Cholinergic Modulation of Binocular Vision.

The endogenous neurotransmitter acetylcholine (ACh) is known to affect the excitatory/inhibitory (E/I) balance of primate visual cortex, enhancing feedforward thalamocortical gain while suppressing corticocortical synapses. Recent advances in the study of the human visual system suggest that ACh is a likely component underlying interocular interactions. However, our understanding of its precise role in binocular processes is currently lacking. Here we use binocular rivalry as a probe of interocular dynamics to determine ACh's effects, via the acetylcholinesterase inhibitor (AChEI) donepezil, on the binocular visual system. A total of 23 subjects (13 male) completed two crossover experimental sessions where binocular rivalry measurements were obtained before and after taking either donepezil (5 mg) or a placebo (lactose) pill. We report that enhanced cholinergic potentiation attenuates perceptual suppression during binocular rivalry, reducing the overall rate of interocular competition while enhancing the visibility of superimposition mixed percepts. Considering recent evidence that perceptual suppression during binocular rivalry is causally modulated by the inhibitory neurotransmitter GABA, our results suggest that cholinergic activity counteracts the effect of GABA with regards to interocular dynamics and may modulate the inhibitory drive within the visual cortex.SIGNIFICANCE STATEMENT Our research demonstrates that the cholinergic system is implicated in modulating binocular interactions in the human visual cortex. Potentiating the transmission of acetylcholine (ACh) via the cholinergic drug donepezil reduces the extent to which the eyes compete for perceptual dominance when presented two separate, incongruent images.

Botulinum toxin in the treatment of partially accommodative esotropia with high AC/A ratio.

PURPOSE: To study the outcome of botulinum toxin (BTX) treatment (group 1) in partially accommodative esotropia with high accommodative convergence/accommodation (AC/A) ratio, in comparison with bilateral medial rectus muscles recessions and posterior fixation (group 2). METHODS: In a retrospective comparative study, children aged 3-8 years old treated between 2011 and 2016, with partially accommodative esotropia with high AC/A ratio, deviation at distance of 10 prism diopters or more, and at least 1 year of follow-up, were included. Visual acuity, alternate prism and cover test, stereoacuity, biomicroscopy, and cycloplegic retinoscopy were carried out at initial, baseline visit, 6 months and 1 year after BTX injection or surgery. Main outcome variables were deviation at distance and near, improvement in stereoacuity, and percentage of success. We used multiple regression or proportional odds analysis to control for potential confounding variables. RESULTS: Of 95 patients, 84 were eligible, 48 children in group 1 and 36 in group 2. Deviation and stereoacuity were similar in the two groups at 6 months, but significantly better in the BTX group at 1 year (median distance deviation 0 prism diopters vs 5 prism diopters, p<0.01), although differences were not clinically relevant. Percentage of success was also significantly better only at 1 year (93% vs 72%, p = 0.01). Change in distance-near disparity was not significantly different in the two groups in the period of study. CONCLUSIONS: Botulinum toxin could be superior to, or as effective as surgery, at middle term, in the treatment of partially accommodative esotropia with high AC/A ratio.

GABAergic Inhibition Gates Perceptual Awareness During Binocular Rivalry.

