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Visual evoked potentials (VEPs) can provide important diagnostic information regarding the functional integrity of the visual system. This document updates the ISCEV standard for clinical VEP testing and supersedes the 2009 standard. The main changes in this revision are the acknowledgment that pattern stimuli can be produced using a variety of technologies with an emphasis on the need for manufacturers to ensure that there is no luminance change during pattern reversal or pattern onset/offset. The document is also edited to bring the VEP standard into closer harmony with other ISCEV standards. The ISCEV standard VEP is based on a subset of stimulus and recording conditions that provide core clinical information and can be performed by most clinical electrophysiology laboratories throughout the world. These are: (1) Pattern-reversal VEPs elicited by checkerboard stimuli with large 1 degree (°) and small 0.25° checks. (2) Pattern onset/offset VEPs elicited by checkerboard stimuli with large 1° and small 0.25° checks. (3) Flash VEPs elicited by a flash (brief luminance increment) which subtends a visual field of at least 20°. The ISCEV standard VEP protocols are defined for a single recording channel with a midline occipital active electrode. These protocols are intended for assessment of the eye and/or optic nerves anterior to the optic chiasm. Extended, multi-channel protocols are required to evaluate postchiasmal lesions.

Multiple sclerosis is a degenerative inflammatory disease of the CNS characterised by immune-mediated destruction of myelin and progressive neuroaxonal loss. Myelin in the CNS is a specialised extension of the oligodendrocyte plasma membrane and clemastine fumarate can stimulate differentiation of oligodendrocyte precursor cells in vitro, in animal models, and in human cells. We aimed to analyse the efficacy and safety of clemastine fumarate as a treatment for patients with multiple sclerosis. We did this single-centre, 150-day, double-blind, randomised, placebo-controlled, crossover trial (ReBUILD) in patients with relapsing multiple sclerosis with chronic demyelinating optic neuropathy on stable immunomodulatory therapy. Patients who fulfilled international panel criteria for diagnosis with disease duration of less than 15 years were eligible. Patients were randomly assigned (1:1) via block randomisation using a random number generator to receive either clemastine fumarate (5·36 mg orally twice daily) for 90 days followed by placebo for 60 days (group 1), or placebo for 90 days followed by clemastine fumarate (5·36 mg orally twice daily) for 60 days (group 2). The primary outcome was shortening of P100 latency delay on full-field, pattern-reversal, visual-evoked potentials. We analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02040298. Between Jan 1, 2014, and April 11, 2015, we randomly assigned 50 patients to group 1 (n=25) or group 2 (n=25). All patients completed the study. The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5–2·9; p=0·0048) when analysing the trial as a crossover. Clemastine fumarate treatment was associated with fatigue, but no serious adverse events were reported. To our knowledge, this is the first randomised controlled trial to document efficacy of a remyelinating drug for the treatment of chronic demyelinating injury in multiple sclerosis. Our findings suggest that myelin repair can be achieved even following prolonged damage. University of California, San Francisco and the Rachleff Family.

The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and efficacy of opicinumab given soon after a first acute optic neuritis episode. This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18–55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3–5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov, number NCT01721161. The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was −3·5 ms (17·3 vs 20·8 [95% CI −10·6 to 3·7]; 17%; p=0·33) in the ITT population, and −7·6 ms in the PP population (14·7 vs 22·2 [−15·1 to 0·0]; 34%; p=0·050) at week 24 and −6·1 ms (15·1 vs 21·2 [−12·7 to 0·5]; 29%; p=0·071) in the ITT population and −9·1 ms (13·2 vs 22·4 [−16·1 to −2·1]; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 [83%] of 41 in each group) and severity of adverse events (two [5%] of 41 severe adverse events with placebo vs three [7%] of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL [SD 0·21] for placebo vs 0·20 mL [0·52] with opicinumab; 27 [77%] of 35 participants with no change in gadolinium-enhancing [Gd+] lesion number with opicinumab vs 27 [79%] of 34 with placebo; mean 0·4 [SD 0·79 for the placebo group and 0·85 for the opicinumab group] new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity [n=2], asymptomatic increase in transaminase concentrations [n=1]) and none of the participants in the placebo group. Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. Biogen.

