Steady-state PERG adaptation: a conspicuous component of response variability with clinical significance.

PURPOSE: To investigate within-test variability of the steady-state PERG (SS-PERG). METHODS: SS-PERGs were recorded in response to black-white horizontal gratings (1.6 cycles/deg, 98% contrast, 15.63 reversals/s, LED display, 25 deg square field, 800 cd/sqm mean luminance) using skin electrodes. PERG and noise (± reference) signals were averaged over 1024 epochs (~ 2.2 min) and Fourier analyzed to retrieve SS-PERG amplitude and phase. SS-PERGs were split into 16 partial averages (samples) of 64 epochs each, and corresponding amplitudes and phases combined in polar coordinates to assess their dispersion (within-test variability). To assess time-dependent variability, samples were clustered in four successive time segments of ~ 33 s each. Amplitude adaptation was defined as amplitude difference between initial and final clusters, and PERG phase adaptation as the corresponding phase difference. To determine the dynamic range of SS-PERG adaptation, recording was performed in normal controls of different age (n = 32) and patients with different severity of optic nerve dysfunction (early manifest glaucoma, EMG, n = 7; non-arteritic ischemic optic neuropathy, NAION, n = 5). RESULTS: Amplitude adaptation was largest in younger controls (amplitude adaptation ÷ noise, SNR = 9.5, 95% CI 13.1, 5.9) and progressively decreased with increasing age (older subjects, SNR = 5.5, 95% CI 9.2, 1.8) and presence of disease (EMG: SNR = 2.4, 95% CI 3.5, 1.4; NAION: SNR = 1.9, 95% CI 6.5,-2.2). In 11 young subjects, amplitude adaptation was repeatable (test-retest in two sessions a week apart; intraclass correlation coefficient = 0.59). Phase adaptation was not significantly different from zero in all groups. CONCLUSIONS: SS-PERG adaptation accounts for a sizeable portion of the within-test variability. As it has robust SNR, sufficient test-retest variability, and is altered in disease, it may have physiological and clinical significance. This study suggests that SS-PERG protocols should include adaptation in addition to SS-PERG amplitude and phase/latency.

Dysfunction of the magnocellular stream in Alzheimer's disease evaluated by pattern electroretinograms and visual evoked potentials.

BACKGROUND: Visuo-spatial disturbances could represent a clinical feature of early stage Alzheimer's disease (AD). The magnocellular (M) pathway has anatomo-physiological characteristic which make it more suitable for detecting form, motion and depth compared with parvocellular one (P). OBJECTIVE: Aim of our study was to evaluate specific visual subsystem involvement in a group of AD patients, recording isoluminant chromatic and luminance pattern electroretinograms and pattern visual evoked potentials. MATERIAL AND METHODS: data were obtained from 15 AD patients (9 females and 6 males, mean age+/-1SD: 77.6+/-4.01 years) not yet undergoing any treatment, and from 10 age-matched healthy controls. Diagnosis of probable AD was clinically and neuroradiologically established. PERGs were recorded monocularly in response to equiluminant red-green (R-G), blue-yellow (B-Y) and luminance yellow-black (Y-Bk) horizontal square gratings of 0.3c/deg and 90% contrast, reversed at 1Hz. VEPs were recorded in response to full-field (14 deg) equiluminant chromatic R-G, B-Y and luminance Y-Bk sinusoidal gratings of 2c/deg, presented in onset (300ms)-offset (700ms) mode, at the contrast levels of 90%. RESULTS: All data were retrieved in terms of peak-amplitude and latency and assessed using the Student's t-test for paired data. Temporal differences of PERGs and VEPs, evoked by Y-Bk grating in AD patients compared with controls, suggest a specific impairment of the magnocellular stream. CONCLUSIONS: Our study support the hypothesis that the impairment of the PERGs and VEPs arising from the magnocellular streams of visual processing may indicate a primary dysfunction of the M-pathways in AD.

