The relationship between retinal cone density and cortical magnification in human albinism.

The human fovea lies at the center of the retina and supports high-acuity vision. In normal visual system development, the highest acuity is correlated with both a high density of cone photoreceptors in the fovea and a magnified retinotopic representation of the fovea in the visual cortex. Both cone density and the cortical area dedicated to each degree of visual space-the latter describing cortical magnification (CM)-steadily decrease with increasing eccentricity from the fovea. In albinism, peak cone density at the fovea and visual acuity are decreased, but seem to be within normal limits in the periphery, thus providing a model to explore the correlation between retinal structure, cortical structure, and behavior. Here, we used adaptive optics scanning light ophthalmoscopy to assess retinal cone density and functional magnetic resonance imaging to measure CM in the primary visual cortex of normal controls and individuals with albinism. We find that retinotopic organization is more varied among individuals with albinism than previously appreciated. Additionally, CM outside the fovea is similar to that in controls, but also more variable. CM in albinism and controls exceeds that which might be predicted based on cone density alone, but is more accurately predicted by retinal ganglion cell density. This finding suggests that decreased foveal cone density in albinism may be partially counteracted by nonuniform connectivity between cones and their downstream signaling partners. Together, these results emphasize that central as well as retinal factors must be included to provide a complete picture of aberrant structure and function in albinism.

Electroretinograms in idiopathic infantile nystagmus, optic nerve hypoplasia and albinism.

PURPOSE: To study electroretinograms in infantile nystagmus syndrome associated with idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism. METHODS: A total of 30 children with idiopathic infantile nystagmus, 18 with optic nerve hypoplasia, and 18 with albinism were studied. Three electroretinogram protocols were applied according to child's age: 58 (mean: 2.0 years) were recorded with skin electrode to Great Ormond Street Hospital protocol, 11 (mean: 5.3 years) with skin electrode to International Society for Clinical Electrophysiology of Vision protocol, and 7 children (mean: 12.2 years) with HK electrode to International Society for Clinical Electrophysiology of Vision protocol. The electroretinograms were compared to those of age-matched controls. RESULTS: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were comparable to controls in all protocols. Electroretinogram amplitudes in idiopathic infantile nystagmus group showed increased white scotopic and photopic electroretinograms in 26 children (skin electrode to Great Ormond Street Hospital protocol), no difference to the controls in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol), and increased rod electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol). Optic nerve hypoplasia group showed increased white scotopic, photopic, and blue electroretinograms in 15 children (skin electrode to Great Ormond Street Hospital protocol); increased 30-Hz electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol); and reduced combined rod-cone, cone, and 30-Hz electroretinograms in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Albinism group showed increased white scotopic, photopic, and 30-Hz electroretinograms in 17 children (skin electrode to Great Ormond Street Hospital protocol), while it showed reduced cone and 30-Hz electroretinograms in 5 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Implicit times were shorter in albinism. CONCLUSION: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were normal with mostly increased electroretinograms, while reduced electroretinograms did not show a specific pattern as in early-onset retinal dystrophies.

Micro-probing enables fine-grained mapping of neuronal populations using fMRI.

The characterization of receptive field (RF) properties is fundamental to understanding the neural basis of sensory and cognitive behaviour. The combination of non-invasive imaging, such as fMRI, with biologically inspired neural modelling has enabled the estimation of population RFs directly in humans. However, current approaches require making numerous a priori assumptions, so these cannot reveal unpredicted properties, such as fragmented RFs or subpopulations. This is a critical limitation in studies on adaptation, pathology or reorganization. Here, we introduce micro-probing (MP), a technique for fine-grained and largely assumption free characterization of multiple pRFs within a voxel. It overcomes many limitations of current approaches by enabling detection of unexpected RF shapes, properties and subpopulations, by enhancing the spatial detail with which we analyze the data. MP is based on tiny, fixed-size, Gaussian models that efficiently sample the entire visual space and create fine-grained probe maps. Subsequently, we derived population receptive fields (pRFs) from these maps. We demonstrate the scope of our method through simulations and by mapping the visual fields of healthy participants and of a patient group with highly abnormal RFs due to a congenital pathway disorder. Without using specific stimuli or adapted models, MP mapped the bilateral pRFs characteristic of observers with albinism. In healthy observers, MP revealed that voxels may capture the activity of multiple subpopulations RFs that sample distinct regions of the visual field. Thus, MP provides a versatile framework to visualize, analyze and model, without restrictions, the diverse RFs of cortical subpopulations in health and disease.

