Glaucoma Rehabilitation Using ElectricAI Transcranial Stimulation (GREAT)-Optimizing Stimulation Protocol for Vision Enhancement Using an RCT.

Purpose: We compared the effect of three different transcranial electrical stimulation (tES) protocols delivered to the occipital lobe on peripheral vision in patients with glaucoma. Methods: A double-masked, placebo-controlled study was conducted with 35 patients with glaucoma. We compared three different tES protocols: anodal transcranial direct current stimulation (a-tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS) against sham stimulation. Each patient attended four stimulation sessions (a-tDCS, tACS, tRNS, and sham) in a random order with at least 48 hours between visits. Stimulation involved placing an anodal electrode over the occipital lobe (Oz) and cathodal electrode on the cheek for 20 minutes. High-resolution perimetry (HRP) and multifocal visual evoked potential (mfVEP) measurements were made before and immediately after stimulation. Changes in HRP detection accuracy/reaction time and mfVEP signal-to-noise ratio (SNR)/latency were analyzed using linear mixed models. Results: Compared to sham, HRP detection accuracy was significantly improved after a-tDCS in both the central 20-degree (b = 0.032, P = 0.018) and peripheral analysis (b = 0.051, P = 0.002). Additionally, mfVEP SNR was significantly increased (b = 0.016, P = 0.017) and the latency was shortened (b = -1.405, P = 0.04) by the a-tDCS in the central 20-degree analysis. In the peripheral analysis, there was a trend toward an enhancement of SNR after a-tDCS stimulation (b = 0.014, P = 0.052), but it did not reach statistical significance; latency was increased after tACS (b = 1.623, P = 0.041). No significant effects were found in comparison to other active tES protocols. Conclusions: A single session of a-tDCS enhances perceptual and electrophysiologic measures of vision in patients with glaucoma. However, the small magnitude of changes observed in HRP (3.2% for accuracy in central and 5.1% in peripheral) did not exceed previous test variability and may not be clinically meaningful. Translational Relevance: a-tDCS holds promise as a potential treatment for enhancing visual function. However, future studies are needed to evaluate the long-term effects and clinical relevance of this intervention using validated measures of perimetric changes in the visual field.

The undeclared use of third-party service providers in academic publishing is unethical: an epistemic reflection and scoping review.

There is a substantial body of scientific literature on the use of third-party services (TPS) by academics to assist as "publication consultants" in scholarly publishing. TPS provide a wide range of scholarly services to research teams that lack the equipment, skills, motivation, or time to produce a paper without external assistance. While services such as language editing, statistical support, or graphic design are common and often legitimate, some TPS also provide illegitimate services and send unsolicited e-mails (spam) to academics offering these services. Such illegitimate types of TPS have the potential to threaten the integrity of the peer-reviewed scientific literature. In extreme cases, for-profit agencies known as "paper mills" even offer fake scientific publications or authorship slots for sale. The use of such illegitimate services as well as the failure to acknowledge their use is an ethical violation in academic publishing, while the failure to declare support for a TPS can be considered a form of contract fraud. We discuss some literature on TPS, highlight services currently offered by ten of the largest commercial publishers and expect authors to be transparent about the use of these services in their publications. From an ethical/moral (i.e., non-commercial) point of view, it is the responsibility of editors, journals, and publishers, and it should be in their best interest to ensure that illegitimate TPS are identified and prohibited, while publisher-employed TPS should be properly disclosed in their publications.

Glaucoma Rehabilitation using ElectricAI Transcranial Stimulation (GREAT)-study protocol for randomized controlled trial using combined perceptual learning and transcranial electrical stimulation for vision enhancement.

