Non-invasive brain stimulation and vision rehabilitation: a clinical perspective

ABSTRACT

Non-invasive brain stimulation techniques allow targeted modulation of brain regions and have emerged as a promising tool for vision rehabilitation. This review presents an overview of studies that have examined the use of non-invasive brain stimulation techniques for improving vision and visual functions. A description of the proposed neural mechanisms that underpin non-invasive brain stimulation effects is also provided. The clinical implications of non-invasive brain stimulation in vision rehabilitation are examined, including their safety, effectiveness, and potential applications in specific conditions such as amblyopia, post-stroke hemianopia, and central vision loss associated with age-related macular degeneration. Additionally, the future directions of research in this field are considered, including the need for larger and more rigorous clinical trials to validate the efficacy of these techniques. Overall, this review highlights the potential for brain stimulation techniques as a promising avenue for improving visual function in individuals with impaired vision and underscores the importance of continued research in this field.

KEYWORDS:

• Amblyopia
• non-invasive brain stimulation
• neuroplasticity
• transcranial magnetic stimulation
• transcranial electrical stimulation
• vision rehabilitation

Introduction

Non-invasive brain stimulation (NIBS) techniques use electrical currents or magnetic fields to stimulate specific areas of the brain by transiently altering the excitability of targeted neural populations.¹ Two commonly used methods are repetitive transcranial magnetic stimulation (rTMS) and transcranial electrical stimulation (tES). Both methods exert an effect on the underlying cortex, including changes in cortical excitability and alterations in various neurotransmitter concentrations, which in turn can influence neural function (Table 1). Although NIBS has historically been employed as a research tool, these methods are now being applied in clinical and therapeutic settings and have emerged as promising tools for improving visual functions.¹⁴

Table 1. Table summarising the key features and proposed mechanisms for TMS and tES.

	Key Features	Proposed mechanisms
TMS	Non-invasive method that stimulates cortical neurons via electromagnetic induction.^Citation2 The induced electric field drives ionic currents, causing localised hyperpolarisation or depolarisation of neuronal membranes. Once the membrane depolarisation reaches a certain threshold, it triggers the firing of action potentials.^Citation3	Modulation of synaptic efficacy and long-term potentiation through NMDA modulation.^Citation4–6 Modulation of GABA-mediated intracortical inhibition.^Citation7–9 Enhanced sensitivity to weak external inputs through stochastic resonance (tRNS).^Citation10 Frequency specific modulation of brain oscillations with (tACS).^Citation11,Citation12
tES	Non-invasive technique that delivers electrical currents to the scalp to modulate neural activity in underlying brain regions.^Citation1 The electrical current applied alters neuronal excitability by altering the membrane permeability of voltage-gated ion channels.^Citation13 Unlike TMS, tES does not directly induce action potentials.

rTMS and tES both evolved as NIBS techniques with applications in psychiatry and neurology. The US Food and Drug administration (FDA) granted approval for the use of rTMS to treat major depressive disorder in 2008, and ongoing clinical trials have facilitated the clinical adoption of rTMS in the US for conditions such as migraine with aura, obsessive compulsive disorder, and smoking cessation.¹⁵ Both rTMS and tES are currently being used in a range of clinical populations and are showing promise as tools for vision rehabilitation. This is an exciting prospect as it opens up the possibility of a novel treatment approach, especially for vision disorders where optical and medical management are the only viable options currently.

In this review, an introductory resource on NIBS techniques and their applications in vision rehabilitation will be provided. Various stimulation techniques and their use in vision-related conditions are discussed, including amblyopia, post-stroke hemianopia, and age-related macular degeneration. This review will offer a high-level understanding of the current state, advancements, and challenges of NIBS in vision rehabilitation. Additionally, emerging trends and future research directions will be explored. By the end of this review, readers will gain insights into different stimulation approaches, their underlying mechanisms, and their potential for improving visual function. The goal of this review is to offer a primer for clinicians and individuals interested in NIBS for vision rehabilitation.

