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Abnormal visual experience during a sensitive period of development disrupts neuronal circuitry in the visual cortex and results in abnormal spatial vision or amblyopia. Here we examined whether playing video games can induce plasticity in the visual system of adults with amblyopia. Specifically 20 adults with amblyopia (age 15-61 y; visual acuity: 20/25-20/480, with no manifest ocular disease or nystagmus) were recruited and allocated into three intervention groups: action videogame group (n = 10), non-action videogame group (n = 3), and crossover control group (n = 7). Our experiments show that playing video games (both action and non-action games) for a short period of time (40-80 h, 2 h/d) using the amblyopic eye results in a substantial improvement in a wide range of fundamental visual functions, from low-level to high-level, including visual acuity (33%), positional acuity (16%), spatial attention (37%), and stereopsis (54%). Using a cross-over experimental design (first 20 h: occlusion therapy, and the next 40 h: videogame therapy), we can conclude that the improvement cannot be explained simply by eye patching alone. We quantified the limits and the time course of visual plasticity induced by video-game experience. The recovery in visual acuity that we observed is at least 5-fold faster than would be expected from occlusion therapy in childhood amblyopia. We used positional noise and modelling to reveal the neural mechanisms underlying the visual improvements in terms of decreased spatial distortion (7%) and increased processing efficiency (33%). Our study had several limitations: small sample size, lack of randomization, and differences in numbers between groups. A large-scale randomized clinical study is needed to confirm the therapeutic value of video-game treatment in clinical situations. Nonetheless, taken as a pilot study, this work suggests that video-game play may provide important principles for treating amblyopia, and perhaps other cortical dysfunctions. ClinicalTrials.gov NCT01223716.

Background Bright light therapy (BLT) has been proved to have beneficial effects on Parkinson’s disease (PD), the mechanisms remained unclear. Improvements of visual pathways might be key to BLT. Objective The aim of this study is to validate whether BLT improves clinical symptoms in PD and explore the possible mechanisms of visual pathways evaluated by optical coherence tomography (OCT), pattern electroretinogram (PERG) and visual evoked potentials (VEP). Methods Twenty-three PD patients were enrolled in this crossover randomized placebo-controlled study. Participants received either one month of BLT or dim light therapy (DLT), separated by one-month wash-out period, followed by another intervention. Participants underwent clinical scales, and visual-related evaluations including OCT, PERG and VEP before and after each intervention. Mixed-effects regression models were used to determine the effect between BLT and DLT on improving the differentials of clinical scales (Δscales), OCT (Δretinal thickness), PERG (ΔPERG values) and VEP (ΔP100 latencies). Correlations between clinical symptoms and visual evaluations improvements were analyzed in PD patients receiving BLT. Results Excessive daytime sleepiness, anxiety, life quality and autonomic function were improved after BLT. Compared with DLT, bilateral ΔN95 latencies for PERG and ΔP100 latencies for VEP were improved after BLT. We did not observe the changes of four quadrants retinal nerve fiber layer (RNFL) thickness after BLT or DLT. Conclusions BLT is a valuable and safe non-pharmacological intervention for improving visual function in PD patients. Significance These findings extend neural mechanisms of BLT to visual pathways improvements.

The childhood condition of visual difficulties caused by brain damage, commonly termed cortical or cerebral visual impairment (CVI), is well established but has no internationally accepted definition. Clarification of its core features is required to advance research and clinical practice. This systematic review aimed to identify the definitions of childhood CVI in the original scientific literature to describe and critically appraise a consensual definition of the condition. MEDLINE, EMBASE, PsychINFO, CINAHL and AMED databases were searched in January 2017. Studies were included if they (1) were published original research, (2) contained a childhood CVI sample, (3) contained a definition of CVI and (4) described their CVI identification/diagnostic method. Thematic analysis identified concepts within definitions and narrative synthesis was conducted. Of 1150 articles, 51 met inclusion criteria. Definitions were subdivided according to detail (descriptive definition, description not reaching definition status and diagnostic/operationalising criteria). Three themes concerning visual deficits, eye health and brain integrity were identified (each containing subthemes) and analysed individually across definitions. The most common themes were ‘visual impairment’ (n=20), ‘retrochiasmatic pathway damage’(n=13) and ‘normal/near normal eye health’ (n=15). The most consensual definition identified here may not be the best quality for advancing our understanding of CVI. We argue for the alternative definition: CVI is a verifiable visual dysfunction which cannot be attributed to disorders of the anterior visual pathways or any potentially co-occurring ocular impairment. We propose reporting guidelines to permit comparison across studies and increase the evidence base for more reliable clinical assessment and diagnosis.