BACKGROUND: Glaucoma patients with irreversible visual field loss often experience decreased quality of life, impaired mobility, and mental health challenges. Perceptual learning (PL) and transcranial electrical stimulation (tES) have emerged as promising interventions for vision rehabilitation, showing potential in restoring residual visual functions. The Glaucoma Rehabilitation using ElectricAI Transcranial stimulation (GREAT) project aims to investigate whether combining PL and tES is more effective than using either method alone in maximizing the visual function of glaucoma patients. Additionally, the study will assess the impact of these interventions on brain neural activity, blood biomarkers, mobility, mental health, quality of life, and fear of falling. METHODS: The study employs a three-arm, double-blind, randomized, superiority-controlled design. Participants are randomly allocated in a 1:1:1 ratio to one of three groups receiving: (1) real PL and real tES, (2) real PL and sham tES, and (3) placebo PL and sham tES. Each participant undergoes 10 sessions per block (~ 1 h each), with a total of three blocks. Assessments are conducted at six time points: baseline, interim 1, interim 2, post-intervention, 1-month post-intervention, and 2-month post-intervention. The primary outcome is the mean deviation of the 24-2 visual field measured by the Humphrey visual field analyzer. Secondary outcomes include detection rate in the suprathreshold visual field, balance and gait functions, and electrophysiological and biological responses. This study also investigates changes in neurotransmitter metabolism, biomarkers, self-perceived quality of life, and psychological status before and after the intervention. DISCUSSION: The GREAT project is the first study to assess the effectiveness of PL and tES in the rehabilitation of glaucoma. Our findings will offer comprehensive assessments of the impact of these treatments on a wide range of brain and vision-related metrics including visual field, neural activity, biomarkers, mobility, mental health, fear of falling, and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov NCT05874258 . Registered on May 15, 2023.

Harnessing brain plasticity to improve binocular vision in amblyopia: An evidence-based update.

Amblyopia is a developmental visual disorder resulting from atypical binocular experience in early childhood that leads to abnormal visual cortex development and vision impairment. Recovery from amblyopia requires significant visual cortex neuroplasticity, i.e. the ability of the central nervous system and its synaptic connections to adapt their structure and function. There is a high level of neuroplasticity in early development and, historically, neuroplastic responses to changes in visual experience were thought to be restricted to a "critical period" in early life. However, as our review now shows, the evidence is growing that plasticity of the adult visual system can also be harnessed to improve vision in amblyopia. Amblyopia treatment involves correcting refractive error to ensure clear and equal retinal image formation in both eyes, then, if necessary, promoting the use of the amblyopic eye by hindering or reducing visual input from the better eye through patching or pharmacologic therapy. Early treatment in children can lead to visual acuity gains and the development of binocular vision in some cases; however, many children do not respond to treatment, and many adults with amblyopia have historically been untreated or undertreated. Here we review the current evidence on how dichoptic training can be used as a novel binocular therapeutic approach to facilitate visual processing of input from the amblyopic eye and can simultaneously engage both eyes in a training task that requires binocular integration. It is a novel and promising treatment for amblyopia in both children and adults.

Vascular dysregulation in glaucoma: retinal vasoconstriction and normal neurovascular coupling in altitudinal visual field defects.

Purpose: Vision loss in glaucoma is not only associated with elevated intraocular pressure and neurodegeneration, but vascular dysregulation (VD) is a major factor. To optimize therapy, an improved understanding of concepts of predictive, preventive, and personalized medicine (3PM) is needed which is based on a more detailed understanding of VD pathology. Specifically, to learn if the root cause of glaucomatous vision loss is of neuronal (degeneration) or vascular origin, we now studied neurovascular coupling (NVC) and vessel morphology and their relationship to vision loss in glaucoma. Methods: In patients with primary open angle glaucoma (POAG) (n = 30) and healthy controls (n = 22), NVC was studied using dynamic vessel analyzer to quantify retinal vessel diameter before, during, and after flicker light stimulation to evaluate the dilation response following neuronal activation. Vessel features and dilation were then related to branch level and visual field impairment. Results: Retinal arterial and venous vessels had significantly smaller diameters in patients with POAG in comparison to controls. However, both arterial and venous dilation reached normal values during neuronal activation despite their smaller diameters. This was largely independent of visual field depth and varied among patients. Conclusions: Because dilation/constriction is normal, VD in POAG can be explained by chronic vasoconstriction which limits energy supply to retinal (and brain) neurons with subsequent hypo-metabolism ("silent" neurons) or neuronal cell death. We propose that the root cause of POAG is primarily of vascular and not neuronal origin. This understanding can help to better personalize POAG therapy of not only targeting eye pressure but also vasoconstriction to prevent low vision, slowing its progression and supporting recovery and restoration. Trial registration: ClinicalTrials.gov, # NCT04037384 on July 3, 2019.