Chromatic pattern-reversal electroretinograms (ChPERGs) are spared in multiple system atrophy compared with Parkinson's disease.

Idiopathic Parkinson's disease (IPD) patients have abnormal visual evoked potentials (VEPs) and pattern electroretinograms (PERGs), attributed to dopaminergic transmission deficiency in visual pathway, probably the retina. VEP abnormalities are not reported in multiple system atrophy (MSA). The aim of this study was to investigate and compare chromatic (Ch) red-green (R-G) and blue-yellow (B-Y), and luminance yellow-black (Y-Bk) PERGs in patients with MSA and IPD. We investigated 6 MSA patients (mean age: 62+/-7.4 years) not undergoing any pharmacological treatment, as well as 12 early IPD patients (mean age: 60.1+/-8.3 years) and 12 age-matched normal observers. ChPERGs were recorded monocularly in response to full-field equiluminant R-G, B-Y and Y-Bk horizontal gratings. In MSA only responses to R-G stimuli showed minimal insignificant changes (slight but not significant amplitude reduction without any significant latency delay); no significant abnormality was detected for B-Y and luminance Y-Bk stimuli. By contrast, in IPD all responses were reduced in amplitude and delayed in latency, above all for B-Y stimuli. Present data indicate that both chromatic and achromatic PERGs are virtually unaffected in MSA, whereas in early IPD they are clearly impaired, suggesting different pathogenic retinal mechanisms and a useful simple tool for distinguishing MSA from IPD.

Requirement of the nicotinic acetylcholine receptor beta 2 subunit for the anatomical and functional development of the visual system.

In the mammalian visual system the formation of eye-specific layers at the thalamic level depends on retinal waves of spontaneous activity, which rely on nicotinic acetylcholine receptor activation. We found that in mutant mice lacking the beta2 subunit of the neuronal nicotinic receptor, but not in mice lacking the alpha4 subunit, retinofugal projections do not segregate into eye-specific areas, both in the dorso-lateral geniculate nucleus and in the superior colliculus. Moreover, beta2-/- mice show an expansion of the binocular subfield of the primary visual cortex and a decrease in visual acuity at the cortical level but not in the retina. We conclude that the beta2 subunit of the nicotinic acetylcholine receptor is necessary for the anatomical and functional development of the visual system.

Equiluminant red-green and blue-yellow VEPs in multiple sclerosis.

The primate visual system is composed by two color-opponent pathways--red-green (R-G) and blue-yellow (B-Y)--subserved by the so-called parvo- and koniocellular streams respectively. The authors' aim was to compare the relative involvement of chromatic visual subsystems in multiple sclerosis (MS). In 30 MS patients with different forms of MS they recorded visual evoked potentials (VEPs) to onset (300 msec) and offset (700 msec) of equiluminant R-G and B-Y sinusoidal gratings of different contrast (90% and 25%). Equiluminance was established psychophysically by establishing the R-G and the B-Y color ratio at which chromatic gratings alternating at 15 and 10 Hz respectively had minimum visibility. The negative wave at stimulus onset with a peak latency of 120 to 160 msec was evaluated. Ordinary VEPs to luminance (LUM) contrast (black-white reversing checkerboards of 15' check size and 50% contrast) were also recorded for comparison. Latencies of R-G VEPs were abnormal in 53.3% and 58.3% of patients at 90% and 25% contrast respectively, whereas abnormal B-Y VEPs were 56.6% and 48.3%. Latencies of LUM VEPs were abnormal in 45% of patients. Interocular latency asymmetries were abnormal in 59.2% and 33.3% of patients for R-G, and 51.8% and 62.9% for B-Y. Latency asymmetries for LUM VEP were abnormal in 46.4% of patients. The higher rate of VEP abnormalities found with equiluminant chromatic stimuli compared with achromatic stimuli confirms the general vulnerability of color-opponent visual pathways in MS, even if the number of patients with abnormal findings was not significantly different when both test conditions were compared. VEPs to R-G and B-Y equiluminant stimuli appear to be involved approximately to the same extent.

