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Visual perceptual learning describes the improvement of visual perception with repeated practice. Previous research has established that the learning effects of perceptual training may be transferable to untrained stimulus attributes such as spatial location under certain circumstances. However, the mechanisms involved in transfer have not yet been fully elucidated. Here, we investigated the effect of altering training time course on the transferability of learning effects. Participants were trained on a motion direction discrimination task or a sinusoidal grating orientation discrimination task in a single visual hemifield. The 4000 training trials were either condensed into one day, or spread evenly across five training days. When participants were trained over a five-day period, there was transfer of learning to both the untrained visual hemifield and the untrained task. In contrast, when the same amount of training was condensed into a single day, participants did not show any transfer of learning. Thus, learning time course may influence the transferability of perceptual learning effects.

Neocortical-hippocampal interactions support new episodic (event) memories, but there is conflicting evidence about the dependence of remote episodic memories on the hippocampus. In line with systems consolidation and computational theories of episodic memory, evidence from model organisms suggests that the cornu ammonis 3 (CA3) hippocampal subfield supports recent, but not remote, episodic retrieval. In this study, we demonstrated that recent and remote memories were susceptible to a loss of episodic detail in human participants with focal bilateral damage to CA3. Graph theoretic analyses of 7.0-Tesla resting-state fMRI data revealed that CA3 damage disrupted functional integration across the medial temporal lobe (MTL) subsystem of the default network. The loss of functional integration in MTL subsystem regions was predictive of autobiographical episodic retrieval performance. We conclude that human CA3 is necessary for the retrieval of episodic memories long after their initial acquisition and functional integration of the default network is important for autobiographical episodic memory performance.

Objectives The evaluation of novel disease modifying drugs requires biomarkers that are simultaneously sensitive to disease state but resistant to the effects of background symptomatic treatment. Saccadic eye movement parameters have been proposed as a neurophysiological biomarker for Parkinson's disease (PD) and so it is important to know how they are affected by dopaminergic medication. Studies to date are conflicting: some have concluded that medication prolongs saccadic latencies while others suggest they are shortened. We aimed to characterise the effects of antiparkinsonian medication on prosaccadic and antisaccadic parameters in a large cohort of PD patients and age matched healthy controls and to survey the current literature in comparison to the study findings. Methods We studied saccades both off and on medication in 38 PD patients and 34 healthy controls (HC). Latencies, amplitudes, velocities, and directional errors were evaluated, using a published standardised protocol. We then combined this study and previously published literature in a meta-analysis of the effects of antiparkinsonian medication on prosaccadic latency (PSL). Results PSL is significantly prolonged by dopaminergic medication in PD, from a mean of 222.7 ms in the OFF medication state to a mean of 236.0 ms in the ON medication state (p = 0.028). This effect size is comparable to the difference between PD OFF medication and healthy control values. There was no statistically significant change in any other saccadic parameter with medication. Of particular note, antisaccadic latency was almost exactly the same on and off medication (means of 414.9 ms and 417.2 ms respectively, p = 0.97), while being almost 20% longer in PD patients compared to healthy controls (HC mean 357.2 ms; PD ON vs HC p = 0.015; PD OFF vs HC p = 0.0066). Conclusion PSL is significantly affected by dopaminergic medication which may complicate its use as a biomarker in drug trials. Antisaccadic latency is particularly interesting in this regard because it shows a large disease effect with no medication effect.

The cortico–basal–ganglia circuit plays a critical role in decision making on the basis of probabilistic information. Computational models have suggested how this circuit could compute the probabilities of actions being appropriate according to Bayes' theorem. These models predict that the subthalamic nucleus (STN) provides feedback that normalizes the neural representation of probabilities, such that if the probability of one action increases, the probabilities of all other available actions decrease. Here we report the results of an experiment testing a prediction of this theory that disrupting information processing in the STN with deep brain stimulation should abolish the normalization of the neural representation of probabilities. In our experiment, we asked patients with Parkinson's disease to saccade to a target that could appear in one of two locations, and the probability of the target appearing in each location was periodically changed. When the stimulator was switched off, the target probability affected the reaction times (RT) of patients in a similar way to healthy participants. Specifically, the RTs were shorter for more probable targets and, importantly, they were longer for the unlikely targets. When the stimulator was switched on, the patients were still faster for more probable targets, but critically they did not increase RTs as the target was becoming less likely. This pattern of results is consistent with the prediction of the model that the patients on DBS no longer normalized their neural representation of prior probabilities. We discuss alternative explanations for the data in the context of other published results.

Visual neglect is considerably exacerbated by increases in visual attentional load. These detrimental effects of attentional load are hypothesised to be dependent on an interplay between dysfunctional inter-hemispheric inhibitory dynamics and load-related modulation of activity in cortical areas such as the posterior parietal cortex (PPC). Continuous Theta Burst Stimulation (cTBS) over the contralesional PPC reduces neglect severity. It is unknown, however, whether such positive effects also operate in the presence of the detrimental effects of heightened attentional load. Here, we examined the effects of cTBS on neglect severity in overt visual search (i.e., with eye movements), as a function of high and low visual attentional load conditions. Performance was assessed on the basis of target detection rates and eye movements, in a computerised visual search task and in two paper-pencil tasks. cTBS significantly ameliorated target detection performance, independently of attentional load. These ameliorative effects were significantly larger in the high than the low load condition, thereby equating target detection across both conditions. Eye movement analyses revealed that the improvements were mediated by a redeployment of visual fixations to the contralesional visual field. These findings represent a substantive advance, because cTBS led to an unprecedented amelioration of overt search efficiency that was independent of visual attentional load.

Background: Recent basic and clinical evidence suggests amiloride may be neuroprotective in multiple sclerosis (MS) through the blockade of the acid sensing ion channel (ASIC). Objective: To examine the neuroprotective efficacy of amiloride in acute optic neuritis (ON). Methods: A total of 48 patients were recruited to a phase 2, double blind, single site, randomised controlled trial. Scanning laser polarimetry (GDx) at 6 months was the primary outcome measure and optical coherence tomography (OCT) and visual and electrophysiological measures were secondary outcome measures. Participants aged 18–55 years, ≤28 days of onset of first episode unilateral ON, were randomised to amiloride (10 mg daily for 5 months) or placebo ( clinicaltrials.gov , NCT 01802489). Results: Intention-to-treat (ITT) cohort consisted of 43 patients; 23 placebo and 20 amiloride. No significant drug-related adverse events occurred. No significant differences were found in GDx ( p = 0.840). Visual evoked potentials (VEP) were significantly prolonged in the amiloride group compared to placebo ( p = 0.004). All other secondary outcome measures showed no significant difference. Baseline analysis of OCT data demonstrated a significant pre-randomisation thinning of ganglion cell layer. Conclusion: Amiloride has not demonstrated any neuroprotective benefit within this trial paradigm, but future neuroprotective trials in ON should target the window of opportunity to maximise potential neuroprotective benefit.