Global brain network modularity dynamics after local optic nerve damage following noninvasive brain stimulation: an EEG-tracking study.

Tightly connected clusters of nodes, called communities, interact in a time-dependent manner in brain functional connectivity networks (FCN) to support complex cognitive functions. However, little is known if and how different nodes synchronize their neural interactions to form functional communities ("modules") during visual processing and if and how this modularity changes postlesion (progression or recovery) following neuromodulation. Using the damaged optic nerve as a paradigm, we now studied brain FCN modularity dynamics to better understand module interactions and dynamic reconfigurations before and after neuromodulation with noninvasive repetitive transorbital alternating current stimulation (rtACS). We found that in both patients and controls, local intermodule interactions correlated with visual performance. However, patients' recovery of vision after treatment with rtACS was associated with improved interaction strength of pathways linked to the attention module, and it improved global modularity and increased the stability of FCN. Our results show that temporal coordination of multiple cortical modules and intermodule interaction are functionally relevant for visual processing. This modularity can be neuromodulated with tACS, which induces a more optimal balanced and stable multilayer modular structure for visual processing by enhancing the interaction of neural pathways with the attention network module.

RoCS: Robotic Curriculum for young Surgeons.

Robotic-assisted procedures gain increasing acceptance for daily surgical routine. However, structured training programs are designed for surgeons with high expertise. Hence, a comprehensive training curriculum was established to ensure a basic competence in robotic abdominal surgery for young surgeons during their residency. The aim of the current work is to propose a feasible and effective training concept. The development process of this training curriculum is based on a comprehensive literature review which led to the concept of "robotic curriculum for young surgeons" (RoCS). It was implemented in the daily routine of a German university hospital starting in 2020. The robotic assessment questionnaire (RAQ) was used for electronic data collection. After the initial phase adjustments, it led to an improvement of the initial version of the curriculum. RoCS is a multimodal training program containing basic training through assistance at the operation table during robotic-assisted operations and basic console training. Key elements are the robotic team time-out (rTTO), perioperative process standardization including feasible personnel scheduling and useful procedure clustering into organ systems, procedural steps and procedural step complexity. Evaluation of standardized communication, performance assessment, patient factors and individual overall workload using NASA Task Load Index is realizable. Flexibility and adaptability to internal organization processes of surgical departments are the main advantages of the concept. RoCS is a strong training tool to meet the specific needs of young surgeons and evaluate their learning success of robotic procedural training. Furthermore, comparison within the different robotic systems should be considered. Further studies are needed to validate a multicenter concept design.

Nanomedicine and drug delivery to the retina: current status and implications for gene therapy.

Blindness affects more than 60 million people worldwide. Retinal disorders, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma, are the leading causes of blindness. Finding means to optimize local and sustained delivery of drugs or genes to the eye and retina is one goal to advance the development of new therapeutics. Despite the ease of accessibility of delivering drugs via the ocular surface, the delivery of drugs to the retina is still challenging due to anatomic and physiologic barriers. Designing a suitable delivery platform to overcome these barriers should enhance drug bioavailability and provide a safe, controlled, and sustained release. Current inventions for posterior segment treatments include intravitreal implants and subretinal viral gene delivery that satisfy these criteria. Several other novel drug delivery technologies, including nanoparticles, micelles, dendrimers, microneedles, liposomes, and nanowires, are now being widely studied for posterior segment drug delivery, and extensive research on gene delivery using siRNA, mRNA, or aptamers is also on the rise. This review discusses the current state of retinal drug/gene delivery and highlights future therapeutic opportunities.

