To our best knowledge, this is the first study to explore the potential therapeutic effect of bilateral tDCS in amblyopic patients. Our results show that the combination of anodal tDCS (a-tDCS) in the amblyopic cortex and cathodal tDCS (c-tDCS) in the healthy cortex applied during a single session can improve visual acuity, presumably through an increase in the amblyopic cortex’s activity, suggested by an increase of the amplitude of VEP. These results add to the growing evidence describing the positive effects of tDCS as a potential treatment in adult patients with amblyopia.
Several studies in recent years suggest that the potential for increased plasticity in the human visual system is preserved in adult life19,20, which would allow interventions such as tDCS, even in short periods, to improve parameters like visual acuity in adult patients with amblyopia. A potential additional mechanism that could explain the improved visual acuity is the anodic stimulation of the amblyopic cortex, which is normally attenuated and suppressed by the contralateral cortex in the untreated amblyopic condition21–24. As observed in previous studies, the amplitude of VEPs is reduced in the amblyopic cortex, suggesting that the cortical response to visual stimuli is decreased in the amblyopic hemisphere11,25,26. The degree of suppression of the activity of the amblyopic cortex is positively correlated with the decrease in visual acuity in these subjects24,27−29. Mukerji et al30 have shown that the decrease in baseline electrical activity in the amblyopic cortex of humans is due to an increased concentration of perineuronal γ-aminobutyric acid (GABA). It has been described that the transcallosal inhibition on the amblyopic cortex is actually due to activity from the contralateral cortex that activates GABAergic neurons, which in turn, stimulate GABA B receptors located in the neurons of the visual system of the amblyopic cortex31,32. In addition, a-tDCS applied to the motor cortex, which causes increased amplitude of the motor evoked potentials, results in a reduction of the GABA concentration in relation to glutamate (assessed by nuclear magnetic resonance imaging spectroscopy). At the same time, c-tDCS produces a decrease in both GABA and glutamate33. This suggests that the molecular mechanism underlying cortical activation with a-tDCS is a decrease in the GABA/Glutamate ratio rather than just a reduction of GABA concentration.
A recent medium-to-large scale study using transcranial magnetic stimulation pulses to evaluate the motor cerebral cortex’s excitability suggests that there are no consistent excitability effects of a-tDCS in healthy motor cortices, as a-tDCS showed no changes in motor evoked potentials34. However, unlike a healthy cortex, the amblyopic visual cortex has been shown to have increased basal levels of GABA, suppressing its activity. Moreover, the positive effects of a-tDCS in the amblyopic cortex, such as an increased contrast sensitivity, do no occur when the same protocol is applied to a healthy cortex or healthy patient11, suggesting that these effects are mediated by a decrease in suppression, and no greater excitability of the amblyopic visual cortex.
One previous study has shown tDCS to increase the expression of brain-derived neurotrophic factor (BDNF)35, which is a remarkably robust, positive modulator of theta-burst induced long-term potentiation (LTP)36. The increased expression of BDNF correlates with improved visual acuity in animal models of amblyopia37. Thus, positive modulation of LTP through increased BDNF is a molecular mechanism other than the GABA/glutamate ratio that could explain the visual acuity improvement obtained in our patients. Likewise, LTP mediated by N-methyl-D-aspartate (NMDA) receptors has been thought to underlie the long-term effects, 48 hours post-stimulation shown by Ding et al11. The LTP-like effect of a-tDCS on the motor cortex seems to be favored by the repetition of the stimulation within a time interval of 30 min38, so a next step in the area of amblyopic visual cortex stimulation would be to develop protocols with multiple sessions, seeking the optimal frequency and number of sessions.
Another mechanism potentially involved in improving visual acuity seen in our study is a decreased transcallosal inhibition on the amblyopic visual cortex39. c-tDCS decreases activity in the healthy visual cortex, like the effects pursued with ocular occlusion treatment, reducing the inhibition it exerts on the contralateral cortex through inhibitory interhemispheric connections11,12. It has previously been described that stimulation with c-tDCS in the visual cortex produces a decrease in the amplitude of the N70 component of VEPs, while stimulation with a-tDCS achieves the opposite effect40. This decrease in the activity of the healthy cortex induced by c-tDCS would, in turn, reduce the activity of the inhibitory interhemispheric connections that come from the healthy cortex to the amblyopic one. Moreover, it has also been described that the unilateral application of c-tDCS in healthy visual cortex reduces transcallosal inhibition in amblyopic patients, improving visual acuity11,12.
In the present study, contrast sensitivity did not show significant improvement after bilateral tDCS. Previous studies have shown inconsistent changes in this variable41–45, probably due to the different techniques used to measure it. Ding et al11 showed a contrast sensitivity improvement but using a Gabor patch test, a different and more sensitive contrast vision assessment than the one used in our study11,46. Despite showing an upward trend, stereopsis was not significantly better in those stimulated with bilateral tDCS (b-tDCS) when compared to controls. However, Titmus test has been reported to be less sensitive than other tests available to quantify stereopsis47, thus using more sensitive tests in the future could reveal a significant improvement in this variable, as seen in another study that applied tDCS in patients with amblyopia10. The upward trend observed in the stereopsis of subjects undergoing b-tDCS suggests that a higher number of patients recruited in a future study could reveal a significant difference in this variable. Thus, the absence of improvement in stereopsis and contrast vision could be due both to the low number of patients and to the low sensitivity of the tests (Titmus test and Pelli-Robson Chart) used to measure these variables.
In this pioneering study, a significant increase in the visual acuity and evoked potential amplitude of the visual cortex was found after bilateral tDCS, suggesting this modality of direct current stimulation could be more effective than previously studied stimulation protocols such as unilateral a-tDCS or c-tDCS. On the other hand, we did not observe effects of bilateral tDCS on contrast vision and stereopsis. Future studies with a higher number of participants could confirm our overall results and compare the effectiveness of unilateral anodal, cathodal and bilateral stimulation in amblyopia, and explore the long-term results of these stimulation protocols. The use of combined anodal and cathodal stimulation as a potential treatment in amblyopia opens new paths for the treatment of a disease that until now was considered practically unmanageable after nine years of age.