Vision modulation, plasticity and restoration using non-invasive brain stimulation – An IFCN-sponsored review

Journal Pre-proofs Review Vision modulation, plasticity and restoration using non-invasive brain stimulation – a review Bernhard A. Sabel, Gregor Thut, Jens Haueisen, Petra Henrich-Noack, Christoph S. Herrmann, Alexander Hunold, Thomas Kammer, Barbara Matteo, Elena G. Sergeeva, Wioletta Waleszczyk, Andrea Antal PII: DOI: Reference:

S1388-2457(20)30035-3 https://doi.org/10.1016/j.clinph.2020.01.008 CLINPH 2009113

To appear in:

Clinical Neurophysiology

Received Date: Revised Date: Accepted Date:

18 April 2019 18 December 2019 2 January 2020

Please cite this article as: Sabel, B.A., Thut, G., Haueisen, J., Henrich-Noack, P., Herrmann, C.S., Hunold, A., Kammer, T., Matteo, B., Sergeeva, E.G., Waleszczyk, W., Antal, A., Vision modulation, plasticity and restoration using non-invasive brain stimulation – a review, Clinical Neurophysiology (2020), doi: https://doi.org/ 10.1016/j.clinph.2020.01.008

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© 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Vision modulation, plasticity and restoration using non-invasive brain stimulation – a review Bernhard A. Sabel1, Gregor Thut2, Jens Haueisen3, Petra Henrich-Noack1,4, Christoph S. Herrmann5,6, Alexander Hunold3, Thomas Kammer7, Barbara Matteo8,9, Elena G. Sergeeva10, Wioletta Waleszczyk11, Andrea Antal1, 12

1Institute

of Medical Psychology, Otto-von-Guericke University Magdeburg, Magdeburg,

Germany 2

Institute of Neuroscience and Psychology, University of Glasgow, United Kingdom

3Institute

of Biomedical Engineering and Informatics, Technische Universität Ilmenau, Ilmenau, Germany 4Clinic

of Neurology with Institute of Translational Neurology, University Clinic Münster, Münster, Germany 5Experimental

Psychology Lab, Department of Psychology, Cluster for Excellence “Hearing for All”, European Medical School, Carl von Ossietzky University, Oldenburg, Germany 6Research

Center Neurosensory Science, Carl von Ossietzky University Oldenburg, Germany

7Department 8SAVIR

of Psychiatry, University of Ulm, Germany

Center, Magdeburg, Germany

9Department

of Medicine and Surgery, University of Milan-Bicocca, Italy

10Department 11Nencki

of Neurology, Boston Children’s Hospital, Harvard Medical School, USA

Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland

12Department

of Clinical Neurophysiology, University Medical Center Göttingen, Göttingen,

Germany

Corresponding Author: Bernhard A. Sabel Institute of Medical Psychology, Medical Faculty, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany Tel: +49 391 672 1800 E-mail: [email protected]

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Highlights 1) Normal/abnormal vision can be modulated by non-invasive stimulation beyond the stimulation period. 2) Clinical impact on plasticity and restoration in patients with low vision is critically evaluated. 3) Challenges are discussed in the field of transcranial/extracranial stimulation of the eye and brain.

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Abstract The visual system has one of the most complex structures of all sensory systems and is perhaps the most important sense for everyday life. Its functional organization was extensively studied for decades in animal and humans, for example by correlating circumscribed anatomical lesions in patients with the resulting visual dysfunction. During the past two decades, significant achievements were accomplished in characterizing and modulating visual information processing using non-invasive stimulation techniques of the normal and damaged human eye and brain. Techniques include transcranial magnetic stimulation (TMS) and low intensity electric stimulation using either direct or alternating currents applied transcranially (tDCS or tACS) near or above the visual cortex, or alternating currents applied transorbitally (trACS). In the case of extracranial stimulation of the visual system the electrodes are attached on the skull above visual structures of the brain, or near the eye, to the eyelids (transpalpebral electrical stimulation - TPES) or the cornea (tanscorneal electrical stimulation TcES). Here, we summarize the state-of-the-art of visual system magnetic and electric stimulation as a method to modulate normal vision, induce brain plasticity, and to restore visual functions in patients. We review this field’s history, models of current flow paths in the eye and brain, neurophysiological principles (e.g. entrainment and after-effects), the effects on vision in normal subjects and the clinical impact on plasticity and vision restoration in patients with low vision, with a particular focus on “off-line” or “aftereffects”. With regard to the therapeutic possibilities, ACS was demonstrated to be effective in patients affected by glaucoma and optic neuropathy, while tDCS and tRNS are most promising for the treatment of amblyopia, hemianopia and myopia. In addition, rTMS applied above the occipital area is a promising approach to treat migraine, neglect and hemianopia. Although the response to these treatment options is better than sham results in double blinded clinical studies, the clinical efficacy is still rather variable and a proportion of patients do not respond. It is therefore imperative to better understand the mechanisms of action to be able to optimize treatment protocols 3

possibly through personalization of brain stimulation protocols. By identifying the current

opportunities and challenges in the field, we hope to provide insights to help improve neuromodulation protocols to restore visual function in patients with visual system damage.

Keywords: visual pathway, tDCS, tRNS, tACS, rTMS.

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1. Introduction The scientific study of modulating visual system function and dysfunction by noninvasive magnetic or current stimulation has gained increasing attention in both basic and clinical research. Such neuromodulation is a powerful tool to alter physiological states in normal vision, and this technique has also clinical potential as it can improve vision in patients that suffer from vision loss. Here, we provide a “consensus” review of the current state of the art which reflects the joint opinion of the authors and is not intended to represent the opinion of all scientists working in this field. Nevertheless, it may motivate and help guide others towards new directions to advance our understanding of normal and abnormal vision, perhaps the most important sense of humans. More than half of the human brain is involved in processing visual information, with approximately 40 distinct brain areas devoted to visual processing alone as well as many other non-visual regions distributed throughout the brain. These areas are involved in processing visual input, synchronizing multisensory and sensorimotor integration, and are modulated by cognition and attention. Much of our knowledge related to the anatomical and functional organization of the visual system has been derived from animal experiments and from studies in healthy humans and patients with visual system disorders. In the latter, the perception deficits are typically correlated, for example, with circumscribed anatomical damage to the eye or brain (e.g. hemianopia) or with altered neurotransmitter levels (e.g. as in Parkinson’s disease). Because such correlations reveal many complex processes or in several cases maladaptive changes, one must use methods to specifically alter or modulate the electrophysiological state of the brain, and then study the impact on brain function to establish a pivotal link. This can be accomplished by neuromodulation with electric or magnetic stimulation. Studying neurophysiological modulation is an important approach for another reason: whereas the anatomy of the adult brain and eye are fairly fixed, the neurophysiological state is 5

variable and subject to a wide variety of influences and fluctuations. This state varies with the level of consciousness and is very sensitive to any pathological disruptions, or internal or external influences that can alter its expression, e.g. in a coma or during an epileptic seizure. Furthermore, function and structure belong together. Functional states depend on the integrity of structure, and these structures can vary significantly between individuals at both the macroand micro-level. Nevertheless, although modulation of the neurophysiological brain network state can be difficult, its modification by targeted interventions can be an asset, opening many new opportunities to study and modulate pathological conditions. Therefore, modulation of these networks has become popular in recent years, and several methods for controlled neuromodulation have been developed and tested. The most common approach is to apply non-invasive transcranial magnetic or electric stimulation to the eye or brain in order to alter excitability and synchronization of neural networks. The effects of such stimulation are separated into “on-line” and “off-line” effects. The on-line effects are those that occur during stimulation, while the off-line effects are those that persist or occur after the end of stimulation (also referred to as “after-effects”). Because the latter are of particular interest for vision restoration in patients, this review focuses on stimulation protocols that can induce such after-effects. For instance, TMS pulses (rTMS) repeated at specific frequencies are known to induce changes in cortical excitability of the stimulated area that persist beyond the duration of stimulation and produce prolonged after-effects. This has been mostly studied in the motor system, where modulation of motor cortex excitability was inferred from changes in motor evoked potentials (MEP) (e.g. Pascual-Leone et al., 1994; Chen et al., 1997; see Maeda et al, 2000 for an early account of outcome variability). In the visual system, changes in visual cortex excitability were inferred from the occurrence of TMS-induced phosphenes, which are perceptions of simple dots or lines induced by direct visual cortex stimulation (e.g. Boroojerdi 6

et al., 2000; Fierro et al., 2005; Brandt et al., 2001; see Caparelli et al., 2012 for outcome variability), and from studies of visual evoked potentials (VEPs) (for studies in humans, see Fumal et al., 2003; Schutter and van Honk, 2003; Bocci et al., 2011; for animal studies see Aydin-Abidin et al., 2006). These studies suggest that repetitive TMS (rTMS) induces not only prolonged motor but also visual cortex after-effects with perceptual co-modulation, when the relevant areas in the occipital cortex are stimulated. Although electrical stimulation of the eye and brain had been attempted in the past centuries, Michael A. Nitsche and Walter Paulus (2000, 2001) were the first to show that neuromodulatory changes in motor cortex excitability are not confined to the stimulation period itself but persist after stimulation has ceased (“after-effect”). Since then, we have witnessed a growing interest in neuromodulation by low intensity, transcranial electrical stimulation (TES), including stimulation of the visual system with either direct (tDCS) or alternating current stimulation (tACS). As with rTMS, both tDCS and tACS can modulate cortical excitability. For example, one of the first on-line effects of tACS on motor responses was demonstrated for sinusoidal stimulation at 1, 10, 15, 30, and 45 Hz over the motor cortex using the recording of MEPs in response to single pulse TMS as well as of reaction times in response to visual stimuli (Antal et al., 2008). With this protocol, only 10 Hz tACS produced significantly faster reaction times. Since then, many studies have also reported tACS aftereffects (see sections below). Neuromodulation can alter visual functions, such as motion- and object-detection, object recognition, attention or visual awareness. Vision-related studies primarily explored the effects of neuromodulation with the following goals: (i) examining the functional specialization of the visual areas, i.e. their necessity and role in perceptual functions as assessed through establishing causal links between neuronal processing and perception, (ii) studying the temporal dynamics of visual processing, (iii) enhancing normal performance, or 7

(iv) restoring visual functions in patients. Some of these studies have used electrophysiological (EEG) and functional neuroimaging (fMRI) markers to document changes following single or repeated stimulation sessions. In this review, we present a current update on visual system modulation from both basic research and clinical perspectives. While it is undisputed that TMS and TES can modify sensory and cognitive functions such as visual perception, the neural mechanisms underlying such effects are still under debate. In principle, there are five approaches that can shed light on this topic: (i) simulations and modeling studies, (ii) recording electrophysiological effects of stimulation in animals, (iii) recording electrophysiological effects of stimulation in humans, and analysis of functional brain network changes, (iv) observing indirect measures of brain activity such as hemodynamic responses, (v) and investigating the effects of stimulation on perception and visually elicited performance. In this paper, we will briefly report results from all these approaches in vision research. Because of the increasing clinical relevance, in section 7 extracranial stimulation methods of the eyes, including transcorneal electrical stimulation (TcES) and transpalpebral electrical stimulation (TPES) are also discussed. We do not review other functional domains, such as the motor system and higher cognitive functions unless the results are relevant for visual performance. These topics have already been reviewed elsewhere (e.g. Stagg et al., 2018).

2. A historical account of electrical stimulation of the primary visual system in humans There are many accounts dating back several centuries of attempts to improve or restore vision by the more or less invasive application of electrical stimuli to the optic nerve or the visual cortex. In 1755, Charles Le Roy attempted to cure a blind man with electricity. He wound wires around the man’s head and attached one wire to his leg. These wires were 8

then connected to a Leyden jar, which sent electric discharges through the patient. Although the patient underwent several such stimulation sessions, he remained blind, but he did experience phosphenes, i.e. visual perception without light entering the eye, probably due to stimulation of the occipital visual cortex. The value of non-invasive electrotherapy for the treatment of optic nerve atrophy and its effects on recovery of vision was already reported as early as 1904 by Ludwig Mann of Breslau (then Germany) (Mann, 1904) who noted that „…the electrotherapy of optic neuropathy was almost completely neglected in the last decades. Both neurologist and ophthalmologists have discontinued systematic experiments with electrical stimulation… In contrast to today, the literature 20-30 years ago shows that clinicians had a greater trust in electrotherapy. In earlier electrophysiological text books and journal publications we find reports of the advantageous effects of electrotherapy in optic nerve atrophies”. Mann referred to several examples, described in the “Handbook of Electrotherapy” published in 1882 by Wilhelm Erb, suggesting that electric stimulation can improve visual functions in patients with optic nerve atrophy (Erb, 1882). Although this success story of electrical stimulation as a way to treat neurological and ophthalmological diseases was widely celebrated in the 1870 to 1890s, this knowledge was later lost after the popular novel “Frankenstein“ discredited electrostimulation in both the medical community and the general public. Another approach was initiated by Foerster (1929), who invasively stimulated the visual cortex of visually impaired patients. He noted that patients reported phosphenes depending on which part of the cortical area was stimulated. Following this report, the first systematic clinical study on electrical stimulation of the visual cortex was carried out in 9

neurological patients during neurosurgery (Penfield and Boldrey, 1937; Penfield and Rasmussen, 1950). During electrical stimulation of the occipital cortex, patients reported seeing dots and spots, which varied depending on the parameters and the focus of the electrical stimulation. Brindley and Lewin (1968) stimulated the occipital cortex of a blind patient with implanted electrodes. The position, color and shape of the phosphenes varied according to the position of the electrodes. Vertical and horizontal stripes, geometrical shapes and even letters could be induced in blind persons using various stimulus combinations. Also more complex phosphene arrays were induced using a 60 to 80 electrode matrix directly implanted into the visual cortex. The matrix was connected to tiny receivers attached to the head that transmitted TV camera signals to the electrode arrays (Kogan et al., 1966; Brindley and Lewin, 1968; Brindley, 1973; Dobelle et al., 1976; Everitt and Rushton, 1978; Hitchcock, 1982; Kompaneets et al., 1982; Shakhnovich et al., 1982). These matrixes were also used to determine the threshold for stimulation using repetitive pulses with various frequencies and pulse intensities. Dobelle and Mladejovsky (1974) determined the current thresholds for phosphenes to be in the range of 2 to 12 mA for a 50 Hz stimulation with electrodes positioned on the pial surface. However, due to the large individual variability of the position of the phosphenes in the visual field even during repeated stimulation sessions using the same electrode pairs, no universal phosphene map could be established. Furthermore, these electrodes were very expensive and complex to manufacture and there was considerable damage of cortical neurons due to the prolonged electric stimulation required for phosphene induction (Pudenz et al., 1977/78). Subsequent clinical studies with invasive microstimulation of the visual cortex used low intensities in a blind person long after visual cortex damage. The patient still experienced phosphenes during electrical stimulation and spatial patterns of high resolution (Bak et al., 1990; Schmidt et al., 1996). During the same period of time, a Russian team stimulated damaged optic nerves with implanted wire electrodes, and reported a significant recovery of 10

vision after three to four weeks of stimulation with a stable improvement of vision for over two years (Bechtereva et al., 1985). These invasive protocols must be viewed as predecessors of today’s non-invasive protocols. Nowadays, non-invasive brain stimulation methods are used which deliver direct (tDCS) or alternating currents (tACS), e.g. using sine wave pattern, through the skull and positioning two or more electrodes near or over the region of interest. While much of this current is directly shunted through the skin of the scalp, a smaller but sufficient portion of the current penetrates the bone to induce an intracranial (or intra-orbital) current. The pattern of the current density distribution or current flow depends on the size and montage of the stimulation electrodes (Neuling et al., 2012) (for modeling see next section).