Role of neurotrophins in the development and plasticity of the visual system: experiments on dark rearing.

An extensive series of studies, beginning with the pioneering experiments of Wiesel and Hubel, have shown that correct visual experience is crucial for the development of the visual system. Several years ago, we put forward the hypothesis that neurotrophic factors of the neurotrophin family (NGF, BDNF, NT-3, NT-4) have a role in mediating the effects of visual experience in the developing visual system. This theory is based on the following experimental results: (a) exogenous supply of neurotrophins during the critical period prevents the effects of monocular deprivation; and (b) transplant of cells releasing NGF allows a normal development of the functional properties of visual cortical neurons in dark-reared rats.

Lack of cortical contrast gain control in human photosensitive epilepsy.

Television and video games may be powerful triggers for visually induced epileptic seizures. To better understand the triggering elements of visual stimuli and cortical mechanisms of hyperexcitability, we examined eleven patients with idiopathic photosensitive epilepsy by recording visually evoked potentials (VEPs) in response to temporally modulated patterns of different contrast. For stimuli of low-medium, but not high, temporal frequency, the contrast dependence of VEP amplitude and latency is remarkably abnormal for luminance contrast (black-white), but not so for chromatic contrast (equiluminant red-green) stimuli. We conclude that cortical mechanisms of contrast gain control for pattern stimuli of relatively low temporal frequency and high luminance contrast are lacking or severely impaired in photosensitive subjects.

BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex.

Maturation of the visual cortex is influenced by visual experience during an early postnatal period. The factors that regulate such a critical period remain unclear. We examined the maturation and plasticity of the visual cortex in transgenic mice in which the postnatal rise of brain-derived neurotrophic factor (BDNF) was accelerated. In these mice, the maturation of GABAergic innervation and inhibition was accelerated. Furthermore, the age-dependent decline of cortical long-term potentiation induced by white matter stimulation, a form of synaptic plasticity sensitive to cortical inhibition, occurred earlier. Finally, transgenic mice showed a precocious development of visual acuity and an earlier termination of the critical period for ocular dominance plasticity. We propose that BDNF promotes the maturation of cortical inhibition during early postnatal life, thereby regulating the critical period for visual cortical plasticity.

Vision in mice with neuronal redundancy due to inhibition of developmental cell death.

Transgenic mice overexpressing bcl-2, due to inhibition of naturally occurring cell death, have much larger brains and optic nerves as compared to wild-type mice. Since developmental cell death is believed to exert a crucial role in establishing the mature neural circuitry and function, we asked the question of whether basic aspects of vision were altered in bcl-2 mice. Local visually evoked potentials (VEPs) in response to patterned stimuli were recorded from the primary visual cortex. The representation of the vertical meridian was displaced by about 15% in the bcl-2 mouse, accounting for brain expansion. However, visual acuity, contrast threshold, and response latency were normal, indicating that compensatory mechanisms can ensure normal basic properties of vision in spite of marked neuronal redundancy.

Losses of hemifield contrast sensitivity in patients with pituitary adenoma and normal visual acuity and visual field.

OBJECTIVE: To detect early losses of contrast sensitivity (CS) in patients with pituitary adenomas, before the occurrence of visual acuity and visual field defects. METHODS: CS has been evaluated in both hemifields of 28 patients with different kinds of pituitary adenoma (mainly intrasellar) and normal visual acuity and visual field, as well as in 15 age-matched controls. Two different stimuli were used: a coarse (0.3 c/deg) dynamic (10 Hz) grating and a finer (2 c/deg) static grating. RESULTS: On average, CS and/or hemifield asymmetry were reduced in patients, whereas perimetric sensitivity was normal. CS losses were more frequent for 2 c/deg static-, as compared with 0.3 c/deg, 10 Hz stimuli. However selective losses for either stimuli were also found. CS losses did not correlate with anatomical measurements (size, chiasm involvement) of tumors as established by MRI scans. CONCLUSIONS: CS evaluation may provide a simple and effective tool for early detection and monitoring of visual dysfunction in patients with pituitary adenoma. The lack of correlation between CS losses and chiasm involvement suggests causes different from chiasmal compression for visual dysfunction.

