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Topography of ganglion cells in human retina
Abstract and Figures
We quantified the spatial distribution of presumed ganglion cells and displaced amacrine cells in unstained whole mounts of six young normal human retinas whose photoreceptor distributions had previously been characterized. Cells with large somata compared to their nuclei were considered ganglion cells; cells with small somata relative to their nuclei were considered displaced amacrine cells. Within the central area, ganglion cell densities reach 32,000--38,000 cells/mm² in a horizontally oriented elliptical ring 0.4--2.0 mm from the foveal center. In peripheral retina, densities in nasal retina exceed those at corresponding eccentricities in temporal retina by more than 300%; superior exceeds inferior by 60%. Displaced amacrine cells represented 3% of the total cells in central retina and nearly 80% in the far periphery. A twofold range in the total number of ganglion cells (0.7 to 1.5 million) was largely explained by a similar range in ganglion cell density in different eyes. Cone and ganglion cell number were not correlated, and the overall cone: ganglion cell ratio ranged from 2.9 to 7.5 in different eyes. Peripheral cones and ganglion cells have different topographies, thus suggesting meridianal differences in convergence onto individual ganglion cells.
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... Early studies overestimated the ganglion cell concentration outside the macula along the horizontal meridian because of confusion with amacrine cell bodies [4,5]. The pattern of amacrine cell density mirrors that of RGCs and peaking between 2 and 6 mm from the center of the fovea [7]. Amacrine cell concentration declines at a slower rate than RGCs following increasing retinal eccentricities. ...
... Amacrine cell concentration declines at a slower rate than RGCs following increasing retinal eccentricities. At the peak ganglion cell density, the proportion of displaced amacrine cells in the GCL has been measured as low as 3%, rising to approximately 70% at the ora serrata [4,7]. ...
Purpose of Review
Degeneration of the maculopapillary bundle (MPB) is a prominent feature in a spectrum of optic neuropathies. MPB-selective degeneration is seen in specific conditions, such as nutritional and toxic optic neuropathies, Leber hereditary optic neuropathy (LHON), and dominant optic atrophy (DOA). Despite their distinct etiologies and clinical presentations, which encompass variations in age of incidence and monocular or binocular onset, these disorders share a core molecular mechanism: compromised mitochondrial homeostasis. This disruption is characterized by dysfunctions in mitochondrial metabolism, biogenesis, and protein synthesis. This article provides a comprehensive understanding of the MPB’s role in optic neuropathies, emphasizing the importance of mitochondrial mechanisms in the pathogenesis of these conditions.
Recent Findings
Optical coherence tomography studies have characterized the retinal nerve fiber layer changes accompanying mitochondrial-affiliated optic neuropathies. Selective thinning of the temporal optic nerve head is preceded by thickening in early stages of these disorders which correlates with reductions in macular ganglion cell layer thinning and vascular atrophy. A recently proposed mechanism underpinning the selective atrophy of the MPB involves the positive feedback of reactive oxygen species generation as a common consequence of mitochondrial dysfunction. Additionally, new research has revealed that the MPB can undergo degeneration in the early stages of glaucoma, challenging the historically held belief that this area was not involved in this common optic neuropathy. A variety of anatomical risk factors influence the propensity of glaucomatous MPB degeneration, and cases present distinct patterns of ganglion cell degeneration that are distinct from those observed in mitochondria-associated diseases.
Summary
This review synthesizes clinical and molecular research on primary MPB disorders, highlighting the commonalities and differences in their pathogenesis.
Key Points (Box)
1. Temporal degeneration of optic nerve fibers accompanied by cecocentral scotoma is a hallmark of maculopapillary bundle (MPB) degeneration.
2. Mechanisms of MPB degeneration commonly implicate mitochondrial dysfunction.
3. Recent research challenges the traditional belief that the MPB is uninvolved in glaucoma by showing degeneration in the early stages of this common optic neuropathy, yet with features distinct from other MPB-selective neuropathies.
4. Reactive oxygen species generation is a mechanism linking mitochondrial mechanisms of MPB-selective optic neuropathies, but in-vivo and in-vitro studies are needed to validate this hypothesis.