Methods

The studies provided in this review are part of a larger systematic review,¹⁴ which employed the following search strategy. Search terms are categorised into two main themes: ‘brain area’ and ‘non-invasive brain stimulation’. Each theme was combined using the Boolean operator ‘AND’ while within each theme, relevant terms were combined using the Boolean operator ‘OR’. The search terms included the terms ‘Primary visual cortex’, ‘V1’, ‘Extrastriate cortex’, ‘V2’, ‘V3’, ‘V3a’, ‘V4’, ‘V5’, ‘Middle temporal’, ‘MT’, ‘Medial superior temporal’, ‘MST’, ‘Occipital pole’, and ‘Occipital lobe’.

The search terms for non-invasive brain stimulation techniques included ‘Transcranial direct current stimulation’, ‘tDCS’, ‘Transcranial alternating current stimulation’, ‘tACS’, ‘Transcranial random noise stimulation’, ‘tRNS’, ‘Transcranial magnetic stimulation’, ‘TMS’, ‘Repetitive transcranial magnetic stimulation’, ‘rTMS’, ‘Continuous theta burst stimulation’, ‘cTBS’, and ‘Theta burst stimulation’, ‘TBS’. Studies were selected for relevance to vision and for a clinical audience for this present review.

While this review does not cover transcorneal and transorbital stimulation, it is worth mentioning that these additional electrical stimulation techniques have demonstrated evidence of being effective for vision rehabilitation (see Perin et al.¹⁶ for review). The diverse nature of visual disorders, which involves distinct structural changes and impairments in different cerebral regions associated with vision, underscores the need for tailored approaches and applications of electrical stimulation in visual rehabilitation.

Transcranial magnetic stimulation

TMS has been used for over three decades to study human brain physiology, and uses a varying magnetic field to induce a brief electric current within nearby brain tissue (Figure 1A).² A single pulse of TMS can trigger action potentials, whereas repeated pulses can have either excitatory or inhibitory effects on neural activity depending on the configuration of the pulse train (Figure 2).

Figure 1. (A) A TMS coil placed over a targeted brain region, and (B) A tES system.

Figure 2. Schematic showing facilitatory and inhibitory TMS and tES protocols. There is no inhibitory tRNS protocol. MSO = maximum stimulator intensity.

Single-pulse TMS, when delivered over the primary visual cortex (V1), can induce visual percepts referred to as phosphenes (spots of light in the visual field)¹⁷ and transient scotomas (visual suppression).¹⁸ Owing to the high temporal fidelity of TMS, single pulses applied during a task can reveal the roles of specific brain areas, and when they are active in connection to the specific task being performed. For instance, single pulse TMS over V1 can impair visual perception when delivered at specific time points relative to the onset of visual stimuli.¹⁹ When multiple stimulation pulses are delivered, rTMS can facilitate or inhibit neuronal firing thresholds.

The excitatory or inhibitory effect on the stimulated brain region depends on whether the pulses are delivered at high (≥5 Hz) or low frequencies (0.1–1 Hz), respectively.²⁰ Theta burst stimulation (TBS) is another form of rTMS, in which pulses are delivered in continuous (cTBS) or intermittent (iTBS) bursts of three 50 Hz pulse trains.²¹ Compared to traditional rTMS paradigms, cTBS and iTBS are becoming more widely used as they provide more powerful, long-lasting effects and require shorter stimulation durations (less than 2–3 minutes). rTMS can produce powerful ‘offline’ effects, where the effects outlast the period of stimulation. Therefore, these protocols are frequently used to examine the role of specific brain regions in plasticity and behaviour.

Transcranial electrical stimulation

Transcranial electrical stimulation (tES) is another form of NIBS, which alters brain activity by passing an electrical current through the cortex, using two or more electrodes placed on the scalp (Figure 1B). The different types of tES include transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS). For each of these tES types, a 1–2 mA current is applied for up to 20 minutes using electrodes that are typically 20–35 cm² in size.²² Each tES type causes different behavioural and neuronal changes owing to the different electrical stimulation patterns used (Figure 2).