Progressive disability in multiple sclerosis occurs because CNS axons degenerate as a late consequence of demyelination. In animals, retinoic acid receptor RXR-gamma agonists promote remyelination. We aimed to assess the safety and efficacy of a non-selective retinoid X receptor agonist in promoting remyelination in people with multiple sclerosis. This randomised, double-blind, placebo-controlled, parallel-group, phase 2a trial (CCMR One) recruited patients with relapsing-remitting multiple sclerosis from two centres in the UK. Eligible participants were aged 18–50 years and had been receiving dimethyl fumarate for at least 6 months. Via a web-based system run by an independent statistician, participants were randomly assigned (1:1), by probability-weighted minimisation using four binary factors, to receive 300 mg/m2 of body surface area per day of oral bexarotene or oral placebo for 6 months. Participants, investigators, and outcome assessors were masked to treatment allocation. MRI scans were done at baseline and at 6 months. The primary safety outcome was the number of adverse events and withdrawals attributable to bexarotene. The primary efficacy outcome was the patient-level change in mean lesional magnetisation transfer ratio between baseline and month 6 for lesions that had a baseline magnetisation transfer ratio less than the within-patient median. We analysed the primary safety outcome in the safety population, which comprised participants who received at least one dose of their allocated treatment. We analysed the primary efficacy outcome in the intention-to-treat population, which comprised all patients who completed the study. This study is registered in the ISRCTN Registry, 14265371, and has been completed. Between Jan 17, 2017, and May 17, 2019, 52 participants were randomly assigned to receive either bexarotene (n=26) or placebo (n=26). Participants who received bexarotene had a higher mean number of adverse events (6·12 [SD 3·09]; 159 events in total) than did participants who received placebo (1·63 [SD 1·50]; 39 events in total). All bexarotene-treated participants had at least one adverse event, which included central hypothyroidism (n=26 vs none on placebo), hypertriglyceridaemia (n=24 vs none on placebo), rash (n=13 vs one on placebo), and neutropenia (n=10 vs none on placebo). Five (19%) participants on bexarotene and two (8%) on placebo discontinued the study drug due to adverse events. One episode of cholecystitis in a placebo-treated participant was the only serious adverse event. The change in mean lesional magnetisation transfer ratio was not different between the bexarotene group (0·25 percentage units [pu; SD 0·98]) and the placebo group (0·09 pu [0·84]; adjusted bexarotene–placebo difference 0·16 pu, 95% CI –0·39 to 0·71; p=0·55). We do not recommend the use of bexarotene to treat patients with multiple sclerosis because of its poor tolerability and negative primary efficacy outcome. However, statistically significant effects were seen in some exploratory MRI and electrophysiological analyses, suggesting that other retinoid X receptor agonists might have small biological effects that could be investigated in further studies. Multiple Sclerosis Society of the United Kingdom.

