Comparison of Continuous Intracortical and Scalp Electroencephalography in Comatose Patients with Acute Brain Injury.

BACKGROUND: Depth electroencephalography (dEEG) is a recent invasive monitoring technique used in patients with acute brain injury. This study aimed to describe in detail the clinical manifestations of nonconvulsive seizures (NCSzs) with and without a surface EEG correlate, analyze their long-standing effects, and provide data that contribute to understanding the significance of certain scalp EEG patterns observed in critically ill patients. METHODS: We prospectively enrolled a cohort of 33 adults with severe acute brain injury admitted to the neurological intensive care unit. All of them underwent multimodal invasive monitoring, including dEEG. All patients were scanned on a 3T magnetic resonance imaging scanner at 6 months after hospital discharge, and mesial temporal atrophy (MTA) was calculated using a visual scale. RESULTS: In 21 (65.6%) of 32 study participants, highly epileptiform intracortical patterns were observed. A total of 11 (34.3%) patients had electrographic or electroclinical seizures in the dEEG, of whom 8 had both spontaneous and stimulus-induced (SI) seizures, and 3 patients had only spontaneous intracortical seizures. An unequivocal ictal scalp correlate was observed in only 3 (27.2%) of the 11 study participants. SI-NCSzs occurred during nursing care, medical procedures, and family visits. Subtle clinical manifestations, such as restlessness, purposeless stereotyped movements of the upper limbs, ventilation disturbances, jerks, head movements, hyperextension posturing, chewing, and oroalimentary automatisms, occurred during intracortical electroclinical seizures. MTA was detected in 18 (81.8%) of the 22 patients. There were no statistically significant differences between patients with MTA with and without seizures or status epilepticus. CONCLUSIONS: Most NCSzs in critically ill comatose patients remain undetectable on scalp EEG. SI-NCSzs frequently occur during nursing care, medical procedures, and family visits. Semiology of NCSzs included ictal minor signs and subtle symptoms, such as breathing pattern changes manifested as patient-ventilator dyssynchrony.

Digital Histopathological Discrimination of Label-Free Tumoral Tissues by Artificial Intelligence Phase-Imaging Microscopy.

Histopathology is the gold standard for disease diagnosis. The use of digital histology on fresh samples can reduce processing time and potential image artifacts, as label-free samples do not need to be fixed nor stained. This fact allows for a faster diagnosis, increasing the speed of the process and the impact on patient prognosis. This work proposes, implements, and validates a novel digital diagnosis procedure of fresh label-free histological samples. The procedure is based on advanced phase-imaging microscopy parameters and artificial intelligence. Fresh human histological samples of healthy and tumoral liver, kidney, ganglion, testicle and brain were collected and imaged with phase-imaging microscopy. Advanced phase parameters were calculated from the images. The statistical significance of each parameter for each tissue type was evaluated at different magnifications of 10×, 20× and 40×. Several classification algorithms based on artificial intelligence were applied and evaluated. Artificial Neural Network and Decision Tree approaches provided the best general sensibility and specificity results, with values over 90% for the majority of biological tissues at some magnifications. These results show the potential to provide a label-free automatic significant diagnosis of fresh histological samples with advanced parameters of phase-imaging microscopy. This approach can complement the present clinical procedures.

Application of Classification Algorithms to Diffuse Reflectance Spectroscopy Measurements for Ex Vivo Characterization of Biological Tissues.

Biological tissue identification in real clinical scenarios is a relevant and unsolved medical problem, particularly in the operating room. Although it could be thought that healthy tissue identification is an immediate task, in practice there are several clinical situations that greatly impede this process. For instance, it could be challenging in open surgery in complex areas, such as the neck, where different structures are quite close together, with bleeding and other artifacts affecting visual inspection. Solving this issue requires, on one hand, a high contrast noninvasive technique and, on the other hand, powerful classification algorithms. Regarding the technique, optical diffuse reflectance spectroscopy has demonstrated such capabilities in the discrimination of tumoral and healthy biological tissues. The complex signals obtained, in the form of spectra, need to be adequately computed in order to extract relevant information for discrimination. As usual, accurate discrimination relies on massive measurements, some of which serve as training sets for the classification algorithms. In this work, diffuse reflectance spectroscopy is proposed, implemented, and tested as a potential technique for healthy tissue discrimination. A specific setup is built and spectral measurements on several ex vivo porcine tissues are obtained. The massive data obtained are then analyzed for classification purposes. First of all, considerations about normalization, detrending and noise are taken into account. Dimensionality reduction and tendencies extraction are also considered. Featured spectral characteristics, principal component or linear discrimination analysis are applied, as long as classification approaches based on k-nearest neighbors (k-NN), quadratic discrimination analysis (QDA) or Naïve Bayes (NB). Relevant parameters about classification accuracy are obtained and compared, including ANOVA tests. The results show promising values of specificity and sensitivity of the technique for some classification algorithms, even over 95%, which could be relevant for clinical applications in the operating room.

