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.

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.

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.

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.

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.

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.

S cones: Evolution, retinal distribution, development, and spectral sensitivity.

S cones expressing the short wavelength-sensitive type 1 (SWS1) class of visual pigment generally form only a minority type of cone photoreceptor within the vertebrate duplex retina. Hence, their primary role is in color vision, not in high acuity vision. In mammals, S cones may be present as a constant fraction of the cones across the retina, may be restricted to certain regions of the retina or may form a gradient across the retina, and in some species, there is coexpression of SWS1 and the long wavelength-sensitive (LWS) class of pigment in many cones. During retinal development, SWS1 opsin expression generally precedes that of LWS opsin, and evidence from genetic studies indicates that the S cone pathway may be the default pathway for cone development. With the notable exception of the cartilaginous fishes, where S cones appear to be absent, they are present in representative species from all other vertebrate classes. S cone loss is not, however, uncommon; they are absent from most aquatic mammals and from some but not all nocturnal terrestrial species. The peak spectral sensitivity of S cones depends on the spectral characteristics of the pigment present. Evidence from the study of agnathans and teleost fishes indicates that the ancestral vertebrate SWS1 pigment was ultraviolet (UV) sensitive with a peak around 360 nm, but this has shifted into the violet region of the spectrum (>380 nm) on many separate occasions during vertebrate evolution. In all cases, the shift was generated by just one or a few replacements in tuning-relevant residues. Only in the avian lineage has tuning moved in the opposite direction, with the reinvention of UV-sensitive pigments.

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.

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.

Electrodiagnostic assessment in optic nerve disease.

PURPOSE OF REVIEW: Complementary electrophysiological techniques can be useful in detecting and localizing dysfunction within the visual pathway. Recent developments are outlined in the context of neuro-ophthalmology. RECENT FINDINGS: The relationship between nerve fibre layer anatomy and the pattern visual evoked potential has been addressed, correlating axonal loss with visual pathway dysfunction. Longitudinal assessment of multiple sclerosis patients has defined parameters affecting the utility of the pattern visual evoked potential as an outcome measure in potential treatment trials. In optic nerve tumours, the pattern visual evoked potential may help identify and monitor the disorder. The pattern electroretinogram assesses retinal ganglion cell function and can identify macular dysfunction, possibly mimicking optic nerve disease clinically. The spatial extent of macular dysfunction can be assessed using the multifocal electroretinogram. Objective visual evoked potential assessment of visual acuity can be important in the management of nonorganic visual loss. The multifocal visual evoked potential is a relatively new technique that is attracting increasing research interest, particularly as a measure of visual field loss, but has yet to be established as a reliable diagnostic tool. SUMMARY: Electrophysiology, combined with clinical and imaging investigations, is a powerful diagnostic and monitoring tool. Macular dysfunction can mimic optic nerve disease in the absence of fundus abnormality.

Short and long term axotomy-induced ERG changes in albino and pigmented rats.

PURPOSE: To investigate the different components of full-field flash electroretinogram (ERG) responses in adult albino and pigmented rats at various time intervals following optic nerve transection (ONT). METHODS: In adult Sprague-Dawley (SD, albino) and Piebald-Viral-Glaxo (PVG, pigmented) rats, the left optic nerve was transected intraorbitally to induce retinal ganglion cell (RGC) death. ERG responses were recorded simultaneously from both eyes beforehand and at 1, 2, 4, and 12 week intervals after ONT. The ERG a- and b-waves and the scotopic threshold responses (STR) were analyzed in scotopic conditions. White light stimuli of intensities ranging from 10(-6) to 10(-4) cd.s.m(-2) were used to record the positive and negative scotopic threshold responses (pSTR and nSTR), while stimulus light intensities ranging from 10(-4) to 10(2) cd.s.m(-2) were used to analyze the a- and b-wave amplitudes of standard ERG recordings. RESULTS: In the albino rats, one week after intraorbital ONT, the STR mean amplitude decreased significantly, to approximately 60% of the values registered for the contralateral eye (p<0.05), which had not been operated on; standard ERG a- and b-waves showed a small reduction in amplitude-to approximately 85%. By two weeks after ONT, the STR mean amplitude was approximately 40% that of the contralateral eye, while the a- and b-wave amplitudes had further decreased to approximately 75%. Four weeks after ONT, the STR had fallen to 60% of that of the contralateral eyes, whereas the a- and b-waves reached values of approximately 90%. Twelve weeks after ONT, the STR remained significantly reduced to approximately 45%, whereas the a- and b-waves reached values of approximately 90%. In the pigmented rats, one week after intraorbital ONT, the mean amplitude had decreased significantly, to approximately 60% for the pSTR and to 80% for the nSTR of the values registered for the intact contralateral eye (p<0.05); while the standard ERG a- and b-waves showed a small reduction in amplitude to approximately 90%. Two weeks after ONT, the STR mean amplitude was approximately 55%, while the a- and b-wave amplitudes had further decreased to approximately 65%. Four weeks after ONT, the STR also was significantly reduced, to only 40%, whereas the a- and b-waves reached values of approximately 60%. Twelve weeks after ONT, the pSTR and nSTR remained significantly reduced to approximately 40% and 70%, respectively; whereas the a- and b-waves reached values of approximately 80%. CONCLUSIONS: Optic nerve injury results in transient reductions of the major ERG components, the a- and b-waves, as well as permanent reductions of the early components of the ERG, the negative and positive scotopic threshold responses. Because ONT induces massive RGC loss, it is likely that permanent reduction in the STR represents a lack of the RGC population, thus highlighting the importance of the STR recordings as an electrophysiological tool for the assessment of RGC function.