•Stimulus-driven theories hold that all salient stimuli capture attention.•goal-driven theories posit that salient but irrelevant stimuli can be inhibited.•despite absent behavioral costs, pop-out distractors captured attention initially.•attention to distractors is withdrawn at a later stage, while it is sustained for targets.•marking stimulus positions speeds up neural processing and improves performance. There is much debate about the neural mechanisms that achieve suppression of salient distracting stimuli during visual search. The proactive suppression hypothesis asserts that if exposed to the same distractors repeatedly, these stimuli are actively inhibited before attention can be shifted to them. A contrasting proposal holds that attention is initially captured by salient distractors but is subsequently withdrawn. By concurrently measuring stimulus-driven and intrinsic brain potentials in 36 healthy human participants, we obtained converging evidence against early proactive suppression of distracting input. Salient distractors triggered negative event-related potentials (N1pc/N2pc), enhanced the steady-state visual evoked potential (SSVEP) relative to non-salient (filler) stimuli, and suppressed contralateral relative to ipsilateral alpha-band amplitudes—three electrophysiological measure associated with the allocation of attention—even though these distractors did not interfere with behavioral responses to the search targets. Furthermore, these measures indicated that both stimulus-driven and goal-driven allocations of attention occurred in conjunction with one another, with the goal-driven effect enhancing and prolonging the stimulus-driven effect. These results provide a new perspective on the traditional dichotomy between bottom-up and top-down attentional allocation. Control experiments revealed that continuous marking of the locations at which the search display items were presented resulted in a dramatic and unexpected conversion of the target-elicited N2pc into a shorter-latency N1pc in association with faster reaction times to the targets.

•Perceptual completion aids vision overcoming stimulus noise and partial information.•ICeffect is a visual evoked potential characterization of perceptual completion.•ICeffect to moving and static stimuli was sorted by motion discrimination abilities.•Individuals adept at motion discrimination exhibited distinct topographies.•Motion discrimination operates synergistically with visual completion. Effective visual perception surmounts noise, partial information and dynamic changes in stimuli, resulting in perceptual completion that is often studied using illusory contour (IC) stimuli. Visual evoked potentials (VEPs) from humans yield a characteristic response – the ICeffect – the VEP difference between responses to the presence vs. absence of ICs with multiple phases at ∼150–200 ms and ∼240–400 ms post-stimulus onset. To address how motion signals and an individual’s capability to discriminate motion may contribute to perceptual completion as indexed by the ICeffect, we recorded 128-channel VEPs from 20 healthy adults. On each trial, they indicated which of two stimulus arrays was perceived to move (through linear changes in stimulus size), independently of the presence/absence of ICs. Participants were sub-divided based on a median split in task performance: those “adept” and “non-adept” at detecting moving stimuli. Over the 240–329 ms post-stimulus period, responses from “adept” individuals were characterized by distinct topographies depending on whether stimuli were moving, whereas for “non-adept” individuals the same topography characterized responses to both moving and static stimuli (p = 0.048; η²ₚ=0.300). Furthermore, the VEP topography characterizing responses to moving ICs positively correlated with an individual’s motion discrimination accuracy (Spearman’s rho(18)= 0.467; p = 0.038). Source modelling of this ICeffect included regions of the lateral inferior occipital cortices, parahippocampal cortices extending into the insula, the precentral cortex, and middle frontal cortex and underscores the role of both low-level and high-level cortices in IC perception. Collectively, these data highlight the interplay between motion discrimination and perceptual completion processes.

•Specific visual and acoustic features are often associated during perception.•One example is the pitch of a tone and the size of a visual object.•We used EEG to study the cerebral origin of such associations.•Steady-state visual evoked potentials suggest an origin near primary visual cortex.•Our results support a low-level account for crossmodal associations. Crossmodal correspondences describe our tendency to associate sensory features from different modalities with each other, such as the pitch of a sound with the size of a visual object. While such crossmodal correspondences (or associations) are described in many behavioural studies their neurophysiological correlates remain unclear. Under the current working model of multisensory perception both a low- and a high-level account seem plausible. That is, the neurophysiological processes shaping these associations could commence in low-level sensory regions, or may predominantly emerge in high-level association regions of semantic and object identification networks. We exploited steady-state visual evoked potentials (SSVEP) to directly probe this question, focusing on the associations between pitch and the visual features of size, hue or chromatic saturation. We found that SSVEPs over occipital regions are sensitive to the congruency between pitch and size, and a source analysis pointed to an origin around primary visual cortices. We speculate that this signature of the pitch-size association in low-level visual cortices reflects the successful pairing of congruent visual and acoustic object properties and may contribute to establishing causal relations between multisensory objects. Besides this, our study also provides a paradigm can be exploited to study other crossmodal associations involving visual stimuli in the future.