Binocular rivalry is a classic experimental tool to probe the neural machinery of perceptual awareness. During rivalry, perception alternates between the two eyes, and the ebb and flow of perception is modeled to rely on the strength of inhibitory interactions between competitive neuronal populations in visual cortex. As a result, rivalry has been suggested as a noninvasive perceptual marker of inhibitory signaling in visual cortex, and its putative disturbance in psychiatric conditions, including autism. Yet, direct evidence causally implicating inhibitory signaling in the dynamics of binocular rivalry is currently lacking. We previously found that people with higher GABA levels in visual cortex, measured using magnetic resonance spectroscopy, have stronger perceptual suppression during rivalry. Here, we present direct causal tests of the impact of GABAergic inhibition on rivalry dynamics, and the contribution of specific GABA receptors to these dynamics. In a crossover pharmacological design with male and female adult participants, we found that drugs that modulate the two dominant GABA receptor types in the brain, GABAA (clobazam) and GABAB (arbaclofen), increase perceptual suppression during rivalry relative to a placebo. Crucially, these results could not be explained by changes in reaction times or response criteria, as determined through rivalry simulation trials, suggesting a direct and specific influence of GABA on perceptual suppression. A full replication study of the GABAB modulator reinforces these findings. These results provide causal evidence for a link between the strength of inhibition in the brain and perceptual suppression during rivalry and have implications for psychiatric conditions including autism.SIGNIFICANCE STATEMENT How does the brain accomplish perceptual gating? Here we use a direct and causal pharmacological manipulation to present insight into the neural machinery of a classic illusion of perceptual awareness: binocular rivalry. We show that drugs that increase GABAergic inhibition in the brain, clobazam (GABAA modulator) and arbaclofen (GABAB modulator), increase perceptual suppression during rivalry relative to a placebo. These results present the first causal link between GABAergic inhibition and binocular rivalry in humans, complementing classic models of binocular rivalry, and have implications for our understanding of psychiatric conditions, such as autism, where binocular rivalry is posited as a behavioral marker of disruptions in inhibitory signaling in the brain.

The Effect of Combined Patching and Citalopram on Visual Acuity in Adults with Amblyopia: A Randomized, Crossover, Placebo-Controlled Trial.

Nonhuman animal models have demonstrated that selective serotonin reuptake inhibitors (SSRIs) can enhance plasticity within the mature visual cortex and enable recovery from amblyopia. The aim of this study was to test the hypothesis that the SSRI citalopram combined with part-time patching of the fellow fixing eye would improve amblyopic eye visual acuity in adult humans. Following a crossover, randomized, double-blind, placebo-controlled design, participants completed two 2-week blocks of fellow fixing eye patching. One block combined patching with citalopram (20 mg/day) and the other with a placebo tablet. The blocks were separated by a 2-week washout period. The primary outcome was change in amblyopic eye visual acuity. Secondary outcomes included stereoacuity and electrophysiological measures of retinal and cortical function. Seven participants were randomized, fewer than our prespecified sample size of 20. There were no statistically significant differences in amblyopic eye visual acuity change between the active (mean ± SD change = 0.08 ± 0.16 logMAR) and the placebo (mean change = -0.01 ± 0.03 logMAR) blocks. No treatment effects were observed for any secondary outcomes. However, 3 of 7 participants experienced a 0.1 logMAR or greater improvement in amblyopic eye visual acuity in the active but not the placebo blocks. These results from a small sample suggest that larger-scale trials of SSRI treatment for adult amblyopia may be warranted. Considerations for future trials include drug dose, treatment duration, and recruitment challenges. This study was preregistered as a clinical trial (ACTRN12611000669998).

Fluoxetine does not enhance the effect of perceptual learning on visual function in adults with amblyopia.

Amblyopia is a common visual disorder that is treatable in childhood. However, therapies have limited efficacy in adult patients with amblyopia. Fluoxetine can reinstate early-life critical period-like neuronal plasticity and has been used to recover functional vision in adult rats with amblyopia. We conducted a Phase 2, randomized (fluoxetine vs. placebo), double-blind, multicenter clinical trial examined whether or not fluoxetine can improve visual acuity in amblyopic adults. This interventional trial included 42 participants diagnosed with moderate to severe amblyopia. Subjects were randomized to receive either 20 mg fluoxetine (n = 22) or placebo (n = 20). During the 10-week treatment period, all subjects performed daily computerized perceptual training and eye patching. At the primary endpoint, the mean treatment group difference in visual acuity improvement was only 0.027 logMAR units (95% CI: -0.057 to 0.110; p = 0.524). However, visual acuity had significantly improved from baseline to 10 weeks in both fluoxetine (-0.167 logMAR; 95% CI: -0.226 to -0.108; p < 0.001) and placebo (-0.194 logMAR; 95% CI: -0.254 to -0.133; p < 0.001) groups. While this study failed to provide evidence that fluoxetine enhances neuroplasticity, our data support other recent clinical studies suggesting that improvement of vision can be accomplished in adults with amblyopia.

