Considering that visual and cognitive symptoms in long-COVID may also be a neuro-vascular “tandem” problem of reduced blood flow (vascular dysregulation, deoxygenation) with associated neural hypometabolism, we hypothesized that the tACS “double-punch” therapy might be able to reduce long-COVID symptoms. As we now show in two patients, a 10 to 13 days NIBS treatment can achieve a remarkably fast and long-lasting recovery of visual fields and cognitive functions, the extent and speed of which were surprising.
In our lab we typically use transorbital alternating current stimulation (tACS) to improve vision in low vision patients. It has a “double-punch effect”: on the one hand, it forces neurons to fire action potentials, and –on the other hand –it enhances blood flow. It is this “double-punch” effect which could explain (partial) restoration of disturbed neural networks in the brain with clinical benefits of improving vision ( Gall et al., 2016 ) and enhancing“brain spacetime”, i.e. very fast network reorganization ( Wu & Sabel 2021 ) (see discussion).
Long-COVID is on the rise and no effective treatment exists yet to improve visual and cognitive impairments. While different biological mechanisms of long-COVID have been discussed ( Proal & VanElzakker 2021 ), physiotherapy and rehabilitation are currently the only approaches to reduce symptoms, but they take weeks or months, with less than satisfactory improvement. Hence, a method is needed to address the root cause of restoring blood flow regulation in the eye and brain and/or improve the synchronization of brain functional connectivity networks ( Nurek et al., 2021 ).
The question arises as to the pathological mechanisms of this wide array of ophthalmological and neuropsychiatric symptoms. The cardinal problem of COVID-19 (SARS COV 2 virus) is the disturbance of blood vessel health with reduce blood flow (deoxygenation) throughout the body ( Buso et al., 2021 ). We believe that very small micro-vessels (with their relatively large vessel wall surface) are at greatest risk. Two pathological mechanisms, thrombosis and vascular damage, influence each other and amplify vascular dysfunction, especially in the venous outflow system. As we propose below, this insufficient blood flow is the cardinal cause of the wide range of central nervous system symptoms: mild or moderate hypoxia impairs neural activity due to metabolic “silencing” of neurons because of oxygen (and glucose?) deprivation. Now neurons can no longer fire action potentials, reducing the flawless interactions of neural communication in a highly dynamic brain functional connectivity network. In fact, healthy mental function depends on a healthy “brain spacetime”, i.e. high speed adaptations of neural networks in the msec. range ( Wu & Sabel, 2021 ). Metabolic (oxygen) deprivation is expected to slow down this neural processing and thus disturb fast networks interactions, impacting neural synchronization and integration. It is the dynamics of the brain network in the msec.-range which determines if functions are normal or abnormal. Hence, if blood flow is not properly regulated, functional impairments are expected such as longer reaction times or greater difficulties in coordinating complex tasks (Bola et al. 2014, Wu & Sabel 2021 ).
The main hall-mark of long-COVID that significantly impacts quality of life are cognitive symptoms ( Hosp et al., 2021 ) of attention and executive functions. The number of cases is on the rise. Hampshire et al. (2021) showed that about 3% of over 12,000 suspected COVID-19 patients developed significant cognitive deficits long after the early infection symptoms had subsided. But the risk is much higher in hospitalized COVID-19 patients, with about 60% experiencing cognitive decline within four months including impaired speech production, learning, memory and executive functions ( Miskowiak et al., 2021 ), and they can suffer abnormalities in mood such as depression, anhedonia and lower stress resilience ( Lamontagne et al., 2021 ). This is not all that surprising given the bilateral hypometabolism of the brain ( Guedj et al., 2021 ).
“Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Common symptoms include fatigue, shortness of breath, cognitive dysfunction but also others and generally have an impact on everyday functioning. Symptoms may be new onset following initial recovery from an acute COVID-19 episode or persist from the initial illness. Symptoms may also fluctuate or relapse over time” ( WHO website 2021 ).