Adaptive and Maladaptive Brain Functional Network Reorganization After Stroke in Hemianopia Patients: An Electroencephalogram-Tracking Study.

Objective: Hemianopia after occipital stroke is believed to be mainly due to local damage at or near the lesion site. However, magnetic resonance imaging studies suggest functional connectivity network (FCN) reorganization also in distant brain regions. Because it is unclear whether reorganization is adaptive or maladaptive, compensating for, or aggravating vision loss, we characterized FCNs electrophysiologically to explore local and global brain plasticity and correlated FCN reorganization with visual performance. Methods: Resting-state electroencephalography (EEG) was recorded in chronic, unilateral stroke patients and healthy age-matched controls (n = 24 each). This study was approved by the local ethics committee. The correlation of oscillating EEG activity was calculated with the imaginary part of coherence between pairs of regions of interest, and FCN graph theory metrics (degree, strength, clustering coefficient) were correlated with stimulus detection and reaction time. Results: Stroke brains showed altered FCNs in the alpha- and low beta-band in numerous occipital, temporal brain structures. On a global level, FCN had a less efficient network organization whereas on the local level node networks were reorganized especially in the intact hemisphere. Here, the occipital network was 58% more rigid (with a more "regular" network structure) whereas the temporal network was 32% more efficient (showing greater "small-worldness"), both of which correlated with worse or better visual processing, respectively. Conclusions: Occipital stroke is associated with both local and global FCN reorganization, but this can be both adaptive and maladaptive. We propose that the more "regular" FCN structure in the intact visual cortex indicates maladaptive plasticity, where less processing efficacy with reduced signal/noise ratio may cause the perceptual deficits in the intact visual field (VF). In contrast, reorganization in intact temporal brain regions is presumably adaptive, possibly supporting enhanced peripheral movement perception.

Restorative Neurology and Neuroscience: Celebrating the 40th volume of an academic journal.

Since the first issue of the academic journal Restorative Neurology and Neuroscience (RNN) was published in 1989, 40 volumes with a total of 1,550 SCI publications have helped advance basic and clinical sciences in the fields of central and peripheral nervous system rescue, regeneration, restoration and plasticity in experimental and clinical disorders. In this way RNN helped advance the development of a range of neuropsychiatric intervention across a broad spectrum of approaches such as drugs, training (rehabilitation), psychotherapy or neuromodulation with current stimulation. Today, RNN remains a focused, innovative and viable source of scientific information in the neurosciences with high visibility in an ever changing world of academic publishing.

Resting-state Functional Connectivity After Occipital Stroke.

BACKGROUND: Resting-state functional magnetic resonance imaging (rsfMRI) reflects spontaneous activation of cortical networks. After stroke, these networks reorganize, both due to structural lesion and reorganization of functional connectivity (FC). OBJECTIVE: We studied FC in chronic phase occipital stroke patients with homonymous visual field defects before and after repetitive transorbital alternating current stimulation (rtACS). METHODS: This spin-off study, embedded in the randomized, sham-controlled REVIS trial, comprised 16 chronic occipital stroke patients with visual field defect and 12 healthy control subjects. The patients underwent rsfMRI at baseline, after two weeks of rtACS or sham treatment, and after two months of treatment-free follow-up, whereas the control subjects were measured once. We used a multivariate regression connectivity model to determine mutual prediction accuracy between 74 cortical regions of interest. Additionally, the model parameters were included into a graph to analyze average path length, centrality eigenvector, centrality degree, and clustering of the network. The patients and controls at baseline and the two treatment groups were compared with multilevel modeling. RESULTS: Before treatment, the patients and controls had similar whole-network prediction accuracy and network parameters, whereas centrality eigenvector differed in perilesional regions, indicating local modification in connectivity. In line with behavioral results, neither prediction accuracy nor any network parameter changed systematically as a result of rtACS rehabilitation compared to sham. CONCLUSIONS: Whole-network FC showed no difference between occipital stroke patients and healthy population, congruent with the peripheral location of the visual network in relation to the high-density cortical core. rtACS treatment in the given setting did not affect FC.