Making robust inferences about the functional neuroanatomy of the brain is critically dependent on experimental techniques that examine the consequences of focal loss of brain function. Unfortunately, the use of the most comprehensive such technique-lesion-function mapping-is complicated by the need for time-consuming and subjective manual delineation of the lesions, greatly limiting the practicability of the approach. Here we exploit a recently-described general measure of statistical anomaly, zeta, to devise a fully-automated, high-dimensional algorithm for identifying the parameters of lesions within a brain image given a reference set of normal brain images. We proceed to evaluate such an algorithm in the context of diffusion-weighted imaging of the commonest type of lesion used in neuroanatomical research: ischaemic damage. Summary performance metrics exceed those previously published for diffusion-weighted imaging and approach the current gold standard-manual segmentation-sufficiently closely for fully-automated lesion-mapping studies to become a possibility. We apply the new method to 435 unselected images of patients with ischaemic stroke to derive a probabilistic map of the pattern of damage in lesions involving the occipital lobe, demonstrating the variation of anatomical resolvability of occipital areas so as to guide future lesion-function studies of the region. © 2012 Elsevier Ltd.

The effects of 4-aminopyridine (4-AP) on downbeat nystagmus (DBN) were analysed in terms of slow-phase velocity (SPV), stance, locomotion, visual acuity (VA), patient satisfaction and side effects using standardised questionnaires.Twenty-seven patients with DBN received 5 mg 4-AP four times a day or placebo for 3 days and 10 mg 4-AP four times a day or placebo for 4 days. Recordings were done before the first, 60 min after the first and 60 min after the last drug administration.SPV decreased from 2.42 deg/s at baseline to 1.38 deg/s with 5 mg 4-AP and to 2.03 deg/s with 10 mg 4-AP (p0.05; post hoc: 5 mg 4-AP: p=0.04). The rate of responders was 57%. Increasing age correlated with a 4-AP-related decrease in SPV (p0.05). Patients improved in the 'get-up-and-go test' with 4-AP (p0.001; post hoc: 5 mg: p=0.025; 10 mg: p0.001). Tandem-walk time (both p0.01) and tandem-walk error (4-AP: p=0.054; placebo: p=0.059) improved under 4-AP and placebo. Posturography showed that some patients improved with the 5 mg 4-AP dose, particularly older patients. Near VA increased from 0.59 at baseline to 0.66 with 5 mg 4-AP (p0.05). Patients with idiopathic DBN had the greatest benefit from 4-AP. There were no differences between 4-AP and placebo regarding patient satisfaction and side effects.4-AP reduced SPV of DBN, improved near VA and some locomotor parameters. 4-AP is a useful medication for DBN syndrome, older patients in particular benefit from the effects of 5 mg 4-AP on nystagmus and postural stability.

Making flexible associations between what we see and what we do is important for many everyday tasks. Previous work in patients with focal lesions has shown that the control of saccadic eye movements in such contexts relies on a network of areas in the frontal cerebral cortex. These regions are reciprocally connected with structures in the basal ganglia although the contribution of these sub-cortical structures to oculomotor control in complex tasks is not well understood. We report the performance of patients with idiopathic Parkinsons disease (PDs) in a test which required learning and switching between arbitrary cue-saccade rules. In Experiment 1 feedback was given following each response which reliably indicated which of the two possible rules was correct. PDs were slower to learn the first cue-saccade association presented, but did not show increased error or reaction time switch costs when switching between two rules within blocks. In a follow up experiment the feedback given by the computer was adjusted to be probabilistic such that executing a response based upon the “correct” rule only resulted in positive feedback on 80% of trials. Under these conditions patients were impaired in terms of response latencies and number of errors. In all conditions PDs showed multi-stepping/hypometria of saccades consistent with a motoric deficit in executing actions based on cognitive cues. The findings are consistent with a role for the nigrostriatal dopamine system in the reinforcement of saccade-response-outcome associations. Intact performance of PDs when associations are not stochastically reinforced suggests that striatal learning systems are complemented by cognitive representations of task rules which are unaffected in the early stages of PD., Highlights • We examine how People with Parkinsons learn rules linking visual cues and saccades. • Patients were slower to learn single colour-saccade direction rule mappings. • Patients made increased errors but no increase in rule “switch costs”. • The deficits related to dopamine and cortico-striatal circuitry. • The findings have relevance for understanding deficits in everyday tasks.

A patient with a lesion confined largely to the right inferior frontal gyrus was found to be impaired on tests of spatial working memory and executive functioning. By contrast, his pattern recognition was good. The patient's selective impairments are consistent with the view that prefrontal cortex contributes to processes involved in spatial working memory. The patient was also tested on a range of oculomotor paradigms, some of which required the temporary suppression of a saccadic response. He was unable to suppress making contra- or ipsilesional reflexive glances to peripheral stimuli on the "anti-saccade" paradigm, but his performance improved on delayed saccade, memory-guided saccade and fixation tasks. Although reflexive glances were observed under these conditions they occurred more frequently in response to contralesional stimuli than ipsilesional ones. Furthermore, the patient had no difficulty in performing anti-point movements with his ipsilesional hand. Thus, his inability to suppress reflexive glances on the anti-saccade task is not due to a generalised problem of "distractibility". The patient's deficits are discussed in terms of models of anti-saccade generation and are related to recent findings regarding the role of prefrontal cortex in working memory and visual attention.

When briefly presented with pairs of words, skilled readers can sometimes report words with migrated letters (e.g., they report hunt when presented with the words hint and hurt). This and other letter migration phenomena have been often used to investigate factors that influence reading such as letter position coding. However, the neural basis of letter migration is poorly understood. Previous evidence has implicated the right posterior parietal cortex (PPC) in processing visuospatial attributes and lexical properties during word reading. The aim of this study was to assess this putative role by combining an inhibitory TMS protocol with a letter migration paradigm, which was designed to examine the contributions of visuospatial attributes and lexical factors. Temporary interference with the right PPC led to three specific effects on letter migration. First, the number of letter migrations was significantly increased only in the group with active stimulation (vs. a sham stimulation group or a control group without stimulation), and there was no significant effect on other error types. Second, this effect occurred only when letter migration could result in a meaningful word (migration vs. control context). Third, the effect of active stimulation on the number of letter migrations was lateralized to target words presented on the left. Our study thus demonstrates that the right PPC plays a specific and causal role in the phenomenon of letter migration. The nature of this role cannot be explained solely in terms of visuospatial attention, rather it involves an interplay between visuospatial attentional and word reading-specific factors.

The brain regions that are critically associated with visual neglect have become intensely disputed. In particular, one study of middle cerebral artery (MCA) stroke patients has claimed that the key brain region associated with neglect is the mid portion of the superior temporal gyrus (STG), on the lateral surface of the right hemisphere, rather than the posterior parietal lobe. Such a result has wide-ranging implications for both our understanding of the normal function these cortical areas and the potential mechanisms underlying neglect. Here, we use novel high resolution MRI protocols to map the lesions of 35 right-hemisphere patients who had suffered either MCA or posterior cerebral artery (PCA) territory stroke. For patients with MCA territory strokes, the critical area involved in all neglect patients was the angular gyrus of the inferior parietal lobe (IPL). Although the STG was damaged in half of our MCA neglect patients, it was spared in the rest. For PCA territory strokes, all patients with neglect had lesions involving the parahippocampal region, on the medial surface of the temporal lobe. PCA patients without neglect did not have damage to this area. We conclude that damage to two posterior regions, one in the IPL and the other in the medial temporal lobe, is associated with neglect. Although some neglect patients do have damage to the STG, our findings challenge the recent influential proposal that lesions of this area are critically associated with neglect. Instead, our results implicate the angular gyrus and parahippocampal region in this role.

