Reaching movements performed without vision of the moving limb are continuously monitored, during their execution, by feedback loops (designated nonvisual). In this study, we investigated the functional anatomy of these nonvisual loops using positron emission tomography (PET). Seven subjects had to "look at" (eye) or "look and point to" (eye-arm) visual targets whose location either remained stationary or changed undetectably during the ocular saccade (when vision is suppressed). Slightly changing the target location during gaze shift causes an increase in the amount of correction to be generated. Functional anatomy of nonvisual feedback loops was identified by comparing the reaching condition involving large corrections (jump) with the reaching condition involving small corrections (stationary), after subtracting the activations associated with saccadic movements and hand movement planning [(eye-arm-jumping minus eye-jumping) minus (eye-arm-stationary minus eye-stationary)]. Behavioral data confirmed that the subjects were both accurate at reaching to the stationary targets and able to update their movement smoothly and early in response to the target jump. PET difference images showed that these corrections were mediated by a restricted network involving the left posterior parietal cortex, the right anterior intermediate cerebellum, and the left primary motor cortex. These results are consistent with our knowledge of the functional properties of these areas and more generally with models emphasizing parietal-cerebellar circuits for processing a dynamic motor error signal.
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Vedakumar Tatavarty;
Alejandro Torrado Pacheco;
Chelsea Groves Kuhnle;
Heather Lin;
Priya Koundinya;
Nathaniel J. Miska;
Keith B. Hengen;
Florence F. Wagner;
Stephen D. Van Hooser;
Gina G. Turrigiano
Mutations in Shank3 are strongly associated with autism spectrum disorders and neural circuit changes in several brain areas, but the cellular mechanisms that underlie these defects are not understood. Homeostatic forms of plasticity allow central circuits to maintain stable function during experience-dependent development, leading us to ask whether loss of Shank3 might impair homeostatic plasticity and circuit-level compensation to perturbations. We found that Shank3 loss in vitro abolished both synaptic scaling and intrinsic homeostatic plasticity, deficits that could be rescued by treatment with lithium. Further, Shank3 knockout severely compromised the in vivo ability of visual cortical circuits to recover from perturbations to sensory drive. Finally, lithium treatment ameliorated a repetitive self-grooming phenotype in Shank3 knockout mice. These findings demonstrate that Shank3 loss severely impairs the ability of central circuits to harness homeostatic mechanisms to compensate for perturbations in drive, which in turn may render them more vulnerable to such perturbations.
Diseases that affect the eye, including photoreceptor degeneration, diabetic retinopathy, and glaucoma, affect 11.8 million people in the US, resulting in vision loss and blindness. Loss of sight affects patient quality of life and puts an economic burden both on individuals and the greater healthcare system. Despite the urgent need for treatments, few effective options currently exist in the clinic. Here, we review research on promising neuroprotective strategies that promote neuronal survival with the potential to protect against vision loss and retinal cell death. Due to the large number of neuroprotective strategies, we restricted our review to approaches that we had direct experience with in the laboratory. We focus on drugs that target survival pathways, including bile acids like UDCA and TUDCA, steroid hormones like progesterone, therapies that target retinal dopamine, and neurotrophic factors. In addition, we review rehabilitative methods that increase endogenous repair mechanisms, including exercise and electrical stimulation therapies. For each approach, we provide background on the neuroprotective strategy, including history of use in other diseases; describe potential mechanisms of action; review the body of research performed in the retina thus far, both in animals and in humans; and discuss considerations when translating each treatment to the clinic and to the retina, including which therapies show the most promise for each retinal disease. Despite the high incidence of retinal diseases and the complexity of mechanisms involved, several promising neuroprotective treatments provide hope to prevent blindness. We discuss attractive candidates here with the goal of furthering retinal research in critical areas to rapidly translate neuroprotective strategies into the clinic.