Adaptability of the Immature Ocular Motor Control System: Unilateral IGF-1 Medial Rectus Treatment.

PURPOSE: Unilateral treatment with sustained release IGF-1 to one medial rectus muscle in infant monkeys was performed to test the hypothesis that strabismus would develop as a result of changes in extraocular muscles during the critical period of development of binocularity. METHODS: Sustained release IGF-1 pellets were implanted unilaterally on one medial rectus muscle in normal infant monkeys during the first 2 weeks of life. Eye position was monitored using standard photographic methods. After 3 months of treatment, myofiber and neuromuscular size, myosin composition, and innervation density were quantified in all rectus muscles and compared to those in age-matched controls. RESULTS: Sustained unilateral IGF-1 treatments resulted in strabismus for all treated subjects; 3 of the 4 subjects had a clinically significant strabismus of more than 10°. Both the treated medial rectus and the untreated ipsilateral antagonist lateral rectus muscles had significantly larger myofibers. No adaptation in myofiber size occurred in the contralateral functionally yoked lateral rectus or in myosin composition, neuromuscular junction size, or nerve density. CONCLUSIONS: Sustained unilateral IGF-1 treatment to extraocular muscles during the sensitive period of development of orthotropic eye alignment and binocularity was sufficient to disturb ocular motor development, resulting in strabismus in infant monkeys. This could be due to altering fusion of gaze during the early sensitive period. Serial measurements of eye alignment suggested the IGF-1-treated infants received insufficient coordinated binocular experience, preventing the establishment of normal eye alignment. Our results uniquely suggest that abnormal signaling by the extraocular muscles may be a cause of strabismus.

A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex.

Early sensory experience instructs the maturation of neural circuitry in the cortex. This has been studied extensively in the primary visual cortex, in which loss of vision to one eye permanently degrades cortical responsiveness to that eye, a phenomenon known as ocular dominance plasticity (ODP). Cortical inhibition mediates this process, but the precise role of specific classes of inhibitory neurons in ODP is controversial. Here we report that evoked firing rates of binocular excitatory neurons in the primary visual cortex immediately drop by half when vision is restricted to one eye, but gradually return to normal over the following twenty-four hours, despite the fact that vision remains restricted to one eye. This restoration of binocular-like excitatory firing rates after monocular deprivation results from a rapid, although transient, reduction in the firing rates of fast-spiking, parvalbumin-positive (PV) interneurons, which in turn can be attributed to a decrease in local excitatory circuit input onto PV interneurons. This reduction in PV-cell-evoked responses after monocular lid suture is restricted to the critical period for ODP and appears to be necessary for subsequent shifts in excitatory ODP. Pharmacologically enhancing inhibition at the time of sight deprivation blocks ODP and, conversely, pharmacogenetic reduction of PV cell firing rates can extend the critical period for ODP. These findings define the microcircuit changes initiating competitive plasticity during critical periods of cortical development. Moreover, they show that the restoration of evoked firing rates of layer 2/3 pyramidal neurons by PV-specific disinhibition is a key step in the progression of ODP.

Vascular endothelial growth factor B prevents the shift in the ocular dominance distribution of visual cortical neurons in monocularly deprived rats.

