Amblyopia or “lazy eye” is defined as the reduction of the best corrected visual acuity (BCVA) of one or both eyes without the presence of any organic cause [1,2]. It is a neurodevelopmental disorder regarding abnormal cortical processing of visual input from both eyes that occurs during the critical period of visual system development, causing several visual defects [1,2,3]. It is the most common vision impairment in children, affecting up to 3.9% of the world population [1,2,4]. The main amblyogenic factors are: (a) Refractive errors, presented as anisometropia, which refers to a significant difference in refractive error between the two eyes, or as high ametropia, which refers to a high refractive error existing in both eyes; (b) strabismus, which is the misalignment of both eyes; and (c) deprivation of visual input, usually due to congenital cataract, eyelid ptosis, corneal opacities, limbal dermoids, or other ocular conditions preventing light from reaching the normal retina [2,5,6]. According to these causes, amblyopia is classified as refractive, strabismic, or deprivation amblyopia. Also, in some cases, amblyopia is due to a combined mechanism. Amblyopia is usually unilateral, and it is defined as visual acuity (VA) worse than 20/30 in an otherwise healthy eye, alongside an interocular visual acuity difference of at least two VA chart lines [1,7]. In bilateral amblyopia, both eyes have a reduced BCVA.

In children younger than 3 years old, strabismus is the most frequent cause of amblyopia (above 80% of cases), followed by mixed mechanism (13%) and refractive error (5%) [8]. In children <7 years old, strabismus and anisometropia are almost equally responsible for amblyopia (38% and 37%, respectively), while the rest of amblyopia cases are due to combined mechanisms [9]. According to other authors, deprivation of visual stimuli accounts for 4% of amblyopia cases [1].

The definition of amblyopia describes just the tip of the iceberg, as it affects a plethora of monocular and binocular functions besides VA. In further detail, amblyopia causes vulnerability to crowding (reduced ability to identify and distinguish a certain object within a pile of objects), poor stereopsis (depth perception), impaired contrast sensitivity (CS), spatial localization, form and motion perception, fixation instability, selective visual attention deficits as well as visuomotor coordination deficits, with great impact on everyday activities [1,2,3].

Perception of depth is a complex process where the brain integrates many different visual cues, some of which are derived from each eye (non-binocular cues), while other information is derived by the summation of visual input from both eyes (binocular cues) [3]. Non-binocular cues include overlapping of objects, perspective-conical projection of objects within distance, and relative size of objects within a scene, as well as lighting and shading over objects [3]. All these cues are essential sensory inputs for developing visuomotor skills during childhood [3,10]. Therefore, discordant binocular experience in early childhood, as is the case with amblyopic individuals, could affect the optimal development of eye-hand coordination. Accurate localization of objects within three-dimensional (3D) space is essential for developing the ability to plan and execute the required hand movements to reach and grasp a target object effectively [3,10]. Neuroimaging studies have shown reduced responses in the cortical regions responsible for depth perception in amblyopic patients [11].

Not all etiological factors have equal amblyogenic potential. For example, astigmatism is known to induce deeper amblyopia compared to hyperopia of equal diopters. Furthermore, strabismus is reported to have a stronger impact on visual functions than anisometropia [2,8,12]. Therefore, strabismic amblyopia patients present greater crowding effect, more severe loss of stereoacuity, greater contrast sensitivity deficits, especially in higher spatial frequencies and poorer performance eye-hand coordination in tasks [10,12]. Also, studies highlight that strabismus patients with amblyopia are less responsive to treatment and show higher regression rates after treatment cessation compared to anisometropia patients [12].

Amblyopia was previously perceived as a monocular disorder. Recent observations have changed this notion. It is now accepted that amblyopia is a result of binocular dysfunction [2,13,14].