3. Current flow modeling in the eye and brain Current flow cannot be measured directly in the human body, and current distribution is therefore typically obtained by modeling current flow. A realistic estimate of the current distribution has several advantages as it (i) helps us to gain insight into field and current patterns in the body, (ii) provides explanations of experimentally observed phenomena, (iii) can help in the development of novel hypotheses and experiments, (iv) is a prerequisite for designing electrode montages for targeted stimulation and, (v) finally, is required for making realistic safety assessments. One instance in which current flow modeling can provide an explanation for experimentally observed phenomena regards phosphenes as a surrogate marker for current flow. Phosphenes can be induced by transorbital ACS applied to the head. Two such current simulations are shown in Figures 1 and 2. There has been a long debate over whether the cortex or the retina is the “generator” of such phosphenes. A recent study by Indahlastari et al. (2018) compared two electrode setups (T7-T8 and Fpz-Oz according to the 10-20 EEG 11

nomenclature) and related them to phosphene perceptions. Higher current densities in the eyes were associated with decreased phosphene generation for the Fpz-Oz montage, but positive association between phosphene perceptions and current densities were observed when the occipital lobe was stimulated (T7-T8 and Fpz-Oz). Hunold et al. (2015) compared three electrode setups (Fig. 1) using current flow simulations of the eye. They found that differences in the amplitude and orientation of the current density in the retina are strongly dependent on the electrode setup. Even relatively low amplitudes in the retina were sufficient to provoke phosphenes with some setups, where 250 µA peak-to-peak amplitudes of a 10 Hz sinusoidal current was sufficient for some volunteers. A computational study by Laakso and Hirata (2013) suggested that stimulation targeting the visual cortex involving frontal or central electrodes can also generate current density amplitudes in the eyes, which are likely large enough to elicit retinal phosphenes. Another study (Gall et al., 2016) simulated current flow with a forehead electrode montage. This revealed high current densities in the eye and optic nerve, as well as current flow in the frontal cortex (Fig. 2). As mentioned above, current flow simulations are a prerequisite for designing electrode montages for targeted stimulation. Standard two-electrode TES is still hampered by the relatively low reliability and predictability of the therapeutic and behavioral effects. Targeted, subject-specific, multi-electrode TES of the brain may overcome this difficulty (see recent reviews of Bikson et al., 2016; Antal et al., 2017), and this needs to be based on individual current flow models using individual geometries and, in some cases, individual conductivities. The resulting subject-specific current distributions might lead to more reproducible and consistent experimental results across individuals. While brain anatomy has considerable inter-subject variability, this is less of a problem for the eyes. In any event, if there are lesions

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or other subject-specific alterations of the eye or brain, conductivity profiles might require individual modeling. Safety considerations for transcranial and transorbital stimulation of the eye and brain can benefit greatly from current simulation work. Both current amplitude and orientation depend on the electrode configurations. Given that the eyes and the skin are good electrical conductors compared to the poorly conducting, bony structure of the skull, even configurations in which the electrodes are far away from the eye can produce considerable current densities in the eye (Laakso and Hirata 2013). Thus, it is quite possible that for certain electrode montages the eyes have a greater current exposure than the brain, and given that the current flow through the skull varies inter-individually by a factor of two or more (Datta et al., 2012) the interpretation of any stimulation effects is considerably restricted because of the eye stimulation confound. In contrast to the brain, eye anatomy varies less across subjects, so that individual current flow models are less critical for safety considerations. Therefore, current flow simulation of the eye is a preferred approach in safety studies. All eye models published to date include significant simplifications. Depending on the requirements of the task, very simple approaches, such as modeling the eye as one compartment (Haueisen et al. 1995) might be sufficient. But state-of-the-art eye modeling includes realistic finite element models of the head in which up to 15 different tissue types are modeled, including nine major eye compartments (cornea, sclera, lens, vitreous humor, aqueous humor, retina, optic nerve, muscles, surrounding fat tissue) and six major head compartments (white matter, gray matter, cerebrospinal fluid, skull compacta, skull spongiosa, skin), whereby the white matter compartment includes anisotropic conductivity values (Güllmar et al. 2010). Subsets of these have been used in previous current flow modeling studies of the eye (Laakso and Hirata 2013, Hunold et al. 2015, Gall et al. 2016, Indahlastari et al. 2018). 13

The construction of the volume conductor models relies on tissue segmentation approaches. Despite advancements in segmentation procedures, fully automatic model construction still has a number of limitations. Especially, models with a high number of segmented tissues might lack accuracy in head regions which contain structures where imaging procedures have limitations due to resolution or contrast restrictions. For example, the head compartments incorporated in the model by Hunold et al. (2015) (Fig. 1) were automatically segmented based on a T1-weighted MRI data set and omitted a realistic representation of the skull base. While this model was sufficient for the desired qualitative comparison of different electrode montages, quantitative evaluation of current densities might require more detailed models still involving manual model construction steps (Indahlastari et al., 2018; Laakso and Hirata, 2013). Current work is improving on these prevailing segmentation issues, for example in the skull base representation with its foramen for blood vessels and nerves (Nielsen et al. 2018) or the inclusion of the dura (Ramon et al., 2014). Another set of limitations in current head and eye model construction approaches is related to anatomical structures adjacent to the actual eye compartments, e.g. the optic canal in the skull base with a diameter of approximately 3–4 mm and length of about 5 mm (Wichmann and Müller-Forell, 2004) and the anisotropically conducting optic nerve with a diameter of 2 mm (Jonas et al., 1988) and a prechiasmatic length of about 20 mm (Wichmann and Müller-Forell, 2004). The influence of these tissues types and model aspects in current flow models remain to be investigated in detail. As previous stimulation studies of the human eye include both eyes open and eyes closed conditions, future modelling studies should address the open question of the influence of the eye lid on the current distribution in the eye. Depending on the electrode positions and further specific study settings, the closed eyelid could act as current shunt given a thickness of

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approximately 2–3 mm (Codner et al., 2008) and an assumed conductivity similar to connective tissue. Driven by the availability of MRI data, the element size of the finite element method (FEM) models currently typically utilize hexahedra with 1 mm side length. For a detailed analysis of the substructures in the eye, such as the retina, this model resolution should be increased in future studies. Moreover, higher resolution MRI data in combination with modified FEM models might allow for more realistic modeling of the internal structures of the eye including more tissue types. Another limitation considers the availability of conductivity values for eye tissue types, which should be addressed in future experimental studies.

4. Transcranial direct current stimulation (tDCS) tDCS changes membrane potentials during stimulation (online), which, in turn, depends on the direction of the electrical current relative to neuronal orientation. It is this orientation that determines whether neurons are depolarized or hyperpolarized, and this affects changes in neuronal activity. In contrast to this online effect of tDCS, the after-effects involve modifications in synaptic plasticity. Nevertheless, while plastic changes occur, the network must still maintain a certain amount of stability that can be reached by the homeostatic control of the balance of excitation and inhibition (Excitation/Inhibition - E/I) balance, see below) (Krause et al., 2013). The dysregulation of the E/I balance (pathologically increased or decreased cortical excitability mainly due the excessive change of GABA and/or Glutamate levels) may lead to symptoms seen in various neuropsychiatric disorders (e.g. autism, schizophrenia, ADHD). tDCS over the visual cortex in humans has been associated with a polarity-specific effect on contrast sensitivity (Antal et al., 2001, Kraft et al., 2010), on the amplitude of visual 15

evoked potentials (VEPs) (Antal et al., 2004a), on the perception of phosphenes (Antal et al., 2003), and on motion perception thresholds (Antal et al., 2004b). The effects on VEPs were reproduced and extended by Wunder et al. (2018). Other studies did not confirm the previously published modulatory effects of tDCS on visual cortex excitability (Brückner and Kammer, 2016), or found an opposite effect (e.g. anodal stimulation had an ‘inhibitory effect’; Costa et al., 2015). These behavioural/physiological effects can be explained by changing the excitability/inhibitory (E/I) ratio by a given stimulation. However, this might highly depend on the baseline E/I ratio (stimulated cortical area, state of the brain, etc). In a healthy subject cathodal stimulation results in reduced VEP amplitude or worse contrast sensitivity. But when decreasing ‘inhibition’, however, it might lead to increased performance by filtering out irrelevant information (Antal et al., 2004a, b, Weiss and Lavidor, 2012). We would like to mention here that in many studies the effect of tDCS on the visual cortex was less pronounced than that over the motor cortex, which corresponds to the results in earlier animal studies (Creutzfeldt et al., 1962) that might be also related to the different E/I ratios of the different cortical areas. Using the same tDCS stimulation parameters of motor cortex to modulate the visual system produces “after-effects” which, however, are much shorter than those observed in the primary motor cortex (10-20 min vs. 60-80 min). The reason for this different response might include the nature of the cortical connections, other factors that influence neuroplasticity and excitatory / inhibitory circuitries, differences in neurotransmitter systems and their levels or neuronal membrane properties, including receptor expression. A fundamental understanding of individual differences in E/I ratio would provide the basis for optimization of the choice of tDCS parameters for each individual in terms of polarity, intensity, duration, etc.

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5 Transcranial alternating current stimulation (tACS): entrainment and synaptic plasticity in the visual cortex Whereas tDCS alters the excitability of neural assemblies, where the existing stimulus has a brain inherent origin or comes from outside (like a visual or auditory stimulus), tACS excites neural activity itself by forcing neurons to fire or by adapting the endogenous firing patterns (oscillations) to the one delivered by the ACS pulses. Most tACS study results are compatible with a two-stage mechanism: one mechanism involves neural “entrainment” that can lead to synchronization of the action potentials of single neurons with an externally applied sine wave (Figure 3). This is the proposed mechanism of the acute “on-line” effects of tACS (see below). Entrainment, however, does not explain the clinically relevant “off-line” or “after-effects”, i.e. how changes in electrophysiological parameters such as the amplitude of a brain oscillation can remain altered far beyond the end of the stimulation (Kasten et al., 2016). This off-line effect most likely is based on synaptic plasticity (Schutter et al.,2018) or brain functional connectivity network reorganization (Bola et al. 2014). The general consensus is that entrainment probably has to be achieved first and sustained over a certain period of time (e.g. 10-30 min) before synaptic plasticity occurs (Strüber et al., 2015). However, more systematic research is still required to clarify this point.

5.1 Entrainment In physics, entrainment describes the process of one oscillator driving another oscillator (Pikovsky and Rosenblum, 2003). During entrainment – also referred to as synchronization – the frequency, phase and amplitude of the driven oscillator can be influenced by the driving oscillator. In principle, every oscillator can be entrained to another oscillator if there is some kind of coupling between the two. One can, for example, speed up the frequency of a pendulum clock by simply giving the pendulum a brief impulse with the 17

hand at a slightly higher frequency than its actual frequency. Entrainment has been demonstrated for neuronal circuits such as the circadian pacemaker cells in the suprachiasmatic nucleus (Winfree, 1980) or the steady-state visual evoked potential (Notbohm et al., 2016). Entrainment is a mechanism that only occurs with oscillators. This implies that in order for tACS to modulate a brain oscillation via entrainment, there has to be a pre-existing sustained brain oscillation before the onset of tACS. Fig. 3A illustrates the mechanism of entrainment. If a brain oscillation is stimulated near its ‘Eigenfrequency,’ e.g. the individual alpha activity of human EEG (roughly 10 Hz), it will be forced to oscillate at the frequency of the driving oscillator. This is considered entrainment of an oscillator by an external driving force (dark gray regions of diagram). If, however, the stimulation frequency is too far from the ‘Eigenfrequency,’ of the oscillations, no synchronization occurs (light gray regions of diagram). If the strength of the external driving force (tACS) increases, the synchronization regions will become wider in frequency. Due to this triangular shape, the synchronization region is referred to as an Arnold tongue. Synchronization can also happen at harmonics (𝑁 ∗ Eigenfrequency) and subharmonics (Eigenfrequency/𝑁), where 𝑁 is an integer. The different Arnold tongues can have different shapes and widths. Importantly, entrainment even works at very low intensities, if the driving frequency is very close to the driven oscillator´s ‘Eigenfrequency’ (Salchow et al., 2016). This is illustrated by the Arnold tongue extending all the way down to almost zero intensity (Fig. 3A).

