Contributions of Brain Microstructures and Metabolism to Visual Field Loss Patterns in Glaucoma Using Archetypal and Information Gain Analyses.

Purpose: To investigate the contributions of the microstructural and metabolic brain environment to glaucoma and their association with visual field (VF) loss patterns by using advanced diffusion magnetic resonance imaging (dMRI), proton magnetic resonance spectroscopy (MRS), and clinical ophthalmic measures. Methods: Sixty-nine glaucoma and healthy subjects underwent dMRI and/or MRS at 3 Tesla. Ophthalmic data were collected from VF perimetry and optical coherence tomography. dMRI parameters of microstructural integrity in the optic radiation and MRS-derived neurochemical levels in the visual cortex were compared among early glaucoma, advanced glaucoma, and healthy controls. Multivariate regression was used to correlate neuroimaging metrics with 16 archetypal VF loss patterns. We also ranked neuroimaging, ophthalmic, and demographic attributes in terms of their information gain to determine their importance to glaucoma. Results: In dMRI, decreasing fractional anisotropy, radial kurtosis, and tortuosity and increasing radial diffusivity correlated with greater overall VF loss bilaterally. Regionally, decreasing intra-axonal space and extra-axonal space diffusivities correlated with greater VF loss in the superior-altitudinal area of the right eye and the inferior-altitudinal area of the left eye. In MRS, both early and advanced glaucoma patients had lower gamma-aminobutyric acid (GABA), glutamate, and choline levels than healthy controls. GABA appeared to associate more with superonasal VF loss, and glutamate and choline more with inferior VF loss. Choline ranked third for importance to early glaucoma, whereas radial kurtosis and GABA ranked fourth and fifth for advanced glaucoma. Conclusions: Our findings highlight the importance of non-invasive neuroimaging biomarkers and analytical modeling for unveiling glaucomatous neurodegeneration and how they reflect complementary VF loss patterns.

GABA decrease is associated with degraded neural specificity in the visual cortex of glaucoma patients.

Glaucoma is an age-related neurodegenerative disease of the visual system, affecting both the eye and the brain. Yet its underlying metabolic mechanisms and neurobehavioral relevance remain largely unclear. Here, using proton magnetic resonance spectroscopy and functional magnetic resonance imaging, we investigated the GABAergic and glutamatergic systems in the visual cortex of glaucoma patients, as well as neural specificity, which is shaped by GABA and glutamate signals and underlies efficient sensory and cognitive functions. Our study shows that among the older adults, both GABA and glutamate levels decrease with increasing glaucoma severity regardless of age. Further, our study shows that the reduction of GABA but not glutamate predicts the neural specificity. This association is independent of the impairments on the retina structure, age, and the gray matter volume of the visual cortex. Our results suggest that glaucoma-specific decline of GABA undermines neural specificity in the visual cortex and that targeting GABA could improve the neural specificity in glaucoma.

Diverging patterns of plasticity in the nucleus basalis of Meynert in early- and late-onset blindness.

Plasticity in the brain is impacted by an individual's age at the onset of the blindness. However, what drives the varying degrees of plasticity remains largely unclear. One possible explanation attributes the mechanisms for the differing levels of plasticity to the cholinergic signals originating in the nucleus basalis of Meynert. This explanation is based on the fact that the nucleus basalis of Meynert can modulate cortical processes such as plasticity and sensory encoding through its widespread cholinergic projections. Nevertheless, there is no direct evidence indicating that the nucleus basalis of Meynert undergoes plastic changes following blindness. Therefore, using multiparametric magnetic resonance imaging, we examined if the structural and functional properties of the nucleus basalis of Meynert differ between early blind, late blind and sighted individuals. We observed that early and late blind individuals had a preserved volumetric size and cerebrovascular reactivity in the nucleus basalis of Meynert. However, we observed a reduction in the directionality of water diffusion in both early and late blind individuals compared to sighted individuals. Notably, the nucleus basalis of Meynert presented diverging patterns of functional connectivity between early and late blind individuals. This functional connectivity was enhanced at both global and local (visual, language and default-mode networks) levels in the early blind individuals, but there were little-to-no changes in the late blind individuals when compared to sighted controls. Furthermore, the age at onset of blindness predicted both global and local functional connectivity. These results suggest that upon reduced directionality of water diffusion in the nucleus basalis of Meynert, cholinergic influence may be stronger for the early blind compared to the late blind individuals. Our findings are important to unravelling why early blind individuals present stronger and more widespread cross-modal plasticity compared to late blind individuals.