Visual prostheses for the restoration of functional vision are currently under development. To guide prosthesis research and allow for an accurate prognosis of functional gain, simulating the experience of a retinal prosthesis in healthy individuals is desirable. Current simulation paradigms lack crucial aspects of the prosthetic experience such as realistic head- and eye-position-dependent image presentation. We developed a simulation paradigm that used a head-mounted camera and eye tracker to lock the simulation to the point of fixation. We evaluated visual acuity, object recognition and manipulation, and wayfinding under simulated prosthetic vision. We explored three ways of optimizing the information content of the prosthetic visual image: Full-Field representation (wide visual angle, low sampling frequency), Region of Interest (ROI; narrow visible angle, high sampling frequency), and Fisheye (high sampling frequency in the center, progressively lower resolution toward the edges). Full-Field representation facilitated visual search and navigation, whereas ROI improved visual acuity. The Fisheye representation, designed to incorporate the benefits of both Full-Field representation and ROI, performed similarly to ROI with subjects unable to capitalize on the peripheral data. The observation that different image representation conditions prove advantageous for different tasks should be taken into account in the process of designing and testing new visual prosthesis prototypes.

The role of the primary visual cortex in visual mental imagery has provided significant debate in the imagery literature. Functional neuroimaging studies show considerable variation depending on task and technique. Patient studies can be difficult to interpret due to the diverse nature of cortical damage. The type of cortical damage in patient SBR is exceedingly rare as it is restricted to the gray matter of the calcarine sulcus. In this study, we show that in spite of his near-complete cortical blindness, SBR exhibits vivid visual mental imagery both behaviorally and when measured with functional magnetic resonance imaging. The pattern of cortical activation to visual mental imagery in SBR is indistinguishable from individual sighted subjects, in contrast to the visual perceptual responses, which are greatly attenuated. Electronic supplementary material The online version of this article (doi:10.1007/s00415-011-6299-z) contains supplementary material, which is available to authorized users.

Searching a cluttered visual scene for a specific item of interest can take several seconds to perform if the target item is difficult to discriminate from surrounding items. Whether working memory processes are utilized to guide the path of attentional selection during such searches remains under debate. Previous studies have found evidence to support a role for spatial working memory in inefficient search, but the role of nonspatial working memory remains unclear. Here, we directly compared the role of spatial and nonspatial working memory for both an efficient and inefficient search task. In Experiment 1, we used a dual-task paradigm to investigate the effect of performing visual search within the retention interval of a spatial working memory task. Importantly, by incorporating two working memory loads (low and high) we were able to make comparisons between dual-task conditions, rather than between dual-task and single-task conditions. This design allows any interference effects observed to be attributed to changes in memory load, rather than to nonspecific effects related to “dual-task” performance. We found that the efficiency of the inefficient search task declined as spatial memory load increased, but that the efficient search task remained efficient. These results suggest that spatial memory plays an important role in inefficient but not efficient search. In Experiment 2, participants performed the same visual search tasks within the retention interval of visually matched spatial and verbal working memory tasks. Critically, we found comparable dual-task interference between inefficient search and both the spatial and nonspatial working memory tasks, indicating that inefficient search recruits working memory processes common to both domains.

Huntington's disease (HD) is genetically determined but with variability in symptom onset, leading to uncertainty as to when pharmacological intervention should be initiated. Here we take a computational approach based on neurocognitive phenotyping, computational modeling, and classification, in an effort to provide quantitative predictors of HD before symptom onset. A large sample of subjects-consisting of both pre-manifest individuals carrying the HD mutation (pre-HD), and early symptomatic-as well as healthy controls performed the antisaccade conflict task, which requires executive control and response inhibition. While symptomatic HD subjects differed substantially from controls in behavioral measures [reaction time (RT) and error rates], there was no such clear behavioral differences in pre-HD. RT distributions and error rates were fit with an accumulator-based model which summarizes the computational processes involved and which are related to identified mechanisms in more detailed neural models of prefrontal cortex and basal ganglia. Classification based on fitted model parameters revealed a key parameter related to executive control differentiated pre-HD from controls, whereas the response inhibition parameter declined only after symptom onset. These findings demonstrate the utility of computational approaches for classification and prediction of brain disorders, and provide clues as to the underlying neural mechanisms.

Summary Within the medial frontal cortex, the supplementary eye field (SEF), supplementary motor area (SMA), and pre-SMA have been implicated in the control of voluntary action, especially during motor sequences or tasks involving rapid choices between competing response plans. However, the precise roles of these areas remain controversial. Here, we study two extremely rare patients with microlesions of the SEF and SMA to demonstrate that these areas are critically involved in unconscious and involuntary motor control. We employed masked-prime stimuli that evoked automatic inhibition in healthy people and control patients with lateral premotor or pre-SMA damage. In contrast, our SEF/SMA patients showed a complete reversal of the normal inhibitory effect—ocular or manual—corresponding to the functional subregion lesioned. These findings imply that the SEF and SMA mediate automatic effector-specific suppression of motor plans. This automatic mechanism may contribute to the participation of these areas in the voluntary control of action.

The frontal cortex and basal ganglia form a set of parallel but mostly segregated circuits called cortico-basal ganglia loops. The oculomotor loop controls eye movements and can direct relatively simple movements, such as reflexive prosaccades, without external help but needs input from “higher” loops for more complex behaviors. The antisaccade task requires the dorsolateral prefrontal cortex, which is part of the prefrontal loop. Information flows from prefrontal to oculomotor circuits in the striatum, and directional errors in this task can be considered a measure of failure of prefrontal control over the oculomotor loop. The antisaccadic error rate (AER) is increased in Parkinson's disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has no effect on the AER, but a previous case suggested that DBS of the globus pallidus interna (GPi) might. Our aim was to compare the effects of STN DBS and GPi DBS on the AER. We tested eye movements in 14 human DBS patients and 10 controls. GPi DBS substantially reduced the AER, restoring lost higher control over oculomotor function. Interloop information flow involves striatal neurons that receive cortical input and project to pallidum. They are normally silent when quiescent, but in PD they fire randomly, creating noise that may account for the degradation in interloop control. The reduced AER with GPi DBS could be explained by retrograde stimulation of striatopallidal axons with consequent activation of inhibitory collaterals and reduction in background striatal firing rates. This study may help explain aspects of PD pathophysiology and the mechanism of action of GPi DBS.SIGNIFICANCE STATEMENTParkinson's disease causes symptoms including stiffness, slowness of movement, and tremor. Electrical stimulation of specific areas deep in the brain can effectively treat these symptoms, but exactly how is not fully understood. Part of the cause of such symptoms may be impairments in the way information flows from one circuit within the brain to another, as a result of overactivity of certain nerve cells. By demonstrating that stimulation of an area called the globus pallidus interna partially reverses deficits in voluntary control of eye movements, this study shows that stimulation can improve information flow between circuits, probably by calming down the overactive cells.