5.2 tACS and the electrophysiology of the human brain Demonstrating the online effect of tACS in the EEG and in magnetoencephalography (MEG) is technically challenging due to the massive electromagnetically induced artifacts. 18

While a complete removal of the artifact is currently not feasible (Kasten et al., 2018a, b), there are methods that can strongly attenuate these artifacts, which allows us to gain insights into the on-line effects of tACS. For example, 10Hz tACS over the occipital cortex or near the eye results in enhanced alpha activity already during stimulation (on-line effect) that continues after the end of stimulation (off-line effect) (Sabel et al., 2011; Helfrich et al., 2014a). In the MEG, which permits physiological recording with complete coverage of the head, spatial filtering has been used to demonstrate the on-line effect (Kasten et al., 2018b; Neuling et al., 2015; Ruhnau et al., 2016). During tACS-EEG, however, recording sites near the stimulation electrodes have to be eliminated from further analysis (Neuling et al., 2015). Alpha oscillations were found to exhibit state-dependent phase coherence to the tACS waveform (Ruhnau et al., 2016), and it has been demonstrated that tACS can modulate eventrelated changes of MEG gamma activity during stimulation (Herring et al., 2019). Due to the aforementioned artifacts, the first studies combining tACS and EEG only investigated the off-line effect of tACS (Zaehle et al., 2010). The authors showed that stimulation of the occipital cortex at the participants’ individual alpha frequency enhanced the amplitude of the alpha activity in the EEG after stimulation compared to before stimulation. This effect depended on the brain state during stimulation, i.e. alpha amplitude was only enhanced by tACS when the subjects had their eyes open but not when they had them closed (Neuling et al., 2013). This off-line effect lasted for at least 70 minutes after the end of a 20minute stimulation session (Kasten et al., 2016). Further evidence of the off-line effect being mediated by synaptic plasticity comes from a study using drugs to modulate synaptic efficacy (Wischnewski et al., 2019): tACS in the beta frequency range only enhanced beta oscillations when a placebo was given. If, however, the N-methyl-D-aspartate (NMDA) receptor antagonist dextromethorphan was

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administered, no such amplitude enhancement was observed. This finding is evidence that tACS can induce synaptic plasticity mediated via NMDA receptors.

5.3 Hemodynamic responses Another approach is to record brain signals during stimulation using measurement modalities that are less susceptible to distortion by tACS. For example, fMRI can be recorded during tACS with little to no distortion (Antal et al., 2014). The exact relationship between EEG oscillations and BOLD responses is not yet fully understood and far from trivial. For the human EEG alpha activity, however, a reverse relationship has been described between the (higher) amplitude of EEG alpha activity and the (lower) BOLD response both in occipital (Moosmann et al., 2003) and in somatosensory cortex (Mullinger et al., 2014). Therefore, a first study combining tACS and fMRI had assumed that entrainment of EEG alpha oscillations by tACS results in an increase of alpha amplitude and, in turn, in a decreased BOLD response. The results showed that tACS at the participant’s individual alpha frequency down-regulates the BOLD response to visual stimuli (Vosskuhl et al., 2016). A subsequent study, however, using 10 Hz tACS instead of the individual alpha frequency could not reproduce the on-line effect on the BOLD response but instead found an off-line effect (Alekseichuk et al., 2016). Yet another study compared different tACS frequencies (10, 16, and 40 Hz) and found that the effects of 10 Hz tACS were opposite of those with 40 Hz tACS (Cabral-Calderin et al., 2016a), supporting the view that tACS-entrained oscillations follow the antagonism between alpha and gamma oscillations that has been described earlier (Helfrich et al., 2016). This group also showed that tACS in the beta frequency range modulated BOLD in a fronto-parietal network (Cabral-Calderin et al., 2016b).

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5.4 tACS and visual perception Importantly, physiological tACS on-line effects do, in fact, directly modulate perceptual processes. The first study detected the effects of tACS on visual perception as the induction of phosphenes in healthy subjects (Kanai et al., 2008). When stimulating the visual cortex with a tACS frequency somewhere in the alpha or beta frequency range, participants reported a visual flicker in the absence of any visual stimulation. Lower or higher tACS frequencies did not provoke such phosphenes. Meanwhile it is assumed that the tACS-induced phosphenes are of retinal origin (Kar et al., 2012; Schutter et al., 2010, for a review see Schutter et al., 2016). In a study on contrast thresholds, tACS was applied above the visual cortex using different frequencies in the gamma range (40, 60, 80 Hz) (Laczó et al., 2012). When participants were requested to detect stationary random dot patterns, no tACS modulation of contrast sensitivity was detected, whereas contrast discrimination thresholds decreased with 60Hz tACS, but not with 40 or 80 Hz compared to sham stimulation. Furthermore, 10 Hz tACS application above the occipital cortex modulated the perception of light emitting diodes in a sinusoidal fashion (Helfrich et al., 2014a), while posterior inter-hemispheric 40 Hz tACS altered the visual perception of motion (Helfrich et al., 2014b). Interestingly, the off-line effects of tACS are also manifested by (i) enhanced EEG alpha amplitudes and (ii) altered perceptual performance. For example, tACS at the individual alpha frequency, delivered above the occipital cortex, led to a significantly improved mental rotation performance (Kasten and Herrmann, 2017), which correlated with the tACS-induced enhancement of EEG alpha power. In conclusion, tACS can modulate visual perception both on-line and off-line. In future studies the following questions should be addressed: (i) Can an Arnold tongue be demonstrated in humans by electrophysiological methods during tACS? (ii) What parameters 21

such as the brain state before or during stimulation determine whether on-line effects of tACS can be observed? (iii) What stimulation parameters such as the duration, frequency, current strength and waveforms determine whether off-line effects of tACS can be observed?

5.

Repetitive TMS and visual modulation TMS delivers magnetic pulses which need to be repeated at a predefined frequency in

order to modulate vision and perception beyond stimulation (to induce “after-effects”). In addition to this “off-line” approach (which is of particular interest for vision modulation, enhancement, and restoration in patients due to its prolonged effects), TMS can also affect visual functions online to stimulation (using “on-line” single pulse TMS or on-line rTMS applied during task performance). The large body of studies using the latter, online approaches is not reviewed here. When using repetitive TMS pulses to induce after-effects, an important decision is which stimulation frequency to select. There are two different rationales that guide this decision. Most TMS studies select certain frequencies to either induce long-term depression (LTD) or long-term potentiation (LTP) (for a comprehensive review, see Rossi et al., 2009). Low stimulation frequencies (below 1 to 5 Hz) are thought to induce LTD, while higher stimulation frequencies (5 Hz and higher) are used for inducing LTP-like effects. This LTP/LTD-inspired approach is typically referred to as repetitive TMS or rTMS. A variant of this approach is theta burst stimulation (TBS). In contrast, a more recent line of research selects the frequency based on the rhythmicity of known neural oscillations of the visual system, such as brain oscillations with a peak frequency in the alpha band (8-14Hz). The premise here is that tuning the stimulation frequency to the underlying brain rhythms promotes these oscillations by entrainment (see 22

above sections on tACS) (Thut et al., 2011a; 2012). This approach is occasionally referred to as rhythmic TMS or rh-TMS to distinguish it from the rTMS approach. Accordingly, these studies base their choice of frequency on the bulk of electrophysiological evidence from human and animal studies that elucidate the relationship between intrinsic brain oscillations and perception (e.g. Fries, 2005; Jensen and Mazaheri, 2010; Fiebelkorn and Kastner, 2019). The associated mechanistic models lead to predictions about the expected behaviour outcome of rh-TMS, and hence help guiding rh-TMS (see Thut et al., 2017). Yet another, third, approach is to employ repeated paired-pulse TMS applied over two areas at specific inter-pulse intervals, a technique known as cortico-cortical paired associative stimulation or ccPAS. This stimulation pattern is thought to strengthen cortico-cortical connectivity by the principle of spike-timing dependent plasticity as shown in Figure 4 (see Romei et al., 2016b for a first application in the visual system). Below, the evidence for modulation of normal vision by rTMS, rh-TMS, repeated ccPAS or TBS is reviewed.

6.1 rTMS at low (1Hz) versus high (10Hz) stimulation frequencies rTMS has been applied to different visual areas of the occipital cortex and the wider visual network in the temporal and parietal lobes. In order to achieve off-line rTMS effects, a considerable number of pulses are typically applied (>=300) with the stimulation lasting between five and 20 minutes depending on which protocol is used (see e.g. Thut and PascualLeone, 2010). These after-effects are then assessed by comparing post-rTMS outcome measures to baseline values as well as to sham stimulation. Most rTMS studies exploring after-effects in the visual system employed inhibitory, low-frequency (1Hz) rTMS and reported after-effects that are consistent with a transient disruption of function of the stimulated cortex (Kosslyn et al., 1999; Hilgetag et a., 2001; Antal et al., 2002; Brighina et al., 2003a; Merabet et al., 2004; Lewald et al., 2004; Grossman 23

et al., 2005; Saint-Amour et al., 2005; Thut et al., 2005; Mevorach et al., 2006; Valero-Cabré et al., 2006; Matsuyoshi et al., 2007; Bolognini et al., 2009; Ling et al., 2009; Thompson et al., 2009; Carmel et al., 2010; Mancini et al., 2011; Mullin and Steeves, 2011; Bourgeois et al., 2013; Kietzmann et al., 2015; Xu et al., 2016; Edwards et al., 2017). This is broadly in line with the current concept of 1Hz-rTMS mechanisms of LTD action. However, very few studies examined the after-effects of high frequency (10-20 Hz) rTMS, and they all reported mixed results (Kim et al., 2005; Jin and Hilgetag, 2008; Dombrowe et al., 2015). Hence, more studies using high frequency protocols are required to establish a dichotomy of after-effects (inhibition versus facilitation, or LTD versus LTP) as a function of stimulation frequency in visual areas of the brain. rTMS over the visual cortex itself has been show to modulate basic visual functions such as contrast sensitivity thresholds (Antal et al., 2002; Ling et al., 2009) and visual discrimination ability (Waterston and Pack, 2010). Here, the choice of the TMS pulse waveform (mono- vs. biphasic) and direction of current flow (posterior-anterior vs. anteriorposterior) can significantly affect TMS efficiency (Antal et al., 2002), while the type of protocol (e.g. low frequency vs. theta burst) does not seem to play a major role (Waterston and Pack, 2010). Visual cortex rTMS also affects various other V1 functions, including contextual orientation processing but not orientation tuning (Ling et al., 2009), binocular fusion (Saint-Amour et al., 2005), component motion perception (Thompson et al., 2009) or visual imagery (Kosslyn et al., 1999). Visual cortex rTMS also interferes with spatial processing in the tactile (Merabet et al., 2004) and auditory modalities (Lewald et al., 2004), an effect that is in line with evidence for cross-modal processing. On the other hand, rTMS over extrastriate visual areas interferes with apparent motion or component motion perception after MT/V5 stimulation (Matsuyoshi et al., 2007; Thompson et al., 2009), with biological motion perception after stimulation of posterior STS 24

(Grossman et al., 2005), with face perception after stimulation of the occipital face area (OFA) (Kietzmann et al., 2015), and object processing (visual, haptic and visuo-haptic) after stimulation of the lateral occipital cortex (LOC) (Mullin and Steeves, 2011; Mancini et al., 2011; Kassuba et al., 2014). Extrastriate cortex rTMS also affects illusory contour perception (Brighina et al., 2003a). rTMS of frontal or parietal areas of the wider visual network can affect vision via the known feedback projections to visual areas. In one study, Silvanto et al. (2006) showed that frontal TMS modulates visual cortex excitability. rTMS over the posterior parietal cortex (PPC) can change perception across the visual fields (VFs) with differential effects of low versus high frequency rTMS. Stimulation with 1 Hz-rTMS over PPC induces a bias away from the VF contralateral to stimulation (Hilgetag et al., 2001), while 10 Hz-rTMS over PPC biases perception towards the contralateral visual field (off-line effects; Kim et al., 2005). This is in line with the concept that low and high frequency rTMS induce opposite effects, probably by modulation of visuo-spatial attention through an rTMS-induced, interhemispheric imbalance of activity in parietal areas and the wider attention network (see Plow et al, 2014 for fMRI support). However, while follow-up studies reported consistent effects of low frequency parietal rTMS with regard to the direction of the induced perceptual bias (e.g. Thut et al., 2005; Valero-Cabré et al., 2006; Bolognini et al., 2009), the results with high frequency parietal rTMS are mixed (see Jin and Hilgetag, 2008; Dombrowe et al., 2015). Other studies using parietal rTMS have revealed a right hemispheric specialization in alerting and orienting (Xu et al., 2016), in the control of inhibition of return (Bourgeois et al., 2013), in salient target selection (Mevorach et al., 2006), feature binding (Esterman et al., 2007), visuo-spatial predictions (Edwards et al., 2017) and in perceptual maintenance during binocular rivalry (Carmel et al., 2010).

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In brief, rTMS over visual areas reliably modulates visual function. Most of the studies revealed disruptive effects after low frequency (1Hz) rTMS, with occasional, concurrent facilitative effects in related functions (likely explained by push-pull effects due to disinhibition: Hilgetag et al., 2001; see also Saint-Amour et al, 2005; Mullin and Steeves, 2011; Xu et al., 2016). But because we still lack data from high frequency protocols, the ability of high frequency rTMS to facilitate and/or restore vision is largely unknown (but see below for occipital theta burst stimulation and rTMS in clinical conditions).