During the worldwide COVID-19 pandemic a large number of initially recovered patients reported different functional complains commonly referred to as “long-COVID” or “post COVID condition” ( Guedj et al., 2021 ). The WHO describes it as a “persistent state of ill health” even of non-hospitalized persons who initially had only mild COVID-19 symptoms but who later progress to symptoms:
The vessel diameter before, during and after light flickering show the dilation capacity of the vessels of interest which was then analysed using different parameters as a function of the branch order in the vascular tree ( Tables 2 and 3 ). To carry out statistical analysis, each vessel was treated as an independent data point (19 arteries, 17 veins). Measurements were only taken if the respective vessel had sufficient contrast to the surrounding fundus with no crossing or bifurcation in the measuring segment, and with a curvature < 30°. The raw data of all vessels was then saved for further analysis. The DVA metrics are displayed in Fig. 4 . Paired sample t -tests were conducted to investigate changes in DVA parameters, before and after therapy for all the measured blood vessels and separately for central and peripheral ones.
To measure vessel dynamics, the retina was video imaged using a fundus camera (Zeiss, Jena, Germany) at 30° field of view. The fundus camera was connected to the DVA-analysis system (DVA 2.0, Imedos, Jena, Germany). To obtain a full image of the patient's central retina, the pupils were dilated with Mydriatics (1 ml solution of 5.0 mg of tropicamide, Pharma Stulln GmbH, Stulln, Germany), and the retina of each eye was then imaged and video recorded during a 5–6 min session for each eye which consisted of three measurement periods: (i) a 50 sec. baseline measurement, (ii) three repeated diffuse luminance 12.5 Hz flicker stimulation periods of 20 sec. each, and (iii) a subsequent 80 sec. post-flicker period. The three 20 sec. flicker stimulation periods were then averaged and the video was analysed for vessel diameter changes over time in the upper and lower retinal sector to assess vessel dilation and vasoconstriction dynamics ( Seifert et al., 2002 , Garhofer et al., 2010 ). In a healthy retina, the light flickering activates retinal neurons which then provokes vessel dilation through neurovascular coupling.
With the DVA we video-recorded vessel diameters before, during, and after flicker light stimulation to quantify the retinal vessel dilation response which informs us of arterial and venous vessel health. Because the retina is central nervous system (CNS) tissue, i.e. with brain-like neurons and vasculature, the DVA can be considered a surrogate biomarker of vascular health of the brain. In fact, DVA revealed already abnormalities in different CNS diseases, including Alzheimer Disease ( Querques et al., 2019 ) and primary open angle (POAG) and normal tension glaucoma (NTG) ( Gugleta et a. 2012 ).
DVA recording of vessel dynamics in the retina and data collection: In patient K.H. we measured vessel dynamics in the retina using the Dynamic Vascular Analyzer (DVA) before and after treatment ( Figs. 3, 4 ). Unlike the angio-OCT, the DVA can differentiate the vessel dilation responses as a function of neuronal activity. Neural activity is triggered by flickering light pulses, and the so induced vessel response can be interpreted as a surrogate marker of vascular dysregulation in the brain.
Patient K.H.: visual fields were assessed with the Oculus Twinfield static perimetry (area 6, 0°–70°, Fast threshold, Stim III, Wetzlar, Germany) approx. 2 weeks before and 2, respectively 3 weeks after NIBS therapy ( Fig. 1 ). At her request, K.H. was also formally tested for her cognitive abilities in the BG Clinical Center (Hamburg) before and after therapy. Here, two cognitive tests were applied to quantify attention, verbal learning and verbal memory using the “Test of Attentional Performance” (TAP, Germany version: “Testbatterie zur Aufmerksamkeitsprüfung”, Version 2.3.1) and the “Auditory Verbal Learning Test (AVLT)” (German Version: “Verbaler Lern- und Merkfähigkeitstest”, VLMT) ( Table 1 ).
Patient K.H. and G.B. received 13 and 10 therapy sessions, respectively, of transcranial alternating current stimulation (tACS) at the SAVIR-Center ( www.savir-center.com ) using the CE-certified SASm-neuromodulation device (SAVIR GmbH, Berlin, Germany). Each session lasted 30–45 min. where currents with density < 2 mAmp were delivered to the eyes and brain while the patient was sitting comfortably on a chair, with electrodes positions near the forehead. Each session was followed by a resting period of around 15 min, while the patient had her eyes covered with a warm mask. Both patients tolerated the treatment well, and no adverse or serious adverse events were noted. In line with the “holistic” SAVIR therapy (SAVIR-Center, Magdeburg, Germany), the patient also received psychological counseling and learned relaxation techniques.