Oculomotor function in the ‘visual dementia’ posterior cortical atrophy (PCA) has received little attention. Shakespeare et al. report impairments in fixation, saccade and smooth pursuit in patients with PCA and typical Alzheimer’s disease, and suggest that oculomotor impairment should be considered a core feature of the PCA syndrome., The clinico-neuroradiological syndrome posterior cortical atrophy is the cardinal ‘visual dementia’ and most common atypical Alzheimer’s disease phenotype, offering insights into mechanisms underlying clinical heterogeneity, pathological propagation and basic visual phenomena (e.g. visual crowding). Given the extensive attention paid to patients’ (higher order) perceptual function, it is surprising that there have been no systematic analyses of basic oculomotor function in this population. Here 20 patients with posterior cortical atrophy, 17 patients with typical Alzheimer’s disease and 22 healthy controls completed tests of fixation, saccade (including fixation/target gap and overlap conditions) and smooth pursuit eye movements using an infrared pupil-tracking system. Participants underwent detailed neuropsychological and neurological examinations, with a proportion also undertaking brain imaging and analysis of molecular pathology. In contrast to informal clinical evaluations of oculomotor dysfunction frequency (previous studies: 38%, current clinical examination: 33%), detailed eyetracking investigations revealed eye movement abnormalities in 80% of patients with posterior cortical atrophy (compared to 17% typical Alzheimer’s disease, 5% controls). The greatest differences between posterior cortical atrophy and typical Alzheimer’s disease were seen in saccadic performance. Patients with posterior cortical atrophy made significantly shorter saccades especially for distant targets. They also exhibited a significant exacerbation of the normal gap/overlap effect, consistent with ‘sticky fixation’. Time to reach saccadic targets was significantly associated with parietal and occipital cortical thickness measures. On fixation stability tasks, patients with typical Alzheimer’s disease showed more square wave jerks whose frequency was associated with lower cerebellar grey matter volume, while patients with posterior cortical atrophy showed large saccadic intrusions whose frequency correlated significantly with generalized reductions in cortical thickness. Patients with both posterior cortical atrophy and typical Alzheimer’s disease showed lower gain in smooth pursuit compared to controls. The current study establishes that eye movement abnormalities are near-ubiquitous in posterior cortical atrophy, and highlights multiple aspects of saccadic performance which distinguish posterior cortical atrophy from typical Alzheimer’s disease. We suggest the posterior cortical atrophy oculomotor profile (e.g. exacerbation of the saccadic gap/overlap effect, preserved saccadic velocity) reflects weak input from degraded occipito-parietal spatial representations of stimulus location into a superior collicular spatial map for eye movement regulation. This may indicate greater impairment of identification of oculomotor targets rather than generation of oculomotor movements. The results highlight the critical role of spatial attention and object identification but also precise stimulus localization in explaining the complex real world perception deficits observed in posterior cortical atrophy and many other patients with dementia-related visual impairment.

Visual stimuli can both inhibit and activate motor mechanisms. In one well-known example, the latency of saccadic eye movements is prolonged in the presence of a fixation stimulus, relative to the case in which the fixation stimulus disappears before the target appears. This automatic sensory-motor effect, known as the gap effect or fixation-offset effect, has been associated with inhibitory connections within the superior colliculus (SC). Visual information is provided to the SC and other oculomotor areas, such as the frontal eye fields (FEF), mainly by the magnocellular geniculostriate pathway, and also by the retinotectal pathway. We tested whether signals in these pathways are necessary to create fixation-related inhibition, by using stimuli invisible to them. We found that such stimuli, visible only to short-wave–sensitive cones (S cones), do produce fixation-related inhibition (including when warning effects were equated). We also demonstrate that this fixation-related inhibition cannot be explained by residual activation of luminance pathways and must be caused by a route separate from that of luminance fixation signals. Thus there are at least two routes that cause fixation-related inhibition, and direct sensory input to the SC or FEF by the magnocellular or retinotectal pathways is not required. We discuss the implications that there may be both cortical and collicular mechanisms.

We describe a novel rehabilitation tool for patients with homonymous hemianopia based on a visual search (VS) paradigm that is portable, inexpensive, and easy to deploy. We hypothesised that by training patients to improve the efficiency of eye movements made in their blind field their disability would be alleviated.Twenty nine patients with homonymous visual field defects (HVFD) without neglect practised VS paradigms in 20 daily sessions over one month. Search fields comprising randomly positioned target and distracter elements, differing by a single feature, were displayed for three seconds on a dedicated television monitor in the patients' homes. Improvements were assessed by examining response time (RT), error rates in VS, perimetric visual fields (VFs) and visual search fields (VSFs), before and after treatment. Functional improvements were measured using objective visual tasks which represented activities of daily living (ADL) and a subjective questionnaire.As a group the patients had significantly shorter mean RT in VS after training (p0.001) and demonstrated a variety of mechanisms to account for this. Improvements were confined to the training period and maintained at follow up. Three patients had significantly longer RT after training. They had high initial error rates which improved with training. Patients performed ADL tasks significantly faster after training and reported significant subjective improvements. There was no concomitant enlargement of the VF, but there was a small but significant enlargement of the VSF.Patients can improve VS with practice. This usually involves shorter RTs, but occasionally a longer RT in a complex speed-accuracy trade-off. These changes translate to improved overall visual function, assessed objectively and subjectively, suggesting that they represent robust training effects. The underlying mechanism may involve the adoption of compensatory eye movement strategies.

Albino mammals lacking melanin in the embryonic retinal pigment epithelium (RPE) have abnormal retinal decussation patterns at the optic chiasm: their uncrossed projections are smaller and arise from fewer, more peripheral temporal retinal ganglion cells than in con-specific wild-types. To determine whether these abnormalities generalize to nonmammalian mutants, we used anterograde and retrograde labeling methods to compare the distribution of retinal projections to the thalamus in adult normal and albino Xenopus frogs. In both pigmentation phenotypes, crossed retinal terminations covered approximately 80% of the neuropil of Bellonci (nB) and corpus geniculatum thalamicum (cgt) and uncrossed inputs occupied, respectively, approximately 75% and 25% of these two main visual centers. In the wild-type frogs and in the albinos, ganglion cells giving rise to the crossed projections were distributed throughout the retina, whereas ipsilaterally projecting cells were confined to a specific ventrotemporal retinal division. This region comprised approximately 40% of the total retinal area, was bordered by a well-defined line of decussation, and contained an average of approximately 3,000 ipsilaterally projecting ganglion cells of equivalent soma sizes in the two pigmentation phenotypes. In summary, we found no evidence of chiasmatic misrouting in the uncrossed retinothalamic projections of albino Xenopus, even though these pathways are substantial in normal frogs and share features in common with mammalian retinogeniculate projections. Our findings suggest that congenital RPE melanin deficiency results in major defects in the development of the retina and its central projections only in mammals.