Auditory brainstem anomalies in human albinos.

Brainstem auditory evoked potentials recorded from human albinos indicate significant hemispheric asymmetry. The asymmetry is symptomatic of differences between decussated and nondecussated auditory pathways in albino and pigmented humans at approximately the level of the superior olivary nuclei. Abnormal decussation of auditory pathways in albinos probably coincides with known visual system anomalies.

Visual system anomalies in human ocular albinos.

Visually evoked potentials recorded from two types of human ocular albinos demonstrated significant hemispheric asymmetry following monocular stimulation. The asymmetry is indicative of disorganization of retinogeniculostriate projections similar to that reported for mammals with total albinism. Abnormal optic projections are associated with lack of ocular pigment and are not associated with any specific generalized pigment defect.

Development of the rat's uncrossed retinotectal pathway and its relation to plasticity studies.

In the normal newborn rat the retinotectal pathway from each eye distributes across the whole area of both the ipsilateral and contralateral superior colliculus. Most of the ipsilateral projection retracts during the first ten postnatal days to produce the normal adult pattern, but retraction fails to occur if one eye is removed at birth.

Optokinetic eye movements in albino rabbits: inversion in anterior visual field.

When visual contrasts are restricted to the anterior sector (90 degrees to 180 degrees) of the albino rabbit's visual field, eye position is dramatically unstable, and when such contrasts are moved, horizontal optokinetic eye movements are inverted: the direction of pursuit is opposite to that of the stimulus. In the posterior visual field stability and optokinetic reactions are normal, as in all parts of the pigmented rabbit's visual field. This phenomenon may be one more of the complex of visual system defects linked to albinism.

Retinal projections to the accessory optic system in pigmented and albino ferrets (Mustela putorius furo).

We investigated if a reduced specificity of the retinal projection to the accessory optic system might be responsible for the loss of direction selectivity in the nucleus of the optic tract and dorsal terminal nucleus (NOT-DTN) and, in consequence of this, the optokinetic deficits in albino ferrets. Under electrophysiological control we performed dual tracer injections into the NOT-DTN and the medial terminal nucleus (MTN). Retrogradely labelled ganglion cells were found in the visual streak, the dorsal, and the ventral retina both after injections into the NOTDTN and the MTN indicating that both nuclei receive input from the same retinal regions. The distribution and spacing of labelled ganglion cells did not differ between pigmented and albino ferrets. However, retinal ganglion cells projecting simultaneously to both the NOT-DTN and the MTN occurred only in albino ferrets. These results suggest that a reduced specificity of the projection pattern of direction specific ganglion cells may contribute to the loss of direction selectivity in the NOT-DTN in albino ferrets.

Albinism: classification, clinical characteristics, and recent findings.

PURPOSE: To describe the clinical characteristics and recent findings in the heterogeneous group of inherited disorders of melanin biosynthesis grouped as "albinism." METHODS: The current classification of albinism, and the cutaneous, ocular, and central nervous system characteristics are presented. Recent clinical findings are summarized. RESULTS: Albinism is now classified based on genes known to be responsible for albinism. Foveal hypoplasia is invariably present and individuals with albinism often have delayed visual development, reduced vision, nystagmus, a positive angle kappa, strabismus, iris transillumination, and absent or reduced melanin pigment in the fundi. A visual-evoked potential can document the excessive retinostriate decussation seen in albinism. Grating acuity can be used to document delayed visual development in preverbal children. Glasses are often needed to improve visual acuity and binocular alignment. CONCLUSIONS: Albinism is caused by several different genes. Heterogeneity in clinical phenotype indicates that expressivity is variable.