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.

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.

Mindfulness Meditation Reduces Intraocular Pressure, Lowers Stress Biomarkers and Modulates Gene Expression in Glaucoma: A Randomized Controlled Trial.

BACKGROUND: Reducing intraocular pressure (IOP) in primary open-angle glaucoma (POAG) is currently the only approach to prevent further optic nerve head damage. However, other mechanisms such as ischemia, oxidative stress, glutamate excitotoxicity, neurotrophin loss, inflammation/glial activation, and vascular dysregulation are not addressed. Because stress is a key risk factor affecting these mechanisms, we evaluated whether mindfulness-based stress reduction can lower IOP and normalize typical stress biomarkers. MATERIALS AND METHODS: In a prospective, randomized trial 90 POAG patients (180 eyes; age above 45 y) were assigned to a waitlist control or mindfulness meditation group which practiced daily for 21 days. We measured IOP (primary endpoint), quality of life (QOL), stress-related serum biomarkers [cortisol, ß-endorphins, IL6, TNF-α, brain-derived neurotrophic factor (BDNF), reactive oxygen species (ROS), total antioxidant capacity (TAC)], and whole genome expression. RESULTS: Between-group comparisons revealed significantly lowered IOP in meditators (OD: 18.8 to 12.7, OS 19.0 to 13.1 mm Hg) which correlated with significantly lowered stress-biomarker levels including cortisol (497.3 to 392.3 ng/mL), IL6 (2.8 to 1.5 ng/mL), TNF-α (57.1 to 45.4 pg/mL), ROS (1625 to 987 RLU/min/104 neutrophils), and elevated ß-endorphins (38.4 to 52.7 pg/mL), BDNF (56.1 to 83.9 ng/mL), and TAC (5.9 to 9.3) (all P<0.001). These changes correlated well with gene expression profiling. Meditators improved in QOL (P<0.05). CONCLUSIONS: A short course of mindfulness-based stress reduction by meditation in POAG, reduces IOP, improves QOL, normalizes stress biomarkers, and positively modifies gene expression. Mindfulness meditation can be recommended as adjunctive therapy for POAG.

Mental stress as consequence and cause of vision loss: the dawn of psychosomatic ophthalmology for preventive and personalized medicine.

The loss of vision after damage to the retina, optic nerve, or brain has often grave consequences in everyday life such as problems with recognizing faces, reading, or mobility. Because vision loss is considered to be irreversible and often progressive, patients experience continuous mental stress due to worries, anxiety, or fear with secondary consequences such as depression and social isolation. While prolonged mental stress is clearly a consequence of vision loss, it may also aggravate the situation. In fact, continuous stress and elevated cortisol levels negatively impact the eye and brain due to autonomous nervous system (sympathetic) imbalance and vascular dysregulation; hence stress may also be one of the major causes of visual system diseases such as glaucoma and optic neuropathy. Although stress is a known risk factor, its causal role in the development or progression of certain visual system disorders is not widely appreciated. This review of the literature discusses the relationship of stress and ophthalmological diseases. We conclude that stress is both consequence and cause of vision loss. This creates a vicious cycle of a downward spiral, in which initial vision loss creates stress which further accelerates vision loss, creating even more stress and so forth. This new psychosomatic perspective has several implications for clinical practice. Firstly, stress reduction and relaxation techniques (e.g., meditation, autogenic training, stress management training, and psychotherapy to learn to cope) should be recommended not only as complementary to traditional treatments of vision loss but possibly as preventive means to reduce progression of vision loss. Secondly, doctors should try their best to inculcate positivity and optimism in their patients while giving them the information the patients are entitled to, especially regarding the important value of stress reduction. In this way, the vicious cycle could be interrupted. More clinical studies are now needed to confirm the causal role of stress in different low vision diseases to evaluate the efficacy of different anti-stress therapies for preventing progression and improving vision recovery and restoration in randomized trials as a foundation of psychosomatic ophthalmology.

Electrical brain stimulation induces dendritic stripping but improves survival of silent neurons after optic nerve damage.