Population receptive field and connectivity properties of the early visual cortex in human albinism.

In albinism, the pathological decussation of the temporal retinal afferents at the optic chiasm leads to superimposed representations of opposing hemifields in the visual cortex. Here, we assessed the equivalence of the two representations and the cortico-cortical connectivity of the early visual areas. Applying fMRI-based population receptive field (pRF)-mapping (both hemifield and bilateral mapping) and connective field (CF)-modeling, we investigated the early visual cortex in 6 albinotic participants and 4 controls. In albinism, superimposed retinotopic representations of the contra- and ipsilateral visual hemifield were observed on the hemisphere contralateral to the stimulated eye. This was confirmed by the observation of bilateral pRFs during bilateral mapping. Hemifield mapping revealed similar pRF-sizes for both hemifield representations throughout V1 to V3. The typical increase of V1-sampling extent for V3 compared to V2 was not found for the albinotic participants. The similarity of the pRF-sizes for opposing visual hemifield representations highlights the equivalence of the two maps in the early visual cortex. The altered V1-sampling extent in V3 might indicate the adaptation of cortico-cortical connections to visual pathway abnormalities in albinism. These findings thus suggest that conservative developmental mechanisms are complemented by alterations of the extrastriate cortico-cortical connectivity.

Interocular transfer of visual memory - Influence of visual impairment and abnormalities of the optic chiasm.

Due to an increased crossing of the optic nerve fibers at the optic chiasm in albinism, the visual cortex receives largely monocular input from the contralateral eye. Here we investigated whether this obstruction of binocular integration at the cortical input stage also impacts on interocular information exchange at the high processing level of visual memory. Interocular transfer (IOT) of visual memory retrieval was tested psychophysically after monocular encoding in 8 albinotic participants and 24 healthy controls. The retrieval performance (hit rate, reaction time, d') was determined when using the same or different eye at encoding. To assess the effect of reduced visual acuity (VA) on recognition, we simulated interocular acuity differences (IOA) in two healthy control groups (each n = 8), i.e., with large (VA: 0.89 vs. 0.12) and small simulated interocular difference (VA: 0.25 vs. 0.12), with the latter matched to that observed in the albinotic participants (VA: 0.20 vs. 0.15). A significant decrease in retrieval performance was observed in controls with simulated strongly reduced VA in one eye (p < 0.0001). For the other conditions and groups, including the albinotic participants, no dependence on VA and no significant difference between using the same or different eye was observed. This indicates interocular transfer and hence interocular information exchange in human albinism. These findings thus provide insights into the scope of plasticity of binocular information processing and inter-hemispherical information flow.

Burden of albinism: development and validation of a burden assessment tool.

