The role of the ventrolateral frontal cortex in inhibitory oculomotor control

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

Visuospatial Sequence Learning without Seeing

Background: The ability to detect and integrate associations between unrelated items that are close in space and time is a key feature of human learning and memory. Learning sequential associations between non-adjacent visual stimuli (higher-order visuospatial dependencies) can occur either with or without awareness (explicit vs. implicit learning) of the products of learning. Existing behavioural and neurocognitive studies of explicit and implicit sequence learning, however, are based on conscious access to the sequence of target locations and, typically, on conditions where the locations for orienting, or motor, responses coincide with the locations of the target sequence. Methodology/Principal findings: Dichoptic stimuli were presented on a novel sequence learning task using a mirror stereoscope to mask the eye-of-origin of visual input from conscious awareness. We demonstrate that conscious access to the sequence of target locations and responses that coincide with structure of the target sequence are dispensable features when learning higher-order visuospatial sequence on a recognition test, even though the trained and untrained recognition sequences were identical when viewed at a conscious binocular level, and differed only at the level of the masked sequential associations. Conclusions/significance: These results demonstrate that unconscious processing can support perceptual learning of higher-order sequential associations through interocular integration of retinotopic-based codes stemming from monocular eye-of-origin information. Furthermore, unlike other forms of perceptual associative learning, visuospatial attention did not need to be directed to the locations of the target sequence. More generally, the results pose a challenge to neural models of learning to account for a previously unknown capacity of the human visual system to support the detection, learning and recognition of higher-order sequential associations where observers are unable to see the target sequence or perform responses that coincide with the structure of the target sequence

Structural organization of the corpus callosum predicts attentional shifts after continuous theta burst stimulation

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

Learning and Recognition of a Non-conscious Sequence of Events in Human Primary Visual Cortex

Published Online: March 03, 2016Human primary visual cortex (V1) has long been associated with learning simple low-level visual discriminations [1] and is classically considered outside of neural systems that support high-level cognitive behavior in contexts that differ from the original conditions of learning, such as recognition memory [2, 3]. Here, we used a novel fMRI-based dichoptic masking protocol—designed to induce activity in V1, without modulation from visual awareness—to test whether human V1 is implicated in human observers rapidly learning and then later (15–20 min) recognizing a non-conscious and complex (secondorder) visuospatial sequence. Learning was associated with a change in V1 activity, as part of a temporo-occipital and basal ganglia network, which is at variance with the cortico-cerebellar network identified in prior studies of ‘‘implicit’’ sequence learning that involved motor responses and visible stimuli (e.g., [4]). Recognition memory was associated with V1 activity, as part of a temporo-occipital network involving the hippocampus, under conditions that were not imputable to mechanisms associated with conscious retrieval. Notably, the V1 responses during learning and recognition separately predicted non-conscious recognition memory, and functional coupling between V1 and the hippocampus was enhanced for old retrieval cues. The results provide a basis for novel hypotheses about the signals that can drive recognition memory, because these data (1) identify human V1 with a memory network that can code complex associative serial visuospatial information and support later nonconscious recognition memory-guided behavior (cf. [5]) and (2) align with mouse models of experiencedependent V1 plasticity in learning and memory [6].This work was supported by the Wellcome Trust (WT073735MA; C.R.R. and C.K.; http://www.wellcome.ac.uk/), the Medical Research Council (UK, 89631; D.S.; http://www.mrc.ac.uk/), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford (C.R.R., C.A.A., and C.K.; http://oxfordbrc.nihr.ac.uk/), and the Dementias and Neurodegenerative Diseases Research Network (C.A.A.; https://www.crn.nihr.ac.uk/dementia)

Palinopsia from a posteriorly placed glioma - an insight into its possible causes

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\u27s 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