Repetitive transorbital alternating current stimulation (rtACS) improves vision in patients with chronic visual impairments and an acute treatment increased survival of retinal neurons after optic nerve crush (ONC) in rodent models of visual system injury. However, despite this protection no functional recovery could be detected in rats, which was interpreted as evidence of "silent survivor" cells. We now analysed the mechanisms underlying this "silent survival" effect. Using in vivo microscopy of the retina we investigated the survival and morphology of fluorescent neurons before and after ONC in animals receiving rtACS or sham treatment. One week after the crush, more neurons survived in the rtACS-treated group compared to sham-treated controls. In vivo imaging further revealed that in the initial post-ONC period, rtACS induced dendritic pruning in surviving neurons. In contrast, dendrites in untreated retinae degenerated slowly after the axonal trauma and neurons died. The complete loss of visual evoked potentials supports the hypothesis that cell signalling is abolished in the surviving neurons. Despite this evidence of "silencing", intracellular free calcium imaging showed that the cells were still viable. We propose that early after trauma, complete dendritic stripping following rtACS protects neurons from excitotoxic cell death by silencing them.

Alternating Current Stimulation for Vision Restoration after Optic Nerve Damage: A Randomized Clinical Trial.

BACKGROUND: Vision loss after optic neuropathy is considered irreversible. Here, repetitive transorbital alternating current stimulation (rtACS) was applied in partially blind patients with the goal of activating their residual vision. METHODS: We conducted a multicenter, prospective, randomized, double-blind, sham-controlled trial in an ambulatory setting with daily application of rtACS (n = 45) or sham-stimulation (n = 37) for 50 min for a duration of 10 week days. A volunteer sample of patients with optic nerve damage (mean age 59.1 yrs) was recruited. The primary outcome measure for efficacy was super-threshold visual fields with 48 hrs after the last treatment day and at 2-months follow-up. Secondary outcome measures were near-threshold visual fields, reaction time, visual acuity, and resting-state EEGs to assess changes in brain physiology. RESULTS: The rtACS-treated group had a mean improvement in visual field of 24.0% which was significantly greater than after sham-stimulation (2.5%). This improvement persisted for at least 2 months in terms of both within- and between-group comparisons. Secondary analyses revealed improvements of near-threshold visual fields in the central 5° and increased thresholds in static perimetry after rtACS and improved reaction times, but visual acuity did not change compared to shams. Visual field improvement induced by rtACS was associated with EEG power-spectra and coherence alterations in visual cortical networks which are interpreted as signs of neuromodulation. Current flow simulation indicates current in the frontal cortex, eye, and optic nerve and in the subcortical but not in the cortical regions. CONCLUSION: rtACS treatment is a safe and effective means to partially restore vision after optic nerve damage probably by modulating brain plasticity. This class 1 evidence suggests that visual fields can be improved in a clinically meaningful way. TRIAL REGISTRATION: ClinicalTrials.gov NCT01280877.

Preclinical model of transcorneal alternating current stimulation in freely moving rats.

PURPOSE: Transcorneal alternating current stimulation (tACS) has become a promising tool to modulate brain functions and treat visual diseases. To understand the mechanisms of action a suitable animal model is required. However, because existing animal models employ narcosis, which interferes with brain oscillations and stimulation effects, we developed an experimental setup where current stimulation via the eye and flicker light stimulation can be applied while simultaneously recording local field potentials in awake rats. METHOD: tACS was applied in freely-moving rats (N = 24) which had wires implanted under their upper eye lids. Field potential recordings were made in visual cortex and superior colliculus. To measure visual evoked responses, rats were exposed to flicker-light using LEDs positioned in headset spectacles. RESULTS: Corneal electrodes and recording assemblies were reliably operating and well tolerated for at least 4 weeks. Transcorneal stimulation without narcosis did not induce any adverse reactions. Stable head stages allowed repetitive and long-lasting recordings of visual and electrically evoked potentials in freely moving animals. Shape and latencies of electrically evoked responses measured in the superior colliculus and visual cortex indicate that specific physiological responses could be recorded after tACS. CONCLUSIONS: Our setup allows the stimulation of the visual system in unanaesthetised rodents with flicker light and transcorneally applied current travelling along the physiological signalling pathway. This methodology provides the experimental basis for further studies of recovery and restoration of vision.

Retinal origin of electrically evoked potentials in response to transcorneal alternating current stimulation in the rat.

