of these particles in biomedicine.

Rod-shaped gold nanoparticles exhibit intense and narrow absorption peaks for light in the far-red and near-infrared wavelength regions, owing to the excitation of longitudinal plasmons. Light absorption is followed predominantly by non radiative de-excitation, and the released heat and subsequent temperature rise cause strong photoacoustic (optoacoustic) signals to be produced. This feature combined with the relative inertness of gold, and its favorable surface chemistry, which permits affinity biomolecule coupling, has seen gold nanorods (AuNR) attracting much attention as contrast agents and molecular probes for photoacoustic imaging. In this article we provide an short overview of the current status of the use of AuNR in molecular imaging using photoacoustics. We further examine the state of the art in various chemical, physical and biochemical phenomena that have implications for the future photoacoustic applications of these particles. We cover the route through fine-tuning of AuNR synthetic procedures, toxicity reduction by appropriate coatings, in vitro cellular interactions of AuNRs, attachment of targeting antibodies, in vivo fate of the particles and the effects of certain light interactions with the AuNR.

Recent reports [Smith and Korgel Langmuir 2008, 24, 644-649 and Smith et al. Langmuir 2009, 25, 9518-9524] have implicated certain hexadecyltrimethylammonium bromide (CTAB) products with iodide impurities, in the failure of a seed-mediated, silver and surfactant-assisted growth protocol, to produce gold nanorods. We used two of the three "suspect" CTAB products and a "good" CTAB product in the protocol, varying silver nitrate solutions in the growth solutions. We obtained excellent gold nanorod samples as witnessed in signature longitudinal plasmon peaks in optical extinction spectra, which we substantiated using electron microscopy. Analysis of these samples using inductively coupled plasma mass spectroscopy (ICP-MS) failed to detect iodide. We subsequently learnt from discussions with Smith et al. that different lot numbers within the same product had been analyzed by our respective laboratories. We can conclude that iodide impurities can vary significantly from lot to lot within a product, to such an extent that there is no guarantee that gold nanorods can be synthesized with one or other CTAB product. Conversely, labeling a CTAB product, identified by a product number or supplier name, as one whose use precludes the formation of nanorods, is also hasty.

An accurate estimation of optical absorption coefficient (microabs) and scattering coefficient (microsca) is important in characterizing nanoparticles for identifying or optimizing applications such as photothermal therapy and photoacoustic imaging. In this exciting period where several fascinating methods have been unveiled for the synthesis of various nanoparticles, the field is still lacking in the availability of efficient characterization methods. We introduce an accurate and simple methodology to optically characterize nanoparticles which could fill the gap. This is based on differential pathlength spectroscopy (DPS), a dual optical fiber approach, originally developed to detect cancer endoscopically by measuring the optical properties of tissue in small interrogation volumes. We expand its use to nanoparticles in a method that allows us to resolve the effects of microabs and microsca in the extinction coefficient of low concentration samples. We outline the measurement protocol using the DPS system and describe the analysis of the data taking additional inputs from electron microscopy and discrete dipole approximation (DDA) simulations. The DPS signal from the sample is first translated into the backscattering coefficient using a calibration constant. Further, the backscattering coefficient is converted via the simulated scattering phase function into the scattering coefficient. With this knowledge and extinction coefficient measured using a conventional photospectrometer, the absorption coefficient is calculated. We prove the validity of the method using spherical and rod-shaped gold nanoparticles, comparing the results with outputs from DDA simulations. We also briefly touch upon the dilemma of the choice of the appropriate dielectric function for gold at the nanoscale.

Gold nanorods have interesting optical properties due to surface plasmon resonance effects. A variety of biomedical applications of these particles have been envisaged and feasibilities demonstrated in imaging, sensing, and therapy based on the interactions of light with these particles. In order to correctly interpret experimental data and tailor the nanorods and their environments for optimal use in these applications, simulations of the optical properties of the particles under various conditions are essential. Of various numerical methods available, the discrete dipole approximation (DDA) approach implemented in the publicly available DDSCAT code is a powerful method that had proved popular for studying gold nanorods. However, there is as yet no universal agreement on the shape used to represent the nanorods and on the dielectric function of gold required for the simulations. We systematically study the influence of these parameters on simulated results. We find large variations in the position of plasmon resonance peaks, their amplitudes, and shapes of the spectra depending on the choice of the parameters. We discuss these in the light of experimental optical extinction spectra of gold nanorods synthesized in our laboratory. We show that much care should be taken and prudence applied before DDA results be used to interpret experimental data and to help characterize nanoparticles synthesized.

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