Normative data for onset VEPs to red-green and blue-yellow chromatic contrast.

OBJECTIVE: To better characterize the properties of chromatic VEPs to onset-offset of red-green and blue-yellow equiluminant patterns, and establish normative values for a set of stimuli able to elicit robust and reliable responses, suitable for the clinical application. METHODS: Chromatic VEPs have been recorded (Oz lead) from 28 normal subjects (age range 20-53 years) in response to monocular presentation of both red-green and blue-yellow equiluminant sinusoidal gratings. Stimuli were generated by a Cambridge VSG/2 card and displayed on a Barco CCID monitor (14x14 deg field size). Spatial frequency, chromaticity, contrast and onset-offset duration were varied. RESULTS: For both red-green and blue-yellow equiluminant stimuli, robust responses have been obtained with gratings of 2 c/deg, presented in onset (300 ms) offset (700 ms) mode, at contrasts ranging from 90 to 6%. In all observers, the VEP waveform consisted mainly of a negative wave at stimulus onset, with a latency rapidly increasing with decreasing contrast. For both red-green and blue-yellow stimuli, the VEP contrast threshold coincided with the psychophysical threshold. CONCLUSIONS: The results complement previous studies aimed at characterizing the properties of chromatic VEPs. In addition, normative data are provided for a set of stimulus characteristics suitable for the clinical routine.

The effects of ageing on reaction times to motion onset.

We have measured reaction time (RT) to motion onset in two groups of subjects (average ages: 70 and 29 years), for horizontal gratings of 1 c deg-1, modulated in either luminance or colour (equiluminant red-green), for various contrasts and speeds. For both old and young subjects, RTs depended on both speed and contrast, being faster at high speeds and high contrasts, and showed a stronger contrast dependency for chromatic gratings. The older subjects were systematically slower than the younger subjects. The difference between old and young RTs varied with condition, being 30-40 ms more at the slow than at the fast speed. The relative difference in RTs in different stimulus conditions shows that at least some of the increase in response time with age has a sensory origin. The results relate well to previous work on visual evoked potentials.

The spatial tuning of steady state pattern electroretinogram in multiple sclerosis.

In normal subjects, the steady-state electroretinogram in response to contrast reversing gratings (PERG), is spatially band-pass tuned in amplitude, with a maximum at intermediate spatial frequencies and an attenuation at lower and higher ones. The amplitude attenuation at low spatial frequencies is believed to reflect centre-surround antagonistic interactions in the receptive fields of inner retinal neurons. The aim of this study was to evaluate the PERG spatial tuning in multiple sclerosis (MS) patients without a previous optic neuritis history. Steady- state PERGs in response to counterphase-modulated (8 Hz) sinusoidal gratings of variable spatial frequency (0.6, 1.0, 1.4, 2.2 and 4.8 c/deg), were recorded from 18 patients with definite or probable MS and no history of optic neuritis (ON-). Nine of them had no signs of subclinical optic nerve demyelination (asymptomatic) in either eye, while nine had symptoms or signs of optic pathways involvement (symptomatic) in one or both eyes. Results were compared with those obtained from 10 MS patients with a previous history of optic neuritis (ON+) in one or both eyes, as well as from 21 age-matched controls. The amplitudes and phases of the responses' 2nd harmonics were measured. Compared with the controls, asymptomatic ON- patients showed selective losses in mean PERG amplitudes at medium and high (1.0-4.8 c/deg) spatial frequencies. Symptomatic ON- patients and ON+ patients had reductions in mean PERG amplitudes, with respect to controls, involving the whole spatial frequency range, but with greater losses at medium-high (1.0-4.8 c/deg) than at lower spatial frequencies. In all patients' groups, the average PERG spatial tuning function differed significantly from that of the controls, assuming a low-pass instead of the normal band-pass shape. The PERG phase was delayed in ON+ but not in ON- patients, as compared to controls. However, the phase delay was independent of spatial frequency. In both ON- and ON+ patients, losses in PERG amplitude and spatial tuning tended to be associated with corresponding abnormalities in perimetric sensitivity, visual acuity, colour vision and transient visual evoked potential (VEP) latency. The results indicate that abnormalities of the spatial tuning of steady-state PERG can be found in MS patients without either optic neuritis or signs of subclinical optic nerve demyelination. These changes may reflect a retinal dysfunction, developing early in the course of MS, due to a loss of specific subpopulations of inner neurons, changes in lateral interactions of their receptive fields, or both.