PURPOSE: Little is known about the physiological mechanisms underlying the reported therapeutic effects of transorbital alternating current stimulation (ACS) in vision restoration, or the origin of the recorded electrically evoked potentials (EEPs) during such stimulation. We examined the issue of EEP origin and electrode configuration for transorbital ACS and characterized the physiological responses to CS in different structures of the visual system. METHODS: We recorded visually evoked potentials (VEPs) and EEPs from the rat retina, visual thalamus, tectum, and visual cortex. The VEPs were evoked by light flashes and EEPs were evoked by electric stimuli delivered by two electrodes placed either together on the same eye or on the eyeball and in the neck. Electrically evoked potentials and VEPs were recorded before and after bilateral intraorbital injections of tetrodotoxin that blocked retinal ganglion cell activity. RESULTS: Tetrodotoxin abolished VEPs at all levels in the visual pathway, confirming successful blockage of ganglion cell activity. Tetrodotoxin also abolished EEPs and this effect was independent of the stimulating electrode configurations. CONCLUSIONS: Transorbital electrically evoked responses in the visual pathway, irrespective of reference electrode placement, are initiated by activation of the retina and not by passive conductance and direct activation of neurons in other visual structures. Thus, placement of stimulating electrodes exclusively around the eyeball may be sufficient to achieve therapeutic effects.

Brain functional connectivity network breakdown and restoration in blindness.

OBJECTIVE: To characterize brain functional connectivity in subjects with prechiasmatic visual system damage and relate functional connectivity features to extent of vision loss. METHODS: In this case-control study, resting-state, eyes-closed EEG activity was recorded in patients with partial optic nerve damage (n = 15) and uninjured controls (n = 13). We analyzed power density and functional connectivity (coherence, Granger causality), the latter as (1) between-areal coupling strength and (2) individually thresholded binary graphs. Functional connectivity was then modulated by noninvasive repetitive transorbital alternating current stimulation (rtACS; 10 days, 40 minutes daily; n = 7; sham, n = 8) to study how this would affect connectivity networks and perception. RESULTS: Patients exhibited lower spectral power (p = 0.005), decreased short- (p = 0.015) and long-range (p = 0.033) coherence, and less densely clustered coherence networks (p = 0.025) in the high-alpha frequency band (11-13 Hz). rtACS strengthened short- (p = 0.003) and long-range (p = 0.032) alpha coherence and this was correlated with improved detection abilities (r = 0.57, p = 0.035) and processing speed (r = 0.56, p = 0.049), respectively. CONCLUSION: Vision loss in the blind is caused not only by primary tissue damage but also by a breakdown of synchronization in brain networks. Because visual field improvements are associated with resynchronization of alpha band coherence, brain connectivity is a key component in partial blindness and in restoration of vision.

Evaluation of two treatment outcome prediction models for restoration of visual fields in patients with postchiasmatic visual pathway lesions.

Visual functions of patients with visual field defects after acquired brain injury affecting the primary visual pathway can be improved by means of vision restoration training. Since the extent of the restored visual field varies between patients, the prediction of treatment outcome and its visualization may help patients to decide for or against participating in therapies aimed at vision restoration. For this purpose, two treatment outcome prediction models were established based on either self-organizing maps (SOMs) or categorical regression (CR) to predict visual field change after intervention by several features that were hypothesized to be associated with vision restoration. Prediction was calculated for visual field changes recorded with High Resolution Perimetry (HRP). Both models revealed a similar predictive quality with the CR model being slightly more beneficial. Predictive quality of the SOM model improved when using only a small number of features that exhibited a higher association with treatment outcome than the remaining features, i.e. neighborhood activity and homogeneity within the surrounding 5° visual field of a given position, together with its residual function and distance to the scotoma border. Although both models serve their purpose, these were not able to outperform a primitive prediction rule that attests the importance of areas of residual vision, i.e. regions with partial visual field function, for vision restoration.

Noninvasive transorbital alternating current stimulation improves subjective visual functioning and vision-related quality of life in optic neuropathy.

