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.

Is Mental Stress the Primary Cause of Glaucoma? / Ist Stress die primäre Ursache von Glaukom?

The prognosis of going blind is very stressful for patients diagnosed with "glaucoma". Worries and fear of losing independence is a constant mental burden, with secondary risks of depression and social isolation. But stress is not only a result of glaucoma but also a possible cause (risk factor). This should not be surprising, given that chronic stress can trigger "psychosomatic" organ dysfunctions anywhere in the body. Why should the organ "eye" be an exception? Indeed, glaucoma patients often suspect that severe emotional stress caused their visual field loss or "foggy vision". The hypothesis that stress is a possible cause of glaucoma is supported by different observations: (i) acute and chronic stress increases intraocular pressure and (ii) long-term stress can lead to vascular dysregulation of the microcirculation in the eye and brain ("Flammer's syndrome"), leading to partial hypoxia and hypoglycaemia (hypo-metabolism). Even if nerve cells do not die, they may then become inactive ("silent" neurons). (iii) Degenerative changes have been reported in the brain of glaucoma patients, affecting not only anterograde or transsynaptic areas of the central visual pathway, but degeneration is also found (iv) in brain areas involved in emotional appraisal and the physiological regulation of stress hormones. There are also psychological hints indicating that stress is a cause of glaucoma: (v) Glaucoma patients with Flammer's syndrome show typical personality traits that are associated with low stress resilience: they often have cold hands or feet, are ambitious (professionally successful), perfectionistic, obsessive, brooding and worrying a lot. (vi) If stress hormone levels and inflammation parameters are reduced in glaucoma patients by relaxation with meditation, this correlates with normalisation of intraocular pressure, and yet another clue is that (vii) visual field improvements after non-invasive current stimulation therapy, that are known to improve circulation and neuronal synchronisation, are much most effective in patients with stress resilient personalities. An appreciation of stress as a "cause" of glaucoma suggests that in addition to standard therapy (i) stress reduction through relaxation techniques should be recommended (e.g. meditation), and (ii) self-medication compliance should not be induced by kindling anxiety and worries with negative communication ("You will go blind!"), but communication should be positive ("The prognosis is optimistic").

How Nanoparticle Physicochemical Parameters Affect Drug Delivery to Cells in the Retina via Systemic Interactions.

Minor changes in the composition of poloxamer 188-modified, DEAE-dextran-stabilized (PDD) polybutylcyanoacrylate (PBCA) nanoparticles (NPs), by altering the physicochemical parameters (such as size or surface charge), can substantially influence their delivery kinetics across the blood-retina barrier (BRB) in vivo. We now investigated the physicochemical mechanisms underlying these different behaviors of NP variations at biological barriers and their influence on the cellular and body distribution. Retinal whole mounts from rats injected in vivo with fluorescent PBCA NPs were processed for retina imaging ex vivo to obtain a detailed distribution of NPs with cellular resolution in retinal tissue. In line with previous in vivo imaging results, NPs with a larger size and medium surface charge accumulated more readily in brain tissue, and they could be more easily detected in retinal ganglion cells (RGCs), demonstrating the potential of these NPs for drug delivery into neurons. The biodistribution of the NPs revealed a higher accumulation of small-sized NPs in peripheral organs, which may reduce the passage of these particles into brain tissue via a "steal effect" mechanism. Thus, systemic interactions significantly determine the potential of NPs to deliver markers or drugs to the central nervous system (CNS). In this way, minor changes of NPs' physicochemical parameters can significantly impact their rate of brain/body biodistribution.

Evaluation of Toxicity and Neural Uptake In Vitro and In Vivo of Superparamagnetic Iron Oxide Nanoparticles.

