Differential effects of high-frequency transcranial random noise stimulation (hf-tRNS) on contrast sensitivity and visual acuity when combined with a short perceptual training in adults with amblyopia
Introduction
Amblyopia is a developmental disorder of spatial vision, it describes a condition in which there is reduced visual functions in one, or (more infrequently) both eye(s), despite optimum optical correction and the absence of overt pathology of the visual system (Ciuffreda et al., 1991). Amblyopia is clinically relevant because, aside from refractive defects, is the most frequent cause of vision loss in children and it occurs in about 2–4% of the population; it reflects the neural impairment which can occur when normal visual development is disrupted (Levi and Li, 2009). The most common aetiologies of amblyopia are untreated strabismus, which consists of a misalignment of the eyes, anisometropia, which is an unequal refractive error between the two eyes, or both strabismus and anisometropia (Giaschi et al., 2015).
Spatial vision abnormalities in amblyopia include reductions in visual acuity (VA), contrast sensitivity function (CSF) (Hess and Howell, 1977), and Vernier acuity as well as spatial distortion (Sireteanu et al., 1993), abnormal spatial interactions (Polat et al., 1997), impaired contour detection (Kovács et al., 2000), deficiencies in stereopsis (Wallace et al., 2011), and more generally, global processing of form and motion (Aaen-Stockdale and Hess, 2008, Constantinescu et al., 2005, Ho et al., 2005, Husk et al., 2012, Simmers et al., 2003, Simmers et al., 2005, Simmers et al., 2006, Simmers and Bex, 2004). Despite some early indications that the retina may be the primary site of amblyopia (Hess, 2001), the current unanimous opinion is that the primary site of neural loss in amblyopia is found at the level of the primary visual cortex (V1) and it is due to an atypical pattern of functional connectivity among neurones selective for orientation and spatial frequency (Polat, 1999, Polat et al., 1997).
Amblyopia was thought to be treatable only if diagnosed within the critical period, that is before ten years of age (Epelbaum et al., 1993, Greenwald and Parks, 1999), due to aged-diminished neural plasticity within the visual cortex that would limit any anatomical, physiological or functional changes (Berardi et al., 2003). Nonetheless, recent studies have reported improvements beyond this period in healthy adults, related to various visual functions following perceptual training (Fiorentini and Berardi, 1981, Karni and Sagi, 1991, Poggio et al., 1992, Sagi, 2011, Schoups et al., 1995); suggesting neuronal plasticity at early levels of the adult visual system (Pourtois et al., 2008, Schoups et al., 2001). Adults with normal vision can improve performance upon practice on many visual tasks, and although learning can be rather specific (to the trained task, stimulus orientation, eye, etc.; Ahissar and Hochstein, 1996; Campana and Casco, 2003; Casco et al., 2001; Fahle et al., 2005; Fiorentini and Berardi, 1981; Karni and Sagi, 1991), under certain conditions it can generalize to untrained visual tasks or functions (Casco et al., 2014, Harris et al., 2012, Jeter et al., 2009, Maniglia et al., 2011, Maniglia et al., 2016, Mastropasqua et al., 2015, Solgi et al., 2013). Interestingly, the visual system of adults with amblyopia shows similar neural plasticity, thus rendering perceptual learning a useful approach for the treatment of amblyopia in adulthood. In the last two decades, marked improvements of various visual functions in adults with amblyopia, following extensive sessions of perceptual learning (PL), have been reported (Astle et al., 2011, Levi and Li, 2009, Li et al., 2005, Polat, 2009). According to Levi and Li (2009) and Camilleri et al. (2014a), the task that was able to produce the largest improvement ratio on both VA and CS measurements was a contrast detection task using the lateral masking paradigm (Polat et al., 2004, Polat and Sagi, 1993). Polat et al. (2004) obtained an improvement of contrast-detection thresholds (ranging from 2.05 to 4.23 times) and improvement in VA (78% gain, equal to 0.25 LogMAR) in adults with amblyopia; they used a training procedure based on the strengthening of facilitatory lateral interactions, by administering a contrast-detection task of a low-contrast central Gabor patch flanked by two high-contrast Gabor patches. Despite the results obtained, the large number of sessions required (from 30 to 80 sessions) to achieve the reported improvements may lead to a high dropout rate.
Another way that has been pursued in the last years for improving visual functions in amblyopia consists in the administration of non-invasive brain stimulation (NIBS) techniques over visual areas. For instance, Thompson et al. (2008) found that a single session of repetitive transcranial magnetic stimulation (rTMS) delivered over the visual cortex temporarily increases contrast sensitivity of the amblyopic eye for high spatial frequencies. The same research group (Clavagnier et al., 2013) also reported that five sessions of inhibitory continuous theta-burst TMS produced a long-term improvement of contrast sensitivity for high spatial frequencies in the amblyopic eye. Other studies focused on the effects of transcranial direct current stimulation (tDCS), for example, a recent study by Castaño-Castaño et al. (2017) demonstrated that in rats monocularly deprived from birth, eight sessions of anodal tDCS on the visual cortex contralateral to the deprived eye produced an almost complete recovery of visual acuity. In human adults, there is evidence that a single session of anodal tDCS over the visual cortex with a concurrent contrast detection or discrimination task, produced the following effects: a) temporarily improved contrast sensitivity in the amblyopic (Ding et al., 2016; Spiegel et al., 2013a) and fellow eye (Ding et al., 2016); b) normalized visual cortical activation in amblyopes. In an fMRI study, Spiegel et al. (2013a) found that following anodal tDCS, the visual cortical response asymmetry in amblyopic patients, which favours the fellow eye, was reduced; c) increased early visual evoked potentials (VEPs) amplitudes, and specifically the difference between the N75 negative peak and the P100 positive peak of both amblyopic and fellow eyes (Ding et al., 2016). Moreover, five sessions of dichoptic training with concurrent anodal tDCS over the occipital cortex produced a larger improvement of stereopsis (but not visual acuity) with respect to the same dichoptic treatment with concurrent Sham stimulation (Spiegel et al., 2013b).