... While numerous OCT parameters are available for this purpose, RNFL is the most appropriate one. Because the macula holds around 50% of the RGCs in the retina, therefore, the health status of all RGCs can only be monitored with the RNFL [24]. Moreover, RNFL is a more sensitive index than other parameters for monitoring glaucoma progression in the early and moderate stages of the disease [19]. ...
Purpose
To characterize glaucoma progression in early-stage patients with retinal nerve fiber layer (RNFL) using the change analysis software (CAS), which was utilized to track RNFL thinning.
Methods
We retrospectively analyzed 92 eyes of 92 patients with early-stage glaucoma. Patients were divided into two subgroups based on their diagnosis of pseudoexfoliation glaucoma (PEG) and primary open-angle glaucoma (POAG). A complete ophthalmologic examination was performed on all patients. Additionally, automated perimetry was conducted on each patient. Furthermore, Fourier-domain optical coherence tomography (OCT) was employed to measure RNFL and central corneal thickness. Using the OCT device’s CAS, we computed the annual rate of total and glaucomatous RNFL thinning for each patient.
Results
A total of 44 PEG and 48 POAG patients were included in the study. The right eye measurements of these patients were analyzed and compared. The two groups were not significantly different in age, gender, and the number of visits per year (p > 0.05, for each). However, the difference between the mean RNFL thickness at baseline (91.39 ± 10.71 and 96.9 ± 8.6 µm) and at the last visit (85.2 ± 15.76 µm and 91.56 ± 9.58 µm) was statistically significant between the two groups (p = 0.043, p = 0.039, respectively). Additionally, the difference in annual RNFL thinning rates (1.43 ± 0.81 µm and 1.07 ± 0.32 µm) between the two groups was statistically significant (p = 0.009).
Conclusion
The annual rate of glaucomatous RNFL loss in early-stage PEG patients (1.23 µm) was higher than in POAG patients (0.87 µm). However, despite these loss rates, scotoma was not detected in the visual field tests of these patients. Therefore, using CAS in the follow-up of early-stage glaucoma patients is a useful alternative for monitoring glaucomatous progression. Furthermore, this method can be utilized in future research for the diagnosis and follow-up of glaucoma in special populations (e.g., those with pathological myopia or high hyperopia) that are not included in normative databases.
... One general trend amongst all eyes was a decrease in z-score responsiveness and sparser labeling as foveal eccentricity increased. A higher z-score at central eccentricities may be due the inability of AOSLO to axially separate overlapping RGCs at the fovea where ganglion cell densities are higher (Curcio and Allen 1990). Subject M1 responded with significantly higher z-scores relative to other experimental eyes, which could be attributed to the older age of that animal a factor that has a profound impact on innate immunity and potentially therefore on viral transduction. ...
High resolution retinal imaging paired with intravitreal injection of a viral vector coding for the calcium indicator GCaMP has enabled visualization of activity dependent calcium changes in retinal ganglion cells (RGCs) at single cell resolution in the living eye. The inner limiting membrane (ILM) is a barrier for viral vectors, restricting transduction to a ring of RGCs serving the fovea in both humans and non-human primates (NHP). We evaluate peeling the ILM prior to intravitreal injection as a strategy to expand calcium imaging beyond the fovea in the NHP eye in vivo. Five Macaca fascicularis eyes (age 3-10y; n=3 individuals; 2M, 1F) underwent vitrectomy and 5 to 6-disc diameter ILM peel centered on the fovea prior to intravitreal delivery of 7m8:SNCG:GCaMP8s. Calcium responses from RGCs were recorded using a fluorescence adaptive optics scanning laser ophthalmoscope. In all eyes GCaMP was expressed throughout the peeled area, representing a mean 8-fold enlargement in area of expression relative to a control eye. Calcium recordings were obtained up to 11 degrees from the foveal center. RGC responses were comparable to the fellow control eye and showed no significant decrease over the 6 months post ILM peel, suggesting that RGC function was not compromised by the surgical procedure. In addition, we demonstrate that activity can be recorded directly from the retinal nerve fiber layer. This approach will be valuable for a range of applications in visual neuroscience including pre-clinical evaluation of retinal function, detecting vision loss, and assessing the impact of therapeutic interventions.
