Diagnosis of multiple sclerosis using optical coherence tomography supported by explainable artificial intelligence.

BACKGROUND/OBJECTIVES: Study of retinal structure based on optical coherence tomography (OCT) data can facilitate early diagnosis of relapsing-remitting multiple sclerosis (RRMS). Although artificial intelligence can provide highly reliable diagnoses, the results obtained must be explainable. SUBJECTS/METHODS: The study included 79 recently diagnosed RRMS patients and 69 age matched healthy control subjects. Thickness (Avg) and inter-eye difference (Diff) features are obtained in 4 retinal layers using the posterior pole protocol. Each layer is divided into six analysis zones. The Support Vector Machine plus Recursive Feature Elimination with Leave-One-Out Cross Validation (SVM-RFE-LOOCV) approach is used to find the subset of features that reduces dimensionality and optimises the performance of the classifier. RESULTS: SVM-RFE-LOOCV was used to identify OCT features with greatest capacity for early diagnosis, determining the area of the papillomacular bundle to be the most influential. A correlation was observed between loss of layer thickness and increase in functional disability. There was also greater functional deterioration in patients with greater asymmetry between left and right eyes. The classifier based on the top-ranked features obtained sensitivity = 0.86 and specificity = 0.90. CONCLUSIONS: There was consistency between the features identified as relevant by the SVM-RFE-LOOCV approach and the retinotopic distribution of the retinal nerve fibres and the optic nerve head. This simple method contributes to implementation of an assisted diagnosis system and its accuracy exceeds that achieved with magnetic resonance imaging of the central nervous system, the current gold standard. This paper provides novel insights into RRMS affectation of the neuroretina.

Influence of sex on chronic steroid-induced glaucoma: 24-Weeks follow-up study in rats.

The objective was to evaluate ocular changes based on sex in steroid-induced glaucoma models in rats comparing healthy controls, over 24 weeks follow-up. Eighty-nine Long-Evans rats (38 males and 51 females) with steroid-induced glaucoma were analysed. Two steroid-induced glaucoma models were generated by injecting poly-co-lactic-glycolic acid microspheres loaded with dexamethasone (MMDEX model) and dexamethasone-fibronectin (MMDEXAFIBRO model) into the ocular anterior chamber. Intraocular pressure was measured by rebound tonometer Tonolab®. Neuroretinal function was analysed using dark- and light-adapted electroretinography (Roland consult® RETIanimal ERG), and structure was analysed using optical coherence tomography (OCT Spectralis, Heidelberg® Engineering) using Retina Posterior Pole, Retinal Nerve Fibre Layer and Ganglion Cell Layer protocols over 24 weeks. Males showed statistically (p < 0.05) higher intraocular pressure measurements. In both sexes and models neuroretinal thickness tended to decrease over time. In the MMDEX model, males showed higher IOP values and greatest percentage thickness loss in the Ganglion Cell Layer (p = 0.015). Females receiving MMDEXAFIBRO experienced large fluctuations in thickness, a higher percentage loss (on average) in Retina Posterior Pole (p = 0.035), Retinal Nerve Fibre Layer and Ganglion Cell Layer than aged-matched males, and the highest thickness loss rate by mmHg. Although no difference was found by sex in dark- and light-adapted electroretinography, increased amplitude in photopic negative response was found in MMDEX males and MMDEXAFIBRO females at 12 weeks. Although both glaucoma models used dexamethasone, different intraocular pressure and neuroretinal changes were observed depending on sex and other influential cofactors (fibronectin). Both sex and the induced glaucoma model influenced neuroretinal degeneration.

Dramatic Differences between the Structural Susceptibility of the S1 Pre- and S2 Postfusion States of the SARS-CoV-2 Spike Protein to External Electric Fields Revealed by Molecular Dynamics Simulations.

In its prefusion state, the SARS-CoV-2 spike protein (similarly to other class I viral fusion proteins) is metastable, which is considered to be an important feature for optimizing or regulating its functions. After the binding process of its S1 subunit (S1) with ACE2, the spike protein (S) undergoes a dramatic conformational change where S1 splits from the S2 subunit, which then penetrates the membrane of the host cell, promoting the fusion of the viral and cell membranes. This results in the infection of the host cell. In a previous work, we showed-using large-scale molecular dynamics simulations-that the application of external electric fields (EFs) induces drastic changes and damage in the receptor-binding domain (RBD) of the wild-type spike protein, as well of the Alpha, Beta, and Gamma variants, leaving a structure which cannot be recognized anymore by ACE2. In this work, we first extend the study to the Delta and Omicron variants and confirm the high sensitivity and extreme vulnerability of the RBD of the prefusion state of S to moderate EF (as weak as 104 V/m), but, more importantly, we also show that, in contrast, the S2 subunit of the postfusion state of the spike protein does not suffer structural damage even if electric field intensities four orders of magnitude higher are applied. These results provide a solid scientific basis to confirm the connection between the prefusion-state metastability of the SARS-CoV-2 spike protein and its susceptibility to be damaged by EF. After the virus docks to the ACE2 receptor, the stable and robust postfusion conformation develops, which exhibits a similar resistance to EF (damage threshold higher than 108 V/m) like most globular proteins.