6.2 Rhythmic TMS at frequencies of brain oscillations Rh-TMS uses repeated pulses with the aim of modulating vision by promoting functional brain oscillations of the visual networks through entrainment. The rate and location of rh-TMS is tuned to the frequency and the anatomical source of the target oscillation. The potential of rh-TMS to promote oscillatory activity by entrainment was originally shown for the parieto-occipital alpha rhythm using EEG concomitant to alpha rh-TMS (Thut et al., 2011b). Entrainment likely originates from progressive phase-reset of ongoing oscillations through the single pulses of the train (Herring et al., 2015). Subsequent rh-TMS/EEG studies have confirmed that rh-TMS can entrain brain oscillations for various frequencies and domains outside the visual system (Hanslmayr et al., 2014; Romei et al., 2016a; Albouy et al., 2017). For rh-TMS, pulses are applied in short trains, usually during a baseline period, and hence prior to a behavioural probe. Behavioural rh-TMS effects are thus observed off-line as for rTMS, but these after-effects (entrainment echoes) tend to dissipate much faster than those after rTMS due to the entrainment fading rapidly after the end of the train (Thut et al., 2011b; Hanslmayr et al., 2014; Romei et al., 2016a; Albouy et al., 2017; see also Herring et al., 2015 for the duration of one EEG impulse response to a single TMS pulse).

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Both visual cortex and parietal rh-TMS at the alpha frequency modulate visual perception. The effects of alpha rh-TMS are inhibitory in the visual field opposite the rh-TMS (Romei et al., 2010), which is in line with the known inhibitory role of alpha oscillations in gating sensory information (Klimesch et al., 2007, Jensen and Mazaheri, 2010). Concurrent to this inhibitory effect, facilitative effects are observed in the visual field ispilateral to rh-TMS (Romei et al., 2010; see Ruzzoli and Soto-Faraco, 2014 for analogous results in the somatosensory system). Hence, alpha rh-TMS over the parietal and visual cortex is biasing perception away from the VF contralateral to TMS, and towards the ipsilateral visual field. Although this behavioural effect matches the direction of biased perception observed after 1 Hz parietal rTMS (Hilgetag et al., 2001), these two effects cannot be explained in the same framework, i.e. the TMS generally suppresses contralateral and enhances ipsilateral perception. This is because rh-TMS only biases perception for stimulation at alpha frequency but not at flanker frequencies (frequency-specificity, Romei et al., 2010), thus formally linking the rh-TMS effects on perception to an intrinsic frequency and not to a general TMS effect. In further support of a link to alpha oscillations, Jaegle and Ro (2014) found that visual perception modulates with the phase after alpha rh-TMS. Other studies focused known, visually related brain oscillations, but cycling at other frequencies have also reported frequency specificity of rh-TMS effects on distinct aspects of visual perception (Romei et al, 2011; Chanes et al., 2013; Quentin et al., 2015; see also Klimesch et al., 2003; Sauseng et al., 2009). In brief, rh-TMS is a promising approach for modulating vision by entrainment of brain oscillations. One of its limitations, however, is the brief duration of the entrainment echoes. Yet, although these echoes are short-lived, tACS and modeling evidence suggests that entrainment may promote brain oscillations in the visual system beyond the stimulation through distinct plasticity mechanisms (see tACS section, Zaehle et al; 2010; Vossen et al., 27

2015). In contrast, there is little evidence that the after-effects of classical low and highfrequency rTMS paradigms are driven by entrainment (Veniero et al, 2015), despite rTMS frequencies crossing intrinsic frequency bands (e.g. high frequency 10 Hz rTMS in alpha band). It is unclear to what extent this is due to not choosing rTMS frequencies to exactly match the intrinsic brain rhythms. It is also unclear to what extent different mechanisms of action (LTP and entrainment) may co-exist or interact, and explain some of the inconsistent findings reviewed above (e.g. see high frequency rTMS).

6.3 Repeated cortico-cortical paised associative stimulation (ccPAS) The principle idea of the ccPAS approach is to stimulate two functionally connected areas with dual site, paired pulse TMS at specific interpulse intervals so that the effects of the two pulses (one pulse per area) interact to strengthen or weaken inter-areal connectivity (through the principle of spike timing dependent plasticity). The approach involves applying repeated paired pulse TMS to two areas (e.g. V5 and V1; Romei et al., 2016b) to achieve longer lasting changes in their connectivity. This was inspired by seminal studies in the motor cortex (see e.g. Rizzo et al., 2009; Arai et al., 2011; Koch et al., 2013; Veniero et al., 2013; Johnen et al., 2015). To date, two studies have used ccPAS in studies of the visual system (Romei et al., 2016b; Chiappini et al., 2018). Romei et al. (2016b) showed that ccPAS over V5 and V1 with the intention to strengthen back projections from extrastriate to primary visual cortex (paired pulse V5->V1 TMS) enhanced perception of visual motion. Chiappini et al. (2018) demonstrated that the specificity of V5->V1 ccPAS was enhanced by presenting unidirectional motion stimuli during ccPAS. With this manipulation, ccPAS strengthens the cortico-cortical neural pathways coding for the viewed motion direction. However, despite these recent achievements and their novelty, the empirical evidence for an effect of the ccPAS 28

approach is still sparse. Future research will show if this approach can modulate both backprojections and forward-projections in the visual system.

6.4 Occipital theta burst stimulation With the introduction of theta-burst stimulation (TBS) in the motor system (Huang et al., 2005) the crucial question arose whether this powerful neuromodulation technique could also modulate excitability in other cortical regions. In the first study addressing the visual system (Franca et al., 2006), two protocols established for the motor system have been applied to the occipital cortex in healthy subjects: continuous TBS (cTBS), and intermittent TBS (iTBS). Excitability of the visual system was probed by means of phosphene thresholds (PTs). In both protocols, the intensity was set to 80% of the individual PT. Only cTBS exhibited the expected modulatory effect, i.e. an inhibition revealed by PT elevation. In contrast, iTBS caused neither a facilitatory effect nor did it change PT at all. In that study a round coil was used instead of a figure-eight coil, the widely accepted standard. In a different study, the subjects performed a perceptual task and visual orientation discrimination was measured as the dependent variable (Waterston and Pack, 2010). It turned out that occipital cTBS applied with a fixed intensity did not impede but rather facilitated orientation discrimination. Since the same effect was observed following a 20-minute stimulation with 1 Hz, the authors concluded that the inhibitory effect in visual cortex might result in an improvement of process due to changes in the signal-to-noise ratio. Similar conclusions were reached following a series of experiments with cTBS (Allen et al., 2014). cTBS at 80% of motor threshold induced both a PT increase as well as an increase in awareness of visual stimuli (direction of an arrow presented in a field of “visual noise”). A magnetic resonance spectroscopy measurement directly following cTBS revealed an increased GABA concentration in the occipital cortex. The inhibitory influence of cTBS on visual 29

cortical networks seems to increase the signal-to-noise ratio, enhancing conscious visual perception. In contrast to the previous results, occipital cTBS at 80% of PT reduced visual discrimination (Rahnev et al., 2013). In a separate experiment the authors demonstrated a decrease in short-range functional connectivity between visual areas using fMRI. This finding is compatible with the proposal that cortical modulation by TMS not only acts locally but also influences remote areas connected to the target area (cf. Chouinard et al., 2003). The influence of occipital TBS on visual acuity has been addressed in a study of peripheral visual acuity using four different intensities (Brückner and Kammer, 2014). Healthy subjects tolerated iTBS as well as cTBS up to intensities of 120% of PT. However, this had no effect on visual acuity measured at 10° from the fixation point in all four quadrants. The same negative result was obtained with 15 min of 1 Hz rTMS. Visual acuity as a task seems to be robust against occipital rTMS, probably due to a complex and distributed visual network. In an attempt to reproduce the results of Franca et al. (2006), PT was chosen to measure changes in excitability following iTBS or cTBS, applied with 100% of PT (Brückner and Kammer, 2015). The modulatory influence of a controlled visual demand subsequent to TBS was also investigated. It turned out that PTs did increase after cTBS, but only when the stimulation was followed by the controlled visual activity task. In contrast, iTBS did not result in any modulation of PT. In most of the above mentioned studies TBS was applied using a figure-eight coil which delivers a focal field, the first study (Franca et al., 2006) was performed with a round coil that gives a less focal field. A systematic comparison of the two coil geometries in the application of cTBS to the occipital cortex using PTs as the dependent variable (Brückner and Kammer, 2016) revealed a more complex scenario. A consistent modulation following cTBS 30

at 80% of PT was not found for any of the coils used. However, with the round coil a positive correlation between baseline PT and induced PT change following cTBS was observed. While subjects with a higher baseline PT tended to increase PT after cTBS, subjects with a lower baseline PT cTBS exhibited in a decrease in PT. Taken together, while TBS is a promising tool for modulating cortical excitability of the visual system, many unresolved questions remain. A central problem is the inconsistency of modulation direction with a given TBS pattern. A meta-analysis on studies in the motor system confirmed the dichotomy originally observed, i.e. an excitatory effect of iTBS and an inhibitory effect of cTBS (Wischnewski and Schutter, 2015). However, with a sample size of n=52 in a within-design a study directly addressed the question of modulation direction (Hamada et al., 2013). Here neither cTBS nor iTBS modulated the cortex in a predictable direction, but all combinations of effects (facilitation vs. inhibition) were observed with both protocols in roughly one fourth of the cases. For the visual system, a similar study with enough subjects to attain an appropriate statistical power remains to be conducted. Furthermore, the influence of the cortex state at the time of stimulation has to be controlled, since state dependent effects might influence the direction of modulation (Silvanto et al., 2008) (see below 6.5). Another interesting field is the influence of coil geometry on modulatory effects. This topic has so far been neglected in rTMS studies.

6.5 Combined approaches: Beyond pure rTMS, TBS and ccPAS Inspired by the results of Siebner et al. (2004) who showed that neuromodulatory effects are state-dependent (following the principles of homeostatic metaplasticity), some attempts have been made to prime visual areas in order to control the state of the cortex prior to or during the stimulation. Silvanto et al. (2007) showed that the effects of off-line TBS of the visual system can be influenced by visual (pre)conditioning, e.g. through passive viewing. 31

Lang et al. (2007) used tDCS over occipital regions before applying high frequency (5 Hz) rTMS but only detected modest effects of preconditioning. In contrast, Bocci et al. (2014) found a significant effect of tDCS preconditioning on both low frequency (1 Hz) and high frequency (5 Hz) rTMS outcomes in the visual system (effect reversal in line with the principles of homeostatic metaplasticity; Siebner et al., 2004). Chiappini et al. (2018) found that V5->V1 ccPAS effects were modulated by concurrent conditioning of visual cortex by viewing of motion stimuli (see above). In summary, there is a general consensus that the brain´s visual system can be modulated by non-invasive electrical or magnetic stimulation bevond the duration of stimulation. We believe that this topic deserves greater scientific attention, particularly in view of the fact that studies in animals and patients have indicated that non-invasive stimulation can be of potential clinical use.

7

Visual system plasticity, restoration and recovery

7.1 Animal models In the past few years, evidence has mounted that low intensity TES may be clinically useful (see below) but the actual mechanisms of action are not fully known and require further research yet. Studies in animals have helped us to shed light on this issue. One effect of transcranial or TcES is to reduce retinal degeneration, or injury to the retina or the optic nerve, and improves visual function. In transcorneal stimulation (TcES) small electrodes are placed onto the surface of the cornea or sclera. Several possible mechanisms to explain these findings have been discussed: (i) promotion of retinal cell survival and regeneration (Fu et al., 2018, Hanif et al., 2016, Henrich-Noack et al., 2013a, Henrich-Noack et al., 2017, Henrich-Noack et al., 2013b, 32

Miyake et al., 2007, Morimoto et al., 2007, Morimoto et al., 2012, Morimoto et al., 2014, Morimoto et al., 2005, Morimoto et al., 2010, Ni et al., 2009, Osako et al., 2013, Rahmani et al., 2013, Schatz et al., 2011, Tagami et al., 2009, Wang et al., 2011, Willmann et al., 2011) and/or (ii) modulation of the rhythmic activity in the visual structures of the brain (Ma et al., 2014, Sergeeva et al., 2015a, Sergeeva et al., 2012). Another approach, i.e. direct current stimulation (DCS) – potentially improves visual function through modulation of the cortical excitatory-inhibitory balance (Castano-Castano et al., 2017, Castano-Castano et al., 2019). The restoration of retinal structure and function following TcES has been extensively investigated in animal models. In a rat model of retinitis pigmentosa, whole-eye electrical stimulation (4 μA at 5 Hz, 30 min twice weekly, from four to 24 weeks of age) significantly improved retinal function as measured by electroretinogram (ERG) oscillatory potentials and optomotor response (Hanif et al., 2016). The effects were associated with increases in gene expression of brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2, caspase 3, and glutamine synthetase at one hour following stimulation (Hanif et al., 2016). Since the treatment induced stronger protection of the retinal ganglion cells (RGCs) than the photoreceptors, it was suggested that post-receptor neurons and the inner retina may be particularly responsive to whole-eye electrical stimulation (Hanif et al., 2016). Preservation of photoreceptors and retinal function in a rat model of retinitis pigmentosa was also observed by a Japanese group using trancorneal ES treatment (3 to 9-weeks old, 50-100 μA at 20 Hz, 1 hour once weekly) (Morimoto et al., 2007). This was confirmed in rabbits with a P347L mutation of rhodopsin, a different model of retinitis pigmentosa (Morimoto et al., 2012). ACS has also been shown to exert neuroprotective and pro-regenerative effects in rodent models of optic neuropathies, including acute nerve injury (Henrich-Noack et al., 2017, Henrich-Noack et al., 2013b, Miyake et al., 2007, Morimoto et al., 2005, Morimoto et al., 2010, Tagami et al., 2009), ischemia (Inomata et al. , 2007) and glaucoma (Fu et al., 33

