Multi-Contrast Magnetic Resonance Imaging of Visual White Matter Pathways in Patients With Glaucoma.

Purpose: Glaucoma is a disorder that involves visual field loss caused by retinal ganglion cell damage. Previous diffusion magnetic resonance imaging (dMRI) studies have demonstrated that retinal ganglion cell damage affects tissues in the optic tract (OT) and optic radiation (OR). However, because previous studies have used a simple diffusion tensor model to analyze dMRI data, the microstructural interpretation of white matter tissue changes remains uncertain. In this study, we used a multi-contrast MRI approach to further clarify the type of microstructural damage that occurs in patients with glaucoma. Methods: We collected dMRI data from 17 patients with glaucoma and 30 controls using 3-tesla (3T) MRI. Using the dMRI data, we estimated three types of tissue property metrics: intracellular volume fraction (ICVF), orientation dispersion index (ODI), and isotropic volume fraction (IsoV). Quantitative T1 (qT1) data, which may be relatively specific to myelin, were collected from all subjects. Results: In the OT, all four metrics showed significant differences between the glaucoma and control groups. In the OR, only the ICVF showed significant between-group differences. ICVF was significantly correlated with qT1 in the OR of the glaucoma group, although qT1 did not show any abnormality at the group level. Conclusions: Our results suggest that, at the group level, tissue changes in OR caused by glaucoma might be explained by axonal damage, which is reflected in the intracellular diffusion signals, rather than myelin damage. The significant correlation between ICVF and qT1 suggests that myelin damage might also occur in a smaller number of severe cases.

Is infantile esotropia subcortical in origin?

Essential infantile esotropia (EIE) is often attributed to a primary disturbance within the visual cortex based upon the findings of monocular horizontal optokinetic asymmetry and correlative horizontal motion detection asymmetry. However, these physiologic aberrations conform to what would be observed if the visual cortex secondarily reconfigured itself to the preexisting subcortical optokinetic motion template. This analysis examines the perspective that the measured cortical aberrations can be explained by prolonged subcortical neuroplasticity, leading to a secondary rewiring of cortical motion pathways. Evolutionary evidence indicates that EIE is generated by subcortical ocular motor centers that subserve nasalward optokinesis. These phylogenetically older subcortical visuo-vestibular pathways include the nucleus of the optic tract, accessory optic system, inferior olive, cerebellar flocculus, and vestibular nucleus. In normal humans, the subcortical visual system becomes inactivated after the first few months of infancy. Mutations or other perturbations that prolong subcortical neuroplasticity may create a persistent simultaneous nasalward optokinetic bias in both eyes to generate infantile esotropia.

The neuro-ophthalmological effects related to long-term occupational exposure to organic solvents in painters.

PURPOSE: Organic solvents are widely used in many industries, and usually, exposure occurs with mixtures of solvents. Organic solvent mixtures are known for their ability to affect tissues of high lipid content including the myelin sheath in the nervous system. The purpose of this work was to study the evidence that long-term (more than 10 years) exposure to organic solvent mixtures among painters can induce neuro-ophthalmological effects on the function of retinal ganglion cells and the optic tract. METHODS: Twenty workers with long-term occupational exposure to mixed organic solvents were compared to 40 control subjects. The controls were matched for age, gender, and demographic characteristics but were not occupationally exposed to any known organic solvents, using the following comparators: visual evoked potential (VEP), electroretinogram (ERG), color vision (CV), and contrast sensitivity (CS) testing. Environmental monitoring was done in the work environment with consideration to the American Conference of Governmental Industrial Hygienists Threshold Limit Values (ACGIH-TLVs). RESULTS: The exposed group had significantly longer latency and higher amplitude of VEP waves especially P100, higher Color Confusion Index (CCI), especially affecting the blue-yellow spectrum, and lower Log CS. There was no significant difference between exposed and nonexposed groups in full-field flash ERG response; however, in the pattern ERG, the exposed group had significantly longer latency of P50, which reflects changes in the retinal ganglion cell. CONCLUSION: Long-term occupational exposure to mixed organic solvents appeared to affect the optic tract functions in the form of increasing latency of VEP response, affecting the quality of CV and decreasing CS. It also affects the retinal ganglion cell layer with increased latency of P50 of the pattern ERG response.

Disruption of visual circuit formation and refinement in a mouse model of autism.