Patient G.B. is a 72-years old female British citizen that runs a successful holiday letting business. Being a former prima ballerina, she has an active lifestyle, goes for long walks and practices Pilates regularly. She does not smoke and consumes little, if any, alcohol. Her medical history revealed no significant medical conditions and the patient reported no current medication. In February 2021 she was vaccinated with AstraZeneca. During the following weeks she reported having had strong headaches, loss of vision in the left eye, loss of balance as well as cognitive impairments. As symptoms continued, she consulted her physician for an ophthalmological exam with the diagnosis of a left paracentral acute middle maculopathy, negative uveitis screen, negative inflammatory markers, negative carotid dopplers. She was prescribed prednisolone (60 mg/day for one week, then 50 mg for the next three weeks). Follow-up head MRI indicated age related involutional change with 1 or 2 nonspecific foci of white matter signals, but no evidence of hemorrhage, infarct or space occupying lesions. MRV venogram indicated no evidence of venous sinus or cortical venous thrombosis.
Patient K.H. is a 40-years old female German citizen who works as a health data processing manager. Her medical history includes migraines since age of 18 yrs, but no other remarkable events and no current medication. She lives an active lifestyle, enjoys working and riding the bike regularly. Both the patient and her husband were diagnosed with COVID-19 in December 2020, but due to a mild course of the disease, hospitalization was not needed. Symptoms included headaches and low level of fever which recovered during 14 days of quarantine, no coughing, no muscle pain. After an additional 2 weeks of holidays, she returned to work for 2 days.
This is a clinical analysis of two patients, K.H. and G.B., who visited our SAVIR-Center in Magdeburg to receive treatment for their vision impairment according to existing SOPs. Data were collected during routine testing and, per request of patient K.H., additional test in the BG Clinic-outpatient service center in Hamburg.
As displayed in Figs. 5–6 , the vascular autoregulation parameters in patient K.H. were markedly impaired before treatment. Central arterial and venous dilation dynamics (large vessel) was at or below the lower limit of the reference window of healthy subjects ( Fig. 5 ), whereas the smaller peripheral vessels, both arteries and veins, were even lower. Interestingly, the peripheral artery fails to dilate, yet it still constricts at the post-flicker time point. This might suggest that the nature of the dysregulation is not only a failure to dilate, but a dilation-independent (paradoxical) constriction which reduces blood flow far below normal levels, a double-punch problem for the small arteries. After NIBS treatment we observed a remarkable recovery of vessel dynamics, and the change was particularly noted in the peripheral arteries and veins, where dilation and constriction capacity of both improved by more than 300% in some parameters. In the peripheral vein the dilation exceeded the normal reference window at follow-up (see Fig. 5 and Tables 2, 3 ). In sum, our observation post-treatment shows that NIBS improves vessel dynamics (dilation/constriction) to normal levels. When viewed together with the visual field findings, both subjective and objective visual field improvements continued in the post-treatment time period, and DVA confirms that NIBS normalizes vessel autoregulation.
Both the intrinsic alertness (tonic alertness) and the phasic alertness improved after the therapy, but it still remained far below the norm (PR in both < 1). The ability to react easily under stimulus selection conditions and the ability to inhibit reactions also improved after the therapy by 23%, which was still below norm (PR 1). The error rate was clearly improved from the first (3 errors, PR 18) to the second appointment (0 errors, PR > 14). Clear improvements were also observed for divided attention, which is the ability to process visual and auditory information in parallel. While, the reaction to auditory stimuli continued to be rated as below average for both measures (PR 1), the reaction to visual stimuli after therapy reached the normal range (PR 21). Furthermore, cognitive flexibility greatly improved, with patient’s performance changing from below average to normal after therapy, both in terms of reaction time (PR 1 vs. PR 34) as well as error rate (PR 7 vs. PR 54). One measure was worse after therapy, but patient reported having been very tired, almost falling asleep during this last task of the test battery. In her judgement this negative result fails to reflect her maximum ability because her working memory did not worsen but actually had improved. Improvements were also noticed on the verbal-episodic memory. Both before and after treatment the immediate word span and learning capacity were classified in the normal average range, while retrieval after interference, delayed retrieval and recognition, though improved, were still classified as below average.