The hypothesized effect of brain stimulation on improvement of visual functions has been attributed to disinhibition of the suppressed processing of information coming from the amblyopic eye, possibly mediated by a reduction of the concentration of the inhibitory neurotransmitter GABA (Ding et al., 2016). A reduction of GABA could also explain the boosting of learning when tDCS was coupled with a visual task (Sale et al., 2010). In fact, a reduction of GABA following anodal tDCS has been documented with magnetic resonance spectroscopy (MRS) (Stagg et al., 2009), and such a reduction has been shown to correlate positively with performance improvement in motor learning and correlate negatively with the change in BOLD signal in area M1 (Kim et al., 2014; Stagg et al., 2011).
Given its potential in boosting the effects of visual training (e.g., Spiegel et al., 2013b), NIBS could be effectively used to reduce the number of training sessions needed to obtain a longer-lasting improvement of visual functions in the amblyopic eye. A recently developed transcranial electrical brain stimulation technique delivering alternating current at random frequencies in the high-frequency range (hf-tRNS), has been shown to be the most efficacious neuromodulatory technique for enhancing and accelerating within-session perceptual learning (PL) (Fertonani et al., 2011, Pirulli et al., 2013). In fact, several studies reported that this technique can boost PL even in normally sighted observers. For example, in a pilot study Campana et al. (2014), used a training regime consisting of contrast detection of a central Gabor patch (target) flanked by two high contrast Gabor patches of the same spatial frequency (i.e., lateral masking paradigm; Polat et al., 2004) for just eight sessions, combined with hf-tRNS in a group of seven amblyopic patients. The results showed an improvement of mean VA of 0.18 LogMAR (53% improvement, ranging from 25% to 111%) in the trained amblyopic eye. The CSF also resulted in strong improvements following training, both in the trained amblyopic eye and in the untrained fellow eye. These results, however, do not explicitly address the contribution of hf-tRNS in such improvement of visual functions, due to the absence of a Sham control group. In light of this, in the present study, a larger sample of participants with amblyopia was recruited. Participants were randomly assigned to either the hf-tRNS or Sham group. All participants were enrolled in a behavioural training regime using the lateral masking paradigm (Campana et al., 2014, Polat et al., 2004) combined with online hf-tRNS or Sham stimulation. The training consisted of eight sessions administered in two weeks. Based on our previous findings (Campana et al., 2014), we hypothesize that hf-tRNS can boost and accelerate the effects of perceptual learning when combined with a short perceptual training regime in adults with amblyopia. Additionally, we predict that hf-tRNS favours the transfer of learning to other non-trained visual functions including VA and CSF. To investigate the effects of online hf-tRNS on the visual system, VA and CSF were assessed for each observer before and after the training.
Section snippets
Apparatus
A 22-in. screen (Philips Brilliance 202P4) with resolution of 1280 × 1024 pixels and with a refresh rate of 60 Hz has been used for both the VA assessment and perceptual training. The screen luminance was calibrated by gamma correction, with γ = 1. Screen luminance was calibrated using Spyder 5 Express (Datacolor, Lawrenceville, New Jersey, USA; http://www.datacolor.com/). The luminance of the screen background was fixed at 31.5 cd/m2. CS was measured with a computer equipped with a VSG2/3
Contrast sensitivity
Fig. 2 shows the CS results separately for the two groups and for the two eyes. CS data were analysed with a mixed ANOVA including Training (pre-training vs. post-training), Eye (amblyopic/trained vs. non-amblyopic/untrained) and Spatial Frequency (0.8, 2.9, 5.8, 9.7, and 14.5 cpd) as within-subjects factors, and Group (hf-tRNS vs. Sham) as the between-subjects factor. When the sphericity assumption was violated, degrees of freedom were corrected with the Greenhouse-Geisser correction.
The ANOVA
Discussion
In this study, amblyopic participants performed a short (8 sessions) monocular perceptual training. The training consisted of a visual contrast detection task (using the lateral masking parading) in combination with non-invasive hf-tRNS. One group of amblyopic participants underwent online hf-tRNS, whereas the group performed the same perceptual training but with Sham (control) stimulation. The results demonstrated that the perceptual training was able to improve CS in amblyopic adults, though
Acknowledgments
G.C is supported by a "Progetto di Ateneo" grant of the University of Padova (grant number: CPDA148575/14). B.M. is supported by a Ph.D. fellowship of the University of Padova; R.C. was supported by a Ph.D. fellowship of the CARIPARO Foundation.
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