Continuous versus discrete robotic feedback for brain-computer interfaces aimed for neurorehabilitation.

Introduction: Brain-Computer Interfaces (BCI) can allow control of external devices using motor imagery (MI) decoded from electroencephalography (EEG). Although BCI have a wide range of applications including neurorehabilitation, the low spatial resolution of EEG, coupled to the variability of cortical activations during MI, make control of BCI based on EEG a challenging task. Methods: An assessment of BCI control with different feedback timing strategies was performed. Two different feedback timing strategies were compared, comprised by passive hand movement provided by a robotic hand orthosis. One of the timing strategies, the continuous, involved the partial movement of the robot immediately after the recognition of each time segment in which hand MI was performed. The other feedback, the discrete, was comprised by the entire movement of the robot after the processing of the complete MI period. Eighteen healthy participants performed two sessions of BCI training and testing, one with each feedback. Results: Significantly higher BCI performance (65.4 ± 17.9% with the continuous and 62.1 ± 18.6% with the discrete feedback) and pronounced bilateral alpha and ipsilateral beta cortical activations were observed with the continuous feedback. Discussion: It was hypothesized that these effects, although heterogenous across participants, were caused by the enhancement of attentional and closed-loop somatosensory processes. This is important, since a continuous feedback timing could increase the number of BCI users that can control a MI-based system or enhance cortical activations associated with neuroplasticity, important for neurorehabilitation applications.

A case report: Upper limb recovery from stroke related to SARS-CoV-2 infection during an intervention with a brain-computer interface.

COVID-19 may increase the risk of acute ischemic stroke that can cause a loss of upper limb function, even in patients with low risk factors. However, only individual cases have been reported assessing different degrees of hospitalization outcomes. Therefore, outpatient recovery profiles during rehabilitation interventions are needed to better understand neuroplasticity mechanisms required for upper limb motor recovery. Here, we report the progression of physiological and clinical outcomes during upper limb rehabilitation of a 41-year-old patient, without any stroke risk factors, which presented a stroke on the same day as being diagnosed with COVID-19. The patient, who presented hemiparesis with incomplete motor recovery after conventional treatment, participated in a clinical trial consisting of an experimental brain-computer interface (BCI) therapy focused on upper limb rehabilitation during the chronic stage of stroke. Clinical and physiological features were measured throughout the intervention, including the Fugl-Meyer Assessment for the Upper Extremity (FMA-UE), Action Research Arm Test (ARAT), the Modified Ashworth Scale (MAS), corticospinal excitability using transcranial magnetic stimulation, cortical activity with electroencephalography, and upper limb strength. After the intervention, the patient gained 8 points and 24 points of FMA-UE and ARAT, respectively, along with a reduction of one point of MAS. In addition, grip and pinch strength doubled. Corticospinal excitability of the affected hemisphere increased while it decreased in the unaffected hemisphere. Moreover, cortical activity became more pronounced in the affected hemisphere during movement intention of the paralyzed hand. Recovery was higher compared to that reported in other BCI interventions in stroke and was due to a reengagement of the primary motor cortex of the affected hemisphere during hand motor control. This suggests that patients with stroke related to COVID-19 may benefit from a BCI intervention and highlights the possibility of a significant recovery in these patients, even in the chronic stage of stroke.

Retinal neurodegeneration in patients with type 2 diabetes mellitus without diabetic retinopathy.

In diabetes mellitus (DM) patients retinal complications were typically considered part of a vascular process. Recent research suggests that retinal degeneration in DM might also be caused by a neuropathy that could precede microvascular alterations. The present work reviews the currently available bibliography about neurodegeneration in patients with type 2 DM (DM2) without diabetic retinopathy (DR). In patients with non-severe, early DM2 without DR and good metabolic control visual function parameters show early abnormalities that precede clinical DR (in which we diagnose with a conventional ophthalmological examination). Using optical coherence tomography (OCT) technology, a reduction in macular and peripapillary thickness has been observed in different studies. Recent researches suggest that systemic complications (especially ischaemia) and a possible microvascular alteration eventually contributes to retinal neurodegeneration, which opens the door to new studies that include new techniques for evaluating the microvascularization of the retinal layers.