Visual Plasticity in Adulthood: Perspectives from Hebbian and Homeostatic Plasticity.

The visual system retains profound plastic potential in adulthood. In the current review, we summarize the evidence of preserved plasticity in the adult visual system during visual perceptual learning as well as both monocular and binocular visual deprivation. In each condition, we discuss how such evidence reflects two major cellular mechanisms of plasticity: Hebbian and homeostatic processes. We focus on how these two mechanisms work together to shape plasticity in the visual system. In addition, we discuss how these two mechanisms could be further revealed in future studies investigating cross-modal plasticity in the visual system.

Awake suppression after brief exposure to a familiar stimulus.

Newly learned information undergoes a process of awake reactivation shortly after the learning offset and we recently demonstrated that this effect can be observed as early as area V1. However, reactivating all experiences can be wasteful and unnecessary, especially for familiar stimuli. Therefore, here we tested whether awake reactivation occurs differentially for new and familiar stimuli. Subjects completed a brief visual task on a stimulus that was either novel or highly familiar due to extensive prior training on it. Replicating our previous results, we found that awake reactivation occurred in V1 for the novel stimulus. On the other hand, brief exposure to the familiar stimulus led to 'awake suppression' such that neural activity patterns immediately after exposure to the familiar stimulus diverged from the patterns associated with that stimulus. Further, awake reactivation was observed selectively in V1, whereas awake suppression had similar strength across areas V1-V3. These results are consistent with the presence of a competition between local awake reactivation and top-down awake suppression, with suppression becoming dominant for familiar stimuli.

Role of Structural, Metabolic, and Functional MRI in Monitoring Visual System Impairment and Recovery.

The visual system, consisting of the eyes and the visual pathways of the brain, receives and interprets light from the environment so that we can perceive the world around us. A wide variety of disorders can affect human vision, ranging from ocular to neurologic to systemic in nature. While other noninvasive imaging techniques such as optical coherence tomography and ultrasound can image particular sections of the visual system, magnetic resonance imaging (MRI) offers high resolution without depth limitations. MRI also gives superior soft-tissue contrast throughout the entire pathway compared to computed tomography. By leveraging different imaging sequences, MRI is uniquely capable of unveiling the intricate processes of ocular anatomy, tissue physiology, and neurological function in the human visual system from the microscopic to macroscopic levels. In this review we discuss how structural, metabolic, and functional MRI can be used in the clinical assessment of normal and pathologic states in the anatomic structures of the visual system, including the eyes, optic nerves, optic chiasm, optic tracts, visual brain nuclei, optic radiations, and visual cortical areas. We detail a selection of recent clinical applications of MRI at each position along the visual pathways, including the evaluation of pathology, plasticity, and the potential for restoration, as well as its limitations and key areas of ongoing exploration. Our discussion of the current and future developments in MR ocular and neuroimaging highlights its potential impact on our ability to understand visual function in new detail and to improve our protection and treatment of anatomic structures that are integral to this fundamental sensory system. LEVEL OF EVIDENCE 3: TECHNICAL EFFICACY STAGE 3: .

Diffusion Kurtosis Imaging Reveals Optic Tract Damage That Correlates with Clinical Severity in Glaucoma.

Glaucoma is a neurodegenerative disease of the visual system and is the leading cause of irreversible blindness worldwide. To date, its pathophysiological mechanisms remain unclear. This study evaluated the feasibility of advanced diffusion magnetic resonance imaging techniques for examining the microstructural environment of the visual pathway in glaucoma. While conventional diffusion tensor imaging (DTI) showed lower fractional anisotropy and higher directional diffusivities in the optic tracts of glaucoma patients than healthy controls, diffusion kurtosis imaging (DKI) and the extended white matter tract integrity (WMTI) model indicated lower radial kurtosis, higher axial and radial diffusivities in the extra-axonal space, lower axonal water fraction, and lower tortuosity in the same regions in glaucoma patients. These findings suggest glial involvements apart from compromised axonal integrity in glaucoma. In addition, DKI and WMTI but not DTI parameters significantly correlated with clinical ophthalmic measures via optical coherence tomography and visual field perimetry testing. Taken together, DKI and WMTI provided sensitive and comprehensive imaging biomarkers for quantifying glaucomatous damage in the white matter tract across clinical severity complementary to DTI.