The visual physiology of the wild type mouse determined with pattern VEPs.

Genetically manipulated mice are important tools for studies on plasticity and degeneration/regeneration in the visual system. However, a description of the basic properties of the visual performance of the wild type mouse is still lacking. To characterize the visual physiology of the wild type (C57BL/6J) mouse we recorded Visual Evoked Potentials (VEPs) from the primary visual cortex. As compared to behavioral methods, VEPs may have the advantage that different aspects of vision can be screened readily and simultaneously in the same animals, including those with poor visual behavior due to motor or learning deficits. Local VEP responses to patterned visual stimuli have been recorded from the binocular visual cortex of anesthetized mice. Spatial (visual acuity, contrast threshold) and temporal (temporal function, response latency, motion sensitivity) aspects of VEPs were evaluated. The mouse VEP acuity was 0.6 c/deg, which is comparable to the behavioral visual acuity. The VEP peak contrast threshold was 5% (no behavioral data are available). Cortical representation of visual coordinates and cortical magnification factor corresponded to those previously reported using single cell recordings. Laminar analysis of VEPs indicated a dipole source in the supragranular layers of the visual cortex as a major response generator. VEPs showed contribution from both eyes, although biased strongly towards the eye contralateral to the recorded cortex. Results provide a comprehensive framework for characterizing visual phenotypes of a variety of transgenic mice.

Disruption of retinoid-related orphan receptor beta changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice.

The orphan nuclear receptor RORbeta is expressed in areas of the central nervous system which are involved in the processing of sensory information, including spinal cord, thalamus and sensory cerebellar cortices. Additionally, RORbeta localizes to the three principal anatomical components of the mammalian timing system, the suprachiasmatic nuclei, the retina and the pineal gland. RORbeta mRNA levels oscillate in retina and pineal gland with a circadian rhythm that persists in constant darkness. RORbeta-/- mice display a duck-like gait, transient male incapability to sexually reproduce, and a severely disorganized retina that suffers from postnatal degeneration. Consequently, adult RORbeta-/- mice are blind, yet their circadian activity rhythm is still entrained by light-dark cycles. Interestingly, under conditions of constant darkness, RORbeta-/- mice display an extended period of free-running rhythmicity. The overall behavioral phenotype of RORbeta-/- mice, together with the chromosomal localization of the RORbeta gene, suggests a close relationship to the spontaneous mouse mutation vacillans described >40 years ago.

Protection of retinal ganglion cells and preservation of function after optic nerve lesion in bcl-2 transgenic mice.

Multicellular organisms face the necessity of removing superfluous or injured cells during normal development, tissue turn-over and in response to damaging conditions. These finalised killings occur throughout a process, commonly called programmed cell death (PCD), which is placed under strict cellular control. PCD is regulated by the products of the expression of a number of genes. This fact raises the intriguing possibility of inhibiting such degenerative processes by operating on some of the controlling genes. Central neurons of transgenic mice overexpressing bcl-2, a powerful inhibitor of PCD, are remarkably resistant to degeneration induced by noxious stimuli. We have explored the ate of retinal ganglion cells and of their axons, when such transgenic animals have been challenged by a lesion of the optic nerve. These results have direct bearing on the possibility of attaining functional restoration of the injured pathway.