A key model for examining the activity-dependent development of primary visual cortex (V1) involves the imbalance in activity between the two eyes induced by monocular deprivation (MD). MD early in life causes dramatic changes in the functional and structural organization of mammalian visual cortex. The molecular signals that mediate the effects of MD on the development of visual cortex are not well defined. Neurotrophic factors are important in regulating the plasticity of visual cortex, but the choice of an appropriate growth factor as well as its delivery has proven difficult. Although vascular endothelial growth factor-B (VEGF-B) is a homolog of the angiogenic factor VEGF-A, it has only minimal angiogenic activity, raising the question of whether this factor has other (more relevant) biological properties. Intrigued by the possibility that VEGF family members affect neuronal cells, we explored whether VEGF-B has a role in the nervous system. In rats, VEGF-B infusion during monocular deprivation (MD) counteracted the normally occurring ocular dominance (OD) shift toward the non-deprived eye so that the deprived eye dominated the VEGF-B-treated cortex after MD. In particular, VEGF-B counteracted the effects of MD without causing detectable alterations in spontaneous discharge or behavior. In conclusion, the simultaneous analysis of visual cortical cell discharge and ocular dominance plasticity suggests that VEGF-B has important effects on the functional architecture of the visual cortex. Therefore, VEGF-B is a new candidate trophic challenge molecule for the visual cortex.

The use of galantamine in the treatment of post-traumatic oculomotor and trochlear nerve palsy.

PURPOSE: To assess the suitability of galantamine for the symptomatic treatment of post-traumatic oculomotor (III) and trochlear (IV) nerve palsy. MATERIAL AND METHODS: The routine ophthalmic and strabological examination was performed in five patients (4 females and 1 male) at the age of 31 to 57 years (mean 40.7) with the post-traumatic ophthalmic complications. Due to the unilateral oculomotor and trochlear nerve palsy, which had not resolved within 2-6 (mean duration of 4 months) months following traffic accident, galantamine was used. Nivalin and Reminyl were administered in iontophoresis and orally, respectively, for 10-18 months (mean duration of 14 months). The ocular muscle motion exercises and prism correction were also used. RESULTS: The increased range of ocular motion (100%), reducing of the angle of strabismus horizontally (40%) and vertically (60%), statistically significant extension of palpebral fissure (60%), and regression of diplopia (80% total without correction) were observed. The binocular vision after treatment in the free- and instrument-space environment were also improved (100% simultaneous perception, fusion 80%, stereopsis 60%). CONCLUSIONS: The early galantamine administration in patient with n. III and n. IV post-traumatic palsy accelerates the resolution of post-traumatic ophthalmic symptoms. It is an effective treatment which offers the elimination of strabismus, diplopia and ptosis, at the same time improvings ocular movements and binocular vision. galantamine, post-traumatic nerve palsy, oculomotor and trochlear nerves.

Nystagmus and reduced visual acuity secondary to drug exposure in utero: long-term follow-up.

PURPOSE: To investigate nystagmus and other visual system abnormalities among children exposed to opiates and benzodiazepines in utero. METHODS: Retrospective case series comprising clinical examination and case note review of 25 children with nystagmus and reduced vision who were exposed to controlled drugs during pregnancy. RESULTS: Twenty-four children were exposed to opiates, of whom 13 were also exposed to diazepam. One child was exposed to diazepam alone. All children had horizontal nystagmus, which was either fine pendular or jerk type. The nystagmus had a latent element in 4 children and 8 adopted a compensatory head posture. Where the time of onset of nystagmus was known, it was always prior to 6 months of age. At least 9 children (36%) had delayed visual maturation. The mean initial logarithm of the minimum angle of resolution binocular best-corrected visual acuity (BCVA) was 0.54 at an average of 22 months of age. Thirteen children were followed up for 6 months or longer and their BCVA improved to 0.4 at an average age of 48 months. The nystagmus was clinically improved in only 5 patients. Electroretinogram testing was normal in the 4 children tested. The only ocular structural abnormality was binocular optic nerve hypoplasia in 2 children. CONCLUSION: Exposure to opiates and benzodiazepines in utero may be associated with permanent nystagmus and reduced visual acuity. This is most likely the result of insult(s) to the central nervous system rather than the eyes.