The Confidence Database.

Understanding how people rate their confidence is critical for the characterization of a wide range of perceptual, memory, motor and cognitive processes. To enable the continued exploration of these processes, we created a large database of confidence studies spanning a broad set of paradigms, participant populations and fields of study. The data from each study are structured in a common, easy-to-use format that can be easily imported and analysed using multiple software packages. Each dataset is accompanied by an explanation regarding the nature of the collected data. At the time of publication, the Confidence Database (which is available at https://osf.io/s46pr/) contained 145 datasets with data from more than 8,700 participants and almost 4 million trials. The database will remain open for new submissions indefinitely and is expected to continue to grow. Here we show the usefulness of this large collection of datasets in four different analyses that provide precise estimations of several foundational confidence-related effects.

Widespread brain reorganization perturbs visuomotor coordination in early glaucoma.

Glaucoma is the world's leading cause of irreversible blindness, and falls are a major public health concern in glaucoma patients. Although recent evidence suggests the involvements of the brain toward advanced glaucoma stages, the early brain changes and their clinical and behavioral consequences remain poorly described. This study aims to determine how glaucoma may impair the brain structurally and functionally within and beyond the visual pathway in the early stages, and whether these changes can explain visuomotor impairments in glaucoma. Using multi-parametric magnetic resonance imaging, glaucoma patients presented compromised white matter integrity along the central visual pathway and around the supramarginal gyrus, as well as reduced functional connectivity between the supramarginal gyrus and the visual occipital and superior sensorimotor areas when compared to healthy controls. Furthermore, decreased functional connectivity between the supramarginal gyrus and the visual brain network may negatively impact postural control measured with dynamic posturography in glaucoma patients. Taken together, this study demonstrates that widespread structural and functional brain reorganization is taking place in areas associated with visuomotor coordination in early glaucoma. These results implicate an important central mechanism by which glaucoma patients may be susceptible to visual impairments and increased risk of falls.

Post-training TMS abolishes performance improvement and releases future learning from interference.

The period immediately after the offset of visual training is thought to be critical for memory consolidation. Nevertheless, we still lack direct evidence for the causal role of this period to perceptual learning of either previously or subsequently trained material. To address these issues, we had human subjects complete two consecutive trainings with different tasks (detecting different Gabor orientations). We applied continuous theta burst stimulation (cTBS) to either the visual cortex or a control site (vertex) immediately after the offset of the first training. In the vertex cTBS condition, subjects showed improvement on the first task but not on the second task, suggesting the presence of anterograde interference. Critically, cTBS to the visual cortex abolished the performance improvement on the first task and released the second training from the anterograde interference. These results provide causal evidence for a role of the immediate post-training period in the consolidation of perceptual learning.

Sensory noise increases metacognitive efficiency.

Metacognitive efficiency quantifies people's ability to introspect into their own decision making relative to their ability to perform the primary task. Despite years of research, it is still unclear how visual metacognitive efficiency can be manipulated. Here, we show that a hierarchical model of confidence generation makes a counterintuitive prediction: Higher sensory noise should increase metacognitive efficiency. The reason for this is that hierarchical models assume that although the primary decision is corrupted only by sensory noise, the confidence judgment is corrupted by both sensory and metacognitive noise. Therefore, increasing sensory noise has a smaller negative influence on the confidence judgment than on the perceptual decision, resulting in increased metacognitive efficiency. To test this prediction, we used a perceptual learning paradigm to decrease sensory noise. In Experiment 1, 7 days of training led to a significant decrease in sensory noise and a corresponding decrease in metacognitive efficiency. Experiment 2 showed the same effect in a brief 97-trial learning for each of 2 different tasks. Finally, in Experiment 3, we combined increasingly dissimilar stimulus contrasts to create conditions with higher sensory noise and observed a corresponding increase in metacognitive efficiency. Our findings demonstrate the existence of a robust positive relationship between across-trial sensory noise and metacognitive efficiency. These results could not be captured by a standard model in which decision and confidence judgments are made based on the same underlying information. Thus, our study provides direct evidence for the existence of metacognitive noise that corrupts confidence but not the perceptual decision. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Functional MRI of Sensory Substitution in the Blind.