Neurodegeneración retiniana en pacientes diabéticos tipo 2 sin retinopatía diabética / Retinal neurodegeneration in patients with type 2 diabetes mellitus without diabetic retinopathy

La retinopatía diabética (RD) tradicionalmente se ha considerado parte de un proceso vascular. Investigaciones recientes sugieren que la degeneración de la retina en la diabetes mellitus (DM) podría ser causada también por una neuropatía y que la neurodegeneración retiniana precedería a las alteraciones microvasculares. El presente artículo revisa la bibliografía existente sobre neurodegeneración en pacientes con DM tipo 2 (DM2) sin RD. En los pacientes con DM2 no severa, temprana, con buen control metabólico y sin RD, las pruebas de función visual muestran anormalidades precoces que anteceden a la aparición de la RD clínica (la que diagnosticamos con una exploración oftalmológica convencional). Utilizando la tomografía de coherencia óptica (OCT) se observa que en estos pacientes existe una disminución en el espesor de distintas capas de la retina, tanto en el área macular como peripapilar. Recientes estudios sugieren que las complicaciones sistémicas (especialmente la isquemia) y una posible alteración microvascular contribuyen a la neurodegeneración retiniana, lo que abre la puerta a nuevos estudios que incluyan nuevas técnicas de evaluación de la microvascularización de las capas internas de la retina como la angio-OCT (AU)

In diabetes mellitus (DM) patients retinal complications were typically considered part of a vascular process. Recent research suggests that retinal degeneration in DM might also be caused by a neuropathy that could precede microvascular alterations. The present work reviews the currently available bibliography about neurodegeneration in patients with type 2 DM (DM2) without diabetic retinopathy (DR). In patients with non-severe, early DM2 without DR and good metabolic control visual function parameters show early abnormalities that precede clinical DR (in which we diagnose with a conventional ophthalmological examination). Using optical coherence tomography (OCT) technology, a reduction in macular and peripapillary thickness has been observed in different studies. Recent researches suggest that systemic complications (especially ischaemia) and a possible microvascular alteration eventually contributes to retinal neurodegeneration, which opens the door to new studies that include new techniques for evaluating the microvascularization of the retinal layers (AU)

Analysis of Retinal Layers in Fibromyalgia Patients with Premium Protocol in Optical Tomography Coherence and Quality of Life.

PURPOSE: To evaluate the inner retinal layers in fibromyalgia (FM) patients compared to control subjects using posterior pole protocol (PPole) analysis in optical coherence tomography (OCT) and to correlate structural retinal changes with subjective quality of life. METHODS: Seventy-four eyes of healthy subjects and 55 eyes of those with FM were analyzed. All subjects underwent retinal evaluation using the PPole protocol for Spectralis OCT (Heidelberg Engineering) to obtain measurements of the retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) in the macular area. The EuroQol (EQ-5D) questionnaire and Fibromyalgia Impact Questionnaire (FIQ) were performed to analyze health-related quality of life. Additionally, the FM group was divided into three groups depending on the disease phenotype (atypical, depressive, and biological). RESULTS: Patients with FM presented with a reduction of the RNFL thickness compared to controls in 17/64 cells of the PPole area, and a reduction of the GCL thickness in 47/64 cells. Depressive FM phenotype showed the greatest number of cells with significant reduction compared with the control group in both RNFL and GCL layers. A correlation between temporal-inferior cells of the GCL and the EuroQol 5D questionnaire results was observed. CONCLUSIONS: Patients with FM present with a reduction of the inner retinal layers in the macular area. This degeneration correlates with disease severity/reduced quality of life in these patients. The PPole protocol for OCT is a non-invasive and fast tool that might help clinicians diagnose and monitor neurodegeneration in FM patients.

Diagnosis of multiple sclerosis using multifocal ERG data feature fusion.

The purpose of this paper is to implement a computer-aided diagnosis (CAD) system for multiple sclerosis (MS) based on analysing the outer retina as assessed by multifocal electroretinograms (mfERGs). MfERG recordings taken with the RETI-port/scan 21 (Roland Consult) device from 15 eyes of patients diagnosed with incipient relapsing-remitting MS and without prior optic neuritis, and from 6 eyes of control subjects, are selected. The mfERG recordings are grouped (whole macular visual field, five rings, and four quadrants). For each group, the correlation with a normative database of adaptively filtered signals, based on empirical model decomposition (EMD) and three features from the continuous wavelet transform (CWT) domain, are obtained. Of the initial 40 features, the 4 most relevant are selected in two stages: a) using a filter method and b) using a wrapper-feature selection method. The Support Vector Machine (SVM) is used as a classifier. With the optimal CAD configuration, a Matthews correlation coefficient value of 0.89 (accuracy = 0.95, specificity = 1.0 and sensitivity = 0.93) is obtained. This study identified an outer retina dysfunction in patients with recent MS by analysing the outer retina responses in the mfERG and employing an SVM as a classifier. In conclusion, a promising new electrophysiological-biomarker method based on feature fusion for MS diagnosis was identified.