When the human primary visual cortex (V1) is damaged, the dominant geniculo-striate pathway can no longer convey visual information to the occipital cortex. However, many patients with such damage retain some residual visual function that must rely on an alternative pathway directly to extrastriate occipital regions. This residual vision is most robust for moving stimuli, suggesting a role for motion area hMT+. However, residual vision also requires high-contrast stimuli, which is inconsistent with hMT+ sensitivity to contrast in which even low-contrast levels elicit near-maximal neural activation. We sought to investigate this discrepancy by measuring behavioral and neural responses to increasing contrast in patients with V1 damage. Eight patients underwent behavioral testing and functional magnetic resonance imaging to record contrast sensitivity in hMT+ of their damaged hemisphere, using Gabor stimuli with a spatial frequency of 1 cycle/°. The responses from hMT+ of the blind hemisphere were compared with hMT+ and V1 responses in the sighted hemisphere of patients and a group of age-matched controls. Unlike hMT+, neural responses in V1 tend to increase linearly with increasing contrast, likely reflecting a dominant parvocellular channel input. Across all patients, the responses in hMT+ of the blind hemisphere no longer showed early saturation but increased linearly with contrast. Given the spatiotemporal parameters used in this study and the known direct subcortical projections from the koniocellular layers of the lateral geniculate nucleus to hMT+, we propose that this altered contrast sensitivity in hMT+ could be consistent with input from the koniocellular pathway.

Repetitive transcranial magnetic stimulation (rTMS) applied over the right posterior parietal cortex (PPC) in healthy participants has been shown to trigger a significant rightward shift in the spatial allocation of visual attention, temporarily mimicking spatial deficits observed in neglect. In contrast, rTMS applied over the left PPC triggers a weaker or null attentional shift. However, large interindividual differences in responses to rTMS have been reported. Studies measuring changes in brain activation suggest that the effects of rTMS may depend on both interhemispheric and intrahemispheric interactions between cortical loci controlling visual attention. Here, we investigated whether variability in the structural organization of human white matter pathways subserving visual attention, as assessed by diffusion magnetic resonance imaging and tractography, could explain interindividual differences in the effects of rTMS. Most participants showed a rightward shift in the allocation of spatial attention after rTMS over the right intraparietal sulcus (IPS), but the size of this effect varied largely across participants. Conversely, rTMS over the left IPS resulted in strikingly opposed individual responses, with some participants responding with rightward and some with leftward attentional shifts. We demonstrate that microstructural and macrostructural variability within the corpus callosum, consistent with differential effects on cross-hemispheric interactions, predicts both the extent and the direction of the response to rTMS. Together, our findings suggest that the corpus callosum may have a dual inhibitory and excitatory function in maintaining the interhemispheric dynamics that underlie the allocation of spatial attention.SIGNIFICANCE STATEMENTThe posterior parietal cortex (PPC) controls allocation of attention across left versus right visual fields. Damage to this area results in neglect, characterized by a lack of spatial awareness of the side of space contralateral to the brain injury. Transcranial magnetic stimulation over the PPC is used to study cognitive mechanisms of spatial attention and to examine the potential of this technique to treat neglect. However, large individual differences in behavioral responses to stimulation have been reported. We demonstrate that the variability in the structural organization of the corpus callosum accounts for these differences. Our findings suggest novel dual mechanism of the corpus callosum function in spatial attention and have broader implications for the use of stimulation in neglect rehabilitation.

Recent accounts have proposed that orbitofrontal cerebral cortex mediates the control of behavior based on emotional feedback and its somatic correlates. Here, we describe the performance of a patient with circumscribed damage to orbitofrontal cortex during a task that requires switching between sensory-motor mappings, contingent on the occurrence of positive and negative reward feedbacks. In this test, normal subjects and other patients with prefrontal damage show an increase in latencies for eye movements towards locations at which a negative feedback was presented on the preceding trial. In contrast, our patient does not show this reward-dependent inhibition of return effect on saccades. She was also found to make an increased rate of ocular refixations during visual search and used a disorganized search strategy in a token foraging task. These findings suggest that orbital regions of the prefrontal cortex mediate an inhibitory effect on actions directed towards locations that have been subject to negative reinforcement. Further, this mechanism seems to play a role in controlling natural search and foraging behavior.

In the antisaccade paradigm, subjects are instructed to fixate a central point, and then move their eyes towards a position in space in the opposite direction but equidistant to a peripheral, sudden onset target. Antisaccade errors occur when subjects are “distracted” by the target and make a saccade towards it. These errors are more common in patients with schizophrenia but the underlying cause remains unclear. To determine whether antisaccade errors simply reflect a general inability to maintain fixation or are the consequence of a more specific deficit in the strategic control of internally generated actions, patients with first-episode schizophrenia and healthy controls performed three saccadic paradigms which shared the core feature of requiring a prepotent saccade to be suppressed, but varied in their concurrent cognitive demands. We found that both groups showed an increase in errors as the cognitive demands increased across task. However, this increase was significantly steeper in the schizophrenic patients than in the controls. We also found that schizophrenic patients were as able as controls to inhibit prepotent saccades towards a target in a paradigm with no other cognitive demands. Possible explanations of these results include reduced working memory resources and impaired motor preparation in schizophrenia.

Cognitive impairment is well recognized in Parkinson's disease (PD), but when it begins to develop is unclear. The aim of this study was to identify early signs of cognitive impairment along with abnormalities in saccadic behavior in newly diagnosed unmedicated PD patients.Nineteen drug-naive PD patients and 20 controls were examined using a battery of tests, including an antisaccade task, phonemic and semantic verbal fluencies, and a switching and rule finding task.With simple tasks, no differences were found between the two groups. However, cognitive performance of the two groups diverged with more complex tasks, occurring independently of PD-related motor impairment. Patients exhibited higher antisaccadic error rates and switch costs in the task switching test, and performed significantly worse in the rule finding task.Certain cognitive domains and saccadic parameters are already significantly impoverished in newly diagnosed Parkinson's patients, even before the initiation of medication.

Background The existence of transsynaptic retrograde degeneration (TRD) in the human visual system has been established, however the dependence of TRD on different factors such as lesion location, size and manner of lesion acquisition has yet to be quantified. Methods We obtained T1-weighted structural and diffusion-weighted images for 26 patients with adult-acquired or congenital hemianopia and 12 age-matched controls. The optic tract (OT) was defined and measured in the structural and diffusion-weighted images, and degeneration assessed by comparing the integrity of tracts in the lesioned and in the undamaged hemisphere. Results OT degeneration was found in all patients with established lesions, regardless of lesion location. In patients with acquired lesions, the larger the initial lesion, the greater is the resulting TRD. However, this was not the case for congenital patients, who generally showed greater degeneration than would be predicted by lesion size. A better predictor of TRD was the size of the visual field deficit, which was correlated with degeneration across all patients. Interestingly, although diffusion-weighted imaging (DWI) is more frequently used to examine white matter tracts, in this study the T1-weighted scans gave a better indication of the extent of tract degeneration. Conclusions We conclude that TRD of the OT occurs in acquired and congenital hemianopia, is correlated with visual field loss, and is most severe in congenital cases. Understanding the pattern of TRD may help to predict effects of any visual rehabilitation training.