BACKGROUND: Albinism comprises a group of autosomal recessive diseases that are characterized by poor vision and a variable hypopigmentation phenotype. A comprehensive literature review showed that no tool can assess the burden experienced by individuals who present with albinism, although such a tool is needed and would be beneficial for clinicians and patients alike. METHOD: The questionnaire was devised using standardized methodology for developing and validating questionnaires on the quality of life of subjects according to the following chronological structure: conceptual phase, development phase, and then validation phase. A multidisciplinary working group was assembled, including experts on questionnaire design and development, dermatologists specializing in care for patients with albinism, and representatives of the Genespoir association. RESULTS: Based on an initial verbatim report, the workgroup compiled a list of items that were transcribed and reformulated into questions. During the validation phase, principal component analysis (PCA) was conducted on the 24 items, which allowed the questionnaire to be reduced to 20 questions [Q]. The standardized regression coefficients were all greater than 0.5 for their corresponding factors. Based on their normalized regression coefficients, each group of questions was linked to one of the following four dimensions, with each dimension consisting of at least three questions: "Live with" (8 Q), "Daily life" (3 Q), "Resignation" (3 Q), and "Fear of the future" (6 Q). All dimensions correlated well with the overall BoA score. Cronbach's α was 0.92 for the entire BoA scale, confirming excellent internal coherence. Intradimensional coherences all demonstrated excellent reliability (α > 0.65). The BoA questionnaire was highly correlated with the SF12, RSES and DLQI validated questionnaires. This outcome confirmed the external validity. CONCLUSION: This questionnaire represents the first specific assessment tool for evaluating the burden of albinism. It is easy to use and relatively quick to complete, which will allow the burden to be evaluated over time with a reproducible questionnaire. To ensure that this questionnaire can be used by as many people as possible, cultural and linguistic validation in US English was conducted with the original French version.

Pigmented and albino rats differ in their responses to moderate, acute and reversible intraocular pressure elevation.

PURPOSE: To compare the electrophysiological and morphological responses to acute, moderately elevated intraocular pressure (IOP) in Sprague-Dawley (SD), Long-Evans (LE) and Brown Norway (BN) rat eyes. METHODS: Eleven-week-old SD (n = 5), LE (n = 5) and BN (n = 5) rats were used. Scotopic threshold responses (STRs), Maxwellian flash electroretinograms (ERGs) or ultrahigh-resolution optical coherence tomography (UHR-OCT) images of the rat retinas were collected from both eyes before, during and after IOP elevation of one eye. IOP was raised to ~35 mmHg for 1 h using a vascular loop, while the other eye served as a control. STRs, ERGs and UHR-OCT images were acquired on 3 days separated by 1 day of no experimental manipulation. RESULTS: There were no significant differences between species in baseline electroretinography. However, during IOP elevation, peak positive STR amplitudes in LE (mean ± standard deviation 259 ± 124 µV) and BN (228 ± 96 µV) rats were about fourfold higher than those in SD rats (56 ± 46 µV) rats (p = 0.0002 for both). Similarly, during elevated IOP, ERG b-wave amplitudes were twofold higher in LE and BN rats compared to those of SD rats (947 ± 129 µV and 892 ± 184 µV, vs 427 ± 138 µV; p = 0.0002 for both). UHR-OCT images showed backward bowing in all groups during IOP elevation, with a return to typical form about 30 min after IOP elevation. CONCLUSION: Differences in the loop-induced responses between the strains are likely due to different inherent retinal morphology and physiology.

Measuring Connectivity in the Primary Visual Pathway in Human Albinism Using Diffusion Tensor Imaging and Tractography.

In albinism, the number of ipsilaterally projecting retinal ganglion cells (RGCs) is significantly reduced. The retina and optic chiasm have been proposed as candidate sites for misrouting. Since a correlation between the number of lateral geniculate nucleus (LGN) relay neurons and LGN size has been shown, and based on previously reported reductions in LGN volumes in human albinism, we suggest that fiber projections from LGN to the primary visual cortex (V1) are also reduced. Studying structural differences in the visual system of albinism can improve the understanding of the mechanism of misrouting and subsequent clinical applications. Diffusion data and tractography are useful for mapping the OR (optic radiation). This manuscript describes two algorithms for OR reconstruction in order to compare brain connectivity in albinism and controls.An MRI scanner with a 32-channel head coil was used to acquire structural scans. A T1-weighted 3D-MPRAGE sequence with 1 mm(3) isotropic voxel size was used to generate high-resolution images for V1 segmentation. Multiple proton density (PD) weighted images were acquired coronally for right and left LGN localization. Diffusion tensor imaging (DTI) scans were acquired with 64 diffusion directions. Both deterministic and probabilistic tracking methods were run and compared, with LGN as the seed mask and V1 as the target mask. Though DTI provides relatively poor spatial resolution, and accurate delineation of OR may be challenging due to its low fiber density, tractography has been shown to be advantageous both in research and clinically. Tract based spatial statistics (TBSS) revealed areas of significantly reduced white matter integrity within the OR in patients with albinism compared to controls. Pairwise comparisons revealed a significant reduction in LGN to V1 connectivity in albinism compared to controls. Comparing both tracking algorithms revealed common findings, strengthening the reliability of the technique.