tDCS is the most commonly used form of tES and involves the one-way propagation of an electrical current between an anodal (positive) and cathodal (negative) electrode.²³ tDCS causes an increase in excitability in cortical regions below the anodal electrode, and a decrease in regions located below the cathodal electrode. tACS uses a sinusoidal current to modulate cortical activity in a frequency-specific manner and can entrain neural oscillations. It has been used to investigate the role of brain oscillations in cognition and perception,²⁴ as well as to treat various neurological and psychiatric disorders such as depression and chronic pain.²⁵ tRNS employs an alternating current with random amplitude and frequency. By enhancing cortical excitability, tRNS promotes the strengthening of neural connections in the stimulated region.²⁶

Rationale for applying NIBS to vision rehabilitation

NIBS is a promising tool for research and clinical use due to its ability to alter cortical excitability, modulate neurotransmitter levels,²⁷ and influence distributed connected neural networks and facilitate the transfer of information between different brain regions.²⁸ In the context of the visual cortex, there is evidence that brain stimulation can open windows of neuroplasticity, which can be harnessed for vision rehabilitation and improving visual function in adults.^29–34

Neuroplasticity refers to the process of changing the strength and efficacy of connections between neurons to improve the overall function of the brain in response to external stimuli over time. The ‘critical period’ of visual development refers to a specific window of time during early development when the visual system is particularly sensitive to environmental input and is capable of rapid and profound changes in response to visual experience. This critical period is a period of heightened neuroplasticity, during which the network of cortical areas that support vision is highly adaptable and can be shaped by sensory experience.³⁵

Beyond this critical period, many areas of the brain, including the visual cortex, become less malleable and more resistant to change. Factors such as declines in gene expression related to neuroplasticity and reductions in neuromodulators such as dopamine and acetylcholine contribute to the closure of the sensitive period and the limited capacity for sensory experience to shape cortical function.³⁶

Despite the closure of the sensitive period for visual development, some degree of neuroplasticity persists in the brain into later childhood, adolescence, and adulthood, as evidenced by studies in amblyopia.³⁷ This indicates that targeted approaches may still be effective in inducing neuroplasticity during these periods outside of the critical period. However, given that the capacity for sensory experiences to shape cortical function declines with age, enhancing neural plasticity becomes critical for effective vision rehabilitation, especially in adults. NIBS represents a promising avenue for manipulating the mechanisms that control cortical plasticity and improving visual function in adults.

The facilitatory and inhibitory effects of NIBS are thought to reflect long-term potentiation or long-term depression like mechanisms, which refer to the strengthening and weakening of synaptic connections, respectively (Figure 3). By inducing long term potentiation or depression, NIBS may be able to modulate the strength and structure of neural connections in the visual cortex, leading to improvements in visual performance. While the exact mechanisms are not yet fully understood, ongoing research focusses on finding key brain circuit elements that regulate brain plasticity and identifying potential therapeutic targets to promote neuroplasticity in the visual system, both during and beyond early life.³⁸

Figure 3. Simplified schematic showing the insertion of a receptor (e.g., NMDA receptor) to the synaptic membrane in response to an increase in intracellular Ca⁺², demonstrating long term potentiation (LTP; top right). Removal of a receptor from the membrane is shown for long term depression (LTD; top left), resulting in a decreased postsynaptic response. Long term potentiation and depression mediate the strengthening and weakening of synaptic connections, respectively, resulting in increased and decreased postsynaptic responses (bottom right and left panels).

Proposed mechanisms of NIBS

Emerging evidence in the literature suggests that NIBS may be a promising way to manage disorders of vision and visual function such as amblyopia, age-related macular degeneration (AMD), hemianopia and other visual field deficits. There is now sufficient evidence to support the effectiveness of NIBS techniques in enhancing visual acuity,³⁹ contrast sensitivity,^40–42 and motion perception^43–45 in typically sighted individuals.

Additionally, NIBS modulates cortical excitability measures such as visual evoked potentials^39,46,47 – see Bello et al.¹⁴ for review. Therefore, NIBS can modulate neural activity in specific regions of the brain involved in visual processing, leading to improvements in visual function. The following sections will explore the various proposed mechanisms of NIBS, providing an overview of how NIBS exerts its effects to modulate behaviour.