Aberrant connectivity is believed to contribute to the pathophysiology of autism spectrum disorder (ASD). Recent neuroimaging studies have increasingly identified such impairments in patients with ASD, including alterations in sensory systems. However, the cellular substrates and molecular underpinnings of disrupted connectivity remain poorly understood. Utilizing eye-specific segregation in the dorsal lateral geniculate nucleus (dLGN) as a model system, we investigated the formation and refinement of precise patterning of synaptic connections in the BTBR T + tf/J (BTBR) mouse model of ASD. We found that at the neonatal stage, the shape of the dLGN occupied by retinal afferents was altered in the BTBR group compared to C57BL/6J (B6) animals. Notably, the degree of overlap between the ipsi- and contralateral afferents was significantly greater in the BTBR mice. Moreover, these abnormalities continued into mature stage in the BTBR animals, suggesting persistent deficits rather than delayed maturation of axonal refinement. Together, these results indicate disrupted connectivity at the synaptic patterning level in the BTBR mice, suggesting that in general, altered neural circuitry may contribute to autistic behaviours seen in this animal model. In addition, these data are consistent with the notion that lower-level, primary processing mechanisms contribute to altered visual perception in ASD. Autism Res 2017, 10: 212-223. © 2016 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.

Changes in DTI parameters in the optic tracts of macaque monkeys with monocular blindness.

For humans and non-human primates, the alteration of the visual pathway's white matter fibers after visual deprivation has been partially explored. However, the changes in the optic tracts after the transection of the optic nerve have not been well characterized. In the current study, we attempted to investigate the differences in optic tracts between normal and unilateral optic nerve transected macaque monkeys using diffusion tensor imaging (DTI). Four healthy neonatal macaque monkeys were randomly divided into 2 groups, with 2 in each group. Group A served as a control group, and Group B underwent unilateral (right eye) optic nerve transection to produce monocular blindness. Sixteen months (Group B16M) and thirty-two months (Group B32M) after optic nerve transection, diffusion tensor imaging was performed on all monkeys. Then, we compared fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in bilateral optic tracts between Group A and Group B and between Group B16M and Group B32M. In both Group B16M and Group B32M, when compared with normal monkeys in Group A, FA was decreased and MD, AD and RD were increased in the bilateral optic tracts of monkeys with monocular blindness. Furthermore, compared with Group B16M, FA was reduced and MD, AD, RD were more obviously increased in the bilateral optic tracts of Group B32M, and noticeable differences in MD, AD and RD were found between the left and right optic tracts in group B32M. We believe that the results of this study would be helpful in investigation of the histological abnormalities of the integrity damage, axonal degeneration and demyelination of optic tracts in macaque monkeys with monocular blindness by DTI parameters in noninvasively and quantitatively.

Repeated Closed Head Injury in Mice Results in Sustained Motor and Memory Deficits and Chronic Cellular Changes.

Millions of mild traumatic brain injuries (TBIs) occur every year in the United States, with many people subject to multiple head injuries that can lead to chronic behavioral dysfunction. We previously reported that mild TBI induced using closed head injuries (CHI) repeated at 24h intervals produced more acute neuron death and glial reactivity than a single CHI, and increasing the length of time between injuries to 48h reduced the cumulative acute effects of repeated CHI. To determine whether repeated CHI is associated with behavioral dysfunction or persistent cellular damage, mice receiving either five CHI at 24h intervals, five CHI at 48h intervals, or five sham injuries at 24h intervals were evaluated across a 10 week period after injury. Animals with repeated CHI exhibited motor coordination and memory deficits, but not gait abnormalities when compared to sham animals. At 10wks post-injury, no notable neuron loss or glial reactivity was observed in the cortex, hippocampus, or corpus callosum. Argyrophilic axons were found in the pyramidal tract of some injured animals, but neither silver stain accumulation nor inflammatory responses in the injury groups were statistically different from the sham group in this region. However, argyrophilic axons, microgliosis and astrogliosis were significantly increased within the optic tract of injured animals. Repeated mild CHI also resulted in microgliosis and a loss of neurofilament protein 200 in the optic nerve. Lengthening the inter-injury interval from 24h to 48h did not effectively reduce these behavioral or cellular responses. These results suggest that repeated mild CHI results in persistent behavioral dysfunction and chronic pathological changes within the visual system, neither of which was significantly attenuated by lengthening the inter-injury interval from 24h to 48h.