Hermansky-Pudlak Syndrome.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder that is associated with oculocutaneous albinism, bleeding diatheses, granulomatous colitis, and highly penetrant pulmonary fibrosis in some subtypes, including HPS-1, HPS-2, and HPS-4. HPS pulmonary fibrosis shows many of the clinical, radiologic, and histologic features found in idiopathic pulmonary fibrosis, but occurs at a younger age. Despite knowledge of the underlying genetic defects, there are currently no definitive therapeutic or preventive approaches for HPS pulmonary fibrosis other than lung transplant.

Abnormally Small Neuromuscular Junctions in the Extraocular Muscles From Subjects With Idiopathic Nystagmus and Nystagmus Associated With Albinism.

PURPOSE: Infantile nystagmus syndrome (INS) is often associated with abnormalities of axonal outgrowth and connectivity. To determine if this manifests in extraocular muscle innervation, specimens from children with idiopathic INS or INS and albinism were examined and compared to normal age-matched control extraocular muscles. METHODS: Extraocular muscles removed during normal surgery on children with idiopathic INS or INS and albinism were immunostained for neuromuscular junctions, myofiber type, the immature form of the acetylcholine receptor, and brain-derived neurotrophic factor (BDNF) and compared to age-matched controls. RESULTS: Muscles from both the idiopathic INS and INS and albinism groups had neuromuscular junctions that were 35% to 71% smaller based on myofiber area and myofiber perimeter than found in age-matched controls, and this was seen on both fast and slow myosin heavy chain isoform-expressing myofibers (all P < 0.015). Muscles from subjects with INS and albinism showed a 7-fold increase in neuromuscular junction numbers on fast myofibers expressing the immature gamma subunit of the acetylcholine receptor. The extraocular muscles from both INS subgroups showed a significant increase in the number and size of slow myofibers compared to age-matched controls. Brain-derived neurotrophic factor was expressed in control muscle but was virtually absent in the INS muscles. CONCLUSIONS: These studies suggest that, relative to the final common pathway, INS is not the same between different patient etiologies. It should be possible to modulate these final common pathway abnormalities, via exogenous application of appropriate drugs, with the hope that this type of treatment may reduce the involuntary oscillatory movements in these children.

Duration sensitivity of neurons in the primary auditory cortex of albino mouse.

Many neurons in the central auditory system of a number of species have been found to be sensitive to the duration of sound stimuli. While previous studies have shown that γ-aminobutyric acid (GABA)-ergic inhibitory input is important for duration sensitivity in the inferior colliculus (IC), it is still unknown whether (GABA)-ergic inhibitory input plays an important role in generating duration sensitivity in the cortex. Using free-field sound stimulation and in vivo extracellular recording, we investigated duration sensitivity in primary auditory cortical (AI) neurons of the Nembutal anesthetized albino mouse (Mus musculus, Km) and examined the effect of the GABAA receptor antagonist bicuculline on AI neuron duration sensitivity. A total of 63 duration tuning curves were measured in AI neurons. Of these, 44% (28/63) exhibited duration sensitive responses, while 43% (27/63) lacked duration sensitivity. The remaining 13% (8/63) exhibited long-pass properties likely reflecting both duration sensitive and insensitive features. We found that duration sensitive neurons had shorter first spike latency (FSL) and longer firing duration (FD) when stimulated with best duration (p < 0.05), while duration insensitive neurons had invariable FSL and FD at different sound durations (p>0.05). Furthermore, 60% (6/10) of duration sensitive neurons and 75% (3/4) long-pass neurons lost duration sensitivity following bicuculline application. Taken together, our results show that cortical neurons in the albino mouse are sensitive to sound duration, and that GABAergic inhibition may play an important role in the formation of de novo duration sensitivity in AI. The possible mechanism and behavioral significance of duration sensitivity in AI neurons is discussed.