2018). Morimoto et al. (2005) observed that TcES (100 μA at 20 Hz) applied for one hour immediately after optic nerve transection rescued axotomized RGCs. This effect was mediated by up-regulation of insulin-like growth factor IGF-1 in retinal Müller cells. The same stimulation applied daily promoted axon regeneration via up-regulation of IGF-1 (Tagami et al., 2009). Fu and co-authors (2018) also showed that the same stimulation protocol applied immediately after intraocular pressure (IOP) increase promoted RGC survival following acute ocular hypertensive injury in an acute glaucoma model in gerbils. RGCs were protected from secondary damage, which was associated with less microglia activation and inflammatory response. The suppression of microglia activation was associated with an increased expression of the anti-inflammatory factor interleukin IL-10 and a corresponding reduction of the pro-inflammatory factors IL-6, COX-2, and NF-B signalling (Fu et al., 2018). These results supported those of an earlier study (Zhou et al., 2012) that showed suppression of the pro-inflammatory interleukin IL-1β and tumour necrosis factor TNF-α in microglia and up-regulation of BDNF and ciliary neurotrophic factor (CNTF) in Müller glia when electrical stimulation was applied to retinal cell cultures in vitro. It is conceivable that ACS can regulate expression of numerous other genes, as was suggested by a transcriptomic study (Willmann et al., 2011). Taken together, studies in animal models indicate that TcES exerts its protective effects in the retina primarily via up-regulation of neurotrophic factors and down-regulation of pro-inflammatory pathways (for review see Sehic et al., 2016). It is interesting to note that the surviving retinal neurons can remain functionally silent (Henrich-Noack et al., 2017). It needs to be further investigated to what extent the retinal neurons protected by TcES are functionally active. Other effects of ACS may be of a vascular nature. For example, vascular changes were noted in the cat retina during and after stimulation (Mihashi et al., 2011, Morimoto et al., 2014), and there is a report of ACS-induced improvement of chorioretinal blood circulation in humans (Kurimoto et al., 2010). 34

Besides extending our understanding of non-invasive TES, animal studies have also advanced the development of retinal prostheses, in which electric pulses are delivered by electrode arrays invasively implanted epiretinally or subretinally. Some studies were focused on the neuroprotective effects of subretinal implants (Pardue et al., 2005), but the initial studies evaluated safety and tolerability of the implants (Bertschinger et al., 2008, Salzmann et al., 2006). They showed only minor cellular disturbances around the implants with no damage to RGCs (Pardue et al. , 2001). Understanding the dynamics of current flow in the retina is not only essential for the development of retinal prostheses but also for non-invasive TcES. It was found that rectangular waveforms activate both the bipolar cells and RGCs (Freeman et al. , 2010). RGCs are more susceptible to short pulses of approximately 150 ms, whereas the neurons of the inner retina respond more strongly to longer pulses (Freeman et al., 2010). A recent study evaluated the depth-resolved retinal physiological responses evoked by TcES by using optical coherence tomography (OCT) (Sun et al., 2019). Intrinsic optical signals (IOSs) were recorded in different retinal layers while ES and flickers were used to stimulate the retina. Both positive and negative IOSs could be evoked by ES in three segmented retinal layers, particularly in the inner retina and subretinal space. The IOSs elicited by flickers increased during the entire stimulation, while those evoked by ES remained at a constant level. Furthermore, the TES-induced IOSs were highly synchronized to the electrical field in the retina. In any case, whether ES is applied via implanted electrodes or non-invasive TcES, the effects are not restricted to the retina and the optic nerve but may extend to higher levels of the visual pathway. As in humans, where transorbital ACS induced improvement of visual function associated with changes in EEG (Bola et al., 2014, Fedorov et al., 2010, Sabel et al., 2011, Gall et al., 2016), studies in a rat model of optic nerve crush showed modulation of brain activity by TcES, i.e. changes of frequency and amplitude, outlasting the stimulation 35

period (Sergeeva et al., 2015a, Sergeeva et al., 2012). However, this effect was most pronounced during the intermediate stages of anesthesia (i.e. activity dependent). Studies in cats using optical imaging of intrinsic signals showed that ES activated both the retina and the visual cortex (Ma et al., 2014, Mihashi et al., 2011, Morimoto et al., 2014, Sun et al., 2018), and higher current intensity and longer pulse duration led to stronger and broader activation of the cortical areas, with the strongest responses to ACS frequencies of 10-20 Hz (Ma et al., 2014). Furthermore, tDCS was found to improve visual functions (Ding et al., 2016), including an animal model of amblyopia. Here the authors noted improvements of visual acuity, presumably via up-regulation of the inhibitory neurotransmitter GABA in the visual cortex (Castano-Castano et al., 2017, Castano-Castano et al., 2019). The question arises whether the pulses of current applied to the eye enforce synchronized action potentials originating in the retina, and then activating higher visual areas such as thalamus, tectum or visual cortex, or if higher visual structures are activated directly by the passive current flow. Although it is a non-trivial task to rule out the second, animal studies support the retinal origin of the transorbital ES effects as well, at least when low intensity current is injected (Foik et al., 2015). Using finite element method models (FEM), Hanif et al. (2016) demonstrated a uniform current density throughout the retina when the stimulating electrode was placed on the cornea and the reference electrode was attached to the mouth. Foik et al. (2015) delivered single current pulses to the rat’s eye that evoked responses in the visual thalamus, superior colliculus and visual cortex. These responses were very similar in shape, but not in timing, to the responses evoked by visual stimulation (Foik et al., 2015). This is in line with previous observations (Inoue and Potts, 1971, Potts et al., 1968). Both the electrical and visual responses were suppressed by blocking sodium channels in the RGCs with tetrodotoxin (Foik et al., 2015). Thus, the activation of RGCs therefore gives rise 36

to the electrically evoked responses in the visual pathway (Foik et al., 2015). Along these lines of reasoning, the integrity of the optic nerve is required to induce the effects of ES on central EEG changes in rats (Sergeeva et al., 2012). However, when high intensity currents are applied, the response can be induced directly in the cortex, as shown with TES (for review see (Karabanov et al., 2019, Krause et al., 2019)). Besides the issues of current density distribution in the eye, current propagation along the visual pathway, and the origins of the changes in brain activity, there are other challenges in using TES in animal models. Most animal studies using TcES are performed in anesthetised animals, and the anesthetics can interfere with brain activity. Sergeeva et al. (Sergeeva et al., 2012) showed that EEG changes could not be induced when applied during deep anesthesia, which is in line with a view that synaptic plasticity in local cortical network depends upon the level of neuronal activity (Crochet et al., 2006). Therefore, development of animal models of TES in non-anesthetized, freely behaving animals will benefit the field (Sergeeva et al., 2015b). Another challenge is the choice of appropriate stimulation parameters, i.e. pulse amplitude and frequency, duration, waveform and time of application. This contrasts with studies in human subjects where the verbal report of phosphenes can be used as an indicator of suitable stimulation parameters (Antal et al., 2003, Fedorov et al., 2011, Gall et al., 2010). However, translational animal studies of TES can contribute to develop safe and optimized therapies for patients, and to help us understand the basic molecular and cellular/physiological mechanisms of action.

7.2. Vision recovery and restoration in humans using non-invasive electrical stimulation (transorbital ACS, tDCS, tACS, tRNS)

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During the past decade, many clinical and experimental studies have been conducted to determine the effects of ES on patients with vision loss. Such studies focused on the treatment of visual impairment and damages affecting the entire visual system, from retina to cortex. Among the investigated ophthalmological conditions treated with low-intensity ES are glaucoma, age-related macular degeneration (AMD), optic nerve damage, optic neuropathy, retinal dystrophy, diabetic retinopathy, retinitis pigmentosa, retinal artery occlusion, amblyopia and myopia. While there is no definitive answer as to which mechanism(s) mediates the vision recovery, existing evidence points towards different possibilities. Because ES can improve vision in a broad spectrum of disorders, this suggests that its mechanism of action might be at a very fundamental, pathology-independent level. As described above, on the molecular level, animal studies suggest that ES increases the expression of neurotrophic factors and upregulates the expression of different retinal genes and proteins, which are associated with neural transmission, including cellular signaling metabolic proteins, immunological factors, and structural proteins. After injuries, such as optic nerve transection, directly injured RGCs are rapidly lost, and so far there are no treatments that can prevent this process. But the secondary loss of RGCs whose axons were not directly damaged can be delayed or even stopped by ES. Whether these neuroprotective effect of ES also exist in the human retina, is an open issue. In any event, on a functional level, neuroprotection would be a mechanism that might explain the prevention of vision loss progression, not one that can explain recovering vision. Traditional textbook knowledge teaches us that vision loss, e.g. after traumatic brain injury, is irreversible, however, the brain has multiple mechanisms to at least partially overcome lost vision. There are many cases of spontaneous recovery of vision after brain or optic nerve trauma (both in animals and humans) showing that the brain is highly dynamic and able to compensate for the damage (for a review see Sabel et al. 2011, Urbanski et al., 38

2014). The underlying neuronal mechanisms depend on the individual pathology. For example, after stroke or traumatic injury of the primary visual pathway spontaneous axonal and dendritic sprouting, processes of unmasking alternative neocortical pathways, neurogenesis and other remodeling processes were observed (Reitsma et al., 2013). In accordance to these processes, patients with homonymous hemianopia often have some residual sensitivity for visual stimuli in their blind visual field. During recovery after vision loss recruitment of the contralesional hemisphere, or recruitment of activity by nearby healthy cortex, including higher order visual areas (Baseler et al., 1999, Huxlin, 2008) were reported. In these regions increased neuronal activity was found, but it remains unclear, whether, and if so, how the intact region affects vision improvement. Nevertheless, these reorganisation processes can be supported or even guided by ES: the underlying assumption is that the neurons, neural assemblies, and networks may be disorganized, with many neurons being in a ‘silent’ mode. Both vision training (exercises) and ES using an ‘optimal’ frequency and intensity can reorganize and reactivate suboptimal neuronal activity and neural networks by increasing synaptic strength (Kasten et al. 1998, Bola et al. 2014, Vanni et al., 2007, Raninen et al., 2007; Casco et al., 2018) (see ES and LTP and/or tACS and neuronal entrainment above). In this case, the final outcome of recovery greatly depends on the number of surviving neurons and their ability to fire action potentials in a coordinated fashion throughout the brain network. Clearly, different vision-enhancing therapies, such as training or ES, could invoke different mechanisms of action. For example, in retinal disorders, reactivation of “silent” neurons could explain recovery, whereas in monohemispheric strokes the disturbed balance between the two hemispheres should be normalised (Corbetta et al., 2005). Here, the intact hemisphere becomes ‘hyperactive’ and produces an above-normal inhibitory modulation of the lesioned hemisphere via transcallosal fibers. In case of motor stroke a ‘facilitatory’ stimulation of the affected hemisphere and the ‘inhibitory’ stimulation of the intact hemisphere has been suggested (Lüdemann-Podubecka et al, 2017). With regard to the visual 39

system, fMRI and MEG also revealed the development of new visual field representations in the contralesional hemisphere in stroke, which are associated with visual field rehabilitation (see e.g. Henriksson et al., 2007), or AC stimulation (Sabel et al., 2019). Therefore, future work needs to address how the potential of the recovering brain and its ability to develop new visual field representations can be best modulated, i.e. whether ES is used to promote the function of the peri-lesional (“original”) neural tissue or enhance (or inhibit) newly developed representations. Figure 5 illustrates “residual vision activation theory” as proposed by one of us (Sabel et al. 2011): after optic nerve damage, for example, the visual field typically has three different functional sectors: (i) “intact” vision (shown in white), (ii) “areas of residual vision” (ARVs) which are partially damaged (grey), and (iii) areas with presumably total damage and blind (black). Regions of partial damage are found in most visual system diseases such as stroke (e.g. hemianopia), and retinal or optic nerve disorders (e.g. glaucoma). Due to longrange, functional connectivity network disturbances, however, the “intact” regions might even be impaired by subtle neurophysiological disturbances that are not readily noticeable (termed “sightblind”) (Bola et al., 2014). These residual structures have a triple handicap, which prevents them from being fully functional: they have fewer neurons, insufficient attentional resources and disturbed temporal processing of neuronal information. The activation hypometabolic cells in these areas provides a possible and rational basis for recovery. As it was mentioned above, not all neurons die after damage to the visual system or during a progressive visual disorder (glaucoma); many survive, some of them remain normal, and others become “silent”, remaining in a hypo-metabolic state (Henrich-Noack et al., 2017). Yet, another possible mechanism of ACS (or ES) is improved blood flow in the eye and brain. Kurimoto et al. (2010) reported transcorneal electrical stimulation to increase chorioretinal blood flow in healthy human subjects and others observed BOLD activity changes during and 40

after tACS in the healthy human brain (Chaieb et al., 2009, Saoite et al. 2013) or tACS (Antal et al., 2011; Holland et al., 2011; Amadi et al., 2013; Polanía et al., 2012, Alekseichuck et al., 2016, Cabral-Calderin et al., 2016, Vosskuhl et al., 2016, Sabel et al., 2019). In summary, several mechanisms of vision recovery are conceivable: (i) reactivation of “silent” neurons and excitability changes in or near the damaged zone, (ii) neurotrophic factors to enhance neural health and promote synaptic plasticity, (iii) reorganization at the brain network systems level in regions of new representations, and (iv) enhanced blood flow and improved vascular autoregulation. Any one of these mechanisms, or combination of several, could take part jn the improvement of neuronal synchronization and reorganization of the functional state of the brain. Therefore, the “mechanism(s)” of recovery is not any one single mechanism alone, but it is rather a combination of several if them. The most frequent protocols are DCS or ACS transcranially and ACS transorbitally. Recently, extracranial stimulation is also applied to the cornea or to the eyelids (TcES, mentioned above in animal studies and transpalpabreal stimulation - TPES). In the case of extracranial stimulation of patients, which stimulates the eye directly, lower current intensities are required compared to those applied transcranially. TcES uses rectangular biphasic current pulses (e.g. 5 ms positive, directly followed by 5 ms negative) at 10-30 Hz for 30 min once a week for 4-8 consecutive weeks. In the case of TPES electrodes are attached to the eyelid, biphasic nonrectangular current pulses are delivered in the alpha-beta EEG frequency range (frequently using 10 Hz) with low intensity (<250 uA). This microstimulation is similar to the transorbital procedure, as it consists of daily TPES applications for ~ 40 minutes for a total of 10 days. To estimate the efficacy of currently published protocols using electrical stimulation, we screened pubmed.org and located the following references which were then analyzed: 41