Long-term corticosteroid-induced chronic glaucoma model produced by intracameral injection of dexamethasone-loaded PLGA microspheres.

PURPOSE: To evaluate a new chronic glaucoma model produced by intracameral injection of dexamethasone-loaded poly lactic-co-glycolic acid microspheres (Dex-PLGA-Ms) over six months. METHODS: Healthy rats received two injections (at baseline and Week 4) of Dex-PLGA-Ms into the anterior chamber of the right eye. Clinical signs and intraocular pressure (IOP) were weekly recorded. The structure of the retina and optic nerve was in vivo evaluated using optical coherence tomography (OCT) every two weeks and functionally using dark- and light-adapted electroretinography at 0-12-24 weeks. Histological studies were also performed. RESULTS: IOP progressively increased up to hypertension (23.22 ± 3.63 mmHg) in both eyes but did so later in left eyes. OCT quantified a decrease in full-thickness retina posterior pole (R), retinal-nerve-fiber layer (RNFL), and ganglion-cell layer (GCL) thickness up to 24 weeks. Right eyes showed higher neuroretinal thickness loss up to week 8. RNFL experienced the highest percentage thickness loss at the inferior-superior axis, while in GCL the inner sectors of the horizontal axis (Nasal-Temporal) suffered the greatest decrease in thickness. Retinal ganglion cell, photoreceptor, and intermediate cell functionality decreased over time. Increased deposition of collagen IV was also found in zonular fibers and the ciliary body. CONCLUSIONS: This work shows the usefulness of drug delivery systems, not to treat pathology but to induce it. Only two injections of Dex-PLGA-Ms in the anterior chamber of rat eyes were enough to progressively create ocular hypertension and subsequent functional and structural neuroretinal degeneration, at least over 6 months.

The SARS-CoV-2 spike protein is vulnerable to moderate electric fields.

Most of the ongoing projects aimed at the development of specific therapies and vaccines against COVID-19 use the SARS-CoV-2 spike (S) protein as the main target. The binding of the spike protein with the ACE2 receptor (ACE2) of the host cell constitutes the first and key step for virus entry. During this process, the receptor binding domain (RBD) of the S protein plays an essential role, since it contains the receptor binding motif (RBM), responsible for the docking to the receptor. So far, mostly biochemical methods are being tested in order to prevent binding of the virus to ACE2. Here we show, with the help of atomistic simulations, that external electric fields of easily achievable and moderate strengths can dramatically destabilise the S protein, inducing long-lasting structural damage. One striking field-induced conformational change occurs at the level of the recognition loop L3 of the RBD where two parallel beta sheets, believed to be responsible for a high affinity to ACE2, undergo a change into an unstructured coil, which exhibits almost no binding possibilities to the ACE2 receptor. We also show that these severe structural changes upon electric-field application also occur in the mutant RBDs corresponding to the variants of concern (VOC) B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil). Remarkably, while the structural flexibility of S allows the virus to improve its probability of entering the cell, it is also the origin of the surprising vulnerability of S upon application of electric fields of strengths at least two orders of magnitude smaller than those required for damaging most proteins. Our findings suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus without further biochemical processing. Moreover, the effect could be used for infection prevention purposes and also to develop technologies for in-vitro structural manipulation of S. Since the method is largely unspecific, it can be suitable for application to other mutations in S, to other proteins of SARS-CoV-2 and in general to membrane proteins of other virus types.

The use of optical coherence tomography in the evaluation of patients with bipolar disorder. / Utilidad de la tomografía de coherencia óptica en la evaluación de los pacientes con trastorno bipolar.