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Minh-Thanh T. Nguyen;
Shruti Vemaraju;
Gowri Nayak;
Yoshinobu Odaka;
Ethan D. Buhr;
Nuria Alonzo;
Uyen Tran;
Mathew Batie;
Brian A. Upton;
Martin Darvas;
Zbynek Kozmik;
Sujata Rao;
Rashmi S. Hegde;
P Michael Iuvone;
Russell N. Van Gelder;
Richard A. Lang
During mouse postnatal eye development, the embryonic hyaloid vascular network regresses from the vitreous as an adaption for high-acuity vision. This process occurs with precisely controlled timing. Here, we show that opsin 5 (OPN5; also known as neuropsin)-dependent retinal light responses regulate vascular development in the postnatal eye. In Opn5-null mice, hyaloid vessels regress precociously. We demonstrate that 380-nm light stimulation via OPN5 and VGAT (the vesicular GABA/glycine transporter) in retinal ganglion cells enhances the activity of inner retinal DAT (also known as SLC6A3; a dopamine reuptake transporter) and thus suppresses vitreal dopamine. In turn, dopamine acts directly on hyaloid vascular endothelial cells to suppress the activity of vascular endothelial growth factor receptor 2 (VEGFR2) and promote hyaloid vessel regression. With OPN5 loss of function, the vitreous dopamine level is elevated and results in premature hyaloid regression. These investigations identify violet light as a developmental timing cue that, via an OPN5–dopamine pathway, regulates optic axis clearance in preparation for visual function.
Measurement of intracranial pressure (ICP) is critical for the evaluation and management of many neurological and neurosurgical conditions. The invasiveness of ICP measurement limits the frequency with which ICP can be evaluated, hampering the clinical care of patients with ICP disorders. Thus, there has been substantial interest in developing noninvasive methods for the assessment of ICP. Numerous approaches have been applied to the problem, although none seems to represent a complete solution. The goal of this review is to familiarize the reader with the currently available methods to noninvasively evaluate ICP.
Background: Several studies have suggested racial differences in the prevalence of optic nerve head drusen (ONHD). We aimed to determine the percentage of patients with ONHD who are black, and to describe the clinical, ophthalmoscopic, and perimetry findings in these patients.
Methods: We conducted a retrospective chart review of all patients with ONHD seen at our institution between 1989 and 2010. Only black patients with ONHD confirmed on either funduscopy or B-scan ultrasonography were included. Demographic and clinical findings in these patients were recorded and analyzed.
Results: Of 196 patients with confirmed ONHD, 10 (5.1%) were black (7 women; ages 8–61 years). Six of the 10 patients had bilateral ONHD. The ONHD were buried in 11 of 16 eyes with ONHD, and exposed in 5 of 16 eyes. Fifteen of 16 eyes with ONHD had small cupless optic nerve heads. Visual fields were normal in 4 of 16 eyes with ONHD. In the other eyes, visual field defects included an enlarged blind spot (5 eyes), constricted field (5 eyes), nasal defect (2 eyes), central defect (1 eye), and generalized depression (1 eye). Visual field defects were present in 4 of 5 eyes (80%) with exposed ONHD and 8 of 11 eyes (72.7%) with buried ONHD. None of the patients were related and none of their examined family members had exposed ONHD on funduscopic examination.
Conclusion: ONHD are rare in blacks, possibly due to the presence of a larger cup-to-disc ratio or a lack of predisposing genetic factors. Visual field defects are common in black patients with both exposed and buried ONHD.
Objective: Non-mydriatic fundus photography by non-ophthalmic trained personnel has recently been shown to be a potential alternative to direct ophthalmoscopy in the emergency department (ED). We evaluated the reliability of a novel quality rating scale and applied this scale to non-mydriatic fundus photographs taken during routine ED patient encounters to determine factors associated with diminished photograph quality.
Design: Prospective, cross-sectional
Participants: 350 patients enrolled in the Fundus photography vs. Ophthalmoscopy Trials Outcomes in the Emergency Department (FOTO-ED) study were photographed by nurse practitioners after <30 minutes of training followed by supervision.
Methods: Photographs of both eyes were graded for quality on two occasions by two neuro-ophthalmologists. Four regions were independently evaluated for quality: optic disc, macula, superior and inferior vascular arcades. Quality as a function of the number of photographs taken was evaluated by Kaplan-Meier analysis. Mixed effects ordinal logistic regression was used to evaluate for predictors of image quality while accounting for the repeated measures design.
Main Outcome Measure: Overall photographic quality (1–5 scale, 5 best).