Superparamagnetic iron oxide nanoparticles (SPIO-NPs) have great potential to be used in different pharmaceutical applications, due to their unique and versatile physical and chemical properties. The aim of this study was to quantify in vitro cytotoxicity of dextran 70,000-coated SPIO-NPs labelled/unlabelled with rhodamine 123, in C6 glioma cells and primary hippocampal neural cells. In addition, we analyzed the in vitro and in vivo cellular uptake of labelled SPIO-NPs. The nanoparticles, with average size of 10⁻50 nm and polydispersity index of 0.37, were synthesized using Massart's co-precipitation method. The concentration-dependent cytotoxicity was quantified by using tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Intracellular localization of SPIO-NPs was detected by confocal laser microscopy. In vivo confocal neuroimaging (ICON) was performed on male Wistar rats after intravitreal injection followed by ex vivo retina whole mount analysis. When used for in vitro testing concentrations in the range of diagnostic and therapeutic dosages, SPIO-NPs proved to be non-cytotoxic on C6 glioma cells for up to 24 h incubation time. The hippocampal cell culture also did not show impaired viability at low doses after 24 h incubation. Our results indicate that our dextran-coated SPIO-NPs have the potential for in vivo drug delivery applications.

Cholinergic Potentiation of Restoration of Visual Function after Optic Nerve Damage in Rats.

Enhancing cortical plasticity and brain connectivity may improve residual vision following a visual impairment. Since acetylcholine plays an important role in attention and neuronal plasticity, we explored whether potentiation of the cholinergic transmission has an effect on the visual function restoration. To this end, we evaluated for 4 weeks the effect of the acetylcholinesterase inhibitor donepezil on brightness discrimination, visually evoked potentials, and visual cortex reactivity after a bilateral and partial optic nerve crush in adult rats. Donepezil administration enhanced brightness discrimination capacity after optic nerve crush compared to nontreated animals. The visually evoked activation of the primary visual cortex was not restored, as measured by evoked potentials, but the cortical neuronal activity measured by thallium autometallography was not significantly affected four weeks after the optic nerve crush. Altogether, the results suggest a role of the cholinergic system in postlesion cortical plasticity. This finding agrees with the view that restoration of visual function may involve mechanisms beyond the area of primary damage and opens a new perspective for improving visual rehabilitation in humans.

Dynamic reorganization of brain functional networks during cognition.

How does cognition emerge from neural dynamics? The dominant hypothesis states that interactions among distributed brain regions through phase synchronization give basis for cognitive processing. Such phase-synchronized networks are transient and dynamic, established on the timescale of milliseconds in order to perform specific cognitive operations. But unlike resting-state networks, the complex organization of transient cognitive networks is typically not characterized within the graph theory framework. Thus, it is not known whether cognitive processing merely changes the strength of functional connections or, conversely, requires qualitatively new topological arrangements of functional networks. To address this question, we recorded high-density EEG while subjects performed a visual discrimination task. We conducted an event-related network analysis (ERNA) where source-space weighted functional networks were characterized with graph measures. ERNA revealed rapid, transient, and frequency-specific reorganization of the network's topology during cognition. Specifically, cognitive networks were characterized by strong clustering, low modularity, and strong interactions between hub-nodes. Our findings suggest that dense and clustered connectivity between the hub nodes belonging to different modules is the "network fingerprint" of cognition. Such reorganization patterns might facilitate global integration of information and provide a substrate for a "global workspace" necessary for cognition and consciousness to occur. Thus, characterizing topology of the event-related networks opens new vistas to interpret cognitive dynamics in the broader conceptual framework of graph theory.

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.

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.

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.

Transcorneal alternating current stimulation induces EEG "aftereffects" only in rats with an intact visual system but not after severe optic nerve damage.