Physically meaningful depolarization metric based on the differential Mueller matrix.

We present a novel depolarization metric for Mueller matrices based on the differential Mueller formalism. The proposed metric relies on the statistical interpretation of the differential Mueller matrix. We show that the differential depolarization index successfully quantifies depolarization even when applied to specific types of Mueller matrices for which some widely used depolarization metrics yield erroneous results. Moreover, the fact that the presented metric is directly linked to the variances and covariances of the elementary anisotropic properties of the sample makes it a valuable tool to quantify depolarization on a physically meaningful basis.

Superficial radially resolved fluorescence and 3D photochemical time-dependent model for photodynamic therapy.

Photodynamic therapy (PDT) dosimetric tools are crucial for treatment planning and noninvasive monitoring by means of fluorescence. Present approaches consider usually a 1D problem, a simple photochemical process, or a spatially homogeneous photosensitizer. In this work, a radially resolved superficial photosensitizer fluorescence and 3D photochemical time-dependent PDT model are presented. The model provides a time-dependent estimation of tissue fluorescence and the photosensitizer and singlet oxygen 3D concentrations. The model is applied to a basal cell carcinoma treated by Metvix topical photosensitizer protocol. The analysis shows the potentiality in treatment planning and monitoring. The fluorescence results are in agreement with previous measurements.

Cytotoxicity analysis of oxazine 4-perchlorate fluorescence nerve potential clinical biomarker for guided surgery.

Biological tissue discrimination is relevant in guided surgery. Nerve identification is critical to avoid potentially severe collateral damage. Fluorescence imaging by oxazine 4-perchlorate (O4P) has been recently proposed. In this work, the cytotoxicity of O4P on U87 human-derived glioma cells has been investigated as a function of concentration and operating room irradiation modes. A custom-built optical irradiation device was employed for controlled optical dosimetry. DNA damage and O4P intracellular localization was also investigated by immunofluorescence and confocal microscopy. The results show that concentration below 100 µM can be considered safe. These results contribute to the assessment of the feasibility of O4P as a nerve biomarker.

Polarimetry of birefringent biological tissues with arbitrary fibril orientation and variable incidence angle.

Polarimetric optical techniques such as polarization microscopy or polarization-sensitive optical coherence tomography normally assume that light is perpendicular to the sample surface and that fibrils of a birefringent biological tissue are arranged in a plane parallel to this surface. The approaches that describe quantitatively polarimetric data from tissues with nonparallel fibril orientation and/or off-axis incidence usually lack a rigorous theoretical analysis. We present a polarimetric model with arbitrary fibril orientation and/or variable incidence angle by means of the extended Jones matrix theory, the polar decomposition, and Poincaré equivalence theorem. The model, suitable for diagnosis or tissue structure analysis, is applied to articular cartilage.

Intra-class variability in diffuse reflectance spectroscopy: application to porcine adipose tissue.

Optical diffuse reflectance spectroscopy (DRS) has great potential in the study, diagnosis, and discrimination of biological tissues. Discrimination is based on massive measurements that conform training sets. These sets are then used to classify tissues according to the biomedical application. Classification accuracy depends strongly on the training dataset, which typically comes from different samples of the same class, and from different points of the same sample. The variability of these measurements is not usually considered and is assumed to be purely random, although it could greatly influence the results. In this work, spectral variations within and between samples of different animals of ex-vivo porcine adipose tissue are evaluated. Algorithms for normalization, dimensionality reduction by principal component analysis, and variability control are applied. The PC analysis shows the dataset variability, even when a variability removal algorithm is applied. The projected data appear grouped by animal in the PC space. Mahalanobis distance is calculated for every group, and an ANOVA test is performed in order to estimate the variability. The results confirm that the variability is not random and is dependent at least on the anatomical location and the specific animal. The variability magnitude is significant, particularly if the classification accuracy is needed to be high. As a consequence, it should be taken generally into account in classification problems.

FDTD-based Transcranial Magnetic Stimulation model applied to specific neurodegenerative disorders.

Non-invasive treatment of neurodegenerative diseases is particularly challenging in Western countries, where the population age is increasing. In this work, magnetic propagation in human head is modelled by Finite-Difference Time-Domain (FDTD) method, taking into account specific characteristics of Transcranial Magnetic Stimulation (TMS) in neurodegenerative diseases. It uses a realistic high-resolution three-dimensional human head mesh. The numerical method is applied to the analysis of magnetic radiation distribution in the brain using two realistic magnetic source models: a circular coil and a figure-8 coil commonly employed in TMS. The complete model was applied to the study of magnetic stimulation in Alzheimer and Parkinson Diseases (AD, PD). The results show the electrical field distribution when magnetic stimulation is supplied to those brain areas of specific interest for each particular disease. Thereby the current approach entails a high potential for the establishment of the current underdeveloped TMS dosimetry in its emerging application to AD and PD.