Background Multifocal visual evoked potential (MF-VEP) assesses a wider visual field than full-field VEP (FF-VEP) and potentially offers a more precise analysis of optic nerve injury and repair following optic neuritis. MF-VEP may offer advantages over FF-VEP as an endpoint in clinical trials of remyelinating therapies. Objective MF-VEP testing was used to study changes in visual pathways in 48% of RENEW [phase II, opicinumab (anti-LINGO-1; BIIB033) vs. placebo after first acute unilateral optic neuritis] participants. Methods This exploratory MF-VEP RENEW substudy compared mean outcomes at weeks 24 and 32 among participants in the intent-to-treat (ITT; n  = 39; 72% female; mean age: 32.3 years) and per-protocol (PP; n  = 31; 71% female; mean age: 32.2 years) populations in affected and fellow eye latency from fellow eye baseline latency and affected and fellow eye amplitude from their own baselines. Treatment differences were evaluated using analysis of covariance (week 24) and a mixed-effect model of repeated measures (week 32). Last observation carried forward was used to impute missing data at week 24. Results A trend for improvement in affected eye MF-VEP latency with opicinumab versus placebo was seen in the ITT and PP populations at weeks 24 and 32. Both treatment groups in the ITT population experienced partial recovery of amplitude in the affected eye at week 32. Notably, the mean change in fellow eye amplitude at weeks 24 and 32 was − 17.57 and − 31.41 nanovolts (nV) in placebo but only − 0.59 and 1.93 nV in the opicinumab group [differences at weeks 24 and 32: 16.98 nV ( p  = 0.050) and 33.33 nV ( p  < 0.01), respectively]. Conclusion Results from this substudy showed advantages of MF-VEP over FF-VEP in multicenter studies of central nervous system reparative therapies and provide novel evidence that fellow eye visual pathway amplitude loss occurs after optic neuritis but can potentially be prevented by opicinumab treatment. Registration ClinicalTrials.gov identifier NCT01721161.

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for visual evoked potentials (VEPs) describes a minimum procedure for clinical VEP testing and encourages more extensive testing. This ISCEV extended protocol is an extension to the VEP standard. It describes procedures for recording multiple VEPs to a range of sizes of pattern stimuli to establish the VEP spatial frequency limit (threshold) and for relating this limit to visual acuity.

Background Bright light therapy (BLT) has been proved to have beneficial effects on Parkinson’s disease (PD), the mechanisms remained unclear. Improvements of visual pathways might be key to BLT. Objective The aim of this study is to validate whether BLT improves clinical symptoms in PD and explore the possible mechanisms of visual pathways evaluated by optical coherence tomography (OCT), pattern electroretinogram (PERG) and visual evoked potentials (VEP). Methods Twenty-three PD patients were enrolled in this crossover randomized placebo-controlled study. Participants received either one month of BLT or dim light therapy (DLT), separated by one-month wash-out period, followed by another intervention. Participants underwent clinical scales, and visual-related evaluations including OCT, PERG and VEP before and after each intervention. Mixed-effects regression models were used to determine the effect between BLT and DLT on improving the differentials of clinical scales (Δscales), OCT (Δretinal thickness), PERG (ΔPERG values) and VEP (ΔP100 latencies). Correlations between clinical symptoms and visual evaluations improvements were analyzed in PD patients receiving BLT. Results Excessive daytime sleepiness, anxiety, life quality and autonomic function were improved after BLT. Compared with DLT, bilateral ΔN95 latencies for PERG and ΔP100 latencies for VEP were improved after BLT. We did not observe the changes of four quadrants retinal nerve fiber layer (RNFL) thickness after BLT or DLT. Conclusions BLT is a valuable and safe non-pharmacological intervention for improving visual function in PD patients. Significance These findings extend neural mechanisms of BLT to visual pathways improvements.