In this paper, we describe a novel approach to the study of problem solving involving the detailed analysis of natural scanning eye movements during the “one-touch” Tower-of-London (TOL) task. We showed subjects a series of pictures depicting two arrangements of colored balls in pockets within the uper and lower halves of a computer display. The task was to plan (but not to execute)the shortest movement sequence required to rearrange the balls in one half of the display (the workspace)to match the arrangement in the opposite half (the Goalspace)and indicate the minimum number of moves required for problem solution. We report that subjects are more likely to look towards the Goalspace in the initial period after picture presentation, but bias gaze towards the Workspace during the middle of trials. Towards the end of a trial, subjects are once again more likely to fixate the Goalspace. This pattern is found regardless of whether the subjects solve problems by rearranging the balls in the lower or uper visual fields, demonstrating that this strategy correlates with discreate phases in problem solving. A second experiment showed that efficient planners direct their gaze selectively towards the problem critical balls in the workspace. In contrast, Individuals who make errors spend more time looking at irrelevant items and are strongly influenced by the movement strategy needed to solve the preceding problem. We conclude that efficient solution of the TOL requires the capacity to generate and flexibly shift between control sets, including those underlying ocular scanning. The role of working memory and the prefrontal cerebral cortex in the task are discussed.

The present study investigated the inhibitory effect of visual distractors on the latency of saccades made by hemianopic and normal human subjects. The latency of saccades made by hemianopic subjects to stimuli in their intact visual field was not affected by visual distractors presented within their hemianopic field. In contrast, the latency of saccades made by normal subjects was increased significantly under distractor conditions. The latency increase was larger for temporal than nasal distractors. The results are inconsistent with previous proposals that the crossed retinotectal pathway from the nasal hemiretina to the superior colliculus may mediate a blindsight inhibitory effect when distractors appear within a hemianopic temporal visual field. Instead, the distractor effect appears to reflect the normal processes involved in saccade target selection which may be mediated by a circuit involving both cortical and subcortical structures.

The latency of 'reflexive' saccades (made in response to peripheral visual stimuli) was compared to that of 'voluntary' saccades performed in anti-saccade and symbolically cued paradigms. Manipulation of visual events at fixation was carefully controlled across all conditions. Reflexive saccade latency was significantly faster than the latency of all forms of voluntary saccades. Importantly, the latency of saccades made after presentation of a symbolic cue at central fixation (voluntary arrow-cue condition) was greater than that made in the anti-saccade paradigm that requires suppression of a reflexive response. It is suggested that the increase in latency of saccades made in the voluntary arrow-cue condition may reflect differences in programming a 'When' trigger signal for saccades made in the absence of a peripheral stimulus.

The authors examined oculomotor function to identify a biomarker of disease progression in genetically confirmed preclinical and early clinical Huntington disease (HD). Initiation deficits of voluntary-guided, but not reflexive, saccades were characteristic of preclinical HD. Saccadic slowing and delayed reflexive saccades were demonstrated in clinical but not preclinical HD. Saccadic measures provide biomarkers of disease progression in both preclinical and early clinical stages of HD.

SynopsisRecent research has shown that some patients with schizophrenia have a severe impairment in the suppression of reflexive saccadic eye movements in the ANTI-saccade task. This saccadic distractibility has previously been found in patients with lesions of dorsolateral prefrontal cortex, implicating an abnormality of prefrontal cortex. The objective of the present study was to determine the contribution of these and other areas to the ANTI-saccadic abnormality in schizophrenia by functional neuroimaging. Using 99mtechnetium-HMPAO high resolution multidetector single-photon emission tomography, regional cerebral blood flow (rCBF) during performance of the ANTI-saccade eye-movement task was compared, by statistical parametric mapping, in ten male schizophrenic patients on stable antipsychotic medication who had a high distractibility error rate on the task, and eight similar patients who had normal distractibility error rates. Compared with the normal error group, the patients with high error rates showed significantly decreased rCBF bilaterally, in the anterior cingulate, insula, and in left striatum. These same patients also had increased perseverative errors on the Wisconsin Card Sort Test.

The neurodegenerative disorder amyotrophic lateral sclerosis may render patients unable to speak or write, so that objective assessment of cognitive impairment, which is commonly of a dysexecutive nature, is challenging. There is therefore a need to develop other methods of assessment that utilize other relatively unaffected motor systems. In this proof-of-principle study a novel eye-tracking version of the trail-making test was compared with performance on the standard written version in a group of healthy volunteers. There was good correlation for speed between both versions of Part B (R(2)=0.73), suggesting that this is a viable method to objectively assess cognitive impairment in disorders where patients are unable to speak or write.

SYNOPSISMost of the previous research reporting abnormalities of rapid re-fixation eye movements (saccades) in patients with schizophrenia has used patients receiving neuroleptic medication. In this study non-neuroleptically medicated schizophrenics were compared with other psychiatric patients using a variety of saccadic paradigms to determine the specificity of saccadic dysfunction. The patient groups consisted of schizophrenics (N = 18), bipolar affectives (N = 18), anxiety neurotics (N = 10) and normal controls (N = 31), none of whom had received neuroleptic medication for the preceding 6 months. Four behavioural paradigms, reflexive, predictive, remembered and ANTI were used to elicit saccades. The primary abnormality in the schizophrenic group was a significantly increased rate of distractibility in the ANTI (saccades made towards the target rather than in an opposite direction) and REM (saccades made prior to the imperative cue) paradigms. The major neuropsychological variable predictive of these errors was Wisconsin card sort perseverative errors. These data, in conjunction with findings from previous neurological research, would seem to provide converging evidence towards dysfunction of prefrontal cortex in schizophrenia.

We report a case of induced oscillopsia caused by deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN). Recent reports have described involuntary oscillopsia during DBS of the PPN that patients have described as trembling vision. Here we substantiate this observation using infra-red eye tracking. It has been suggested that this phenomenon might be used as an indicator of accurate targeting of the PPN with DBS. Our observations suggest that this phenomenon may not be related to a constricted anatomical structure and therefore such practise may be unwise. Scrutiny has led us to believe that the oscillopsia in our patient is not caused by direct stimulation of the oculomotor nerve as suggested in a previous report, but by stimulation of fibres in the uncinate fasciculus of the cerebellum and the superior cerebellar peduncle, which in turn stimulate the saccadic pre-motor neurones in the brainstem.

We present data for a patient, GY, with a right hemianopia caused by traumatic damage to the left occipital cortex. Previous studies have established that this patient has residual vision which enables him to detect and localize transient stimuli presented to his 'blind' hemifield. We have now examined spectral responses associated with this residual vision by using two-colour incremental threshold methods to measure II-spectral functions, and a white light background to examine spectral data for 'colour-opponent' characteristics. We report that both methods yield normal spectral response characteristics for GY's 'blind' hemifield. We have also investigated the patient's ability to identify, verbally, coloured stimuli presented to his 'blind' hemifield, and found that, in 'forced choice' experiments, he achieves a high proportion of correct responses to large stimuli. The patient reported that in threshold detection measurements his responses were based on the presence or absence of a percept associated with transient light stimulation of the 'blind' hemifield (residual vision), whereas colour naming was achieved without conscious perception of colour ('blindsight').