Polarimetric study of birefringent turbid media with three-dimensional optic axis orientation.

Recent approaches to the analysis of biological samples with three-dimensional linear birefringence orientation require numerical methods to estimate the best fit parameters from experimental measures. We present a novel analytical method for characterizing the intrinsic retardance and the three-dimensional optic axis orientation of uniform and uniaxial turbid media. It is based on a model that exploits the recently proposed differential generalized Jones calculus, remarkably suppressing the need for numerical procedures. The method is applied to the analysis of samples modeled with polarized sensitive Monte Carlo. The results corroborate its capacity to successfully characterize 3D linear birefringence in a straightforward way.

Photosensitizer absorption coefficient modeling and necrosis prediction during Photodynamic Therapy.

The development of accurate predictive models for Photodynamic Therapy (PDT) has emerged as a valuable tool to adjust the current therapy dosimetry to get an optimal treatment response, and definitely to establish new personal protocols. Several attempts have been made in this way, although the influence of the photosensitizer depletion on the optical parameters has not been taken into account so far. We present a first approach to predict the spatio-temporal variation of the photosensitizer absorption coefficient during PDT applied to dermatological diseases, taking into account the photobleaching of a topical photosensitizer. This permits us to obtain the photons density absorbed by the photosensitizer molecules as the treatment progresses and to determine necrosis maps to estimate the short term therapeutic effects in the target tissue. The model presented also takes into account an inhomogeneous initial photosensitizer distribution, light propagation in biological media and the evolution of the molecular concentrations of different components involved in the photochemical reactions. The obtained results allow to investigate how the photosensitizer depletion during the photochemical reactions affects light absorption by the photosensitizer molecules as the optical radiation propagates through the target tissue, and estimate the necrotic tumor area progression under different treatment conditions.

Thermal injury models for optical treatment of biological tissues: a comparative study.

The interaction of optical radiation with biological tissues causes an increase in the temperature that, depending on its magnitude, can provoke a thermal injury process in the tissue. The establishment of laser irradiation pathological limits constitutes an essential task, as long as it enables to fix and delimit a range of parameters that ensure a safe treatment in laser therapies. These limits can be appropriately described by kinetic models of the damage processes. In this work, we present and compare several models for the study of thermal injury in biological tissues under optical illumination, particularly the Arrhenius thermal damage model and the thermal dosimetry model based on CEM (Cumulative Equivalent Minutes) 43°C. The basic concepts that link the temperature and exposition time with the tissue injury or cellular death are presented, and it will be shown that they enable to establish predictive models for the thermal damage in laser therapies. The results obtained by both models will be compared and discussed, highlighting the main advantages of each one and proposing the most adequate one for optical treatment of biological tissues.

Polarimetric analysis of the human cornea measured by polarization-sensitive optical coherence tomography.

Corneal polarimetry measurement has been the object of several papers. The results of techniques like polarization-sensitive optical coherence tomography (PS-OCT), scanning laser polarimetry, or polarization microscopy are contradictory. Some studies propose a biaxial-like birefringence pattern, while others postulate that birefringence grows at corneal periphery. Several theoretical approaches were proposed for the interpretation of these measurements, but they usually lack accuracy and an adequate consideration of the nonnormal incidence on the tissue. We analyze corneal polarization effects measured by PS-OCT. In vivo and in vitro PS-OCT images of the human cornea are acquired. PS-OCT measurements are apparently not in agreement with the biaxial-like birefringence pattern. We present a polarimetric model of the human cornea based on the extended Jones matrix formalism applied to multilayered systems. We also apply the Poincaré equivalence theorem to extract optic axis orientation and birefringence. The results show that for a fibrils orientation pattern composed by alternating circular and radial fibrils, the birefringence is biaxial-like at the corneal center, and there is an almost circularly symmetric high-birefringence area at corneal periphery. The model could be useful for diagnosis of corneal diseases or corneal compensation in retinal polarimetric imaging.

Photodynamic effects on basal cell carcinoma with topical Photosensitizer.

Photodynamic therapy (PDT) is a potential cancer therapy used in several clinical fields. Its application in dermatology following a fixed protocol usually generates good results. However, some cases of basal cell carcinoma show tumour persistence. The poor response observed in this type of pathology, whose lesions penetrate in the deeper layers of the skin, could be attributed to an insufficient accumulation of the PS (Photosensitizer) in deeper tissues. The development of accurate models could propose the adequate treatment dosimetry for those problematic cases in order to maximize the efficiency of the PDT treatment outcome. In this work we present a PDT model that tries to predict the photodynamic effect on the skin affected by a basal cell carcinoma with a topically administered photosensitizer. The results obtained allow us to know the evolution of the cytotoxic agent in order to estimate the necrotic area adjusting parameters such as the optical power, the photosensitizer concentration, the incubation and exposition time or the diffusivity and permeability of the damaged tissue.