Noninvasive alternating current stimulation can induce vision restoration in patients with chronic optic nerve damage and results in electroencephalogram (EEG) aftereffects. To better understand the mechanisms of action, we studied such EEG "aftereffects" of transcorneal alternating current stimulation (tACS) at the chronic posttraumatic state in rats. EEG baseline was recorded from visual cortex under ketamine/xylazine narcosis of healthy rats and rats with chronic severe optic nerve crush. One week later, both groups were again anesthetized and stimulated transcorneally twice for 12 min each time. tACS-induced changes were compared with baseline EEG. Over the course of 65 min narcosis baseline EEG revealed a shift from a dominant delta power to theta. This shift was significantly delayed in lesioned animals compared with healthy controls. tACS applied during the late narcosis stage in normal rats led to significantly increased theta power with a parallel shift of the dominating peak to higher frequency which outlasted the stimulation period by 15 min (aftereffects). EEG in lesioned rats was not significantly changed. In rodents, tACS can induce neuroplasticity as shown by EEG aftereffects that outlast the stimulation period. But this requires a minimal level of brain activation because aftereffects are not seen when tACS is applied during deep anesthesia and not when applied to animals after severe optic nerve damage. We conclude that tACS is only effective to induce cortical plasticity when the the retina can be excited.

In vivo visualisation of nanoparticle entry into central nervous system tissue.

Because the potential neurotoxicity of nanoparticles is a significant issue, characterisation of nanoparticle entry into the brain is essential. Here, we describe an in vivo confocal neuroimaging method (ICON) of visualising the entry of fluorescent particles into the parenchyma of the central nervous system (CNS) in live animals using the retina as a model. Rats received intravenous injections of fluorescence-labelled polybutyl cyanoacrylate nanoparticles that had been synthesised by a standard miniemulsion polymerisation process. We performed live recording with ICON from before and up to 9 days after particle injection and took photomicrographs of the retina. In addition, selective retrograde labelling of the retinal ganglion cells was achieved by stereotaxic injection of a fluorescent dye into the superior colliculus. Using ICON, we observed vascular kinetics of nanoparticles (wash-in within seconds), their passage to the retina parenchyma (within minutes) and their distribution (mainly cellular) under in vivo conditions. For the detection of cell loss--which is important for the evaluation of toxic effects--in another experiment, we semi-quantitatively analysed the selectively labelled retinal neurons. Our results suggest that the dye per se does not lead to neuronal death. With ICON, it is possible to study nanoparticle kinetics in the retina as a model of the blood-brain barrier. Imaging data can be acquired within seconds after the injection, and the long-term fate of cellular uptake can be followed for many days to study the cellular/extracellular distribution of the nanoparticles. ICON is thus an effective and meaningful tool to investigate nanoparticle/CNS interactions.

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.

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.

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.

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.

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.

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.

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.

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.

Ocular Dominance and Functional Asymmetry in Visual Attention Networks.

Purpose: The dorsal attention network (DAN) and the ventral attention network (VAN) are known to support visual attention, but the influences of ocular dominance on the attention networks are unclear. We aimed to explore how visual cortical asymmetry of the attention networks correlate with neurophysiological oscillation and connectivity markers of attentional processes. Methods: An oddball task with concentric circle stimuli of three different sizes (i.e., spot size of 5°, 20°, or 30° of visual angle) was used to vary task difficulty. Event-related oscillations and interareal communication were tested with an electroencephalogram-based visual evoked components as a function of ocular dominance in 30 healthy subjects. Results: Accuracy rates were higher in the dominant eyes compared with the nondominant eyes. Compared with the nondominant eyes, the dominant eyes had higher theta, low-alpha, and low-beta powers and lower high-alpha powers within the nodes of VAN and DAN. Furthermore, visual information processed by the dominant and nondominant eye had different fates, that is, the dominant eyes mainly relied on theta and low-alpha connectivity within both the VAN and the DAN, whereas the nondominant eyes mainly relied on theta connectivity within the VAN and high-alpha connectivity within the DAN. The difference in accuracy rate between the two eyes was correlated with the low-alpha oscillations in the anterior DAN area and low-alpha connectivity of the left DAN. Conclusions: The ocular dominance processing and interareal communication reveal a cortical asymmetry underlying attention, and this reflects a two-way modulatory mechanism within attention networks in the human brain.