The brainstem efferent acoustic chiasm in pigmented and albino rats.

The present study examined whether structural peculiarities in the brain-efferent pathway to the organ of Corti may underlie functional differences in hearing between pigmented and albino individuals of the same mammalian species. Pigmented Brown-Norway rats and albino Wistar rats received unilateral injections of an aqueous solution of the retrograde neuronal tracer Fluorogold (FG) into the scala tympani of the cochlea to identify olivocochlear neurons (OCN) in the brainstem superior olivary complex. After five days, brains were perfusion-fixed and brainstem sections were cut and analyzed with respect to retrogradely labeled neurons. Intrinsic neurons of the lateral system were located exclusively in the ipsilateral lateral superior olive (LSO) in both groups. Shell neurons surrounding the LSO and in periolivary regions, which made up only 5-8% of all OCN, were more often contralaterally located in albino than in pigmented animals. A striking difference was observed in the laterality of neurons of the medial olivocochlear (MOC) system, which provided more than one third of all OCN. These neurons, located in the rostral periolivary region and in the ventral nucleus of the trapezoid body, were observed contralateral to 45% in pigmented and to 68% in albino animals. Our study, the first to compare the origin of the olivocochlear bundle in pigmented and albino rats, provides evidence for differences in the crossing pattern of the olivocochlear pathway. These were found predominantly in the MOC system providing the direct efferent innervation of cochlear outer hair cells. Our findings may account for the alterations in auditory perception observed in albino mammals including man.

Loss of binocular vision as direct cause for misrouting of temporal retinal fibers in albinism.

In humans, the nasal retina projects to the contralateral hemisphere, whereas the temporal retina projects ipsilaterally. The nasotemporal line that divides the retina into crossed and uncrossed parts coincides with the vertical meridian through the fovea. This normal projection of the retina is severely altered in albinism, in which the nasotemporal line shifted into the temporal retina with temporal retinal fibers cross the midline at the optic chiasm. This study proposes the loss of binocular vision as direct cause for misrouting of temporal retinal fibers and shifting of the nasotemporal line temporally in albinism. It is supported by many observations that clearly indicate that loss of binocular vision causes uncrossed retinal fibers to cross the midline. This hypothesis may alert scientists and clinicians to find ways to prevent or minimize the loss of binocular vision that may occur in some diseases such as albinism and early squint. Hopefully, this will minimize the misrouting of temporal fibers and improve vision in such diseases.

Ostracism of an albino individual by a group of pigmented catfish.

Physiological and behavioural constraints hinder albino individuals. Albino animals are rare in the wild; this trait is associated with easy detection by predators, non-native or damaged environments, and exclusively aphotic environments in total darkness. The social aspect of albinism is reported only for human beings, and the effect is distinguishable in time and space when social benefits, are used to a limited the extent. Thus far, the social consequences of albinism for animals remain unknown. We used socially established groups of the pigmented catfish, (Silurus glanis), to observe space and temporal distance detachment of albino specimens in laboratory conditions. The albino fish were separated at larger distances from the group than pigmented individuals with the same social status determined by familiarity, and this asymmetry also varied in time. Albinism-related ostracism results in a solitary existence, usually followed by enhanced predation risk. The motivation for an individual's exclusion from a group appears to be the avoidance of the predation risk that increases not only for an odd individual but also for conspecifics within a group. Our findings indicate a role for albinism in behavioural processes related to sociality in a group of conspecifics.

Vigabatrin can enhance electroretinographic responses in pigmented and albino rats.