BACKGROUND: Noninvasive repetitive transorbital alternating current stimulation (rtACS) can improve visual field size in patients with optic nerve damage, but it is not known if this is of subjective relevance. We now assessed patient reported outcomes to determine the association between visual field changes and vision-related quality of life (QoL). METHODS: Patients having visual field impairments long after optic nerve damage (mean lesion age 5.5 years) were randomly assigned to a rtACS (n = 24) or sham stimulation group (n = 18). Visual fields and patient reported outcome measures (vision-related QoL: National Eye Institute Visual Function Questionnaire, NEI-VFQ and health-related QoL: Short Form Health Survey, SF-36) were collected before and after a 10-day treatment course with daily sessions of 20 to 40 minutes. The primary outcome measure was the percent change from baseline of detection ability (DA) in defective visual field sectors as defined by computer-based high resolution perimetry (HRP). Secondary outcome parameters included further HRP parameters as well as static and kinetic perimetry results. Changes in QoL measures were correlated with changes in primary and secondary outcome measures in both groups. RESULTS: DA increase in the defective visual field was significantly larger after rtACS (41.1 ± 78.9%, M ± SD) than after sham stimulation (13.6 ± 26.3%), P < 0.05. While there was a significant increase of DA in the whole tested HRP visual field after rtACS (26.8 ± 76.7%, P < 0.05), DA in sham-stimulation patients remained largely unchanged (2.7 ± 20.2%, ns). Results of secondary outcome measures (static and kinetic perimetry) provided further evidence of rtACS efficacy. Improvements in NEI-VFQ subscale "general vision" were observed in both groups but were larger in the rtACS group (11.3 ± 13.5, Z = -3.21, P < 0.001) than in the sham group (4.2 ± 9.4, Z = -1.73, P < 0.05) with a significant difference between groups (Z = -1.71, P < 0.05). DA change and some NEI-VFQ domains were correlated (r = 0.29, P < 0.05), but no significant correlations were observed between DA and SF-36 results. CONCLUSIONS: rtACS facilitates vision restoration after unilateral, long-term optic nerve lesion as assessed both by objective DA changes and improvements in some NEI-VFQ subscales. Both were positively but low correlated, which suggests that factors other than visual field size also contribute to improved vision-related QoL.

Repetitive transorbital alternating current stimulation in optic neuropathy.

BACKGROUND: Visual field defects after optic nerve damage typically show a limited capacity for spontaneous and treatment-induced recovery. OBJECTIVE: Repetitive transorbital alternating current stimulation (rtACS) was applied to the damaged optic nerve to evaluate visual functions after stimulation. METHODS: A 27-years-old male patient suffering left optic nerve atrophy with nearly complete loss of vision 11 years after atypical traumatic damage was treated transorbitally with biphasic 10-15 pulse trains of rtACS (10-30 Hz, < 600 µA, 30-40 min daily for 10 days) which produced phosphenes. RESULTS: After rtACS treatment detection ability of super-threshold stimuli increased from 3.44% to 17.75% and mean perimetric threshold from 0 dB to 2.21 dB at final diagnostics. CONCLUSION: This improvement of vision may be due to increased neuronal synchronization, possibly involving strengthening of synaptic transmission along the central visual pathway.

Non-invasive alternating current stimulation induces recovery from stroke.

BACKGROUND: Recovery of post-stroke deficits can be achieved by modulating neuroplasticity with non-invasive brain stimulation. To evaluate potential effects of repetitive transorbital alternating current stimulation (rtACS) on stroke recovery we carried out a randomized, drug-controlled clinical trial. METHODS: Ninety-eight patients that had suffered ischemic stroke 21.4 months earlier were randomly assigned to either group D (n=30) receiving conventional drug therapy, group ACS (n=32) treated for 12 days with rtACS, or group D/ACS (n=36) receiving combined drug therapy/rtACS. Stroke severity level (SSL) was assessed by the NIH-NINDS stroke scale before and after treatment and at a 1-month follow-up to evaluate motor impairments (weakness, ataxia), sensory loss, visual field defects, and cortical deficits (aphasia, neglect). At each time point standard EEG recordings (10-20 system) were conducted. RESULTS: Before therapy SSL was moderate (9.18 ± 0.78) without significant group difference (F =0.86, p=0.43). After 12 days of treatment, SSLs of groups ACS and D/ACS significantly improved by 22.5% and 25.1% over baseline, respectively, with no such change in the control group D (+3%). SSL improvements were mainly due to recovery of motor, sensory, and speech functions. After 1-month follow-up, an additional improvement of 9.7% and 9.4% was seen for the group ACS and D/ACS which led to a total change of +32.3% and +34.7% over baseline. EEG recordings revealed greater interhemispheric synchrony between both temporal lobes which were positively correlated with clinical outcome. CONCLUSIONS: Non-invasive rtACS applied to post-stroke patients can modulate brain plasticity and induce recovery from neurological deficits long after the early post lesion recovery is over.