Binocular perception is achieved in normally-sighted individuals by the integration of the input from both eyes in the visual cortex [11,14]. These incoming signals are similar enough to get correlated and fused together, and each eye contributes equally to the perceived image [11,14]. Binocularity is established promptly at birth through complex excitatory and inhibitive neuronal circuitry in the early visual cortex [11,15]. During early infancy, between 3 to 5 months of age, neural connections increase massively in this area [11,15]. During early childhood, these synapses constantly change, leading to either the strengthening of correct connections or the inhibition of incorrect connections [15]. Frequent use of a certain neural connection promotes synaptic strengthening, and the opposite happens to idle connections [15]. This process is defined as neuroplasticity. The time period where these important changes take place is referred to as the critical period, and for the development of vision, it is known to extend until 7 years of age [15]. Neuroplasticity beyond that period is thought to gradually decline until adulthood. Thus, children are most susceptible to developing amblyopia during the first 2–3 years of life, and the risk gradually decreases until the end of the critical period, when the visual system matures and retinocortical pathways become strongly established [15]. As recent studies revealed, the adult cortex still retains a considerable amount of neuroplasticity [15,16]. In amblyopic individuals, under binocular viewing conditions, the brain receives dissimilar and conflicting visual input from corresponding retinal points, which can cause confusion and diplopia [14]. In order to prevent this situation, the brain inhibits the information from the eye that is either receiving a blurry image (in anisometropia), becomes misaligned (in strabismus), or receives no input (in deprivation amblyopia) [14]. This mechanism is referred to as suppression in favor of the dominant eye, causing the “weaker” eye to become amblyopic [14]. The depth of suppression is positively associated with the amount of VA reduction [14,17]. Researchers, using specially designed dichoptic VA charts, showed that the amblyopic eye scored higher acuity when the fellow eye was occluded, but in binocular viewing conditions, it performed worse as a result of suppression from the dominant eye [17]. This effect was present in naive amblyopic and supposedly treated patients as well [17]. These findings support previous observations suggesting that amblyopia is indeed the result of binocular dysfunction.

Suppression is marked across the whole amblyopic visual field, but it is stronger in the foveal region, creating a distinct functionally blind area called suppression scotoma [14,18,19]. Luminance and contrast sensitivity thresholds are elevated within that area, form and motion information are suppressed, and objects presented within the scotoma do not become consciously aware [14,18,19]. Recent studies show that the information from the amblyopic eye, though strongly suppressed from conscious perception, still remains available for binocular processing [18].

Discordant visual signals from the two eyes have a major effect on the primary visual cortex V1 neurons during the early critical period of development, altering neural circuitry [11,14,16,20,21]. Beyond infancy, the effect of dissimilar visual input results in fixation instability, with the development of abnormal fixation eye movements (FEMs), eccentric fixation, and greater VA loss [2,20,22]. The presence of nystagmus in amblyopic patients is associated with more severe visual impairment [20].

As recent research data unveiled the role of binocular dysfunction in the etiology of amblyopia, treatment approaches have been shifted toward that direction [2,14,19]. Novel amblyopia therapies are based on the principles of perceptual learning (PL). PL can be defined as improved sensory perception or execution performance as a result of practice, achieved by repetitive exposure to certain stimuli or repetitive execution of certain physical tasks [16,23,24]. The basic principle behind the training effects of perceptual learning is that repetitive stimulation causes strong and synchronous activation of certain cellular populations along the neuronal pathway, mediating a specific neurosensory task and promoting synaptic strengthening between those neurons (Hebbian plasticity) [16]. The result is permanent neuroplastic changes through training, with consequent improvement in neurosensory response [14,16]. These principles applied in visual functions could be an effective treatment for amblyopia deficits. The effect of PL in shaping neural plasticity on the visual cortex and subsequent in rebalancing interocular dominance has been demonstrated in amblyopia patients through changes in the amplitude of steady-state visually evoked potentials (SSVEP) measured before and after a number of treatment sessions [25,26], while other researchers in an ongoing study aim to confirm the same effect by detecting changes in functional Magnetic Resonance Imaging (f-MRI) of treated patients [27].