Our results demonstrate that a single session of a-tDCS can transiently increase VEP amplitude and contrast sensitivity in adult patients with amblyopia. Specifically, a-tDCS increased VEP amplitude and contrast sensitivity for amblyopic eyes. Similar effects were found for control eyes, however fellow eyes of patients with amblyopia did not show increased contrast sensitivity following a-tDCS. Importantly, increases did not occur following c- or s-tDCS, indicating that the effects were specific to a-tDCS and were not due to within session learning.

The results of this study contribute to a growing literature indicating that non-invasive brain stimulation can modulate contrast sensitivity in adults with amblyopia39,54,55. A possible mechanism for the a-tDCS effects we report is reduced inhibition within the visual cortex. Visual input from the amblyopic eye is subject to attenuation56 and suppression18,19,31 which may contribute to the weakened cortical response to information from the amblyopic eye22. The magnitude of suppression is positively correlated with the loss of visual acuity29,30,31,32 and contrast sensitivity18,19 in humans and primates with strabismic or anisometropic amblyopia and reducing suppression may result in improvements in both visual acuity and stereopsis33,36,57. This suggests that suppression is an important contributor to the visual deficits associated with amblyopia. The inhibitory neurotransmitter GABA is involved in suppression of cortical inputs from one eye in cat models of strabismus51. GABA has also been implicated as one of a suite of mechanisms that gate recovery from amblyopia in adult rodents52. This role of GABA is directly relevant to a-tDCS effects because magnetic resonance spectroscopy measurements have shown that a-tDCS reduces the relative concentration of GABA when applied to the motor cortex44. Furthermore, a-tDCS induced reductions in motor cortex GABA have been associated with enhanced learning of a motor task, providing a link between changes in GABA and behavioral performance46. It is possible that a-tDCS reduces GABA within the visual cortex and therefore reduces chronic suppression of inputs from the amblyopic eye. This, combined with the excitatory effects of a-tDCS, may lead to a transient enhancement of the cortical response to amblyopic eye inputs in the form of an increased VEP amplitude and improved contrast sensitivity. Future work will test this hypothesis by assessing the effect of a-tDCS on measures of interocular suppression in patients with amblyopia.

We observed a dissociation between the a-tDCS induced increases in VEP amplitude that occurred for all eyes and the increases in contrast sensitivity that only occurred for amblyopic and control eyes. Fellow eyes did not show significant improvements in contrast sensitivity relative to baseline following a-tDCS. The increases in VEP amplitude are likely to reflect increased cortical excitability, a well-documented effect of a-tDCS within the motor cortex40. Therefore, our results suggest that the contrast sensitivity improvements induced by a-tDCS are not solely due to increased excitability. This finding raises the possibility that the improvements in contrast sensitivity may be more closely related to reduced inhibition/suppression within the visual cortex. While the control observers did not exhibit suppression under normal viewing conditions, a level of binocular competition or rivalry was introduced by the monocular viewing conditions used within the experiment (i.e. patching of the non-viewing eye). This may have been reduced by a-tDCS, leading to enhanced contrast sensitivity relative to baseline and sham. On the other hand, patching of the amblyopic eye would not induce rivalrous conditions for the fellow eye because suppressive interactions are biased in favor of the fellow eye18. Therefore no improvements in fellow eye contrast sensitivity would be expected following a-tDCS if reduced inhibition is involved.

An alternative explanation relates to the concept of homeostatic metaplasticity, whereby non-invasive brain stimulation acts to return a neural system to homeostasis58. Under this explanation, a-tDCS would have had a greater effect on neural populations preferring information from the amblyopic eye that have low levels of baseline activation. This explanation would also account for the trend towards more pronounced inhibitory effects of c-tDCS on fellow eye VEP amplitudes and contrast sensitivity. This is because fellow eye neural populations have a higher level of activation22 and are therefore likely to be more susceptible to the effects of inhibitory stimulation protocols. It is unclear how homeostatic metaplasticity relates to our control eye results. Based on the current data, we are not able to discriminate between these two explanations.

In addition to its effects on GABA, tDCS may also enhance expression of brain derived neurotropic factor (BDNF)59 and increased BDNF levels have been linked with recovery from adult amblyopia in animal models60. Furthermore, the aftereffects of tDCS rely on the function of NMDA receptors61. This has led to the suggestion that a-tDCS has long term potential (LTP) - like effects. NMDA receptor dependent changes in synaptic strength have been linked to recovery of ocular dominance plasticity animal models of amblyopia62 and may underlie the increases in VEP amplitude and contrast sensitivity we report. We favor an explanation based on temporary changes in inhibition and excitation because LTP and BDNF effects are gradual, whereas the effects we observed were rapid. It is possible, however, that LTP-like changes underlie the longer-term effects of a-tDCS on VEP amplitude that we observed for amblyopic eyes 48 hours after stimulation.

Previous studies into the effects of tDCS on the healthy visual cortex have generated conflicting results. In terms of VEPs, a-tDCS has been reported to increase and c-tDCS decrease VEP amplitude63, however opposite results have also been observed64. Furthermore, tDCS has been reported to have no effect on flash VEPs65. The results from previous studies investigating tDCS induced changes in contrast sensitivity are similarly variable. Antal et al.66 found that c-tDCS decreased static and dynamic contrast sensitivity, whereas a-tDCS had no reliable effect. Using threshold perimetry, Kraft et al.67 found that a-tDCS enhanced contrast sensitivity within the central 2 degrees of the visual field whereas c-tDCS had no effect. More recently Costa et al.68 also found that a-tDCS increased contrast sensitivity on threshold perimetry, but only in the periphery. Finally, an absence of acute tDCS effects on contrast sensitivity have been reported53,69. These discrepancies could be due to differences in visual stimuli, viewing conditions, tDCS parameters and electrode placement. However, individual differences between the participants taking part in each of these studies may also contribute to these discrepancies as a number of factors such as BDNF polymorphisms and hormone levels have been found to alter the response to tDCS70. In the current study, electrophysiological and behavioral measures were made in the same participants and the polarity specific effects were consistent across both measures; a-tDCS tended to increase VEP amplitude and contrast sensitivity whereas c-tDCS had the opposite effect. These results are in a good agreement with the established polarity dependent effects of motor cortex tDCS40 and support the use of tDCS to modulate visual cortex function.

Reducing the duration of tDCS to 10 minutes did not change the pattern of results in control participants. Whether this is also the case for patients with amblyopia remains to be tested. The effect of repeated doses of a-tDCS also remains an open question and the exploration of ways to prolong the effects of a-tDCS is an important next step in this field.

Although the effects of tDCS were consistent between the VEP and contrast sensitivity measurements, we did not find a direct correlation between the changes in VEP and changes in contrast sensitivity. This may be due to the very different nature of the stimuli used to elicit VEPs and measure contrast sensitivity. The lack of a direct correlation may also reflect different neural mechanisms for the two effects, as described above.

These results indicate that a-tDCS can temporarily increase contrast sensitivity in adults with amblyopia in agreement with previous studies54. It has also previously been reported that a-tDCS can enhance the effect of dichoptic treatment on stereopsis in adults with amblyopia71. Further work using standard clinical outcome measures such as visual acuity is required to assess whether a-tDCS alone has any clinical relevance for the treatment of amblyopia in adulthood.