Microarray analysis of choroid/RPE gene expression in marmoset eyes undergoing changes in ocular growth and refraction.

PURPOSE: Visually guided ocular growth is facilitated by scleral extracellular matrix remodeling at the posterior pole of the eye. Coincident with scleral remodeling, significant changes in choroidal morphology, blood flow, and protein synthesis have been shown to occur in eyes undergoing ocular growth changes. The current study is designed to identify gene expression changes that may occur in the choroid/retinal pigment epithelium (RPE) of marmoset eyes during their compensation for hyperopic defocus as compared to eyes compensating for myopic defocus. METHODS: Total RNA was isolated from choroid/RPE from four common marmosets (Callithrix jacchus) undergoing binocular lens treatment using extended wear soft contact lenses of equal magnitude but opposite sign (+/-5 diopter [D]). After reverse transcription, cDNA was labeled and hybridized to a human oligonucleotide microarray and gene transcript expression profiles were determined. Real-time polymerase chain reaction (PCR) and western blot analysis were used to confirm genes and proteins of interest, respectively. RESULTS: Microarray analyses in choroid/RPE indicated 204 genes were significantly changed in minus lens-treated as compared with plus lens-treated eyes (p<0.05, Student's t-test). Differential choroid/RPE expression of protein tyrosine phosphatase, receptor type, B (PTPRB), transforming growth factor beta-induced (TGFBI), and basic fibroblast growth factor 2 (FGF-2) were confirmed by real-time PCR. TGFBIp was confirmed at the protein level by western blot analysis in marmoset and human cornea, choroid/RPE, and sclera. CONCLUSIONS: The present study demonstrated that significant gene expression changes occur in the marmoset choroid/RPE during visually guided ocular growth. The identification of novel candidate genes in choroid/RPE of marmoset eyes actively accelerating or decelerating their rates of ocular elongation may elucidate the choroidal response during the regulation of postnatal ocular growth and may lead to the identification of choroid/RPE signaling molecules that participate in scleral remodeling.

Influences of perinatal dioxin load to visual motion and oddball stimuli examined with an EEG and MEG analysis.

OBJECTIVE: With MEG and EEG the effect of perinatal dioxin load of 38 healthy 7- to 12-year-old children was studied to assess possible disturbances of visual development. METHODS: Latencies and amplitudes of the motion (N2 with subcomponents) and oddball responses (N200 and P3b) were analysed after age correction. RESULTS: With increasing load, latencies increased and the amplitudes of the oddball components tended to be reduced. The latency increase between the high- and low-loaded children was about 13 ms (P<0.004) and the oddball response showed an amplitude decrease of 12% (P=0.009). CONCLUSIONS: It may be concluded that, during the end-80s/early-90s, exposure to background levels in industrialized regions seems to have resulted in small underdevelopment or damage to visual motion processing and visual cognition. SIGNIFICANCE: Since dioxin pollution by incinerators still exists in many regions in developing countries and also still, although at a smaller scale, in the industrialized world, perinatal loads of similar magnitude and possibly more as measured in this study may occur and as a consequence might affect the developing brain.

Disturbances of visual information processing in early states of psychosis and experimental delta-9-tetrahydrocannabinol altered states of consciousness.