Efficient 3D numerical approach for temperature prediction in laser irradiated biological tissues.

Temperature prediction in biological tissues irradiated by an optical source is frequently required in some medical applications, like Thermotherapy, Hyperthermia or tissue ablation. In this work we propose a new numerical approach to solve the bio-heat equation. It is based on the two steps 3D modified Du Fort-Frankel algorithm, which allows a better convergence, more accuracy and a faster computation than previous numerical methods developed by other authors. The model also includes adaptive spatial mesh and time step refinement. These improved results for opto-thermal temperature distribution could be used for choosing appropriate laser treatment parameters in medical praxis.

Photochemical approach of photodynamic therapy applied to skin.

Photodynamic Therapy (PDT) is a recent treatment modality that allows malignant tissue destruction. The technique provides a localized effect and good cosmetic results. The application of PDT is based on the inoculation of a photosensitizer and the posterior irradiation by an optical source. This radiation chemically activates the drug and provokes reactions that lead to tissue necrosis. Nowadays there are fixed clinical PDT protocols that make use of a particular optical dose and photosensitizer amount. These parameters are independent of the patient and the lesion. In this work we present a PDT model that tries to predict the effect of the treatment on the tissue. The 3D optical propagation of radiation is calculated by means of the Radiation Transport Theory (RTT) model, solved via a Monte Carlo numerical model. Once the optical energy is obtained, a complex photochemical model is employed. This model takes into account the electronic transitions between molecular levels and particles concentrations. The data obtained allow us to estimate the destroyed area. The optical power of the source, the exposition time and the optochemical characteristics of the tissue can be varied. This implies that these parameters could be adjusted to the particular pathology we are dealing with. As a consequence, the treatment would be more efficient. We apply the model to the skin, due to the fact that PDT is commonly applied on it.

Application of polarimetry group theory for characterization of biological tissues via mueller coherency matrix analysis.

Optical characterization of biological tissues provides advantages like the non-invasive or non-contact characters, or an increased image resolution. The use of the polarization information, apart from the intensity, leads to new data for a better diagnosis. In this work, we use the Group Theory applied to polarimetry to analyse the polarization behaviour of samples. The SU(4)-O+(6) homomorphism allows us to obtain the Mueller Coherency matrix from the Mueller matrix, and applying the target decomposition theorem, which provides information on tissue structure and separates different polarization effects by means mainly of the eigenvalues and eigenvectors, tissue imaging contrast can be increased. The analysis is applied to glucose suspensions of polystyrene spheres of different concentrations, whose behaviour can be modelled by means of single or multiple scattering depending on the concentration, either in the Rayleigh or Mie regimes. The results could be applied to cell cultures, where cancerous cells grow without control, or even to some anemia pathologies, where the number of erythrocytes in blood decreases.

Modeling thermotherapy in vocal cords novel laser endoscopic treatment.

Vocal cords pathologies can be classified in difficulty of movement, lesion formation, and difficulty or lack of mucosal wave movement. There are therapies for the first two cases, but the last one presents nowadays no efficient solution. In this paper, a novel laser endoscopic thermotherapy treatment is proposed to improve vocal cords vibration in sulcus vocalis or slight scars by increasing temperature around 8 degrees C. To predict the availability of this treatment, a complete model of laser-tissue interaction is shown. Optical propagation radiation transport theory model is solved with a Monte Carlo approach, spatial-temporal thermal distributions are obtained via a bioheat equation, and thermal damage uses an Arrhenius integral. Two widely used lasers, Nd:YAG (1,064 nm) and KTP (532 nm), with different source powers, exposition times, and distances to vocal cords are considered to investigate the availability of an efficient and safe laser treatment.

Mueller matrix group theory formalism for tissue imaging polarimetry contrast increase.

Optical characterization techniques provide a new approach to diagnostic imaging, with features such as a noninvasive or nonionizing character, as long as a resolution improvement. Intensity based measurements could be not enough for certain cases, and polarization information should be also used as a contrast parameter. Imaging polarimetry could be useful in many biomedical applications like dermatology or ophthalmology. Furthermore, it could be applied to the study of internal tissues through the use of optical fiber endoscopes, much less invasive that conventional biopsy. In this work the use of polarization parameters like the entropy factor, polarization components crosstalks or linear and circular polarization degrees is proposed as a way of improving tissue imaging contrast.