Palinopsia is a distortion of processing in the visual system in which images persist or recur after the visual stimulus has been removed. It is a dysfunction of the association areas at the junction of temporal, occipital and parietal lobes and can be triggered by any lesion or dysfunction in this region. Here, the authors report the case of a patient with a glioma involving this region of the brain, who presented with palinopsia that subsequently disappeared once the tumour was surgically debulked. In the few cases of palinopsia that have been published so far, no such case has ever been reported. Furthermore, we took an insight into this rare and elusive phenomenon's causes and suggested Bayesian inference as a possible cause. The authors also mentioned visual evoked potentials as a useful test to be considered in future palinoptic patients.

The saccadic eye movements of nine patients with Parkinson's disease were compared to those of nine age-matched controls in two paradigms generating volitional saccades. In both paradigms, subjects had to make delayed saccades to peripheral LED targets: a peripheral target appeared 700 msec before a buzzer sounded, the buzzer being the signal to make a saccade to the target. In the first paradigm (“centre-off”), the fixation target was extinguished simultaneously with buzzer onset. In the second (“centre-remain”) it was not extinguished until 1000 msec later. The results showed that for outward saccades in both paradigms, there was no difference between Parkinsonian patients and controls, but saccadic latencies were significantly shorter in the “centre-remain” paradigm. The initial outward saccades were indistinguishable from the normal, reflex saccades of the same subjects. However, saccades returning to the centre (a type of remembered target saccade) were hypometric and showed multistepping. Both effects were more pronounced in patients with Parkinson's disease. The significance of these findings in terms of current hypotheses about the nature of the Parkinsonian saccadic deficit is discussed.

The direction of the current induced by transcranial magnetic stimulation (TMS) over the motor cortex has been observed to influence the threshold and latency of evoked muscle responses. This study investigates the effect of TMS-induced current orientation (ICO) over the prefrontal cortex, on a specific cognitive task (memory-guided saccade). TMS was applied with a figure-of-eight coil, placed at one of eight different orientations over the prefrontal cortex. The most effective ICO was antero-lateral, which is a different optimal ICO from that seen over the hand area of the motor cortex. This demonstrates that ICO can alter the effect of TMS on cognitive functions and that ICO is an independent variable that should not be ignored when designing TMS studies.

Summary Background Huntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects adults in mid-life. Our aim was to identify sensitive and reliable biomarkers in premanifest carriers of mutated HTT and in individuals with early HD that could provide essential methodology for the assessment of therapeutic interventions. Methods This multicentre study uses an extensive battery of novel assessments, including multi-site 3T MRI, clinical, cognitive, quantitative motor, oculomotor, and neuropsychiatric measures. Blinded analyses were done on the baseline cross-sectional data from 366 individuals: 123 controls, 120 premanifest (pre-HD) individuals, and 123 patients with early HD. Findings The first participant was enrolled in January, 2008, and all assessments were completed by August, 2008. Cross-sectional analyses identified significant changes in whole-brain volume, regional grey and white matter differences, impairment in a range of voluntary neurophysiological motor, and oculomotor tasks, and cognitive and neuropsychiatric dysfunction in premanifest HD gene carriers with normal motor scores through to early clinical stage 2 disease. Interpretation We show the feasibility of rapid data acquisition and the use of multi-site 3T MRI and neurophysiological motor measures in a large multicentre study. Our results provide evidence for quantifiable biological and clinical alterations in HTT expansion carriers compared with age-matched controls. Many parameters differ from age-matched controls in a graded fashion and show changes of increasing magnitude across our cohort, who range from about 16 years from predicted disease diagnosis to early HD. These findings might help to define novel quantifiable endpoints and methods for rapid and reliable data acquisition, which could aid the design of therapeutic trials. Funding CHDI/High Q Foundation.

This study was intended to investigate the neural signals related to oculomotor and visual activity during horizontal saccades in humans and to explore the potential of using such signals as a functional marker for localizing the periventricular and periaqueductal gray. We recorded the local field potentials (LFPs) via implanted electrodes in the rostrolateral part of the periventricular and periaqueductal gray in four patients (six electrodes) who underwent deep brain stimulation for treatment of neuropathic pain. The functional composition of the saccade-related LFPs under different visual conditions was characterized using time-frequency analysis, and it was correlated with the anatomic placement of the electrodes on the postoperative magnetic resonance images. The magnitude of oculomotor signals varied predictably with the proximity of the recording electrode to the superior colliculus; the oculomotor activity was represented specifically in the alpha (8-13 Hz) and theta (4-8 Hz) bands for saccades and in the alpha band for fixation, whereas the visual activity was represented in the delta band (1-3 Hz) of the LFPs. The compound LFP signals of the superior colliculus embrace the synchronized population activity of multimodalities, which can be differentiated in the frequency domain. This is the first time LFP signals of the human superior colliculus have been characterized. Such signals may be used as a functional marker for electrode placement in the periventricular and periaqueductal gray for modulation of pain.

A case is presented of a patient who underwent insertion of a periaqueductal grey electrode for the relief of chronic pain. Shortly after insertion, the patient developed a left-sided ocular tilt reaction (OTR). The electrode tip, initially to the right of the midline, was then withdrawn slightly so that it was now on the left side. Stimulation at this point gave rise to a worsening of the tilt reaction, in addition to bilateral counter-clockwise torsional nystagmus. Computerized tomography and stereotactic coordinates indicated that the tip of the electrode was finally situated in the region of the left interstitial nucleus of Cajal (INC). The production of an OTR by stimulation in this region is similar to the phenomenon previously reported in monkeys and cats. The side of the OTR is consistent with previous evidence, suggesting that the utricular pathways cross between medulla and midbrain.

Multiple lines of evidence indicate that an anatomically discrete region within the dorsal medial frontal cortex--the supplementary eye field (SEF)--is involved in oculomotor control. To delineate this role further, repetitive transcranial magnetic stimulation (rTMS; 10 Hz, 500 ms) was administered either immediately after the presentation of three-step saccade sequences, or, immediately before response execution of memory-guided saccades. In addition, the effects of changes to visuospatial and temporal order demands were examined by contrasting performance in the presence and the absence of target location information. Results revealed that the SEF supports the processing of spatial information relevant to saccade amplitude. Independently of the time of stimulation, saccade gain was reduced by rTMS applied over the SEF, though only when response execution was performed in the absence of target location information. These results provide evidence of a causal role for the SEF in oculomotor control in the absence of visual feedback.

