Dear Dr., Non-strabismic, non-amblyopic intermittent central suppression (ICS) has been the crux of the challenge I have in accepting the conventional wisdom of suppression development: “Diplopiaphobia.” Reconciling the on-again, off-again intermittent loss of visual sensation that is ICS with cortical inhibition (often defined as masking at the cortex1) as the proposed visual sensation shut-down mechanism is just hard. That inhibition must not only be intermittent, but alternating from side to side (in 80% of ICS patients) uncontrolled by some sort of volitional switch in fixation as occurs sometimes in alternating strabismus. Those shortcomings led me to explore how the vision science on visibility might apply to this intermittent type of suppression2. My starting point was that the visual neurology is, well, the visual neurology. That is, whether strabismus is present or not, the neurology responsible for the suppression is in its basic construction - or perhaps in its beginning construction - the same, assuming no gross genetic or trauma-caused defects. The conventional wisdom, then, would hold that strabismus or anisometropia, through diplopiaphobia shuts down recognition of the visual signal for one side at the cortex and that defines suppression. But, if we redefine loss of the visual signal as vision science might, that is, as a loss of visibility (Troxlerʼs Perceptual Fading, possibly ICS2), that loss of visibility is positioned as a more afferent - maybe more primary - visual sensory defect rather than being entirely secondary to misalignment or anisometropia. If accurate, an early interruption of visibility (visual sensation) changes the time course of sensory anomalies from current thought. With diplopiaphobia, although unstated, there’s always a sense that “the organism” actively decides over time that diplopia doesn’t work well. The diplopia comes first. If instead the sensory loss becomes more primary, the time-frame to defect may contract. And, in development of neurology and potential defects in development, time is of the essence. Exploring the consequences of loss of visibility to our view of the development of binocularity defects means putting that loss of visibility into the moving framework of time - inserting loss of visibility into the development of the visual neurology through time. But, moving the sensory defect from the cortex to the more afferent location of loss of visibility at or near the LGN also means any loss of visibility now affects development further upstream neurologically. Loss of visibility at the LGN, if developmentally early enough, has consequences for development at the cortex, versus the cortex interfering with its own development through masking. Science fiction has used intervention in the fourth dimension (time) as a vehicle for stories for decades. But, here we have real-life consequences through time from an early disturbance in information transfer. Assuming loss of visibility (that is, Troxlerʼs fading) may be responsible for the loss of sensation of intermittent central suppression led to the first suggested visual-behavioral consequence that I termed “visual dyslexia.” In this view, loss of visibility contributes to such classic behavioral descriptions of “dyslexia” as reading letters and words “backwards.” Loss of visibility not only creates fixation instability, but also surprisingly strong filling-in of the area that has lost visibility.3 “Backwards” could easily be a short word seen correctly with one eye paired with a filled-in area from the fellow eye further confused (and variably confused?) by fixation instability. That the filling-in is strong enough to create rivalry with the “normally-seeing” eyeʼs image adds to the sense of loss-of-visibility variability in the central perception. This combination of a normal image conflicting with fixation-unstable filling-in could turn that short word into a variable visual mush - but a mush that has some “normal” characteristics from the nonsuppressed eyeʼs image. Perhaps “seeing backwards” should be replaced with “confused image.” Importantly, this would move some of the visual part of “dyslexia” from a cortical perceptual problem to a pre-cortical variable defect in the visual percept coming to the cortex. In amblyopia, again, suppression has traditionally been considered entirely secondary to misalignment (“diplopiaphobia”) and/or to blur in refractive amblyopia, presumably mediated by an active sort-of organismic decision against diplopia or blur. Schor, et al1 studied the 72 msec open time in his 7 Hz alternation paradigm with amblyopia and compared that with a common stimulus asynchrony in masking experiments to suggest masking at the cortex is responsible for the suppression. In masking experiments, a brief target stimulus can be made “invisible” if it is immediately preceded or followed by another (“masking”) stimulus. A masking stimulus to one eye can erase the target stimulus to the other eye. In much of the vision science, masking is studied by preceding or following a target stimulus at different inter-stimulus intervals to look at how the visual neurology responds4. The thrust for binocularity is that one eyeʼs masking of the less favored fellow eyeʼs image (weaker? turned? blurred?) might explain the suppression on a neurological level. So, masking could be a perfect explanation for suppression... except again for ICS. The intermittency and alternation are still pretty hard to explain with masking. Loss of visibility (aka Troxlerʼs fading) actually might support development of a cortical masking “suppression.” Poletti and Rucci5 