Visual cortex functionality in the blind has been shown to shift away from sensory networks toward task-positive networks that are involved in top-down modulation. However, how such modulation is shaped by experience and reflected behaviorally remains unclear. This study evaluates the visual cortex activity and functional connectivity among congenitally blind, acquired blind, and sighted subjects using blood-oxygenation-level-dependent functional MRI during sensory substitution tasks and at rest. We found that primary visual cortex activity due to active interpretation not only depends on the blindness duration, but also negatively associates with behavioral reaction time. In addition, alterations in visual and task-positive functional connectivity progress over the duration of blindness. In summary, this work suggests that functional plasticity in the primary visual cortex can be reshaped in the blind over time, even in the adult stage. Furthermore, the degree of top-down activity in the primary visual cortex may reflect the speed of performance during sensory substitution.

Feature-Specific Awake Reactivation in Human V1 after Visual Training.

Brain activity patterns exhibited during task performance have been shown to spontaneously reemerge in the following restful awake state. Such "awake reactivation" has been observed across higher-order cortex for complex images or associations. However, it is still unclear whether the reactivation extends to primary sensory areas that encode simple stimulus features. To address this question, we trained human subjects from both sexes on a particular visual feature (Gabor orientation) and tested whether this feature will be reactivated immediately after training. We found robust reactivation in human V1 that lasted for at least 8 min after training offset. This effect was not present in higher retinotopic areas, such as V2, V3, V3A, or V4v. Further analyses suggested that the amount of awake reactivation was related to the amount of performance improvement on the visual task. These results demonstrate that awake reactivation extends beyond higher-order areas and also occurs in early sensory cortex.SIGNIFICANCE STATEMENT How do we acquire new memories and skills? New information is known to be consolidated during offline periods of rest. Recent studies suggest that a critical process during this period of consolidation is the spontaneous reactivation of previously experienced patterns of neural activity. However, research in humans has mostly examined such reactivation processes in higher-order cortex. Here we show that awake reactivation occurs even in the primary visual cortex V1 and that this reactivation is related to the amount of behavioral learning. These results pinpoint awake reactivation as a process that likely occurs across the entire human brain and could play an integral role in memory consolidation.

Stimulus expectation alters decision criterion but not sensory signal in perceptual decision making.

Humans are more likely to report perceiving an expected than an unexpected stimulus. Influential theories have proposed that this bias arises from expectation altering the sensory signal. However, the effects of expectation can also be due to decisional criterion shifts independent of any sensory changes. In order to adjudicate between these two possibilities, we compared the behavioral effects of pre-stimulus cues (pre cues; can influence both sensory signal and decision processes) and post-stimulus cues (post cues; can only influence decision processes). Subjects judged the average orientation of a series of Gabor patches. Surprisingly, we found that post cues had a larger effect on response bias (criterion c) than pre cues. Further, pre and post cues did not differ in their effects on stimulus sensitivity (d') or the pattern of temporal or feature processing. Indeed, reverse correlation analyses showed no difference in the temporal or feature-based use of information between pre and post cues. Overall, post cues produced all of the behavioral modulations observed as a result of pre cues. These findings show that pre and post cues affect the decision through the same mechanisms and suggest that stimulus expectation alters the decision criterion but not the sensory signal itself.

Overlearning hyperstabilizes a skill by rapidly making neurochemical processing inhibitory-dominant.

Overlearning refers to the continued training of a skill after performance improvement has plateaued. Whether overlearning is beneficial is a question in our daily lives that has never been clearly answered. Here we report a new important role: overlearning in humans abruptly changes neurochemical processing, to hyperstabilize and protect trained perceptual learning from subsequent new learning. Usually, learning immediately after training is so unstable that it can be disrupted by subsequent new learning until after passive stabilization occurs hours later. However, overlearning so rapidly and strongly stabilizes the learning state that it not only becomes resilient against, but also disrupts, subsequent new learning. Such hyperstabilization is associated with an abrupt shift from glutamate-dominant excitatory to GABA-dominant inhibitory processing in early visual areas. Hyperstabilization contrasts with passive and slower stabilization, which is associated with a mere reduction of excitatory dominance to baseline levels. Using hyperstabilization may lead to efficient learning paradigms.