Modulation of NMDA receptors

N-methyl-D-aspartate (NMDA) receptors are a subtype of glutamate receptors, and the activation of pre- and postsynaptic NMDA receptors is a characteristic of long term potentiation and depression. The activation of postsynaptic NMDA receptors induces an influx of Ca⁺², triggering a cascade of intracellular signalling pathways that lead to long term changes in synaptic strength.⁴⁸ Studies using pharmacological agents and motor cortex NIBS have provided indirect evidence for the involvement of NMDA receptors in long-term potentiation, depression-like changes, and the therapeutic effects of NIBS. For example, dextromethorphan, an NMDA receptor antagonist, blocked the effects of anodal and cathodal tDCS, indicating the role of NMDA receptors in tDCS-induced neuroplasticity.⁴ Another study showed that D-Cycloserine, a partial NMDA receptor agonist, prolonged the duration of increased cortical excitability induced by anodal tDCS.⁵ Additionally, memantine, an NMDA receptor antagonist, blocked the after-effects of cTBS and iTBS, further supporting the importance of NMDA receptors in producing lasting effects of TBS.⁶

NIBS techniques may also trigger the release of neurotrophic factors, such as BDNF, which play crucial roles in nervous system development and maintenance. Blood derived neurotrophic factor (BDNF) is one such protein, which affects synaptic plasticity and NMDA receptor function.⁴⁹ The expression of BDNF genes can affect synaptic plasticity in both animal and human cortex, influencing the efficacy of NIBS techniques.^50,51

GABA-mediated intracortical inhibition

While BDNF and NMDA receptors are involved in promoting synaptic plasticity, GABA-mediated intracortical inhibition is another possible mechanism that has been identified through which NIBS may enhance neuroplasticity in the visual cortex. GABA is an inhibitory neurotransmitter that regulates neural activity and synaptic plasticity in the brain, and gating neuroplasticity within the mature visual cortex.^38,52

Recent studies have shown that intracortical inhibition is a critical limiting factor for cortical plasticity in adults and that reducing it can significantly enhance plasticity in the adult visual cortex – see Karmarker and Dan⁵³ for review. However, the direction of GABA modulation following excitatory and inhibitory NIBS protocols in the visual cortex is inconsistent,^54–56 and remains an area of ongoing study.

Local GABA levels are correlated with behaviour in both the primary motor and visual cortices – see Li et al.⁵⁷ for review. Visual cortex rTMS has demonstrated improvements in visual acuity and other visual functions in adults with amblyopia.²⁹ Repeated sessions of visual cortex cTBS have led to long-lasting improvements in visual functions such as visual acuity, stereoacuity, and suppressive balance (a measure of binocular function) in adults with amblyopia.³²

Evidence from animal studies suggest the reduction in GABA-mediated cortical inhibition from visual cortex NIBS may explain the observed improvements in amblyopic visual function.⁵⁸ This idea is supported by previous studies of the human motor cortex, which have extensively investigated GABAergic activity and shown that specific TMS protocols^7,8 and anodal tDCS⁹ can reduce GABA concentration in this area, potentially leading to similar effects in the visual cortex.

Improving signal to noise ratio within neural systems

Stochastic resonance refers to the phenomenon where previously undetectable or sub-threshold stimuli can become detectable by adding an appropriate level of noise.⁵⁹ tRNS applied over the visual cortex improves visual stimulus detection⁶⁰ and motion discrimination,⁶¹ and this is attributed to tRNS inducing random activity in target neurons, increasing sensitivity to external inputs. Applying tRNS and other NIBS techniques that harness stochastic resonance holds promise for vision rehabilitation, due to its potential in facilitating the detection of weak signals and promoting learning and neural plasticity.⁶⁰ Notably, visual cortex tRNS has demonstrated improvements in contrast sensitivity and visual acuity in individuals with amblyopia,⁶² highlighting the potential of NIBS techniques to enhance visual function and provide new treatment options for visual impairments.