Significance Statement
This research presents a groundbreaking advancement in visual neuroscience through the development of a novel technique involving the peeling of the inner limiting membrane (ILM) in conjunction with intravitreal injection to expand functional recording capabilities in the living primate eye. By utilizing high-resolution retinal imaging coupled with a viral vector-mediated expression of the calcium indicator GCaMP, the study achieves unprecedented visualization and assessment of retinal ganglion cell (RGC) activity at single-cell resolution. Importantly, the technique enables recording from regions of the retina previously inaccessible, significantly broadening the area for calcium imaging beyond the fovea. The results demonstrate stable RGC function post-procedure, suggesting minimal impact on retinal physiology. This innovative approach holds significant promise for diverse applications in visual neuroscience, including pre-clinical evaluation of retinal function, detection of vision loss, and evaluation of therapeutic interventions. Overall, the study represents a major step forward in understanding and potentially treating retinal degenerative disorders, offering new avenues for research and development in vision restoration.
... Furthermore, it has been shown that the visual performance is better, at least in adult participants (for the lack of effect in children and adolescents, see Carrasco et al., 2022), for stimuli over the lower when compared to the upper part of the vertical meridian 9 , a phenomenon called vertical meridian asymmetry Page 3/15 (VMA). The neural correlates of these polar angle asymmetries (PAAs) proved to be mainly rooted in the distribution of photoreceptors and midget retinal ganglion cells, which show higher densities along the horizontal when compared to the vertical meridian, and along the lower compared to the upper vertical meridian [10][11][12] . The visual eld representation in the macaque's primary visual cortex (V1) shows also HVA as the largest surface area is allocated to the horizontal meridian 13 . ...
Polar angle asymmetries (PAAs), the differences in perceptual experiences and performance across different regions of the visual field are present in various paradigms and tasks of visual perception. Currently, research in this area is sparse, particularly regarding the influence of PAAs during perceptual illusions, highlighting a gap in visual cognition studies. We aim to fill this gap by measuring PAAs across the visual field during an illusion applied to test conscious vision widely. Motion-induced blindness (MIB) is an illusion when a peripheral target disappears from consciousness as the result of a continuouslymoving background pattern. During MIB we separately measured the average disappearance time of peripheral targets in eight equidistant peripheral visual field positions. Our results indicate a significant variation in MIB disappearance times as a function of peripheral target position. Specifically, we found shorter disappearance times along cardinal compared to oblique directions, and along the horizontal compared to the vertical meridian. Our results suggest specific consistencies between visual field asymmetries and conscious visual perception.
... These horizontal-vertical and upper-lower anisotropies consistently emerge for many elements of vision, including orientation discrimination and contrast sensitivity [11][12][13], and have been linked with the retinotopic organisation of the visual system [14]. At the retinal level, the density of retinal ganglion cells is higher along the horizontal vs. vertical meridian [15,16]. In early visual cortex (V1-V3), smaller population receptive fields (pRFs) have been found along the horizontal vs. vertical meridian and the lower vs. upper field, highlighting variations in visual field sampling [17,18]. ...
Visual abilities tend to vary predictably across the visual field–for simple low-level stimuli, visibility is better along the horizontal vs. vertical meridian and in the lower vs. upper visual field. In contrast, face perception abilities have been reported to show either distinct or entirely idiosyncratic patterns of variation in peripheral vision, suggesting a dissociation between the spatial properties of low- and higher-level vision. To assess this link more clearly, we extended methods used in low-level vision to develop an acuity test for face perception, measuring the smallest size at which facial gender can be reliably judged in peripheral vision. In 3 experiments, we show the characteristic inversion effect, with better acuity for upright faces than inverted, demonstrating the engagement of high-level face-selective processes in peripheral vision. We also observe a clear advantage for gender acuity on the horizontal vs. vertical meridian and a smaller-but-consistent lower- vs. upper-field advantage. These visual field variations match those of low-level vision, indicating that higher-level face processing abilities either inherit or actively maintain the characteristic patterns of spatial selectivity found in early vision. The commonality of these spatial variations throughout the visual hierarchy means that the location of faces in our visual field systematically influences our perception of them.
... We modeled the RGC soma density using the following function: was the radius of the umbo, the area in the center of the fovea devoid of RGCs. To reflect the human RGC density described in (58,59), we set the parameters to ...