(Gall et al. 2010, 2011, 2016, Sabel et al. 2011, Fedorov et al. 2011, Ozeki et al. 2013, Schatz et al. 2011, 2017, Bola et al. 2014, Inomata et al. 2007, Fujikado et al. 2006, Sehic et al. 2016, Schmidt 2013, Naycheva et al. 2012, 2013, Fujikado et al. 2006, 2007, Anastassiou et al. 2013, Shinoda et al. 2008, Alber et al. 2017, Cowey et al. 2013, Ding et al. 2016, Halko et al. 2011, Kim et al. 2016, Olma et al. 2013, Plow et al. 2011, 2012a,b, Spiegel et al. 2013a,b, Therune et al. 2011, Camilleri et al. 2014, 2016, Campana et al. 2014, Fertonani et al. 2015, Pirulli et al. 2013). All prospective, double-blind, randomized, sham-controlled studies including 409 patients reported a statistically significant improvement compared to baseline and/or to the sham-controlled groups. Visual improvements were varied but covering different outcome measures, including improved VA or best corrected VA, enlarged VF, improved contrast sensitivity and stereoacuity and subjective improvements described by the patients. These patients who suffered from a variety of visual impairments typically had one or more benefits from the ES. Using ACS, 155 patients with optic nerve damage, glaucoma and 22 with AMD were treated. Applying TcES 76 patients with retinitis pigmentosa and retinal dystrophy, using tDCS 77 patients with amblyopia, 66 patients with hemianopia and 14 with grapheme color synaesthesia participated in different studies. tRNS was applied in 46 myopic patients. There are numerous open label, clinical observational studies and case reports including a total of at least 1267 treated patients reporting similar improvements such as improved VA, enlarged VF, improved contrast sensitivity and subjective improvements described by the patients (ACS: 480 with glaucoma, 13 with visual synesthesia, 21 with AMD, 11 with different visual pathway lesions, transcorneal ES: 8 with optic neuropathy, 23 with retinitis pigmentosa and retinal dystrophy, 97 with retinal and optic nerve injuries, 8 with retinal artery occlusion; tDCS: 7 with amblyopia and 14 with hemianopia; tRNS: 7 with amblyopia). 42

7.2.1 Stimulation of the transorbital area and the eye: vision restoration Concerning the treatment of central retinal vision loss due to AMD, in 21 patients Shinoda and colleagues (Shinoda et al., 2008) showed that TPES could improve visual acuity. They used 800 uA with sessions lasting 20 minutes and which were repeated 4 times per day. The protocol consisted of a monophasic pulse with a frequency of 290 Hz for 1 min., 31 Hz for 2 min., 8.9 Hz for 10 min., and 0.28 Hz for 7 min. Later, Anastassiou et al. published a randomized study, which showed that five consecutive days of TPES with frequencies ranging from 5 to 80 Hz, and a current less than 220 μA can increase the visual functions in patients affected by dry AMD (12 patients in the actively stimulated group and 10 in the sham group) (Anastassiou et al., 2013). Inomata et al., (2007) and later Oono et al. (2011) conducted the first encouraging case studies in patients with retinal artery occlusion (central or branch). However, the first randomized, sham stimulation-controlled pilot study of TcES in retinal artery occlusion showed no effect (Naycheva et al., 2013). Ten patients received ACS and 3 sham in six weekly sessions lasting 30 min each (20 Hz, individually adapted electrical PT intensities). The authors observed improvements in electrophysiological parameters, but no significant functional improvement was detected. Retinitis pigmentosa was treated with TcES in a randomized trial (Schatz et al., 2011). There was some improvement in the visual field area and a greater scotopic b-wave amplitude after six weeks of treatment. Twenty-four patients underwent stimulation for 30 min. (5-ms biphasic pulses; 20 Hz; DTL electrodes) / week for 6 consecutive weeks. The patients were randomly assigned to one of three groups: sham, 66%, or 150% of individual electrical PT. Nevertheles, different results were reported by the same group in a study lasting one year in 43

which electrical stimulation seemed to prevent a worsening of the pathological findings (Schatz et al., 2017). Fifty-two patients showed a trend of prevention of VF loss when stimulated at 200% of the PT, and an improvement in the ERG waves. At a later time, a randomized controlled trial with six weekly, 30-minute sessions of TcES (20 Hz, < 750 μA) proved effective in the treatment of retinitis pigmentosa with significant enhancement of visual acuity, perimetry, contrast sensitivity and retinal blood flow compared to sham therapy (Bittner et al., 2018). Through re-treatment after few weeks or months, electrical stimulation seemed to prevent the loss of vision (Bittner and Seger, 2018). So far, optic neuropathy is the most investigated condition for which ES has been tested. A pilot trial in glaucoma showed that 10 Hz TPES with up to 100 μA using biphasic nonrectangular pulses applied daily for 40 minutes ten days had a hypotensive effect on intraocular pressure in open angle glaucoma patients (altogether 46 patients, 58 eyes treated and 20 ‘naive’) (Gil-Carrasco et al. 2018). Similarly, in a small study, TcES could improve visual field defects (Ota et al. 2018). Though only 4 patients were treated (5 eyes), the treatment was given for a longer period (18.2 times over a period of 49.8 months) using biphasic electric pulses (10ms, 20Hz). A current that evoked a phosphene that the subject perceived in the whole visual area was delivered continuously for 30 min. Humphrey VF testing was performed after every third treatment. When changes in mean deviation (MD) values were evaluated, there was a significant positive linear relationship between changes in MD values and the number of treatments. In one study, 446 patients affected by optic nerve damage due to traumatic brain injury, inflammation, brain tumor or vascular lesions were treated with transorbital ACS in an open-label, clinical observational study (Fedorov et al., 2011). The results after ten days of stimulations (25-40 min each, frequencies < 20 Hz, current < 1000 μA) showed long-lasting improvements in acuity and visual field size. The study particularly showed that visual acuity 44

(VA) increased significantly in both eyes, and VF size increased in the right and left eye by 7.1% and 9.3%, respectively. VF enlargement was present in 40.4% of the patients’ right and 49.5% of their left eyes. A second ten-day course conducted six months later in a subset of 62 patients resulted in additional significant improvements of VA. In subsequent studies, a total of about 150 patients with optic neuropathy were tested in prospective, double-blind, randomized, placebo-controlled trials to further assess the effect of transorbital ACS (Gall et al., 2011, 2016; Sabel et al., 2011). In a clinical trial (Sabel et al., 2011) patients with chronic partial optic nerve lesions were treated with ACS (n = 12) or placebo-stimulation (n = 10). ACS was delivered transorbitally for 40 minutes on 10 days. ACS) was applied by four stimulation electrodes placed at or near the eyeball with eyes closed. The passive electrode was positioned on the wrist of the right arm. Stimulation frequencies were between the individual alpha-range (min) and the flicker fusion frequency (max). Visual outcome measures and EEG were measured before and after treatment. ACS, but not placebo, led to significant improvement of a VF detection deficit by 69%, and also significantly improved temporal processing of visual stimuli, detection performance in static perimetry, and visual acuity. These changes were associated with alpha-band changes in the EEG power spectra. Visual improvements were stable for at least 2-months. In another study, patients with chronic visual field impairments (mean lesion age 5.5 years) after optic nerve damage were randomly assigned to 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 current intensities used for stimulation were always below 500 uA. Four active stimulation electrodes were placed at or near the right and left eyeballs, the return electrode. Pulse shape was either square (n=11) or sinus (n=13). The 45

stimulating electrodes delivered current trains and current thresholds were automatically adjust by the stimulation device to them to the individual PTs for a 10-day treatment period a frequency of 5-30 Hz. Current thresholds were defined as the value of the electrical PT, with eyes closed. Stimulation frequencies were adjusted as a function of individual alpha-ranges (minimum) obtained from background EEG recordings at baseline and the flicker fusion frequency (maximum) that was measured daily before the stimulation session. Therefore, stimulation parameters varied between patients and between sessions in the same patient. Detection ability increase in the defective visual field was significantly larger after rtACS than after sham stimulation. Improvements in NEI-VFQ subscale ‘‘general vision’’ were observed in both groups but were larger in the ACS group, than in the sham group. The most comprehensive methodological study (multicenter, prospective, randomized, double-blind, sham-controlled trial) with the largest sample size (91 subjects) was carried out by Gall et al. (2016). In this study subjects suffering from various pathologies (glaucoma, AION, other causes of optic atrophy) underwent ten sessions of ACS (up to 40 min, frequency < 25 Hz, current < 1000 μA) which led to significant visual field improvements compared to the sham stimulation groups (see Figure 6 for selected cases). The results showed that the patients treated with transorbital ACS had a mean improvement of the visual fields of 24.0% above baseline, which was significantly greater than after sham-stimulation (2.5%). This improvement persisted for at least two months. 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. Subjective change was evaluated with the NEI-VFQ scales and compared between groups. Immediately after the stimulation there was an improvement in “general health and mental distress” in the sham-group but not in the tACS group, with no significant difference between groups. After two months both groups reported subjective benefits in the “visual field defect and related impairments” (rtACS > sham) and “general health and mental distress” (rtACS < 46

sham), again with no significant difference between groups. Due to the possibility that patients with monocular impairment may not experience a severe reduction in vision-related quality of life, QoL, only patients with binocular loss were analyszed, i.e., excluding those with an intact fellow eye. Here, rtACS-patients reported a significant increase in “visual field defect and related impairments” scale after stimulation, with no significant difference between groups. In the sham-group there was a significant increase in the NEI-VFQ “general health and mental distress”. About 60% of the patients treated with rtACS were subjectively satisfied with the treatment and 30% were aware of vision improvements. The blinding procedure was deemed successful, because there was no significant difference between the two groups with regard to the satisfaction with the therapy. These results present strong evidence that ACS leads to long lasting visual field improvements.

7.2.2 Transcranial direct current stimulation (tDCS) and vision restoration In several studies tDCS was applied to treat hemianopia due to traumatic brain injuries and stroke. Along these lines, several studies have successfully combined stimulation and vision training in stroke patients (Plow et al. 2011, 2012a, 2012b; Alber et al. 2017). The rational for combining the two methods was based on the fact that tDCS can boost brain excitability whereas activation is induced by behavioral training. Thus, tDCS is effective only when combined with vision training. In these studies (Plow et al. 2011, 2012a, 2012b; Alber et al. 2017) one group received only vision training (Plow et al., 11 patients, Alber et al., 7 patients) (Vision Restoration Therapy, Kasten et al., 1998), while the second group received vision training plus additional treatment of anodal tDCS over the occipital cortex (Plow et al, altogether 11 patients, Alber et al., 7 patients). The intensity of tDCS was 2mA, the sessions lasted 20-30 min, and the therapy duration varied from ten days to three months. The studies

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highlighted significant improvements in the visual field outcomes when the rehabilitative exercises were combined with anodal tDCS. tDCS over the occipital cortex was also shown to be effective in neuro-rehabilitation and in improving the visual function in amblyopia. Training plus anodal tDCS over Oz (single or multiple sessions of 2 mA, lasting for 20 min) resulted in increased VEPs, improved contrast sensitivity (Ding et al. 2016, 21 patients, single session), and stereo-acuity (Spiegel et al., 2013a,b, 13 patients, sham controlled single session and 16 patients, 5 sessions, sham controlled respectively), while cathodal tDCS over V1 controlateral to amblyopic eye (2 mA, 20 min, single session, 12 patients) resulted in an improvement of visual acuity (Bocci et al. 2018).