PURPOSE: To evaluate the effects of the antiepileptic medication vigabatrin (VGB) on the retina of pigmented rats. METHODS: Scotopic and photopic electroretinograms were recorded from dark- and light-adapted Long-Evans (pigmented) and Sprague Dawley (albino) rats administered, daily, 52-55 injections of 250 mg·kg(-1)·day(-1) VGB or 25-26 injections of 500 mg·kg(-1)·day(-1) VGB, or a corresponding number of sham injections. Sensitivity and saturated amplitude of the rod photoresponse (S, Rm(P3)) and postreceptor response (1/σ, Vm) were derived, as were sensitivity and amplitude of the cone-mediated postreceptor response (1/σ(cone), Vm(cone)). The oscillatory potentials and responses to a series of flickering lights (6.25, 12.5, 25 and 50 Hz) were studied in the time and frequency domains. A subset of rats' eyes was harvested for Western blotting or histology. RESULTS: Of the parameters derived from dark-adapted ERG responses, in both pigmented and albino rats, VGB repeatedly and reliably enhanced electroretinographic parameters; no significant ERG deficits were noted. No significant alterations were observed in ER/oxidative stress or in the Akt cell death/survival pathway. There were migrations of photoreceptor nuclei toward the RPE and outgrowths of bipolar cell dendrites into the outer nuclear layer in VGB-treated rats; these were never observed in sham-treated animals. CONCLUSIONS: Although VGB is associated with retinal dysfunction in patients and VGB toxicity has been demonstrated by other laboratories in the albino rat, in our pigmented and albino rats, VGB did not induce deficits in, but rather enhanced, retinal function. Nonetheless, retinal neuronal dysplasia was observed.

Síndrome de Hermansky-Pudlak: descripción de un caso / Hermansky-Pudlak syndrome: A case report

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Retinal pigment epithelium findings in patients with albinism using wide-field polarization-sensitive optical coherence tomography.

PURPOSE: To investigate pigmentation characteristics of the retinal pigment epithelium (RPE) in patients with albinism using wide-field polarization-sensitive optical coherence tomography compared with intensity-based spectral domain optical coherence tomography and fundus autofluorescence imaging. METHODS: Five patients (10 eyes) with previously genetically diagnosed albinism and 5 healthy control subjects (10 eyes) were imaged by a wide-field polarization-sensitive optical coherence tomography system (scan angle: 40 × 40° on the retina), sensitive to melanin contained in the RPE, based on the polarization state of backscattered light. Conventional intensity-based spectral domain optical coherence tomography and fundus autofluorescence examinations were performed. Retinal pigment epithelium-pigmentation was analyzed qualitatively and quantitatively based on depolarization assessed by polarization-sensitive optical coherence tomography. RESULTS: This study revealed strong evidence of polarization-sensitive optical coherence tomography to specifically image melanin in the RPE. Depolarization of light backscattered by the RPE in patients with albinism was reduced compared with normal subjects. Heterogeneous RPE-specific depolarization characteristics were observed in patients with albinism. Reduction of depolarization observed in the light backscattered by the RPE in patients with albinism corresponds to expected decrease of RPE pigmentation. The degree of depigmentation of the RPE is possibly associated with visual acuity. Findings suggest that different albinism genotypes result in heterogeneous levels of RPE pigmentation. CONCLUSION: Polarization-sensitive optical coherence tomography showed a heterogeneous appearance of RPE pigmentation in patients with albinism depending on different genotypes.

Was skin cancer a selective force for black pigmentation in early hominin evolution?

Melanin provides a crucial filter for solar UV radiation and its genetically determined variation influences both skin pigmentation and risk of cancer. Genetic evidence suggests that the acquisition of a highly stable melanocortin 1 receptor allele promoting black pigmentation arose around the time of savannah colonization by hominins at some 1-2 Ma. The adaptive significance of dark skin is generally believed to be protection from UV damage but the pathologies that might have had a deleterious impact on survival and/or reproductive fitness, though much debated, are uncertain. Here, I suggest that data on age-associated cancer incidence and lethality in albinos living at low latitudes in both Africa and Central America support the contention that skin cancer could have provided a potent selective force for the emergence of black skin in early hominins.