Results: We evaluated 1734 photographs. Inter- and intra-observer agreements between neuro-ophthalmologists were very good (weighted kappa:0.84–0.87). Quality of the optic disc area was better than those of other retinal areas (p<0.002). Kaplan-Meier analysis showed that if a high-quality photograph of an eye was not obtained by the third attempt it was unlikely that one would be obtained at all. A 10 second increase in the inter-photograph interval before a total of forty seconds increased the odds of a one unit higher quality rating by 1.81 times (95%CI: 1.68–1.98), and a ten year increase in age decreased the odds by 0.76 times (95%CI: 0.69–0.85). Black patients had 0.42 times (95%CI: 0.28–0.63) the odds of a one unit higher quality rating compared to whites.
Conclusions: Our 5-point scale is a reliable measure of non-mydriatic photograph quality. The region of interest, interphotograph interval, age, and race are significant predictors of image quality for non-mydriatic photographs taken by nurse practitioners in the ED. Addressing these factors may have a direct impact on the successful implementation of non-mydriatic fundus photography into the ED.
Previous studies have reported inconsistent results when comparing spatial imagery performance in the blind and the sighted, with some, but not all, studies demonstrating deficits in the blind. Here, we investigated the effect of visual status and individual preferences (“cognitive style”) on performance of a spatial imagery task. Participants with blindness resulting in the loss of form vision at or after age 6, and age- and gender-matched sighted participants, performed a spatial imagery task requiring memorization of a 4 × 4 lettered matrix and subsequent mental construction of shapes within the matrix from four-letter auditory cues. They also completed the Santa Barbara Sense of Direction Scale (SBSoDS) and a self-evaluation of cognitive style. The sighted participants also completed the Object-Spatial Imagery and Verbal Questionnaire (OSIVQ). Visual status affected performance on the spatial imagery task: the blind performed significantly worse than the sighted, independently of the age at which form vision was completely lost. Visual status did not affect the distribution of preferences based on self-reported cognitive style. Across all participants, self-reported verbalizer scores were significantly negatively correlated with accuracy on the spatial imagery task. There was a positive correlation between the SBSoDS score and accuracy on the spatial imagery task, across all participants, indicating that a better sense of direction is related to a more proficient spatial representation and that the imagery task indexes ecologically relevant spatial abilities. Moreover, the older the participants were, the worse their performance was, indicating a detrimental effect of age on spatial imagery performance. Thus, spatial skills represent an important target for rehabilitative approaches to visual impairment, and individual differences, which can modulate performance, should be taken into account in such approaches.
11-cis-retinal is the light-sensitive component in rod and cone photoreceptors, and its isomerization to all-trans retinal in the presence of light initiates the visual response. For photoreceptors to function normally, all-trans retinal must be converted back into 11-cis-retinal through a series of enzymatic steps known as the visual cycle. The interphotoreceptor retinoid-binding protein (IRBP) is a proposed retinoid transporter in the visual cycle, but rods in Irbp−/− mice have a normal visual cycle. While rods are primarily responsible for dim light vision, the ability of cones to function in constant light is essential to human vision and may be facilitated by cone-specific visual cycle pathways. We analyzed the cones in Irbp−/− mice to determine whether IRBP has a cone-specific visual cycle function. Cone electroretinogram (ERG) responses were reduced in Irbp−/− mice, but similar responses from Irbp−/− mice at all ages suggest that degeneration does not underlie cone dysfunction. Furthermore, cone densities and opsin levels in Irbp−/− mice were similar to C57BL/6 (wild-type) mice, and both cone opsins were properly localized to the cone outer segments. To test for retinoid deficiency in Irbp−/− mice, ERGs were analyzed before and after intraperitoneal injections of 9-cis-retinal. Treatment with 9-cis-retinal produced a significant recovery of the cone response in Irbp−/− mice and shows that retinoid deficiency underlies cone dysfunction. These data indicate that IRBP is essential to normal cone function and demonstrate that differences exist in the visual cycle of rods and cones.
An 80-year-old white woman with a history of hyperthyroidism treated with radioactive iodine ablation, gastroesophageal reflux disease complicated by Barrett esophagus, osteoarthritis, breast cancer status post-bilateral mastectomy, and diverticulosis presented with severe left-sided headache and diplopia. Three weeks prior to presentation, she developed a sharp pain located over the left temporal, parietal, and occipital regions. It was associated with exquisite scalp tenderness. Over the next few days, the pain progressed, involving the left side of the face, including the periorbital region. There was no radiation of the pain, and she had little relief with over-the-counter acetaminophen. She also experienced earache, sore throat, and left jaw pain with mastication.