From molecular mechanisms to global brain networks, atypical fluctuations are the hallmark of neurodegeneration. Yet, traditional fMRI research on resting-state networks (RSNs) has favored static and average connectivity methods, which by overlooking the fluctuation dynamics triggered by neurodegeneration, have yielded inconsistent results. The present multicenter study introduces a data-driven machine learning pipeline based on dynamic connectivity fluctuation analysis (DCFA) on RS-fMRI data from 300 participants belonging to three groups: behavioral variant frontotemporal dementia (bvFTD) patients, Alzheimer's disease (AD) patients, and healthy controls. We considered non-linear oscillatory patterns across combined and individual resting-state networks (RSNs), namely: the salience network (SN), mostly affected in bvFTD; the default mode network (DMN), mostly affected in AD; the executive network (EN), partially compromised in both conditions; the motor network (MN); and the visual network (VN). These RSNs were entered as features for dementia classification using a recent robust machine learning approach (a Bayesian hyperparameter tuned Gradient Boosting Machines (GBM) algorithm), across four independent datasets with different MR scanners and recording parameters. The machine learning classification accuracy analysis revealed a systematic and unique tailored architecture of RSN disruption. The classification accuracy ranking showed that the most affected networks for bvFTD were the SN + EN network pair (mean accuracy = 86.43%, AUC = 0.91, sensitivity = 86.45%, specificity = 87.54%); for AD, the DMN + EN network pair (mean accuracy = 86.63%, AUC = 0.89, sensitivity = 88.37%, specificity = 84.62%); and for the bvFTD vs. AD classification, the DMN + SN network pair (mean accuracy = 82.67%, AUC = 0.86, sensitivity = 81.27%, specificity = 83.01%). Moreover, the DFCA classification systematically outperformed canonical connectivity approaches (including both static and linear dynamic connectivity). Our findings suggest that non-linear dynamical fluctuations surpass two traditional seed-based functional connectivity approaches and provide a pathophysiological characterization of global brain networks in neurodegenerative conditions (AD and bvFTD) across multicenter data.

In order to test the hypothesis that in primary open angle glaucoma (POAG), an important cause of irreversible blindness, a spreading of neurodegeneration occurs through the brain, we performed multimodal MRI and subsequent whole-brain explorative voxelwise analyses in 13 advanced POAG patients and 12 age-matched normal controls (NC). Altered integrity (decreased fractional anisotropy or increased diffusivities) of white matter (WM) tracts was found not only along the visual pathway of POAG but also in nonvisual WM tracts (superior longitudinal fascicle, anterior thalamic radiation, corticospinal tract, middle cerebellar peduncle). POAG patients also showed brain atrophy in both visual cortex and other distant grey matter (GM) regions (frontoparietal cortex, hippocampi and cerebellar cortex), decreased functional connectivity (FC) in visual, working memory and dorsal attention networks and increased FC in visual and executive networks. In POAG, abnormalities in structure and FC within and outside visual system correlated with visual field parameters in the poorer performing eyes, thus emphasizing their clinical relevance. Altogether, this represents evidence that a vision disorder such as POAG can be considered a widespread neurodegenerative condition.

Human behavior can be remarkably shaped by experience, such as the removal of sensory input. Many studies of conditions such as stroke, limb amputation, and vision loss have examined how removal of input changes brain function. However, an important question yet to be answered is: when input is lost, does the brain change its connectivity to preferentially use some remaining inputs over others? In individuals with healthy vision, the central portion of the retina is preferentially used for everyday visual tasks, due to its ability to discriminate fine details. When central vision is lost in conditions like macular degeneration, peripheral vision must be relied upon for those everyday tasks, with some portions receiving “preferential” usage over others. Using resting‐state fMRI collected during total darkness, we examined how deprivation and preferential usage influence the intrinsic functional connectivity of sensory cortex by studying individuals with selective vision loss due to late stages of macular degeneration. Specifically, we examined functional connectivity between category‐selective visual areas and the cortical representation of three areas of the retina: the lesioned area, a preferentially used region of the intact retina, and a non‐preferentially used region. We found that cortical regions representing spared portions of the peripheral retina, regardless of whether they are preferentially used, exhibit plasticity of intrinsic functional connectivity in macular degeneration. Cortical representations of spared peripheral retinal locations showed stronger connectivity to MT, a region involved in processing motion. These results suggest that the long‐term loss of central vision can produce widespread effects throughout spared representations in early visual cortex, regardless of whether those representations are preferentially used. These findings support the idea that connections to visual cortex maintain the capacity for change well after critical periods of visual development. In macular degeneration (MD) patients, a central retinal lesion can cause the loss of central vision and preferential usage of parts of the peripheral retina. We find that preferred and non‐preferred peripheral representations in early visual cortex grow stronger connectivity to middle temporal area in MD patients compared to controls.