Heterogeneity of NIBS effects

Several factors can influence individual responses to NIBS techniques for inducing plasticity. While there is currently limited research specifically focussed on factors affecting the induction of plasticity in the human visual cortex, animal studies have provided evidence of significant sex differences in processes relevant to cortical plasticity.^63,64 A retrospective analysis combining data from three previous studies, including 24 females and 22 males, found that females exhibited stronger facilitatory effects when anodal tDCS was applied to the visual cortex.⁶⁵ While this study is the only one specifically examining the visual cortex, other studies have indicated that sex differences may be influenced by hormone levels. For example, a study on the motor cortex showed reduced plasticity in older post-menopausal females compared to pre-menopausal females.⁶⁶

Furthermore, hormonal variations across the menstrual cycle may further influence short-term plasticity induced by rTMS.⁶⁷ Genetic factors, such as polymorphisms of neurotrophins like BDNF Val66Met variant, also contribute to individual responses to NIBS, affecting the effectiveness of protocols like tDCS and TBS,⁶⁸ which rely on NMDA receptors for their aftereffects.^4,6

Other factors, such as physical activity,^69,70 time of measurement,⁷¹ attention,^72,73 pharmacology,^4,6,7 age,^66,74 and genetics⁵⁰ have been found to influence individual responses to NIBS. However, studies investigating these factors primarily focus on non-visual cortex areas, and there is a lack of systematic evidence and large-scale studies specifically examining their relevance to vision rehabilitation. Despite this, considering these factors is important when evaluating the efficacy of NIBS targeting the visual cortex, as it can help understand individual variability in response to NIBS and potentially optimise its effectiveness in vision rehabilitation.

Risk factors

While NIBS has shown promise in improving visual function, there are potential risks associated with its use in visual rehabilitation or in a clinical or research setting. Risks may vary based on the NIBS technique, stimulation parameters, and individual characteristics. Potential risks include headache and discomfort, cognitive and mood effects, and visual disturbances, and the rare risk of inducing seizures, especially in individuals with epilepsy or neurological conditions.⁷⁵ Headache and discomfort are usually transient and can be managed with over-the-counter pain relievers.

NIBS techniques may also induce changes in cognitive or mood states, particularly in individuals with pre-existing psychiatric or neurological conditions, but the clinical significance is not yet fully understood. Additionally, NIBS techniques may interfere with the function of medical devices such as pacemakers or cochlear implants, requiring careful screening and monitoring during stimulation.

The potential risks of NIBS in visual rehabilitation are low but should be weighed against the potential benefits. Established safety guidelines^75–77 and use of screening questionnaires⁷⁸ can be used by the researcher or by treating physicians to assess the risk/benefit ratio of administering NIBS. To minimise adverse events, thorough patient screening and monitoring of stimulation parameters by trained professionals are crucial, considering potential risks and side effects. These considerations are particularly important as the number of at-home stimulation studies increase,^79,80 and brain stimulator devices become more accessible direct to consumers. The home use tDCS guidelines by Charvet et al.⁸¹ provide valuable guidance on the safe and effective use of at-home stimulation devices for clinical research and practice.

Eye care practitioners, like optometrists in primary care, could play a valuable role in monitoring individuals using at-home brain stimulator devices. Their expertise in eye care and community accessibility makes them well-placed to assess the safety and effectiveness of NIBS interventions. Collaboration between eyecare professionals and researchers is necessary to establish appropriate monitoring protocols and identify relevant clinical tests for assessing the effectiveness of at-home NIBS in specific visual functions. For example, in the context of vision rehabilitation, optometrists can conduct regular perimetry tests to assess improvements in the visual field when NIBS is being used to enhance residual function in individuals with glaucoma.

Advancements and challenges in NIBS for visual rehabilitation

The field of NIBS for visual rehabilitation is currently an active area of research, with many studies investigating the potential applications in improving visual function for various conditions. These conditions include amblyopia,^{29,31,32,62,82,83} post-stroke hemianopia,^33,84–88 and central vision loss resulting from conditions such as AMD.^34,89 While the results thus far are promising, there is still much to be explored or understood.

Studies on the effectiveness of NIBS in treating amblyopia have revealed improvements in several visual functions. Ding et al.⁸² applied anodal tDCS to individuals with amblyopia which resulted in enhanced contrast sensitivity and larger visual evoked potential amplitudes in the amblyopic eye. Similar improvements in contrast sensitivity have been observed following rTMS,²⁹ cTBS,³⁰ and anodal tDCS.³¹ Additionally, cTBS has been found to improve visual acuity, suppressive imbalance, and stereoacuity in individuals with amblyopia.³²

Combination approaches, such as anodal tDCS with dichoptic video gaming, have also demonstrated the potential to enhance the recovery of stereopsis in adults with amblyopia.^31,90 The growing evidence supports the efficacy of NIBS in amblyopia and shows promising results.