as well as Komatsu3 suggest loss of visibility (Troxler’s) might be a loss of contrast to the point of disappearance. That certainly makes sense if the actual fade is a loss of Parvocellular signal triggered by an insufficiently strong Magnocellular signal. Or, as said elsewhere, “if the M-pathway fails, the P-pathway fades.”6 Reducing contrast supports masking of the weaker signal.7 So, a relatively brief loss of visibility (loss of contrast) on one side could trigger, or if not trigger, then at least facilitate, masking on the reduced-contrast side. That loss of contrast, however, is not at the cortical level where masking is thought to occur, but at the level of the LGN. This signal loss, then, is afferent and would therefore, if early enough in development, deprive the visual cortex of the signal it needs to develop normally. The result would be impaired activity in the cortical visual neurology since “neurons that don’t fire together, probably don’t wire together.” If accurate, this would inflict, at least to some degree, a deprivation component on the cortex in virtually all forms of amblyopia. This discussion ignores the initial trigger for the loss of visibility, the “chicken or egg” argument in the neural development. We need to be careful with this on at least two counts: We need to not allow ourselves to use that as an excuse for lack of success in therapy, but we also need to pay attention to any developing neurology research that may suggest ways to “re-start” development. This interference in visibility at the LGN may be what Hess has described as a monocular pathway attenuator at the LGN in amblyopia.9 Also worth exploring is whether anisometropic refractive error and amblyopia would become co-morbid secondary to signal dropout at the LGN rather than the amblyopia being entirely secondary to the anisometropia. Kotulak and Schor8 suggest a Troxler’s fade (loss of visibility) will have some effect on accommodation since the loss of visual signal occurs neurologically prior to accommodation control. So, how could that affect a developing visual system? Perhaps if the effect on input to accommodation is compromised early enough, emmetropization on one side might be affected and therefore loss of visibility would become part of the development of anisometropia in amblyopia versus the anisometropia being the trigger for all anomalies. But one of the parts of loss of visibility that has not been looked at extensively in any clinical sense is the filling-in that occurs with loss of visibility. Again, let’s project that into a very early stage of neural development in an infant, remembering that perceptual filling-in is strong enough to create rivalry with the normally seeing side.3 The filling-in is a cortical calculation, beyond V-1, apparently projected down to the LGN since rivalry occurs at the LGN.10,11 And, filling-in is just that - fill-in - filler - nothing with content, sort of like the middle section of that last movie you paid real money to see. But, is it conceivable that such a strong filling-in with non-content at a very early stage of development could create real interference with such basic sensitivity as direction of motion in the affected eye? If so, could that contribute to some of the measurements we get in anomalous correspondence/anomalous projection? Not enough is known about perceptual filling-in to go much beyond speculation. And nothing that I’ve seen suggests anything about how early that filling-in develops, although this is the same cortical calculation process that fills in the optic nerve head’s natural blind spot. Therefore, we might suggest that it is an early-established cortical function. All these thoughts await experimental verification of some sort, but, if there is any accuracy at all, perhaps understanding these things will aid development of new efficacious, efficient and safe therapies. Eric Hussey 1. Schor, C., Terrell, M. & Peterson, D. Contour interaction and temporal masking in strabismus and amblyopia. Am. J. Optom. Physiol. Opt. 1976; 53: 217–223. 2. Hussey ES. Is anti-suppression the quest for visibility? Accepted, Optometry and Visual Performance. 2015. 3. Komatsu H: The neural mechanisms of filling-in. Nature Reviews/Neuroscience 2006; 7: 220-231. 4. Macknik S, Livingstone M. Neuronal correlates of visibility and invisibility in the primate visual system. Nature Neuroscience 1998;1(2):144-149. 5. Poletti M, Rucci M: Eye movements under various conditions of image fading. Journal of Vision 10(3):6, 1–18, http://journalofvision.org/10/3/6/, doi:10.1167/10.3.6. 6. Hussey ES: Binocular visual sensation in reading II: Implications of a unified theory. Journal of Behavioral Optometry 2002; 13(3):66-70. 7. Foley, J. M. Forward–backward masking of contrast patterns: The role of transients. Journal of Vision 2011,11(9):15, 1–24, http://www.journalofvision.org/content/11/9/15, doi:10.1167/11.9.15. 8. Kotulak JC, Schor CM. The accommodative response to subthreshold blur and to perceptual fading during the Troxler phenomenon. Perception 1986; 15:7-15. 9. Huang, P.-C., Baker, D. H., & Hess, R. F. (2012). Interocular suppression in normal and amblyopic vision: Spatio- temporal properties. Journal of Vision, 12(11):29, 1–12, http:// www.journalofvision.com/content/12/11/29, doi:10.1167/12. 11.29. 10. Lee S-H, Blake R. V1 activity is reduced during binocular rivalry. J of Vision 2002; (618-626), http://journalofvision.org/2/9/4/ DOI 10:1167/2.9.4. 11. Wunderlich K, Schneider KA, Kastner S. Neural correlates of binocular rivalry in the human lateral geniculate nucleus. Nat Neurosc 2005; 8(11):1595-1602.