Blast-induced traumatic brain injury (bTBI), frequently observed in modern warfare, often presents without overt clinical symptoms initially, yet can involve visual impairment. However, the underlying mechanisms and long-term outcomes of visual dysfunction following blast exposure (BE) remain poorly understood. This study aimed to investigate the potential delayed effects of BE on visual function. A bTBI mouse model was established using a biological shock tube. Neurological deficits were assessed via the modified neurological severity score, while visual function was evaluated at multiple time points using flash visual evoked potentials (F-VEP) and a light-dark shuttle box. Ultrastructural evidence of damage was obtained through transmission electron microscopy (TEM). Inflammatory and pyroptosis markers were localized and quantified via immunofluorescence staining and Western blotting. Neuronal damage was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining combined with neuron-specific nuclear protein (NeuN) immunofluorescence labeling. To assess therapeutic potential, MCC950 was administered to bTBI mice, and visual function was re-evaluated. The results demonstrated that visual dysfunction emerged at 24 hours post BE, followed by a transient recovery, and reappeared at 28 days post BE. Early demyelination of the optic nerve and later pyroptosis of neurons in the visual cortex were identified as key pathological features. MCC950 treatment effectively mitigated neuroinflammation and neuronal pyroptosis, thereby ameliorating late-phase visual dysfunction. These findings collectively suggest that BE leads to biphasic visual dysfunction, driven by distinct mechanisms at different stages. Early intervention targeting nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation may represent a promising therapeutic strategy to prevent late-phase visual impairment. Moreover, non-invasive F-VEP provides a sensitive and practical approach for assessing visual injury in bTBI.

Hallucinations constitute one of the most representative and disabling symptoms of schizophrenia. Several Magnetic Resonance Imaging (MRI) findings support the hypothesis that distinct patterns of connectivity, particularly within networks involving the hippocampal complex (HC), could be associated with different hallucinatory modalities. The aim of this study was to investigate HC connectivity as a function of the hallucinatory modality, that is, auditory or visual. Two carefully selected subgroups of schizophrenia patients with only auditory hallucinations (AH) or with audio-visual hallucinations (A+VH) were compared using the following three complementary multimodal MRI methods: resting state functional MRI, diffusion MRI and structural MRI were used to analyze seed-based Functional Connectivity (sb-FC), Tract-Based Spatial Statistics (TBSS) and shape analysis, respectively. Sb-FC was significantly higher between the HC, the medial prefrontal cortex (mPFC) and the caudate nuclei in A+VH patients compared with the AH group. Conversely, AH patients exhibited a higher sb-FC between the HC and the thalamus in comparison with the A+VH group. In the A+VH group, TBSS showed specific higher white matter connectivity in the pathways connecting the HC with visual areas, such as the forceps major and the inferior-fronto-occipital fasciculus than in the AH group. Finally, shape analysis showed localized hippocampal hypertrophy in the A+VH group. Functional results support the fronto-limbic dysconnectivity hypothesis of schizophrenia, while specific structural findings indicate that plastic changes are associated with hallucinations. Together, these results suggest that there are distinct connectivity patterns in patients with schizophrenia that depend on the sensory-modality, with specific involvement of the HC in visual hallucinations.

Altered gamma activity is associated with epilepsy. Gamma entrainment using sensory stimuli (GENUS), a non-invasive, exogenous stimulation by rhythmic 40 Hz light flicker, strengthens gamma activity in the primary visual cortex (V1) and suppresses spike generation. Here, we assessed the effect of GENUS on epileptogenesis in male mice with status epilepticus induced by pilocarpine. We found that GENUS immediately increased gamma activity and reduced epileptiform spikes in epileptic mice. After six weeks of GENUS treatment in epileptic mice, significant reductions were observed in neuronal loss and gliosis, brain hyperexcitability was ameliorated, and epilepsy-related behavioral performance was improved. We determined that the increased 40 Hz oscillations and reduced seizure susceptibility induced by GENUS were dependent on the visual circuit associated with ON-OFF direction-selective retinal ganglion cells, glutamatergic neurons in the shell of the dorsal lateral geniculate nucleus, and parvalbumin-expressing fast-spiking interneurons in the superficial 2/3 layer of V1. Whether and how gamma entrainment using sensory stimuli (GENUS) has a role in antiepileptogenesis is not fully understood. Here authors show that GENUS reduces seizure susceptibility in male mice. These effects are mediated via specific visual neural pathway.

Background Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients. Methods Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials. Results Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm 3 ) compared with healthy controls (pRNFL = 99 ± 6 μm, p  < 0.001; GCIP = 1.97 ± 0.11 mm 3 , p  < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm 3 ; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p  = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients ( p  < 0.001), but not in AQP4-IgG-positive patients. Conclusions Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.