Non-invasive brain microcurrent stimulation therapy of long-COVID-19 reduces vascular dysregulation and improves visual and cognitive impairment.

BACKGROUND: An effective treatment is needed for long-COVID patients which suffer from symptoms of vision and/or cognition impairment such as impaired attention, memory, language comprehension, or fatigue. OBJECTIVE: Because COVID-19infection causes reduced blood flow which may cause neuronal inactivation, we explored if neuromodulation with non-invasive brain stimulation using microcurrent (NIBS), known to enhance blood flow and neuronal synchronization, can reduce these symptoms. METHODS: Two female long-COVID patients were treated for 10-13 days with alternating current stimulation of the eyes and brain. While one patient (age 40) was infected with the SARS CoV-2 virus, the other (age 72) developed symptoms following AstraZeneca vaccination. Before and after therapy, cognition was assessed subjectively by interview and visual fields quantified using perimetry. One patient was also tested with a cognitive test battery and with a retinal dynamic vascular analyser (DVA), a surrogate marker of vascular dysregulation in the brain. RESULTS: In both patients NIBS markedly improved cognition and partially reversed visual field loss within 3-4 days. Cognitive tests in one patient confirmed recovery of up to 40-60% in cognitive subfunctions with perimetry results showing stable and visual field recovery even during follow-up. DVA showed that NIBS reduced vascular dysregulation by normalizing vessel dynamics (dilation/constriction), with particularly noticeable changes in the peripheral veins and arteries. CONCLUSIONS: NIBS was effective in improving visual and cognitive deficits in two confirmed SARS-COV-2 patients. Because recovery of function was associated with restoration of vascular autoregulation, we propose that (i) hypometabolic, "silent" neurons are the likely biological cause of long-COVID associated visual and cognitive deficits, and (ii) reoxygenation of these "silent" neurons provides the basis for neural reactivation and neurological recovery. Controlled trials are now needed to confirm these observations.

Interhemispheric Cortical Network Connectivity Reorganization Predicts Vision Impairment in Stroke.

Stroke is one of the main causes of disability in human beings, and when the occipital lobe is affected, this leads to partial vision loss (homonymous hemianopia). To understand brain mechanisms of vision loss and recovery, graph theory-based brain functional connectivity network (FCN) analysis was recently introduced. However, few brain network studies exist that have studied if the strength of the damaged FCN can predict the extent of functional impairment. We now characterized the brain FCN using deep neural network analysis to describe multiscale brain networks and explore their corresponding physiological patterns. In a group of 24 patients and 24 controls, Bi-directional long short-term memory (Bi-LSTM) was evaluated to reveal the cortical network pattern learning efficiency compared with other traditional algorithms. Bi-LSTM achieved the best balanced-overall accuracy of 73% with sensitivity of 70% and specificity and 75% in the low alpha band. This demonstrates that bi-directional learning can capture the brain network feature representation of both hemispheres. It shows that brain damage leads to reorganized FCN patterns with a greater number of functional connections of intermediate density in the high alpha band. Future studies should explore how this understanding of brain FCN can be used for clinical diagnostics and rehabilitation.

Reorganization of Brain Functional Connectivity Network and Vision Restoration Following Combined tACS-tDCS Treatment After Occipital Stroke.