Recent data on alterations of the endogenous cannabinoid system in schizophrenia have raised the question of its functional role in this disease. The psychoactive compound of Cannabis sativa, delta-9-tetrahydrocannabinol (Delta9-THC), has been shown to induce psychotic symptoms, but it is unknown to what extend prodromal states of psychoses are reflected by these experimental approaches. This study compares four groups of subjects: antipsychotic-naïve patients suffering from acute paranoid schizophrenic or schizophreniform psychosis (SZ), patients in the prodromal state (IPS), healthy controls without any pharmacological intervention (HC) and a second group of healthy volunteers who were orally administered synthetic Delta9-THC (Dronabinol) (HC-THC). Neither SZ and IPS nor HC received the experimental drug. All subjects were assessed using the Brief Psychiatric Rating Scale (BPRS) and the Binocular Depth Inversion Illusion Test (BDII). The latter represents a sensitive measure of impaired visual information processing that manifests in various experimental and naturally occurring psychotic states. BDII values were well comparable in SZ, IPS and HC-THC, and all groups differed significantly to HC. The BPRS revealed no significant difference between HC-THC and IPS while both were significantly different from SZ and HC, respectively. Our results suggest that Delta9-THC-induced altered states of consciousness may serve as a useful tool for modeling psychotic disorders, particularly their prodromal states. Furthermore, they provide insight into the perceptual and psychopathological alterations induced by Delta9-THC, which is essential for the understanding of the pro-psychotic effects of herbal cannabis preparations with highly enriched Delta9-THC content.

Early alcohol exposure impairs ocular dominance plasticity throughout the critical period.

Animal models of fetal alcohol syndrome (FAS) have revealed an impairment of sensory neocortex plasticity. Here, we examine whether early alcohol exposure leads to a permanent impairment of ocular dominance plasticity (OD) or to an alteration in the timing of the critical period. Ferrets were exposed to alcohol during a brief period of development prior to eye opening and effects of monocular deprivation examined during early, mid and late critical period. Single-unit electrophysiology revealed markedly reduced OD plasticity at every age examined. This finding provides evidence that early alcohol exposure does not affect the timing or duration of the critical period of OD plasticity and suggests an enduring impairment of neural plasticity in FAS.

Chronic melatonin and binocular plasticity in Xenopus frogs.

The topographic binocular maps in the optic tectum of Xenopus frogs are notable both for their dramatic plasticity during development and for the high expression of melatonin receptors in the circuitry contributing to those binocular maps. The goal of this study was to determine whether melatonin contributes to the control of binocular tectal plasticity. During development, rotation of one eye leads to compensatory rewiring of ipsilateral maps. The effect of 3-4 months of chronic 20 or 200 nM melatonin on this rewiring was tested by electrophysiological mapping. No decrease in plasticity was observed. In adult Xenopus, rotation of one eye normally does not lead to rewiring of the ipsilateral projection, although adults can exhibit plasticity if they have been dark-reared or have been treated as adults with NMDA. We tested whether exposure to 20-200 nM melatonin during and after the normal critical period would similarly extend plasticity. Eye rotation in adults that had been treated with melatonin did not demonstrate retained plasticity. These results show that melatonin does not reduce the normally high plasticity characteristic of young Xenopus nor does it increase the normally low plasticity of adult Xenopus.

Effects of ayahuasca on binocular rivalry with dichoptic stimulus alternation.

RATIONALE: During binocular rivalry, two incompatible images are presented to each eye and these monocular stimuli compete for perceptual dominance, with one pattern temporarily suppressed from awareness. One variant of stimulus presentation in binocular rivalry experiments is dichoptic stimulus alternation (DSA), when stimuli are applied to the eyes in rapid reversals. There is preliminary report that in contrast with healthy controls, schizophrenic patients can maintain binocular rivalry even at very high DSA rates. OBJECTIVE: The study was undertaken to investigate whether binocular rivalry survives high rates of DSA induced by the South American hallucinogenic beverage ayahuasca. METHODS: Ten individuals who were participating in ayahuasca ceremonials were requested to volunteer for binocular rivalry tests (DSA=0, 3.75, 7.5, 15 and 30 Hz) without and after drinking the brew. RESULTS: Ingestion of ayahuasca increased mean dominance periods both in standard binocular rivalry conditions (no DSA) and tests with DSA. At higher DSA rates (15 and 30 Hz) the total length of dominance periods was longer on the brew. CONCLUSION: It is discussed that ayahuasca-induced survival of binocular rivalry at high DSA rates may be related to slow visual processing and increased mean dominance periods may result from hallucinogen-induced alteration of gamma oscillations in the visual pathways.