7.2.3 Transcranial random noise stimulation (tRNS) and vision restoration Another type of AC stimulation, high frequency transcranial random noise stimulation (hf-tRNS), was found to be successful in the treatment of amblyopic eyes as well (eight 25min sessions, 1.5mA, 100-640 Hz); better visual acuity and contrast sensitivity were achieved when tRNS of the occipital cortex of 7 patients was combined with training (Campana et al. 2014). Moret et al. (2018) detected improvements in visual acuity in ten amblyopic patients treated with 8 sessions hf-tRNS, which was not seen with sham stimulation (n=10). However, improved contrast sensitivity was observed in both groups (Moret et al. 2018). Positive effects of tRNS combined with training were also reported for myopia. In the first study 8 participants carried out a 2-week (eight sessions) behavioral training using a contrast detection task combined with online tRNS (Camilleri et al. 2014, 2016). The second group of eight participants underwent the same training protocol but without tRNS. In the second single blind study by using three different groups of participants the same research 48

group tested the efficacy of a short training (8 sessions) using a contrast-detection task with concurrent hf-tRNS in comparison with the same training with sham stimulation or hf-tRNS with no concurrent training. In both studies myopia patients had improvements in contrast sensitivity and visual acuity treated by perceptual training and tRNS over the occipital cortex (eight 25-min sessions, 1.5mA, 100-640 Hz) (Camilleri et al. 2014, 2016). In a recent study three patient with homonymous hemi-or quadrantanopia received hf tRNS over the visual cortex bilaterally (O1-O2, ten 20-min sessions, 1 mA, 100-640 Hz, 2 patients received sham stimulation). tRNS boosted visual learning in these patients with chronic cortical blindness, leading to recovery of motion processing in the blind field after just 10 days of training, a period too short to elicit an enhancement with training alone (Herpich et al., 2019). Compared to tDCS, the neuronal mechanisms of tRNS are still not known. It was suggested that the effect of tRNS might be based on stochastic resonance (Antal and Herrmann, 2016, Fertonani and Miniussi, 2017, Pavan et al., 2019). tRNS may increase synchronization of neuronal firing by amplifying subthreshold activity and, as a consequence, this reduces the amount of endogenous noise. This process can lead to enhanced or improved perception due to the increased signal-to-noise ratio. In conclusion, over the past decade, a number of independent studies have demonstrated positive effects of ES delivered to the visual pathway by different means: transorbitally, transcorneally, transpalpebrally and transcranially. Due to the large heterogeneity of the conditions, the great variety of stimulation methodologies, and the small sample sizes of most studies, further investigations and more controlled, large scale studies are needed to better assess the therapy-pathology relationship. Only one ACS study (Gall et al. 2016) was a multicenter, randomized trial with positive outcome; it is the first to date to translate experimental studies to routine clinical care.

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Up to now, ACS seems to be effective in patients affected by optic neuropathy, using ~ 10 Hz stimulation frequency, while its efficacy in retinal pathologies requires further controlled clinical trials and larger sample sizes. Regarding tDCS and tRNS, the clinical efficacy requires parallel behavioral training, and it is currently most promising for the treatment of amblyopia, hemianopia and myopia (e.g. anodal stimulation over the affected hemisphere and/or cathodal stimulation over the healthy side). With regard to the question of mechanisms of action, there are still many open questions. While it was proposed that NIBS modulates the excitability and related activity of the brain and achieves entrainment, blood flow might also improve in parallel and vice versa.

7.3 Vision restoration: human studies with TMS Given the evidence for the ability of rTMS, rh-TMS, ccPAS and TBS (see 6.1 -6.5) to modulate vision in healthy participants beyond the duration of stimulation as reviewed above, these protocols are promising for clinical applications. In the search for methods, studies have so far explored the potential benefits of rTMS and TBS. Such applications are guided by the findings of dysfunctional cortical excitability, in which case ‘facilitatory’ stimulation is applied over cortical areas where excitability is lower than normal and ‘inhibitory’ stimulation is applied over cortical areas, where the activity is abnormally high. The majority of the clinical studies aimed at modulating visual areas in the occipital lobe, including in migraine patients who experience visual auras (e.g. Bohotin et al., 2002; Brighina et al., 2002; Fierro et al. 2003; Fumal et al., 2006; Palermo et al., 2009; Omland et al., 2014), and in patients with occipital stroke suffering visual hallucinations of the Charles Bonnet type (Merabet et al., 2003; Meppelink et al., 2010), or suffering continuous visual phosphene hallucinations (Rafique et al., 2016). These rTMS studies have in common that they addressed pathological conditions with “positive”, i.e. pseudo-hallucination-like sensory phenomena (see Muller et 50

al., 2012 for a safety review). Other studies treated stroke patients with visual field defects (Guerrero Solano et al., 2017; El Nahas et al., 2019), patients with photosensitive epilepsy (Bocci et al., 2016) or amblyopia (Thompson et al., 2008). rTMS applied to parietal areas helped to restore visual bias in neglect (e.g. Brighina et al., 2003b; Kim et al., 2013; Agosta et al., 2014; Yang et al., 2015; Cha and Kim; 2016; for review see Kashiwagi et al., 2018). Applications of rTMS in migraine patients are guided by the findings of dysfunctional cortical excitability (reviewed in Brighina et al., 2009). Migraine patients have an impaired habituation of VEP to repeated visual stimuli (Bohotin et al., 2002; Fumal et al., 2006) and high frequency (10Hz) rTMS was found to normalize VEP habituation (Bohotin et al., 2002; Fumal et al., 2006; but see Omland et al., 2014). High frequency (10-20Hz) rTMS also reduced migraine frequency, duration and intensity (reviewed in Stilling et al., 2019). However, there is no consensus as to whether these effects in migraine are due to the upregulation of a hypoactive or the down-regulation of a hyperactive visual cortex. The finding that 10Hz rTMS normalized impaired habituation in these patients has been interpreted to support the hypotheses of up-regulation of a hypoactive cortex (Bohotin et al., 2002) (see LTP-like effects in healthy participants). However, other explanations are conceivable, such as atypical susceptibility of the visual cortex to rTMS in migraine, i.e. 10Hz rTMS having an inhibitory effect to maintain homeostatic plasticity. In support of the latter interpretation, low frequency (1Hz) rTMS induced paradoxical, facilitative effects in migraine patients (Brighina et al., 2002; Fierro et al. 2003; see also Palermo et al., 2009). Studies in other patient groups have shown the following: (i) low frequency rTMS (1Hz) over visual areas transiently reduced visual hallucinations (three case reports: Merabet et al., 2003; Meppelink et al., 2010; Rafique et al., 2016), (ii) low frequency (0.5Hz) rTMS over the visual cortex in patients with photosensitive epilepsy led to a suppression of their typically enhanced VEPs in the stimulated hemisphere, but to further enhancement in the 51

contralateral hemisphere (Bocci et al., 2016), (iii) high frequency (10Hz) rTMS over perilesional occipital cortex in stroke patients with visual field defects positively influenced visual recovery (Guerrero Solano et al., 2017; El Nahas et al., 2019), and (iv) high frequency (10Hz) rTMS temporarily improved contrast sensitivity in the adult amblyopic visual cortex suggesting latent plasticity (Thompson et al., 2008). Finally, in patients with left unilateral spatial neglect, low frequency (1Hz) rTMS of the parietal cortex in the intact left hemisphere was able to improve line bisection performance (Brighina et al., 2003b; Cha and Kim; 2016), relive visual extinction (Agosta et al., 2014) and normalize other tests of neglect (Cha and Kim; 2016). Kim et al. (2013) reported improved line bisection performance after high-frequency (10Hz) rTMS of the lesioned parietal cortex (see also Yang et al. 2015 for a comparison between 1Hz, 10Hz and cTBS in neglect). cTBS is also a promising protocol for clinical application (Clavagnier et al., 2013). In one study, five adult amblyopic patients were treated with occipital cTBS for five consecutive days. Contrast sensitivity of the amblyopic eye improved during the stimulation week. In two subjects, this improvement was still present 19 and 78 days after stimulation, respectively. The authors speculate that cTBS has an inhibitory influence on the brain representations of the fellow eye onto the amblyopic eye.

8

Clinical use of non-invasive brain stimulation: Safety The assessment of the clinical risks is based on a systematic analysis of existing

studies. To date, several thousand healthy volunteers and or patients have been treated with a non-invasive electrical stimulation of the visual system. A total of more than 1,850 patients

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have been described in the literature with no report of any serious adverse event (SAE) in any of the studies using tDCS, tACS, and RNS for this purpose (see also Antal et al., 2017). In order to assess the safety of current stimulation, all extracted studies were analyzed for reports of adverse events (AE). Reported AEs for TES were: itching, tingling and warmth sensation underneath the stimulation electrode, which have been regularly reported as local effects. Mild headache, drowsiness or poor sleep, blood pressure fluctuations, dizziness and general fatigue have been reported as rare cases of more generalized AEs. When using ES to restore vision, the most common reported AEs are the same as those observed in other medical applications: itching, tingling and warmth sensation underneath the stimulation electrode. With regard to tDCS, a recent review (Bikson et al., 2016) analyzed the AEs of tDCS. The authors assessed the frequency of serious AEs (SAE) related to the stimulation parameters intensity, duration, density, charge, and charge density. Considering more than 33,000 sessions in more than 1,000 subjects, they concluded that the protocols used for the humans did not produce any SAE or irreversible injury. No AEs were reported when tDCS was performed in patients. Analyzing the studies of tDCS for restoring the visual system with a total of 164 patients, we did not find any SAE (Campana et al., 2014; Alber et al., 2017; Cowey et al., 2013; Halko et al., 2011; Kim et al., 2016; Olma et al., 2013; Plow et al., 2011; Plow et al., 2012a; Plow et al., 2012b; Ding et al., 2016; Spiegel et al., 2013a; Spiegel et al., 2013b). The only AEs described in the literature on tDCS for visual improvement are “occasional itching or tingling” (Alber et al., 2017) and “slight tingling sensation under the electrodes” (Spiegel et al., 2013b). Olma et al. (2013) reported one patient with a skin irritation due to the NaCl solution and one patient with chest pain. It must be mentioned that only one patient in these studies withdrew because of

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discomfort (Spiegel et al., 2013a); and the authors stated: “there were no AEs during or following tDCS". Stimulation with ACS seems preferable to tDCS. Fertonani et al. (2015) found that the application of tACS induced fewer sensations than tDCS. Anodal tDCS was more annoying than other types of TES. An analysis of the studies aimed at restoring vision using ACS (Sabel et al., 2011; Gall et al., 2016; Gall et al., 2011; Fedorov et al., 2011; Schmidt et al., 2013; Gall et al., 2010; Gall et al., 2011; Bola et al., 2014; Anastassiou et al., 2013; Shinoda et al., 2008) revealed the following: of the 627 treated persons, there were rare cases (<10%) of cutaneous sensations with transorbital ACS, and sporadic cases (<5%) of mild headache, general fatigue, dizziness or blood pressure fluctuations. In sum, these mild accompanying effects are benign and raise little, if any, concerns about the safety of ACS for vision restoration. TcES uses small metal wire electrodes or contact lenses that are placed on the cornea. This is not very comfortable for patients and focuses the current onto a very small surface of the cornea. This treatment was performed in 194 visually impaired patients (Ozeki et al., 2013; Naycheva et al., 2012; Schatz et al., 2011; Inomata et al., 2007; Fujikado et al., 2006; Fujikado et al., 2007; Naycheva et al., 2013; Oono et al., 2011; Schatz et al., 2017). The following local effects were reported: foreign body sensation, dry eye, and transient superficial keratitis. About 15% of the patients with TcES reported dry eye and <3% reported foreign body sensations in the eye. Six percent of the patients suffered a transient superficial or punctate keratitis (non-detectable in the slit lamp examination) that had healed by the following day. The only AE after TcES considered to be serious was dermatitis on both superior lids. This occurred in a 62-year-old man (Shinoda et al. 2008) and the researchers decided to discontinue the treatment. This AE could be related to the electrode material. In fact, TcES is 54

applied with some electrodes directly in contact with the cornea, one of the most sensitive parts of the body, and it should therefore be used with great caution if at all. In studies applying tRNS to the visual cortex (Camilleri et al., 2014; Camilleri et al., 2016; Campana et al., 2014) no patient reported any AEs during or after treatment. Two studies with a total of 197 participants compared the effects of tRNS and tDCS (Fertonani et al, 2011; Pirulli et al., 2013) and analyzed the AEs in several stimulation conditions. The authors asked their subjects to rate the sensations occurring during stimulation on a Likert scale of 1 to 5. The participants reported the following AEs: skin irritation, pain, burning, heat, itch, iron taste, fatigue. The incidence and intensity of these effects was low. In summary, available studies report a low incidence and the low level of severity of AEs in more than 1,850 patients who had undergone stimulation of the visual system with tDCS, ACS, tRNS in different institutions and using different treatment protocols. TcES wireelectrode stimulation seems to be the least preferable technique because of the, albeit small, risk of serious AEs. However, long-term effects of the stimulation are beyond two months were not studied, and a publication bias may or may not exist of not reporting adverse effects. These observations in connection with stimulation of the visual system are similar to those reported with stimulation of other functional domains. They are in agreement with a 2017 report by a group of 35 eminent scientists worldwide who published guidelines for TES (Antal et al., 2017). They found mild AEs (headache, fatigue following stimulation, prickling, burning sensations) occurring during tDCS at peak-to-baseline intensities of 1–2 mA and during tACS at peak-to-peak intensities above 2 mA. Because AEs are also frequently reported by individuals receiving placebo stimulation, their conclusion was that low-intensity TES using a stimulation current of less than 4 mA and with a daily stimulation duration of less than 60 minutes was safe. Fewer adverse events were reported with AC stimulation than with DC stimulation. 55