Objective: Non-invasive brain stimulation (NIBS) is already known to improve visual field functions in patients with optic nerve damage and partially restores the organization of brain functional connectivity networks (FCNs). However, because little is known if NIBS is effective also following brain damage, we now studied the correlation between visual field recovery and FCN reorganization in patients with stroke of the central visual pathway. Method: In a controlled, exploratory trial, 24 patients with hemianopia were randomly assigned to one of three brain stimulation groups: transcranial direct current stimulation (tDCS)/transcranial alternating current stimulation (tACS) (ACDC); sham tDCS/tACS (AC); sham tDCS/sham tACS (Sham), which were compared to age-matched controls (n = 24). Resting-state electroencephalogram (EEG) was collected at baseline, after 10 days stimulation and at 2 months follow-up. EEG recordings were analyzed for FCN measures using graph theory parameters, and FCN small worldness of the network and long pairwise coherence parameter alterations were then correlated with visual field performance. Result: ACDC enhanced alpha-band FCN strength in the superior occipital lobe of the lesioned hemisphere at follow-up. A negative correlation (r = -0.80) was found between the intact visual field size and characteristic path length (CPL) after ACDC with a trend of decreased alpha-band centrality of the intact middle occipital cortex. ACDC also significantly decreased delta band coherence between the lesion and the intact occipital lobe, and coherence was enhanced between occipital and temporal lobe of the intact hemisphere in the low beta band. Responders showed significantly higher strength in the low alpha band at follow-up in the intact lingual and calcarine cortex and in the superior occipital region of the lesioned hemisphere. Conclusion: While ACDC decreases delta band coherence between intact and damaged occipital brain areas indicating inhibition of low-frequency neural oscillations, ACDC increases FCN connectivity between the occipital and temporal lobe in the intact hemisphere. When taken together with the lower global clustering coefficient in responders, these findings suggest that FCN reorganization (here induced by NIBS) is adaptive in stroke. It leads to greater efficiency of neural processing, where the FCN requires fewer connections for visual processing.

Spacetime in the brain: rapid brain network reorganization in visual processing and recovery.

Functional connectivity networks (FCN) are the physiological basis of brain synchronization to integrating neural activity. They are not rigid but can reorganize under pathological conditions or during mental or behavioral states. However, because mental acts can be very fast, like the blink of an eye, we now used the visual system as a model to explore rapid FCN reorganization and its functional impact in normal, abnormal and post treatment vision. EEG-recordings were time-locked to visual stimulus presentation; graph analysis of neurophysiological oscillations were used to characterize millisecond FCN dynamics in healthy subjects and in patients with optic nerve damage before and after neuromodulation with alternating currents stimulation and were correlated with visual performance. We showed that rapid and transient FCN synchronization patterns in humans can evolve and dissolve in millisecond speed during visual processing. This rapid FCN reorganization is functionally relevant because disruption and recovery after treatment in optic nerve patients correlated with impaired and recovered visual performance, respectively. Because FCN hub and node interactions can evolve and dissolve in millisecond speed to manage spatial and temporal neural synchronization during visual processing and recovery, we propose "Brain Spacetime" as a fundamental principle of the human mind not only in visual cognition but also in vision restoration.

Fluorescently Labeled PLGA Nanoparticles for Visualization In Vitro and In Vivo: The Importance of Dye Properties.

Fluorescently labeled nanoparticles are widely used for evaluating their distribution in the biological environment. However, dye leakage can lead to misinterpretations of the nanoparticles' biodistribution. To better understand the interactions of dyes and nanoparticles and their biological environment, we explored PLGA nanoparticles labeled with four widely used dyes encapsulated (coumarin 6, rhodamine 123, DiI) or bound covalently to the polymer (Cy5.5.). The DiI label was stable in both aqueous and lipophilic environments, whereas the quick release of coumarin 6 was observed in model media containing albumin (42%) or liposomes (62%), which could be explained by the different affinity of these dyes to the polymer and lipophilic structures and which we also confirmed by computational modeling (log PDPPC/PLGA: DiI-2.3, Cou6-0.7). The importance of these factors was demonstrated by in vivo neuroimaging (ICON) of the rat retina using double-labeled Cy5.5/Cou6-nanoparticles: encapsulated Cou6 quickly leaked into the tissue, whereas the stably bound Cy.5.5 label remained associated with the vessels. This observation is a good example of the possible misinterpretation of imaging results because the coumarin 6 distribution creates the impression that nanoparticles effectively crossed the blood-retina barrier, whereas in fact no signal from the core material was found beyond the blood vessels.