Night Watch in One Brain Hemisphere during Sleep Associated with the First-Night Effect in Humans.

We often experience troubled sleep in a novel environment [1]. This is called the first-night effect (FNE) in human sleep research and has been regarded as a typical sleep disturbance [2-4]. Here, we show that the FNE is a manifestation of one hemisphere being more vigilant than the other as a night watch to monitor unfamiliar surroundings during sleep [5, 6]. Using advanced neuroimaging techniques [7, 8] as well as polysomnography, we found that the temporary sleep disturbance in the first sleep experimental session involves regional interhemispheric asymmetry of sleep depth [9]. The interhemispheric asymmetry of sleep depth associated with the FNE was found in the default-mode network (DMN) involved with spontaneous internal thoughts during wakeful rest [10, 11]. The degree of asymmetry was significantly correlated with the sleep-onset latency, which reflects the degree of difficulty of falling asleep and is a critical measure for the FNE. Furthermore, the hemisphere with reduced sleep depth showed enhanced evoked brain response to deviant external stimuli. Deviant external stimuli detected by the less-sleeping hemisphere caused more arousals and faster behavioral responses than those detected by the other hemisphere. None of these asymmetries were evident during subsequent sleep sessions. These lines of evidence are in accord with the hypothesis that troubled sleep in an unfamiliar environment is an act for survival over an unfamiliar and potentially dangerous environment by keeping one hemisphere partially more vigilant than the other hemisphere as a night watch, which wakes the sleeper up when unfamiliar external signals are detected.

Location specific sleep spindle activity in the early visual areas and perceptual learning.

Visual perceptual learning (VPL) is consolidated during sleep. However, the underlying neuronal mechanisms of consolidation are not yet fully understood. It has been suggested that the spontaneous brain oscillations that characterize sleep stages are indicative of the consolidation of learning and memory. We investigated whether sleep spindles and/or slow-waves are associated with consolidation of VPL during non-rapid eye movement (NREM) sleep during the first sleep cycle, using magnetoencephalography (MEG), magnetic resonance imaging (MRI), and polysomnography (PSG). We hypothesized that after training, early visual areas will show an increase in slow sigma, fast sigma and/or delta activity, corresponding to slow/fast sleep spindles and slow-waves, respectively. We found that during sleep stage 2, but not during slow-wave sleep, the slow sigma power within the trained region of early visual areas was larger after training compared to baseline, and that the increase was larger in the trained region than in the untrained region. However, neither fast sigma nor delta band power increased significantly after training in either sleep stage. Importantly, performance gains for the trained task were correlated with the difference of power increases in slow sigma activity between the trained and untrained regions. This finding suggests that slow sigma activity plays a critical role in the consolidation of VPL, at least in sleep stage 2 during the first sleep cycle.

The first-night effect suppresses the strength of slow-wave activity originating in the visual areas during sleep.

Our visual system is plastic and adaptive in response to the stimuli and environments we experience. Although visual adaptation and plasticity have been extensively studied while participants are awake, little is known about what happens while they are asleep. It has been documented that sleep structure as measured by sleep stages using polysomnography is altered specifically in the first sleep session due to exposure to a new sleep environment, known as the first-night effect (FNE). However, the impact of the FNE on spontaneous oscillations in the visual system is poorly understood. How does the FNE affect the visual system during sleep? To address this question, the present study examined whether the FNE modifies the strength of slow-wave activity (SWA, 1-4Hz)-the dominant spontaneous brain oscillation in slow-wave sleep-in the visual areas. We measured the strength of SWA originating in the visual areas during the first and the second sleep sessions. Magnetoencephalography, polysomnography, and magnetic resonance imaging were used to localize the source of SWA to the visual areas. The visual areas were objectively defined using retinotopic mapping and an automated anatomical parcellation technique. The results showed that the strength of SWA was reduced in the first sleep session in comparison to the second sleep session, especially during slow-wave sleep, in the ventral part of the visual areas. These results suggest that environmental novelty may affect the visual system through suppression of SWA. The impact of the FNE may not be negligible in vision research.