9

Discussion According to previous studies and the results from our own laboratories, low intensity TES

is a promising method to induce acute as well as prolonged modulation of visual cortical excitability and activity. This provides the basis for the recent evidence that tDCS and ACS can be used as tools to promote changes of visual system activity with corresponding perceptual and behavioral vision improvements both in normal subjects and in patients with visual system disorders such as glaucoma, optic nerve damage and stroke. However, the response to such treatment is still rather variable, as some patients experience marked improvements in some visual functions while others do not respond. Therefore, more effort is needed to determine the factors that influence this response variability in order to optimize treatment outcome. As a first suggestion, EF modelling for targeting predefined areas for stimulation, including subjectspecific current optimization can be helpful and results in increased efficacy and safety. However, although modelling studies can provide good estimate of the EF, the relation to time integrated EF on the cortex is not simple (Miranda et al. , 2009, Ruffini et al. , 2013). The other possibility is to test a given protocol in animal models. However, there are still many uncertainties how to translate animal study results to human experiments. Threshold approximation obtained from rat experiments was estimated to be over one order of magnitude higher compared to clinical protocols in humans (Bikson et al. , 2016b). In order to better understand the underlying mechanisms of ES on vision and vision restoration, significant efforts have been made to monitors the effects of the electrical stimulation with imaging and electrophysiological methods such as fMRI and EEG (Halko et al. 2011; Schmidt et al 2013, Bola et al 2014, Sabel et al. 2019). With these techniques one can not only determine local changes in brain activity but can also explore changes in brain functional connectivity (Figure 7). The combination of these techniques is very valuable and will enable us to better 56

comprehend the localization, time course and functional specifications of a given brain area involved in visual tasks and the local and global mechanisms of recovery during and after stimulation. Considering the treatment of neuropsychiatric disorders, both rTMS and TES offer potential for higher efficacy and a lower number of AEs relative to pharmacotherapy or electroconvulsive therapy. As a result, the importance of these techniques and the therapeutic possibilities are exponentially increasing. The most successful example in the brain stimulation field has been the treatment of major depressive disorder, which was approved in several countries for clinical treatment. As per today's state of the art, the pathological conditions considered in this paper here still await therapies that lead to long lasting and full recovery of visual function. Therefore, in the guidelines for clinical practice (Lefaucheur et al., 2017) there is still no recommendation with regard to the treatment of visual impairments. Nevertheless, no recommendation does not mean that there is no evidence, the studies described above have already demonstrated a significant improvement of vision and show that ES can be regarded as a new frontier in visual neurorehabilitation. Complete recovery of vision loss is not to be expected, and was never observed, because the presumed mechanism of action is the activation of residual vision in only partially injured brain regions, not in regions of complete blindness (Sabel et al. 2011). For areas of the visual system with complete destruction of the neuronal substrate, there is no chance of improvement by electrical stimulation, and these visual field sectors remain blind. With regard to clinical applications, there is now a growing body of evidence that rhythmic stimulation is a useful tool in visual neurorehabilitation. TES can alter cortical activity by using rhythmic electrical stimulation to reduce behaviorally maladaptive brain oscillation patterns. It can also be used to induce adaptive changes by reinstating synchronization in the affected functional networks and thus improve visual functions as 57

shown in patients with optic nerve damage (Bola et al. 2014). One main drawback in the field of TES-induced vision modulation is that there is currently only one published multi-center, randomized clinical trial using ACS, and there are none using tDCS protocols (Gall et al., 2016). Therefore, more effort is essential to define the optimal stimulation parameters to maximize outcome. This requires a systematic effort to uncover the precise relationships between stimulation strength, frequency duration and current distribution on the one hand and visual improvements on the other. Here, the principle discussed above of current flow simulations in combination with regional and global brain oscillations will be informative. It should encourage translational progress of this technology and move it faster from bench to bedside. Furthermore, so far, there is little research investigating the relationship between E/I balance and individual applications. The assessment of this balance in different neurological and psychiatric disorders will help to refine treatment strategies in the future. It is currently unknown whether (besides tDCS) also tACS and tRNS can modulate the E/I ratio. This also requires further exploration. Yet, it is still an open issue how low intensity TES can influence non-neuronal elements, e.g. glial cells’ activity (e.g., Gellner et al. 2016). From a technical point of view, TES aims at improving eye and optic nerve function, by altering excitability/activity changes of the visual pathway. Function and excitability can be modified in two directions: modulate cortical oscillation by resetting synchronization and/or by inducing entrainment. Another possible mechanism is an approach that was already suggested 50 years ago, but which has not received much attention in recent years. This is rehabilitation of visual nerve function by normalising the blood supply to the eye, nerve and brain. Abnormal blood supply can result in visual nerve atrophy (Tron, 1968; Nemtseev, 1971; Elashco, 1972; Marmur, 1974; Kolotova, 1980; Cowan and Knox, 1982), and when neurovascular coupling fails, and the blood vessels 58

do not dilate properly due to disturbed autoregulation (vascular dysregulation, VD) (Sabel et al. 2018), neurons may die or become “locked in” a hypo-metabolic, “silenced” state (Henrich-Noack et al., 2013a; Yu et al., 2013). In fact, vascular dysregulation is a well-known problem in patients with optic nerve damage (OND) secondary to to glaucoma (Flammer et al., 2013) as well as in mild Alzheimer disease (Kotilar et al., 2017), cognitive impairment (Lesage et al., 2009), depression (Malan et al., 2016) and pathological type of cardiac beat-tobeat variation (Flammer et al., 2013). Among other mechanisms, autoregulation is linked to extracellular potassium which is elevated in the extracellular compartment of active neurons, and which - through capillary K+-sensing - sends small electric signals upstream to trigger dilation of the vessel (Longden et al., 2017). If this autoregulation fails, hypometabolic neurons may possibly survive, but are unable to produce action potentials (“silent survivors”). Following this argumentation, if TES has an effect on vascular regulation, it would be a fundamentally new mechanism of neural recovery: the microcurrents induced by the stimulation could mimic endogenous potassium ion signalling and thus initiate dilation of the dysregulated vessels in eye and brain (see Sabel et al. 2018). With regard to TMS, many studies targeting the neuronal mechanisms of visual processing have employed protocols that can lead to after effects (rTMS, rhTMS, ccPAS and TBS), with most of these studies examining the effects of rTMS and TBS, while rhTMS and ccPAS are newer approaches for which less empirical evidence is available. However, even for rTMS and TBS, inspite of the clinical promise of these protocols as suggested by the reviewed patient-studies above, we know little about their utility for visual restoration. This is partially due to a lack of studies into those protocols with a potential facilitatory effect (high frequency rTMS), the limited number of studies available in any specific patient group, and the outcome variability which is unexplained so far even in healthy participants. The boundary between facilitatory and disruptive effects will likely be determined not only by 59

TMS parameters (protocol, coil etc.) but also by factors such as concurrent task-demands, individual (patho)physiology and anatomy. Furthermore, the neural impact of any external stimulus is determined not only by the stimulus properties themselves but also by the baseline activation state of the targeted brain region, e.g. by state-specific effects of stimulation on homeostatic- or meta-plasticity. Therefore, the scientific challenge in terms of visual restoration by TMS will be to gather further information on these factors and their interaction with effects on visual functions in specific patient groups. Taking together, in spite of the increasing therapeutic success transcranial and extracranial stimulation in visual disorders, there are still open questions with respect to the general clinical use of these methods in the ophthalmology and neuroophthalamology. Concerning other directions (e.g. the modulation of cognitive processing) the efficacy of ES (mainly tDCS) and replicability of the ES studies were recently critized (e.g. Horvath et al., 2015). Indeed, the results of several published studies could not be replicated by other groups (see, e.g. Vannorsdall et al., 2016; Medina and Cason, 2017; Bikson et al., 2018). However, it is unclear if there is really no effect of tDCS or if these studies were simply underpowered. Nevertheless, many unanswered questions persist regarding how the differences in parameters of stimulation protocols might impact treatment efficacy, which kind of stimulation is best for which condition and what are the possible ways forward to reduce outcome variability. The field still suffers generally from the large variety of treatment protocols and a general ambiguity concerning the specification of parameters and their nomenclature (Bikson et al., 2019). Currently, based on their different neuronal mechanisms, ACS seems to be effective in patients affected by optic neuropathy, while tDCS and tRNS are most promising for the treatment of amblyopia, hemianopia (stroke) and myopia. rTMS over the occipital area is also used to treat migraine, neglect and hemianopia, applied either as a monotherapy or as augmentation to physio- or pharmacological therapy. Although the response to these treatment options is better than sham results in RCTs, a proportion of patients do not respond. 60

It is therefore imperative to explore the causes of this uncontrolled variability and – based on this understanding - seek optimization of the treatment protocol perhaps through personalization of brain stimulation. Although to date the appropriate place of these techniques in the therapeutic decision tree is still not defined and universally accepted, in summary, there is good evidence for beneficial effects of transcranial and extracranial stimulation for the modulation and restoration of vision in normal subjects and in patients suffering low vision. We agree with the recent review by Perin et al. (2019) who concluded there is some conclusive evidence for certain ACS protocols but that further studies are needed to optimize existing stimulation strategies and determine which protocol is best for which of the different visual system disorders. In any event, the current evidence is encouraging and should motivate others to advance the field of vision restoration and recovery towards a brighter future of patients with low vision or partial blindness.

Acknowledgements We thank Sylvia Prilloff for her help with regard to the preparation of the manuscript.

Conflict of interest We would like to declare that B. Sabel is shareholder of a vision rehabilitation day clinic. The authors have no conflicts of interest, financial or otherwise, and all concur with the conditions of submission of the manuscript in the present form.

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Legends

Figure 1. Simulating current flow in the eye. A: Volume conductor model of the head with attached electrodes. The incision at the right eye allows for an internal view of the types of eye and brain tissues, which are color-coded. B and C: Current density distribution of three electrode setups: ring electrode around eye and patch electrode at Oz (left column), unilateral patch electrodes above and below the eye (middle column) and bilateral patch electrodes (right column). B: magnitude in a sagittal slice through the whole head model; C: coronal (upper row) and sagittal (lower row) view on orientation (arrows) and magnitude (color scale) in the stimulated retina. Note the logarithmic scaling. L: left, R: right, P: posterior, A: anterior.

Figure 2. Simulating current flow in the brain. Non-invasive current stimulation of the brain requires a stimulator that sends low-level pulses (up to 2 mA) to electrodes positioned on the skull. The forehead electrode montage shown here is used to treat patients with optic nerve damage. It is applied for about 30 min/day for a ten-day period (Gall et al. 2016). Current density computer simulations show that the current enters the eye and optic nerve and passes through the skull to the frontal and pre-frontal cortex (Sabel et al., unpublished).

Figure 3. Theory of entrainment. Left: Inside the so-called Arnold tongue (entrainment, dark gray), the driven oscillator (‘Eigenfrequency’ = 10 Hz) is entrained to the external driving force. Outside this region, the driven oscillator exhibits its own properties (no entrainment, light gray). Top right: In experiments with rats, multiunit activity was entrained to sinusoidal electrical currents applied to the cortex, i.e. the cells fired during some phases of 62

the sinusoidal stimulation but not during others. Bottom right: If, however, the current was not applied to the cortex, MUA was not entrained, i.e. showed no relation to the phase of the sinusoidal stimulation. This is taken as evidence of entrainment (adapted from Fröhlich and McCormick, 2010).

Figure 4. Spike timing-dependent plasticity and recurrent loops. Top left: Spike timingdependent plasticity: synaptic weights are increased if a post-synaptic potential follows a presynaptic spike (long-term potentiation, LTP), and decreased if a post-synaptic potential occurs prior to a pre-synaptic spike (long-term depression, LTD). Top right: Schematic illustration of a network simulation: A driving neuron establishes a recurrent loop with multiple other neurons. The total synaptic delay, ∆t, (i.e., the sum of both delays of the loop) varied between 20 and 160 ms. The driving neuron was stimulated with a 10 Hz spike train. Bottom: Synaptic weights of the back-projection as a function of the total synaptic delay of the recurrent loops: Grey dots display synaptic weights at the start of the simulation, black dots represent synaptic weights after the end of simulation. External 10 Hz stimulation of the driving neuron resulted in increased weights for recurrent loops with a total delay roughly between 80 and 100 ms corresponding to about 10-12 Hz (red region), and reduced synaptic weights for loops with total delays outside this interval (blue region). Note, that the highest synaptic weights are seen at delays slightly below 100 ms, i.e., for loops with a resonance frequency slightly above the stimulation frequency of 10 Hz (adapted from Zaehle et al., 2010).

Figure 5. Residual vision and desynchronization. This graph is a cartoon that serves as a conceptual guide to how the number of surviving neurons and their ability to fire synchronously enables visual field function. After optic nerve damage, for example, the visual field typically has three different functional sectors: (i) “intact” vision (shown in white), (ii) 63

“areas of residual vision” (ARVs) which are partially damaged (grey), and (iii) areas with presumably total damage and blind (black). Note, however, that “intact” regions might have subtle neurophysiological disturbances that are not readily noticed (termed “sightblind”). The three functional sectors can be identified by visual field tests (perimetry) that plot a patient’s ability to detect small visual dots on ambient backgrounds. As the bottom panel illustrates, the visual state depends on two main factors: the number of surviving cells, and how well neural assemblies can fire in a synchronized manner. These different “shades of vision” are found in most visual system diseases such as stroke (e.g. hemianopia), retinal or optic nerve disorders (e.g. glaucoma).

Figure 6. Activating residual vision. Examples of visual field recovery in two patients before and after ten days of ACS treatment. We show here visual fields before and after ACS in a patient with diabetic retinopathy and in one with traumatic optic nerve damage. The visual field of the trauma patient had an additional three months of relaxation and eye yoga exercises. Note that visual field recovery emerges mostly from the grey regions (relative scotomas or “areas of residual vision”). ACS: Alternating current stimulation.

Figure 7. Brain functional network reorganization. The upper part of the figure shows coherence network graphs in a healthy subjects and in a glaucoma patient, with black dots representing standard EEG electrode positions. Resting state EEG, with eyes closed was recorded in healthy and visually impaired patients before and after ACS treatment. Previous data reveal that the most pronounced between-group differences occur in the alpha II band, as graphs of patients show fewer edges between occipital and frontal nodes and in the frontal region, whereas they have more short-range connections in the central area. After ten days of 64

ACS treatment, this network structure is partially restored (Bola et al., 2014) which correlates with visual performance. Lower panel: As the brain functional connectivity recovers, so does stimulus detection ability, measured by HRP (Sabel, 2016). Here the increase of the white and grey squares shows an improvement in visual performance. ACS: Alternating current stimulation; HRP: high-resolution perimetry.

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