Prevention of Hippocampal Neuronal Damage and Cognitive Function Deficits in Vascular Dementia by Dextromethorphan.

Dextromethorphan (DM) is a non-competitive antagonist of NMDA receptors and a widely used component of cough medicine. Recently, its indication has been extended experimentally to a wide range of disorders including inflammation-mediated central nervous system disorders such as Parkinson disease (PD) and multiple sclerosis (MS). In this study, we investigate whether DM treatment has protective effects on the hippocampal neuron damage induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]), an animal model of vascular dementia (VaD). Sprague-Dawley (SD) (10 weeks of age) rats were subjected to the 2VO, and DM was injected intraperitoneally once per day for 37 days. Neuron death, glial activation, and cognitive function were assessed at 37 days after 2VO (0.2 mg/kg, i.p., "DM-0.2" and 2 mg/kg, i.p., "DM-2"). DM-2 treatment provided protection against neuronal death and glial activation in the hippocampal CA1 subfield and reduced cognitive impairment induced by 2VO in rats. The study also demonstrates that activation of the Nrf2-HO-1 pathway and upregulation of superoxide dismutase (SOD) play important roles in these effects. These results suggest that DM is effective in treating VaD and protecting against oxidative stress, which is strongly implicated in the pathogenesis of VaD. Therefore, the present study suggests that DM treatment may represent a new and promising protective strategy for treating VaD.

Effects of environmental enrichment on blood vessels in the optic tract of malnourished rats: A morphological and morphometric analysis.

OBJECTIVES: This study aimed to compare the effects of environmental enrichment in nourished (on a diet containing 16% protein) and malnourished (on a diet containing 6% protein) rats during the critical period of brain development, specifically focusing on the optic nerve. METHODS: By means of morphologic and morphometric assessment of the optic nerve, we analyzed the changes caused by diet and stimulation (environmental enrichment) on postnatal day 35, a time point ideal for such morphological analysis since developmental processes are considered complete at this age. RESULTS: Malnourished animals presented low body and brain weights and high body-to-brain weight ratio compared to well-nourished rats. Furthermore, malnourished animals showed morphological changes in the optic nerve such as edema and vacuolization characterized by increased interstitial space. The malnourished-stimulated group presented lesions characteristic of early protein malnutrition but were milder than lesions exhibited by malnourished-non-stimulated group. The morphometric analysis revealed no difference in glial cell density between groups, but there was significantly higher blood vessel density in the stimulated rats, independent of their nutritional condition. DISCUSSION: Our data indicate that protein malnutrition imposed during the critical period of brain development alters the cytoarchitecture of the optic nerve. In addition, we affirm that a 1-hour exposure to an enriched environment everyday was sufficient for tissue preservation in rats maintained on a low-protein diet. This protective effect might be related to angiogenesis, as confirmed by the increased vascular density observed in morphometric analyses.

Axonal Terminals Exposed to Amyloid-ß May Not Lead to Pre-Synaptic Axonal Damage.

BACKGROUND: Synaptic deficits and neuronal loss are the major pathological manifestations of Alzheimer's disease. However, the link between the early synaptic loss and subsequent neurodegeneration is not entirely clear. Cell culture studies have shown that amyloid-ß (Aß) applied to axonal terminals can cause retrograde degeneration leading to the neuronal loss, but this process has not been demonstrated in live animals. OBJECTIVE: To test if Aß applied to retinal ganglion cell axonal terminals can induce axonal damage in the optic nerve and optic tract in mice. METHODS: Aß was injected into the terminal field of the optic tract, in the left lateral geniculate nucleus of wildtype C57BL/6 mice. Following the injection, monthly diffusion tensor imaging was performed. Three months after the injection, mice underwent visual evoked potential recordings, and then sacrificed for immunohistochemical examination. RESULTS: There were no significant changes seen with diffusion tensor imaging in the optic nerve and optic tract 3 months after the Aß injection. The myelin and axons in these regions remained intact according to immunohistochemistry. The only significant changes observed in this study were delayed transduction and reduced amplitude of visual evoked potentials, although both Aß and its reversed form caused similar changes. CONCLUSION: Despite the published in vitro studies, there was no significant axonal damage in the optic nerve and optic tract after injecting Aß onto retinal ganglion cell axonal terminals of wildtype C57BL/6 mice.