Neural information processing requires accurately timed action potentials arriving from presynaptic neurons at the postsynaptic neuron. However, axons of ganglion cells in the human retina feature low axonal conduction speeds and vastly different lengths, which poses a challenge to the brain for constructing a temporally coherent image over the visual field. Combining results from microelectrode array recordings, human behavioral measurements, transmission electron microscopy, and mathematical modelling of the retinal nerve fiber layer, we demonstrate that axonal propagation speeds compensate for variations in axonal length across the human retina including the fovea. The human brain synchronizes the arrival times of action potentials at the optic disc by increasing the diameters of longer axons, which increases their propagation speeds.
... Since ganglion cells appear to be the primary retinal neurons involved in PD, with nearly half of them being populated within 4.5 mm of fovea centralis, thicknesses of foveal and parafoveal macular regions are likely to show an inverse correlation with PD duration. [30,31] In the present study, we observed a significant inverse correlation between ipsilateral temporal parafoveal thickness and PD duration. Although worsening of dopaminergic deficit with increasing disease duration is expected to result in progressive RNFL thinning, the peripapillary RNFL parameters in our PD patients did not show a significant negative correlation with PD duration. ...
Background and Objective
While optical coherence tomography (OCT) is explored as a potential biomarker in Parkinson’s disease (PD), technetium-99m-labeled tropane derivative ( 99m Tc-TRODAT-1) single-photon emission computed tomography (SPECT) imaging has a proven role in diagnosing PD. Our objective was to compare the OCT parameters in PD patients and healthy controls (HCs) and correlate them with 99m Tc-TRODAT-1 parameters in PD patients.
Materials and Methods
This cross-sectional study included 30 PD patients and 30 age- and gender-matched HCs. Demographic data, PD details including Movement Disorders Society Unified Parkinson’s Disease Rating Scale-III (MDS-UPDRS-III) and Hoehn–Yahr (HY) staging, and OCT parameters including macular and peripapillary retinal nerve fiber layer (RNFL) thickness in bilateral eyes were recorded. PD patients underwent 99m Tc-TRODAT-1 SPECT imaging. The terms “ipsilateral” and “contralateral” were used with reference to more severely affected body side in PD patients and compared with corresponding sides in HCs.
Results
PD patients showed significant ipsilateral superior parafoveal quadrant (mean ± standard deviation [SD] = 311.10 ± 15.90 vs. 297.57 ± 26.55, P = 0.02) and contralateral average perifoveal (mean ± SD = 278.75 ± 18.97 vs. 269.08 ± 16.91, P = 0.04) thinning compared to HCs. Peripapillary RNFL parameters were comparable between PD patients and HCs. MDS-UPDRS-III score and HY stage were inversely correlated to both ipsilateral (Spearman rho = -0.52, P = 0.003; Spearman rho = -0.47, P = 0.008) and contralateral (Spearman rho = -0.53, P = 0.002; Spearman rho = -0.58, P < 0.001) macular volumes, respectively. PD duration was inversely correlated with ipsilateral temporal parafoveal thickness (ρ = -0.41, P = 0.02). No correlation was observed between OCT and 99m Tc-TRODAT-1 SPECT parameters in PD patients.
Conclusion
Compared to HCs, a significant thinning was observed in the ipsilateral superior parafoveal quadrant and the contralateral average perifoveal region in PD patients. Macular volume and ipsilateral temporal parafoveal thickness were inversely correlated with disease severity and duration, respectively. OCT and 99m Tc-TRODAT-1 SPECT parameters failed to correlate in PD patients.
Electrical stimulation of the visual nervous system could improve the quality of life of patients affected by acquired blindness by restoring some visual sensations, but requires careful optimization of stimulation parameters to produce useful perceptions. Neural correlates of elicited perceptions could be used for fast automatic optimization, with electroencephalography as a natural choice as it can be acquired non-invasively. Nonetheless, its low signal-to-noise ratio may hinder discrimination of similar visual patterns, preventing its use in the optimization of electrical stimulation. Our work investigates for the first time the discriminability of the electroencephalographic responses to visual stimuli compatible with electrical stimulation, employing a newly acquired dataset whose stimuli encompass the concurrent variation of several features, while neuroscience research tends to study the neural correlates of single visual features. We then performed above-chance single-trial decoding of multiple features of our newly crafted visual stimuli using relatively simple machine learning algorithms. A decoding scheme employing the information from multiple stimulus presentations was implemented, substantially improving our decoding performance, suggesting that such methods should be used systematically in future applications. The significance of the present work relies in the determination of which visual features can be decoded from electroencephalographic responses to electrical stimulation-compatible stimuli and at which granularity they can be discriminated. Our methods pave the way to using electroencephalographic correlates to optimize electrical stimulation parameters, thus increasing the effectiveness of current visual neuroprostheses.