Inverse stimuli in perimetric performance reveal larger visual field defects: implications for vision restoration.

PURPOSE: When studying the efficacy of vision restoration training (VRT), near-threshold and super-threshold perimetry revealed visual field enlargements whereas the Scanning Laser Ophthalmoscope (SLO) did not. Because the SLO procedure differs in many parameters from the other perimetric tests (task difficulty, inability to reveal relative defects, inverse stimulus presentation, bright red background) the question arises which of these parameters might be responsible for such discrepancies in outcome. We have therefore simulated with a computer-based campimetry test some of the SLO parameters and compared performance with that in standard perimetry. METHODS: A 46-year old female patient was evaluated with computer-based high resolution perimetry (HRP) using detection tasks of "positive" (bright) stimuli on grey background. Performance was compared with an SLO-like task using "inverse" black target stimuli on red background. RESULTS: Detection rate was 89% when the stimuli were positive (HRP) but dropped to 79.6% and 80.4% in the SLO-like "inverse" stimulation mode with red background, and striped red background, respectively. The number of false positives increased from 8.5 when a grey background was used, to 9.8 and 9.5 for plain red and striped red background, respectively. Reaction times were prolonged from 384 ms using a grey background to 412 ms and 391 ms using a plain red and striped red background, respectively. Thus, visual fields tested with SLO-like "inverse" stimuli showed larger scotomata and prolonged reaction time. CONCLUSIONS: Inverse stimulus detection on red background is apparently a more difficult task for hemianopic patients than standard perimetric protocols (such as those used in Tuebinger Automatic Perimetry or HRP). The difference in stimulus features might explain why VRT-induced visual field enlargements could not be observed with the SLO. Our findings also suggest that vision restoration training does not improve all aspects of vision, such as inverse, chromatic stimulus detection.

Vision- and health-related quality of life before and after vision restoration training in cerebrally damaged patients.

PURPOSE: The aim of the study was to examine if improvements of stimulus detection performance in visual field tests after intensive visual training of the visual field border zone in patients with visual field defects are associated with changes in self-reported vision- and health-related quality of life (QoL). METHODS: We studied a clinical sample of 85 patients suffering from visual field loss after brain damage that underwent repetitive, daily light stimulation (vision restoration training, VRT) of the visual field border and the blind visual field for up to 75 hrs (N=16) or 150 hrs (N=69). Stimulus detection was quantified in the central visual field with a campimetric method before and after intervention. Health-related QoL was assessed by the Health-Survey SF-36 and vision-related QoL by the 39-item National Eye Institute Visual Function Questionnaire (NEI-VFQ). RESULTS: Both vision- and health-related QoL measures improved after VRT. Significant increases were found in 8 out of 12 NEI-VFQ and 3 out of 8 SF-36 subscales. Of the 85 participants 6% showed a decrease in stimulus detection performance, 42% showed an increase of less than 5% detected stimuli, 24% showed an increase of 5-10% detected stimuli and 28% of more than 10% detected stimuli. Changes in campimetric stimulus detection rates were related to NEI-VFQ subscales point differences general vision (3 points), difficulty with near vision activities (4 points), limitations in social functioning due to vision (4 points) and driving problems (12 points). There was no relation of visual field changes to changes in SF-36 component and subscale scores. CONCLUSIONS: The NEI-VFQ is a valuable measure of self-reported visual impairment in patients with visual field defects. Stimulation of the visual field by training may lead to improvements of vision-related QoL which were correlated with the extent of visual field enlargements.

Acute moderate alcohol consumption affects cardiovascular responses in healthy males with different tolerance levels.

We investigated the effect of acute moderate alcohol consumption or placebo on respiratory sinus arrhythmia (RSA) in 48 healthy participants with different levels of alcohol tolerance but no abuse. In the electrocardiogram recording, auditory stimuli were presented at defined points in the respiratory cycle, which allows a non-invasive measure of CNS control over RSA. After alcohol consumption we found a decrease in RSA with auditory stimulation. Moreover, individuals with low tolerance showed only a slight change in the RSA after alcohol intake compared to baseline, whereas the placebo drink led to a reduced RSA. In subjects with high alcohol tolerance, alcohol consumption led to a reduction of RSA, with no change after placebo. These results suggest a centrally driven influence on RSA that is changed by alcohol ingestion depending upon subjects' levels of alcohol tolerance.