RELATING CELLULAR ASSOCIATION WITH LIPOSOME CYTOTOXICITY IN HUMAN ENDOTHELIAL CELLS

INTRODUCTION Interactions with the endothelium play a key role in the behaviour of intravenously administered nanoparticle drug carriers[1]. Hence, quantifying cellular association (membrane adhesion and cell internalization) of liposomes with endothelial cells is an effective screening method of biocompatibility and success of new drug carriers. Current methods are inaccurate as concentration does not necessarily equate to local cellular association. The focus of this experiment is to quantify the cellular association between liposomes and two types of human endothelial cells and compare the associations with cells’ cytotoxic response. Cellular association of liposomes as well as cell viability were quantified on cellular level at different concentrations of liposomes. METHODS Two different types of cells, Human Umbilical Vein Endothelial cell, which is a common cell type used in vitro studies, and Human MicroVascular Cell, which is more accurate representation of in vivo, were used[2]. HUVEC and HMVEC were cultured and passaged onto chamber slides using standard cell culture techniques. The confluent cells were exposed to fluorescent liposomes with hydrodynamic diameter of 90.4 nm at concentrations ranging from 0.08nM to 8nM for 24 hours, membrane stained with CellMask Deep Red and fixed with paraformaldehyde, following same protocols for both types of cells. Cell viability on exposure to the same concentration range of liposomes was determined using Vialight assay using manufacturer protocols. Z-stacks of the treated cells were obtained using Olympus Fluoview FV1000 confocal microscope. Region of interest, limited by cell membranes, was set using the membrane stain channel using ImageJ. The region of interest was superimposed onto the fluorescent liposome channel to determine exclusively the fluorescence of cell adhered and cell internalized liposomes RESULTS Compared to HUVECs, higher cellular association of liposomes was observed for HMVC as shown in Figure 1.While cellular association of liposomes increased with concentration, cell viability was in the range of 85 to nearly 100% for the concentration range of 0.08-4 nM with no significant difference. Only at 8 nM, cell viability decreased significantly to approximately 62 %. DISCUSSION AND CONCLUSIONS Liposome cellular association provide insight into the cytotoxicity and the endothelial cytotoxicity of the liposomes at low concentration of 8nM raises cautions on documented innocuous properties of liposomes. Cytotoxicity and cellular association upon comparison showed exponential relationship. Because the cytotoxicity and cellular association relationship is exponential, slight over-administration can cause severe toxicity. 8nM is lower than concentration of current intravenous liposome-based drug doxorubicin[3]. High toxicity and exponential relationship raise caution on the importance of proper safe dosage

RELATING QUANTUM DOT ASSOCIATION WITH HUMAN ENDOTHELIAL CELLS WITH THEIR CYTOTOXIC EFFECTS

INTRODUCTION Advances in the field of nanotechnology have enabled researchers to pursue biomedical applications of nanoparticles. Quantum dots are commonly used fluorescent probes because they are brighter and less prone to photobleaching than other fluorophores [1]. However, despite the advantages, potential for toxicity must be acknowledged. Quantum dots are commonly made with toxic metal elements, which can cause oxidative stress [2]. Cadmium ions have been shown to disrupt mitochondria activity, leading to cell death [2]. Quantum dots have been shown to attach to the cell membrane as well as be internalized through endocytic mechanisms [3]. In this study, we aim to quantify quantum dot association and compare results from cytotoxicity assays for identical conditions, relating cellular association with cytotoxicity. METHODS Human Umbilical Vein Endothelial Cells (HUVECs) and Human Micro-vascular Endothelial Cells (HMVECs) were cultured in static conditions in 8-well chamber slides then exposed to amino-PEG quantum dots at a concentration of 0.2nM to 200nM. After exposure for 24 hours, the cells were washed, fixed, and stained. Z-stacks were obtained using an Olympus Fluoview FV1000 confocal microscope. Images were analyzed using ImageJ software to quantify mean fluorescence intensity within the defined region of interest, selected from the boundaries of stained cell membranes. Statistical analysis using one-way Analysis of Variance (ANOVA) and post-hoc Tukey HSD test was performed. Finally, Vialight assay was used to test cell viability after exposure to quantum dots under the same experimental conditions used for association experiments. RESULTS Exposure to different concentrations of quantum dots results in significant changes in the observed fluorescence intensity per area. Non-linear dependence of cellular association of quantum dots on exposure concentration was observed. A representative example of mean fluorescence intensity of quantum dots associated with HUVECs is shown in Figure 1.A significant decrease in the viability of HUVECs was observed on exposure to quantum dots (30-50% cell viability relative to 100% for non-exposed cells). However, no significant difference in cell viability was observed between 0.2nM to 200nM concentrations. DISCUSSION AND CONCLUSIONS Nanoparticle association studies play a vital role in predicting cell viability in nanoparticle cytotoxicity studies. The non-linear trend observed suggests that for the range of concentrations examined, cellular association does not increase linearly with exposure concentration, and that cytotoxicity can be related to association, rather than just to exposure concentration. This experiment provides an approach to advance future studies relating cellular association to cytotoxicity