Patient G.B.: Visual Field Index (VFI) showed no central but peripheral visual field deficits with improvements from 97% to 99% in the right eye and from 92% to 95% in the left eye. Mean deviation values decreased from –2.91 dB to –1.92 dB in the right eye and from –5.62 dB to –3.06 dB in the left eye (approaching the age norm). Computer-based high-resolution perimetry confirms improvement: detection accuracy slightly increased from 95.42% to 96.83% in the right eye and from 93.66% to 96.48% in the left eye, with improved mean reaction time pre/post for the right (411/380 ms) and left eye (445/411 ms). Visual acuity measures (5 m, without correction) indicated improvements for both eyes. While testing the right eye before the treatment, the patient could only distinguish light and shapes on the visual chart, but after NIBS we were able to measure the visual acuity at a value of 0.25 (decimal). In the left eye visual acuity improved from 0.42 to 0.75. MARS letter test of contrast sensitivity (Oculus, Wetzlar, Germany) showed normal contrast sensitivity with small improvements for the binocular measures (pre/post = 1.64/1.76) and monocular left eye (pre/post = 1.68/1.72), with values remaining unchanged for the right eye (1.68) ( Fig. 2 ).
Patient K.H.: Visual fields recovered noticeably in the right eye, where mean sensitivity (MS) and mean defect (MD) at the three time points (pre-, 2 wks post- and 3 wks post- therapy) were as follows: MS = 13.92 dB, 16.56 dB and 16.53 dB; MD = 1.66, –0.98 and –0.95. In the left eye, no changes were observed two weeks after the therapy, with values remaining stable for MS (13.8 dB) and MD (1.78). During follow-up, however, visual field improvements were noted. Now MS for the left eye was 16.33 dB and MD was –0.75 ( Fig. 1 ).
Both patients had intact central but impaired peripheral field defects. In the description below, note that visual field defects are represented by positive mean deviation values (MD) in Oculus perimetry patient (K.H.) while negative values in Humphrey perimetry patient (G.B.). Both patients showed some recovery in their visual field with different dynamics as now described:
G.B.’s subjective recovery after therapy: After therapy G.B. subjectively noticed improvements in her vision, reporting a clearer picture and an enlarged peripheral visual field (“I am able to see everything around me which is life changing”) and that her eyes were now “working together again”. G.B. also felt to have improved cognitively: she was more comfortable to walk around, and reading was not as tiring as before. She felt much more alert and brighter, could now carry-on conversations with her children again, could remember what she was just doing before, no longer struggling for words, and being able to plan and to remember things better. She felt ready to go back to work in her business. In sum, she felt a lot more positive which was a “huge blessing” for her.
G.B.’s subjective complaints before therapy: at her first consultation mid-Sept 2021, i.e. before NIBS, G.B. reported difficulties concentrating and focusing her attention, word-finding difficulties, short-term memory difficulties, and not being able to work any longer. She described her vision in the right eye as being normal, but unclear “broken-up” in her left eye. She felt unsafe to walk around.
K.H. subjective recovery after therapy: after NIBS therapy, K.H. subjectively reported having no more episodes of sudden visual acuity loss, and she noticed significant improvements of her mental state already after the third therapy session. This consolidated during the remaining time of the therapy (“The brain fogginess was suddenly gone and my mind is clear again”). She was able to engage in conversations again, did no longer get so easily distracted by simultaneous stimuli, was now able again to focus her attention on particular aspects of the situation, and she felt able again to make plans and follow them through. And she could attend to her child and household tasks with no more difficulties in carrying out everyday tasks, and she started going back to work. This recovery was stable as of Nov. 27, 2021.
During her first consultation in mid-September 2021, the patient reported still having difficulties finding words, slowed reaction time, short-term memory deficits (e.g., forgets the beginning of the sentence while reading), attention deficits (e.g., not being able to concentrate on one among multiple stimuli), and she did not feel confident enough to drive her car anymore. She still had sudden episodes when her vision was unclear and unfocused. These episodes were not occurring as often as before, but remained a continuous source of concern.