Non-invasive electrical brain stimulation for vision restoration after stroke: An exploratory randomized trial (REVIS).

BACKGROUND: Occipital strokes often cause permanent homonymous hemianopia leading to significant disability. In previous studies, non-invasive electrical brain stimulation (NIBS) has improved vision after optic nerve damage and in combination with training after stroke. OBJECTIVE: We explored different NIBS modalities for rehabilitation of hemianopia after chronic stroke. METHODS: In a randomized, double-blinded, sham-controlled, three-armed trial, altogether 56 patients with homonymous hemianopia were recruited. The three experiments were: i) repetitive transorbital alternating current stimulation (rtACS, n = 8) vs. rtACS with prior cathodal transcranial direct current stimulation over the intact visual cortex (tDCS/rtACS, n = 8) vs. sham (n = 8); ii) rtACS (n = 9) vs. sham (n = 9); and iii) tDCS of the visual cortex (n = 7) vs. sham (n = 7). Visual functions were evaluated before and after the intervention, and after eight weeks follow-up. The primary outcome was change in visual field assessed by high-resolution and standard perimetries. The individual modalities were compared within each experimental arm. RESULTS: Primary outcomes in Experiments 1 and 2 were negative. Only significant between-group change was observed in Experiment 3, where tDCS increased visual field of the contralesional eye compared to sham. tDCS/rtACS improved dynamic vision, reading, and visual field of the contralesional eye, but was not superior to other groups. rtACS alone increased foveal sensitivity, but was otherwise ineffective. All trial-related procedures were tolerated well. CONCLUSIONS: This exploratory trial showed safety but no main effect of NIBS on vision restoration after stroke. However, tDCS and combined tDCS/rtACS induced improvements in visually guided performance that need to be confirmed in larger-sample trials.NCT01418820 (clinicaltrials.gov).

Exploring the systemic delivery of a poorly water-soluble model drug to the retina using PLGA nanoparticles.

During the drug development process, many pharmacologically active compounds are discarded because of poor water solubility, but nanoparticle-based formulations are increasingly proposed as a solution for this problem. We therefore studied the distribution of nanoparticulate carriers and the delivery of their poorly water-soluble cargo to a structure of the central nervous system, the retina, under naive and pathological conditions. The lipophilic fluorescent dye coumarin 6 (Cou6) was encapsulated into poly(lactic-co-glycolic acid) PLGA nanoparticles (NPs). After intravenous administration in rats, we analyzed the distribution of cargo Cou6 and of the NP carrier covalently labeled with Cy5.5 in healthy animals and animals with optic nerve crush (ONC). In vivo real-time retina imaging revealed that Cou6 was rapidly released from PLGA NPs and penetrated the inner blood-retina barrier (BRB) within 15 min and PLGA NPs were gradually eliminated from the retinal blood circulation. Ex vivo microscopy of retinal flat mounts indicated that the Cou6 accumulated predominantly in the extracellular space and to a lesser extent in neurons. While the distribution of Cou6 in healthy animals and post ONC was comparable at early time point post-operation, the elimination of the NPs from the vessels was faster on day 7 post ONC. These results demonstrate the importance of considering different kinetics of nano-carrier and poorly water-soluble cargo, emphasizing the critical role of their parenchymal distribution, i.e. cellular/extracellular, and function of different physiological and pathological conditions.