Cytidine-5'-diphosphocholine improves visual acuity, contrast sensitivity and visually-evoked potentials of amblyopic subjects.

PURPOSE: Cytidine-5'-diphosphocholine (CDP-choline) therapy is currently used to improve the consciousness level in patients with brain lesions and as a complement to levodopa therapy in Parkinson's disease. Recently, the substance has been shown to improve the visual acuity (VA) of both eyes of adults with amblyopia. This study aims at establishing whether Contrast Sensitivity (CS) and visually-evoked potentials (VEPs) also change after CDP-choline treatment. METHODS: VA, CS, and VEPs were measured in a group of amblyopic volunteers (n = 10, mean age 24.8 years) before treatment with Neuroton (CDP-choline, 1 g/day intramuscularly [IM] for 15 days) and the day after termination of the same. CS was evaluated, using a forced-choice, automatic procedure (QUEST: Watson and Pelli, 1983). Steady-state VEPs were recorded in response to counterphased (8 Hz) sinusoidal gratings (2 c/deg) of different contrasts. RESULTS: On average, after treatment, VA improved 1.4-1.5 lines in the amblyopic eyes and 0.4 lines in the normal eyes. CSs improved in both dominant and amblyopic eyes by about 3 dB. VEPs increased in amplitude (about 30%) and advanced in phase (about 0.2 pi rad). Amplitude and phase changes were not correlated. CONCLUSIONS: Treating adult amblyopes with CDP-choline has the effect of improving their VA, CS and VEPs. Changes occur in both eyes, although to different extents, and resemble those previously reported for levodopa treatment.

Transplant of polymer-encapsulated cells genetically engineered to release nerve growth factor allows a normal functional development of the visual cortex in dark-reared rats.

Visual experience is necessary for the normal development of the visual system. Dark-reared mammals show abnormal vision when reintroduced into a normal environment. The absence of visual experience during the critical period results in reduced and/or inappropriate neural responses in visual cortical neurons. The change in electrical activity induced by dark rearing is probably reflected by the modulation of specific unknown molecules. Neurotrophins are present in the developing visual cortex and their production depends on visually driven electrical activity. Recent findings support the possibility that an important link between electrical activity in the visual pathway and correct development of visual properties is represented by neurotrophins. We advance the hypothesis that the visual abnormalities present in dark-reared animals could be due to a decreased production of a neurotrophin secondary to the lack of visual stimulation. We report that some properties of visual cortical response such as receptive field size, orientation selectivity, adaptation to repeated stimulation, response latency and visual acuity are virtually normal in dark-reared rats transplanted with polymer-encapsulated baby hamster kidney cells genetically engineered to release nerve growth factor.

Responses to chromatic and luminance contrast in glaucoma: a psychophysical and electrophysiological study.

Increasing anatomical evidence indicates that large retinal ganglion cells (M-cells) are preferentially damaged in primary open angle glaucoma (OAG), while the smaller ganglion cells (P-cells) are relatively spared. In 13 patients with defined OAG and modest visual field defects, we evaluated the responses to stimuli that are expected to involve primarily the function of the P-pathway and compared them with those of control subjects. The psychophysical contrast sensitivity (CS), the PERG and the VEPs were measured for red-green gratings of pure chromatic contrast, as well as yellow-black gratings of pure luminance contrast. As compared with controls, OAG patients had reduced CS for both luminance and chromatic contrast stimuli by about 6 dB. PERGs and VEPs to luminance stimuli were little affected, whereas those to chromatic stimuli were both reduced in amplitude and delayed. These results indicate that visual dysfunction in glaucoma is not selective for the M-pathway, and that responses to equiluminant colour-contrast stimuli may be of diagnostic value.