For hemianopia, a combined approach of NIBS and visual training^33,84–86 is more effective in restoring visual function, particularly in the visual field, compared to NIBS alone.^87,88 The timing of stimulation may also impact its efficacy, with evidence suggesting that applying stimulation during the acute or subacute phase after stroke, when plasticity is at its highest, may be more beneficial.⁹¹

To date, there are comparatively fewer studies on the use of NIBS for vision rehabilitation in central vision loss. Research in this area often focusses on specific visual phenomena found in peripheral vision, such as visual crowding and lateral masking. Lateral masking is a visual phenomenon where a central target Gabor patch is presented between two flanker patches of the same orientation, and the ability to detect the target can either be increased (collinear facilitation) or decreased (collinear inhibition) depending on the distance between the target and the flankers.

Intensive perceptual learning (visual training) can reduce collinear lateral inhibition in peripheral vision,⁹³ and recent work by Raveendran et al.⁹² demonstrated that visual cortex anodal tDCS can reduce collinear inhibition in typically-sighted individuals. More recently, Raveendran et al.³⁴ were able to replicate this effect in individuals with AMD, offering a potential approach to improving residual visual function in central vision loss. In a recent randomised, double-blind clinical study, combined visual cortex anodal tDCS and perceptual learning of a rapid serial visual presentation reading task was shown to be effective in improving English reading individuals with AMD.⁸⁹

Despite the promising results, challenges remain in developing optimal treatment protocols for different types of visual impairments. The optimal parameters for NIBS, such as duration, intensity, and location of stimulation, are still being investigated, and there is no consensus on the best rehabilitative approach for different types of visual impairment. Understanding the specific mechanisms by which NIBS exerts its effects on the visual system is also a challenge, and may vary depending on the NIBS technique and individual characteristics. As more evidence becomes available, it can guide the design of optimal NIBS protocols for larger clinical trials in targeted populations, ultimately advancing the field of vision rehabilitation.

Future directions

For NIBS to be a viable therapeutic intervention for vision rehabilitation, it should be able to induce long-lasting changes in behaviour and function, in either individuals with or without visual impairment. In terms of the underlying neurophysiology, by modulating mechanisms that control the strength of synaptic plasticity in the cortex, NIBS has the potential to fill a gap in the management and rehabilitation of visual impairments.

Despite the challenges that exist in the field, the field of NIBS for visual rehabilitation is rapidly advancing. Firstly, recent developments employ combination approaches, in which the potential benefits of combining NIBS with other rehabilitation methods, such as visual training, are being explored.

Secondly, there is growing recognition that optimal parameters for NIBS may vary depending on individual characteristics, such as age, genetics, cognitive status, and the location and extent of the lesion or damage. Personalised approaches to NIBS, which tailor the stimulation parameters to the individual, may lead to more targeted and effective interventions.

Third, new NIBS techniques with greater precision or deeper penetration of neural tissue than existing techniques are being developed. For example, high-definition TMS and tES are emerging techniques that may have potential applications in visual rehabilitation.

Lastly, there is increasing interest in understanding the long-term effects of NIBS on visual function. While many studies have demonstrated short-term improvements in visual acuity or other outcomes, it is not yet clear how long these effects last or whether they lead to meaningful improvements in daily life.

Overall, the field of NIBS for visual rehabilitation is developing rapidly, and there is significant potential for future research and clinical applications. As the field evolves, it is likely that more targeted and effective NIBS interventions will be developed, leading to novel ways of managing visual disorders and improved outcomes for individuals with visual impairments or deficits.

Acknowledgements

InnoHK initiative and the Hong Kong Special Administrative Region Government.

Disclosure statement

Both authors are co-inventors of a patent that combines non-invasive brain stimulation and perceptual learning for the treatment of presbyopia.

Additional information

Funding

The work was supported by the InnoHK initiative and the Hong Kong Special Administrative Region Government.