Statistical characteristics of finger-tapping data in Huntington’s disease

Measuring the rate of finger tapping is a technique commonly used as an indicator of impairment in degenerative neurological conditions, such as Huntington’s disease. The information it provides can be greatly enhanced by analysing not simply the overall tapping rate, but also the statistical characteristics of the individual times between each successive response. Recent technological improvements in the recording equipment allow the responses to be analysed extremely quickly, and permit modification of the task in the interest of greater clinical specificity. Here we illustrate its use with some pilot data from a group of manifest HD patients and age-matched controls. Even in this small cohort, differences in the responses are apparent that appear to relate to the severity of the disease as measured by conventional behavioural tests

EFFECT OF PEG COATING ON NANOPARTICLE DIFFUSION THROUGH TUMOUR EXTRACELLULAR MATRIX

INTRODUCTION Nanoparticle drug delivery systems have the potential to improve current cancer treatments through encapsulating cytotoxic agents and delivering them to specific sites in the body. One such class of particle, liposomes, has already found some commercial success [1]. Liposomes are vesicles composed of a lipid bi-layer surrounding an aqueous solution. Poly(ethylene) glycol (PEG) surface coating is commonly used to improve the hydrophilicity of liposomes, thereby increasing their stability in aqueous solutions. Furthermore, PEG limits the binding of blood antigens, which minimizes opsonisation and phagocytosis, extending circulation time in the blood stream. When applied to the surface of liposomes at lower molecular weights and surface densities, PEG adopts a “mushroom” conformation, in which adjacent chains of PEG do not interact laterally, therefore portions of the bi-layer remain exposed [2]. However, at higher molecular weights and surface densities, the “brush” conformation is adopted; where lateral interactions occur between neighbouring PEG strands and provide complete coverage of the lipid bi-layer [2]. This study will investigate the effect of varying PEG molecular weight and surface density on liposome transport through tumour extracellular matrix. METHODS Seven different formulations of liposomes were synthesized using a modification of the lipid extrusion method described in [1]. Molecular weight and surface density values were chosen to include both PEG conformations. The Type I collagen hydrogel was prepared with a collagen concentration of 2.5mg/mL. Confocal Microscopy was used to track the liposome transport into the gels via the bilayer incorporated Rhodamine dye. While simple collagen hydrogels may not capture all of the complexity of native tumour ECM, they allow for more carefully controlled conditions than in vivo models. Images were taken every 30 minutes until the 900 minute mark. RESULTS As shown in Figure 1, the liposomes with a lower PEG loading (DOPC, 5, 10% PEG 1000, 5, 10% PEG 2000), all accumulated at the interface of the hydrogel, and had identical diffusion coefficients. The 5% and 10% PEG 5000 however, accumulated significantly less and therefore had a much greater diffusion coefficient.DISCUSSION AND CONCLUSIONS The liposomes with low PEG surface density, and DOPC control liposomes shown in Figure 1, are all within the “mushroom” conformation of PEG [2] and therefore would all have exposed bilayer which is not shielded by the PEG strands. The formulations that penetrated deeply were notably only higher PEG surface densities (5 and 10% PEG 5000) which literature suggests would have been in the “brush” conformation [2]. This suggests that the high PEG surface densities sterically shielded the liposomes, and reduced the electrostatic interactions between the hydrogels and the liposomes, allowing increased diffusion

No Effect of Anodal Transcranial Direct Current Stimulation (tDCS) Over hMT+ on Motion Perception Learning

Background: Human visual cortical area hMT+, like its homolog MT in the macaque monkey, has been shown to be particularly selective to visual motion. After damage to the primary visual cortex (V1), patients often exhibit preserved ability to detect moving stimuli, which is associated with neural activity in area hMT+. As an anatomical substrate that underlies residual function in the absence of V1, promoting functional plasticity within hMT+ could potentially boost visual performance despite primary visual cortical damage.Objective: To establish in healthy participants whether it is possible to use transcranial direct current stimulation (tDCS) over hMT+ to potentiate learning of visual motion direction discrimination.Methods: Twenty-one participants were trained daily for 5 days on a visual motion direction discrimination task. Task difficulty was increased as performance improved, by decreasing the proportion of coherently moving dots, such that participants were always performing at psychophysical threshold. tDCS, either anodal or sham, was applied daily during 20 min of training. Task performance was assessed at baseline and at the end of the training period. Performance was also compared with a third group of 10 participants from an earlier study who had undergone the same procedures but without tDCS.Results: All participants showed improved task performance both during and after training. Contrary to our hypothesis, anodal tDCS did not further improve performance compared to sham stimulation or no stimulation. Bayesian statistics indicated weak evidence in favor of the null hypothesis.Conclusion: This study found no evidence for a robust effect of anodal tDCS over hMT+ on visual motion direction discrimination learning in the young healthy visual system, although more subtle effects may have been missed in the relatively small sample size