The functional field of view (FFV) is the part of the visual field centred around the current gaze position that the visual system can process in detail. Its size depends partly on physiological limitations, but its adaptability is largely determined by cognitive factors. For example, changes in the FFV often reflect the demands of a given task: it shrinks with high task demands and expands with easier tasks. Here, we placed an upright or inverted target among distractors. We manipulated the visibility of the search array during gaze-contingent search with small (6°), medium (12°) and large (18°) apertures. Aperture size affected performance, improving it when it increased from 6° to 12°, but not from 12° to 18°, suggesting an upper bound of the 'natural' aperture for this specific task. Furthermore, our results suggest that the FFV does not change in size in response to stimulus inversion.
The structure of the human, but mainly of the rhesus monkey, retina as examined by Golgi-staining techniques is described and interpreted on evidence from both light and electron microscopy. One type of rod bipolar cell and two types of cone bipolar cell are recognized. The rod bipolar is exclusively connected to rods. The midget bipolar is postsynaptic to only one cone but each cone is also presynaptic to a diffuse cone (flat) bipolar. Such flat bipolar cells are in synaptic relationship with about seven cones. No other bipolar cell types have been found. The brush bipolar of Polyak is interpreted as probably a distorted rod bipolar, while Polyak's centrifugal bipolar is a misinterpretation of the morphology of diffuse amacrine cells. When presumptive centrifugal bipolars were observed they appeared to be a developmental stage of amacrine cells. In the outer plexiform layer two types of horizontal cell have been defined. Each type of horizontal cell has a single axon and two kinds of horizontal cell axon terminals are recognized. In the inner plexiform layer there are two main classes of amacrine cells: the stratified amacrines and the diffuse amacrines. Each class of amacrine has a wide variety of shapes. Polyak's midget ganglion cell is confirmed and his five other kinds of ganglion cell are classified into diffuse and stratified ganglion cells according to the level at which their dendrites branch within the inner plexiform layer. A fuller summary is given by the diagram and in the legend of figure 98, p. 174. A new type of midget bipolar is described in the Appendix (p. 177).
Neurogenesis in the ventricular layer and the development of cell topography in the ganglion cell layer have been studied in whole-mounts of human fetal retinae. At the end of the embryonic period mitotic figures were seen over the entire outer surface of the retina. By about 14 weeks gestation mitosis had ceased in central retina and differentiation of photoreceptor nuclei was evident within a well-defined area which constituted about 2% of total retina area. This area was approximately centered on the site of the putative fovea, identified by the exclusive development of cone nuclei at that location. The area of retina in which mitosis had ceased increased as gestation progressed. By mid-gestation mitosis in the ventricular layer occupied about 77% of the outer surface of the retina and by about 30 weeks gestation mitosis in the ventricular layer had ceased. Cell density distributions in the ganglion cell layer were nonuniform at all stages studied (14–40 weeks). Densities were highest at about 17 weeks gestation, and by mid-gestation the adult pattern of cell topography was present with maps showing elevated cell densities in posterior retina and along the horizontal meridian. Cell densities generally declined throughout the remainder of the gestation period, except in the posterior retina, where densities in the perifoveal ganglion cell layer remained high during the second half of gestation. There is a rapid decline in cell density in the foveal ganglion cell layer toward the end of gestation, and it is suggested that the persistence of high densities in the perifoveal region may be related to migration of cells away from the developing fovea. The total population of cells in the ganglion cell layer was highest (2.2–2.5 million cells) between about weeks 18 and 30 of gestation. After this the cell population declined rapidly to 1.5–1.7 million cells. It is suggested that naturally occurring neuronal death is largely responsible for this decline.