K.H. subjective complaints before therapy : approximately four weeks after her COVID infection in December 2020, K.H. reported an episode of not feeling well, having lost strength and not being able to get out of bed. The symptoms continued in January with the patient having a constant feeling of weakness, not being able to go for walks anymore, having difficulty even with small activities like showering or washing her hair, and she had a strong sleeping urge (up to 18 hrs/day). In the next months, K.H. had trouble doing the housework (e.g. could not cook anymore or do the typical household chores). She noticed severe cognitive deficits: being forgetful, feeling overwhelmed, had difficulties finding words, holding conversations, or doing multiple tasks simultaneously. She also noticed changes in her vision, episodes of occasionally losing acuity (foggy vision) and being unable to focus anything even for very short periods of time. These visual impairments were rather short, lasting only a few minutes at a time. In June 2021, she began a six week rehabilitation program that included computer-based cognitive rehabilitation training, relaxation therapy (progressive muscle relaxation and breathing exercises), occupational therapy, as well as music and dance therapy. However, rehabilitation did not help her cognitive abilities much, but she learned how to relax and better cope with her situation (increased acceptance, less self-blaming).
4 Discussion
Because there is no effective treatment of long-COVID patients’ visual and cognitive impairments, we tested the therapeutic effects of NIBS to explore if a short-term, 10-day treatment could reduce the long-COVID symptoms and recover some vision, attention, memory, language comprehension, and/or fatigue. We reasoned that since NIBS is known to enhance blood flow, it might also be effective to reduce vascular dysregulation, thereby improving neuronal synchronization of brain functional connectivity networks and achieving some recovery from the long-COVID symptoms. In both of our cases, clear recovery was already noted on days 3–4, the extent and speed of which was rather surprising. NIBS improved vision in both patients, and patient K.H. improved in almost all subtests of a cognitive testing battery, some of which recovered up to 40–60%. In this patients vascular dysregulation was found to markedly improved, with increased dilation dynamics in both the artery and vein which was > 300% above baseline in the smallest microvessels. Both of our patients went back to work after therapy. Thus, the ability of NIBS to trigger recovery of blood flow and improve neurological function is an exciting new option to help long-COVID patients regain their mental functions, an issue which is of growing concern.
4.2 COVID-19 and cognition Besides the more subtle vision symptoms, long-COVID patients can develop much more serious neurological symptoms such as cognitive impairments of attention and executive functions. Hampshire et al. (2021) analyzed over 12.000 suspected COVID-19 patients and showed that 386 (= 3,04%) recovered from early symptoms but later developed significant cognitive deficits as assessed by the web-based Great British Intelligence Test. Compared to less affected patients, the more affected cohort had more cases with cognitive impairments (Liu et al., 2021). In a cohort of hospitalized COVID-19 patients cognitive symptoms were reported to be most pronounced, with 59% –65% experiencing significant cognitive impairments within four months with marked neurological dysfunctions such as verbal learning skills and executive functions. Long-COVID patients can also suffer from abnormalities in mood functions, including depression, anhedonia and lower stress resilience (Lamontagne et al., 2021). The recognition that severe lung dysfunction can lead to lower brain oxygen levels (Miskowiak et al., 2021) and bilateral hypometabolism in multiple brain regions (Guedj et al., 2021) points our way to possible mechanisms of the neurological symptoms.
4.3 COVID-19, vascular regulation and blood flow Indeed, a key hallmark of COVID infection and neuronal dysfunction is dysregulated blood flow as recent brain imaging studies attest. Hypometabolism was described by Hosp et al. (2021) in frontoparietal brain regions and by Guedj et al. (2021) in bilateral rectal/orbital gyrus and the right temporal lobe, amygdala and hippocampus with an extension to the right thalamus. These blood flow changes were associated with different symptoms such as hyposmia, anosmia, pain, insomnia, memory and other cognitive impairments. Given these global metabolic changes in the brain it may be that the underlying mechanism of visual and cognitive impairment is not only of neuronal but possibly also of vascular origin. Before discussing the neurovascular mechanism of recovery, we shall summarize what can be learned from our observations and discuss the findings in the context of the existing literature.