Bipolar disorder (BD) is a mental disorder characterised by episodes of extremal mood changes. In recent years, some researchers found neurodegeneration in patients with BD using Magnetic Resonance Imaging. Evaluation of the optic nerve and the retinal layers using optical coherence tomography (OCT) has proved to be a useful, non-invasive tool for diagnosis and monitoring of neurodegenerative diseases. Accordingly, a decrease in the retinal nerve fibre layer and the ganglion cell complex measured by OCT was found in patients with BD in different studies, suggesting that BD is a neurodegenerative process in addition to a psychiatric disorder. Therefore, the neuro-ophthalmological evaluation of these patients could be used as a marker for diagnosis of this disease. This work analyses literature on retinal degeneration in bipolar disorder patients, and evaluates the ability of OCT devices in the detection of neuronal degeneration affecting the different retinal layers in these patients, and its possible role in the diagnosis and monitoring of the disease.

Early diagnosis of multiple sclerosis by OCT analysis using Cohen's d method and a neural network as classifier.

BACKGROUND: The consequences of inflammation, demyelination, axonal degeneration and neuronal loss in the central nervous system, typical of the development of multiple sclerosis (MS), are manifested in thinning of the retina and optic nerve. The purpose of this work is to diagnose early-stage MS patients based on analysis of retinal layer thickness obtained by swept-source optical coherence tomography (SS-OCT). METHOD: OCT (Triton® SS-OCT device -Topcon, Tokyo, Japan-) recordings were obtained from 48 control subjects and 48 recently diagnosed MS patients. The following thicknesses were measured on a 45 × 60 grid: retinal nerve fibre layer (RNFL), ganglion cell layer (GCL+), GCL++, retinal thickness and choroid. Using Cohen's d effect size, it was determined the regions and layers with greatest capacity to discriminate between control subjects and patients. Points exceeding the threshold set were used as inputs for an automatic classifier: support vector machine and feed-forward neural network. RESULTS: In MS at clinical onset the layer with greatest discriminant capacity is GCL++ [AUC = 0.83] which exhibits a horseshoe-like macular topographic distribution. It is followed by retina, GCL+ and RNFL; choroidal thicknesses do not provide discriminatory capacity. Using a neural network as a classifier between controls and MS patients, obtains sensitivity of 0.98 and specificity of 0.98. CONCLUSIONS: This work suggest that OCT may serve as an important complementary role to other clinical tests, particularly regarding neurodegeneration. It is possible to characterise structural alterations in retina and diagnose early-stage MS with high degree of accuracy using OCT and artificial neural networks.

Formation of Periodic Nanoridge Patterns by Ultrashort Single Pulse UV Laser Irradiation of Gold.

A direct comparison of simulation and experimental results of UV laser-induced surface nanostructuring of gold is presented. Theoretical simulations and experiments are performed on an identical spatial scale. The experimental results have been obtained by using a laser wavelength of 248 nm and a pulse length of 1.6 ps. A mask projection setup is applied to generate a spatially periodic intensity profile on a gold surface with a sinusoidal shape and periods of 270 nm, 350 nm, and 500 nm. The formation of structures at the surface upon single pulse irradiation is analyzed by scanning and transmission electron microscopy (SEM and TEM). For the simulations, a hybrid atomistic-continuum model capable of capturing the essential mechanisms responsible for the nanostructuring process is used to model the interaction of the laser pulse with the gold target and the subsequent time evolution of the system. The formation of narrow ridges composed of two colliding side walls is found in the simulation as well as in the experiment and the structures generated as a result of the material processing are categorized depending on the range of applied fluencies and periodicities.

Brimonidine-LAPONITE® intravitreal formulation has an ocular hypotensive and neuroprotective effect throughout 6 months of follow-up in a glaucoma animal model.

Intravitreal administration is widely used in ophthalmological practice to maintain therapeutic drug levels near the neuroretina and because drug delivery systems are necessary to avoid reinjections and sight-threatening side effects. However, currently there is no intravitreal treatment for glaucoma. The brimonidine-LAPONITE® formulation was created with the aim of treating glaucoma for extended periods with a single intravitreal injection. Glaucoma was induced by producing ocular hypertension in two rat cohorts: [BRI-LAP] and [non-bri], with and without treatment, respectively. Eyes treated with brimonidine-LAPONITE® showed lower ocular pressure levels up to week 8 (p < 0.001), functional neuroprotection explored by scotopic and photopic negative response electroretinography (p = 0.042), and structural protection of the retina, retinal nerve fibre layer and ganglion cell layer (p = 0.038), especially on the superior-inferior axis explored by optical coherence tomography, which was corroborated by a higher retinal ganglion cell count (p = 0.040) using immunohistochemistry (Brn3a antibody) up to the end of the study (week 24). Furthermore, delayed neuroprotection was detected in the contralateral eye. Brimonidine was detected in treated rat eyes for up to 6 months. Brimonidine-LAPONITE® seems to be a potential sustained-delivery intravitreal drug for glaucoma treatment.