Huntington's disease is caused by a known genetic mutation and so potentially can be diagnosed many years before the onset of symptoms. Neuropathological changes have been found in both striatum and frontal cortex in the pre-symptomatic stage. Disruption of cortico-striatal white matter fibre tracts is therefore likely to contribute to the first clinical signs of the disease. We analysed diffusion tensor MR image (DTI) data from 25 pre-symptomatic gene carriers (PSCs) and 20 matched controls using a multivariate support vector machine to identify patterns of changes in fractional anisotropy (FA). In addition, we performed probabilistic fibre tracking to detect changes in ‘streamlines’ connecting frontal cortex to striatum. We found a pattern of structural brain changes that includes putamen bilaterally as well as anterior parts of the corpus callosum. This pattern was sufficiently specific to enable us to correctly classify 82% of scans as coming from a PSC or control subject. Fibre tracking revealed a reduction of frontal cortico-fugal streamlines reaching the body of the caudate in PSCs compared to controls. In the left hemispheres of PSCs we found a negative correlation between years to estimated disease onset and streamlines from frontal cortex to body of caudate. A large proportion of the fibres to the caudate body originate from the frontal eye fields, which play an important role in the control of voluntary saccades. This type of saccade is specifically impaired in PSCs and is an early clinical sign of motor abnormalities. A correlation analysis in 14 PSCs revealed that subjects with greater impairment of voluntary-guided saccades had fewer fibre tracking streamlines connecting the frontal cortex and caudate body. Our findings suggest a specific patho-physiological basis for these symptoms by indicating selective vulnerability of the associated white matter tracts.

It has been proposed that the inferior/ventrolateral frontal cortex plays a critical role in the inhibitory control of action during cognitive tasks. However, the contribution of this region to the control of eye movements has not been clearly established. Here, we describe the performance of a group of 23 frontal lobe damaged patients in an oculomotor rule switching task for which the association between a centrally presented visual cue and the direction of a saccade could change from trial to trial. A subset of 16 patients also completed the standard antisaccade task. Ventrolateral damage was found to be a significant predictor of errors in both tasks. Analysis of the rate at which patients corrected errors in the rule switching task also revealed an important dissociation between left and right hemisphere damaged patients. Whilst patients with left ventrolateral damage usually corrected response errors with secondary saccades, those with right hemisphere lesions often failed to do so. The results suggest that the inferior frontal cortex forms part of a wider frontal network mediating inhibitory control over stimulus elicited eye movements. The critical role played by the right ventrolateral region in cognitive tasks may arise due to an additional functional specialization for the monitoring and updating of task rules.

INTRODUCTION: Neurodegeneration is a widely accepted contributor to the development of long-term disability in multiple sclerosis (MS). While current therapies in MS predominantly target inflammation and reduce relapse rate they have been less effective at preventing long-term disability. The identification and evaluation of effective neuroprotective therapies within a trial paradigm are key unmet needs. Emerging evidence supports amiloride, a licenced diuretic, as a neuroprotective agent in MS through acid sensing ion channel blockade. Optic neuritis (ON) is a common manifestation of MS with correlates of inflammation and neurodegeneration measurable within the visual pathways. Amiloride Clinical Trial In Optic Neuritis (ACTION) will utilise a multimodal approach to assess the neuroprotective efficacy of amiloride in acute ON.METHODS AND ANALYSIS: 46 patients will be recruited within 28 days from onset of ON visual symptoms and randomised on a 1:1 basis to placebo or amiloride 10 mg daily. Double-blinded treatment groups will be balanced for age, sex and visual loss severity by a random-deterministic minimisation algorithm. The primary objective is to demonstrate that amiloride is neuroprotective in ON as assessed by scanning laser polarimetry of the peripapillary retinal nerve fibre layer (RNFL) thickness at 6 months in the affected eye compared to the unaffected eye at baseline. RNFL in combination with further retinal measures will also be assessed by optical coherence tomography. Secondary outcome measures on brain MRI will include cortical volume, diffusion-weighted imaging, resting state functional MRI, MR spectroscopy and magnetisation transfer ratio. In addition, high and low contrast visual acuity, visual fields, colour vision and electrophysiology will be assessed alongside quality of life measures.ETHICS AND DISSEMINATION: Ethical approval was given by the south central Oxford B research ethics committee (REC reference: 13/SC/0022). The findings from ACTION will be disseminated through peer-reviewed publications and at scientific conferences.TRIAL REGISTRATION NUMBER: EudraCT2012-004980-39, ClinicalTrials.gov Identifier: NCT01802489.

Purpose Severe visual impairment can have a profound impact on personal independence through its effect on mobility. We investigated whether the mobility of people with vision low enough to be registered as blind could be improved by presenting the visual environment in a distance-based manner for easier detection of obstacles. Methods We accomplished this by developing a pair of "residual vision glasses" (RVGs) that use a head-mounted depth camera and displays to present information about the distance of obstacles to the wearer as brightness, such that obstacles closer to the wearer are represented more brightly. We assessed the impact of the RVGs on the mobility performance of visually impaired participants during the completion of a set of obstacle courses. Participant position was monitored continuously, which enabled us to capture the temporal dynamics of mobility performance. This allowed us to find correlates of obstacle detection and hesitations in walking behavior, in addition to the more commonly used measures of trial completion time and number of collisions. Results All participants were able to use the smart glasses to navigate the course, and mobility performance improved for those visually impaired participants with the worst prior mobility performance. However, walking speed was slower and hesitations increased with the altered visual representation. Conclusions A depth-based representation of the visual environment may offer low vision patients improvements in independent mobility. It is important for further work to explore whether practice can overcome the reductions in speed and increased hesitation that were observed in our trial.

Visual search for target items embedded within a set of distracting items has consistently been shown to engage regions of occipital and parietal cortex, but the contribution of different regions of prefrontal cortex remains unclear. Here, we used fMRI to compare brain activity in 12 healthy participants performing efficient and inefficient search tasks in which target discriminability and the number of distractor items were manipulated. Matched baseline conditions were incorporated to control for visual and motor components of the tasks, allowing cortical activity associated with each type of search to be isolated. Region of interest analysis was applied to critical regions of prefrontal cortex to determine whether their involvement was common to both efficient and inefficient search, or unique to inefficient search alone. We found regions of the inferior and middle frontal cortex were only active during inefficient search, whereas an area in the superior frontal cortex (in the region of FEF) was active for both efficient and inefficient search. Thus, regions of ventral as well as dorsal prefrontal cortex are recruited during inefficient search, and we propose that this activity is related to processes that guide, control and monitor the allocation of selective attention.

Right-hemisphere patients with left neglect often demonstrate abnormal visual search, re-examining stimuli to the right while ignoring those to the left. But re-fixations alone do not reveal if patients misjudge whether they have searched a location before. Here, we not only tracked the eye movements of 16 neglect patients during search, but also asked them to click a response button only when they judged they were fixating a target for the very first time. “Re-clicking” on previously found targets would indicate that patients erroneously respond to these as new discoveries. Lesions were mapped with high-resolution MRI. Neglect patients with damage involving the right intraparietal sulcus or right inferior frontal lobe “re-clicked” on previously found targets on the right at a pathological rate, whereas those with medial occipito-temporal lesions did not. For the intraparietal sulcus patients, the probability of erroneous re-clicks on an old target increased with time since first discovering it; whereas for frontal patients it was independent of search time, suggesting different underlying mechanisms in these two types of patient. Re-click deficits correlated with degree of leftward neglect, mainly due to both being severe in intraparietal cases. These results demonstrate that misjudging previously searched locations for new ones can contribute to pathological search in neglect, with potentially different mechanisms being involved in intraparietal versus inferior frontal patients. When combined with a spatial bias to the right, such deficits might explain why many neglect patients often re-examine rightward locations, at the expense of items to their left.