4.5 NIBS and recovery of cognition Besides suffering low vision, both or our patients suffered serious cognitive deficits from which they recovered significantly, though not completely, at the end of the therapy. The efficacy of the treatment on the subjective and objective level was surprisingly fast and relevant in everyday life. Both patients reported to function better in daily life, being able to converse and manage multitasks again, and both were able to go back to work shortly after completing therapy. Unlike in the visual system, we cannot directly relate retinal vessel responses to functional improvements. Yet, regarding brain cognition, it is reasonable to argue that, like in the retina, the treatment has the most pronounced effect on smaller brain vessels. After all, retinal tissue is ontogenetically very similar to, or identical with, brain tissue. While we need to await larger sample studies, we predict that vasodilation recovery in the retina should also correlate with cognitive recovery. That NIBS can be used to treat cognitive impairments is also not new. For example, anodal tDCS treatment of Alzheimer patients or persons affected by mild cognitive impairment (MCI) leads to short-term improvements in verbal fluency, especially if combined with cognitive training (Chu et al., 2021). For review, see the meta-analysis by Begemann et al. (2020) of 82 studies (n = 2784 patients) showing small but significant improvements of working memory and attention following transcranial magnetic stimulation (TMS) or transcranial Direct Current Stimulation (tDCS) (Begemann et al., 2020, Chu et al., 2021).
4.6 Vascular recovery: A mechanisms of improvements in vision and cognition? Our findings inspired us to speculate about the fundamental recovery mechanisms and the physiological / biological underpinnings of blood flow regulation in long-COVID. Consideration of viral infection and the role of blood flow is therefore needed. Let us first consider the neurovascular consequences of the virus infection: the SARS-COV 2 viruses can trigger thrombotic events by impacting any or all of the three factors of the “Virchow-triade” (Rudolph Virchow, 1846): (i) changes in the vessel wall or damage to the endothelium, (ii) hypocirculation (“stasis”) of the blood, and (iii) hyper-coagulability, i.e. a change in blood composition. Specifically, SARS-COV 2 leads to vascular dysfunction hypoxia and altered capillary transit time (Østergaard et al., 2021). Others found increased levels of acute phase protein with reactive hypergammaglobinaemia which, in turn, increases blood viscosity which negatively impacts hemodynamic properties of the blood (Joob et al., 2021). In addition, the SARS-COV 2 virus damages the vascular endothelium causing an inflammatory response (endothelitis) with swelling of the endothelial vessel wall and damage to the adjacent pericytes (Libby et al., 2020). This, in turn, causes reduction of the inner diameter of the blood vessels which reduces oxygen and glucose/nutrient delivery to the cells (here: neurons). At a molecular level it is conceivable that the SARS-COV 2 virus activates aryl hydrocarbon receptors (AhRs) and up-regulates diverse AhR-dependent effectors down-stream, resulting in a “Systemic AhR Activation Syndrome” (SAAS) (Turski et al., 2020). Of note, even small diameter changes can massively influence blood flow: according to a simplified model of the Hagen-Poiseuille equation, the volume flow (blood volume as a function of time) critically depends on the inner radius of the vessel. Therefore, any diameter change alters volume flow by the fourth power (assuming blood pressure is stable). For example, if endothelial cell swelling reduces the radius of a very small vessel to half (all other factors being constant), blood flow is reduced down to 6.25% (1/16!) of its normal value. If both, blood stasis and diameter reduction are present simultaneously, blood clots in the vascular system are likely. It is evident that such thrombotic events in large vessels can cause immediate clinical symptoms requiring emergency care. However, it is easily conceivable that functional impairments can also be caused by smaller micro-vessel diameter at or near the capillary (unless the number of affected micro-vessels is small). The effect can be capillary congestion, reducing or arresting oxygen supply in the local tissue. Because neural function is particularly sensitive to oxygen deprivation –neuronal processing of action potentials is very fast with local energy peaks -, vascular dysregulation can trigger neurological deficits in different domains (vision, hearing, cognition, etc.). In fact, vascular dysregulation is not limited to neural tissue but it can also affect many other organs (Golubnitschaja, 2019). In sum, it is evident that vascular dysfunction impacts neuronal functioning, but what is the role of blood vessel health and auto-regulation in recovery?