Impaired balance in developmental dyslexia? A meta-analysis of the contending evidence

Background: Developmental dyslexia is typically defined by deficits in phonological skills, but it is also associated with anomalous performance on measures of balance. Although balance assessments are included in several screening batteries for dyslexia, the association between impairments in literacy and deficits in postural stability could be due to the high co-occurrence of dyslexia with other developmental disorders in which impairments of motor behaviour are also prevalent. Methods: We identified 17 published studies that compared balance function between dyslexia and control samples and obtained effect-sizes for each. Contrast and association analyses were used to quantify the influence of hypothesised moderator variables on differences in effects across studies. Results: The mean effect-size of the balance deficit in dyslexia was .64 (95% CI = .44-.78) with heterogeneous findings across the population of studies. Probable co-occurrence of other developmental disorders and variability in intelligence scores in the dyslexia samples were the strongest moderator variables of effect-size. Conclusions: Balance deficits are associated with dyslexia, but these effects are apparently more strongly related to third variables other than to reading ability. Deficits of balance may indicate increased risk of developmental disorder, but are unlikely to be uniquely associated with dyslexia.

Contrast masking in strabismic amblyopia: attenuation, noise, interocular suppression and binocular summation

To investigate amblyopic contrast vision at threshold and above we performed pedestal-masking (contrastdiscrimination) experiments with a group of eight strabismic amblyopes using horizontal sinusoidal gratings (mainly 3 c/deg) in monocular, binocular and dichoptic configurations balanced across eye (i.e. five conditions). With some exceptions in some observers, the four main results were as follows. (1) For the monocular and dichoptic conditions, sensitivity was less in the amblyopic eye than in the good eye at all mask contrasts. (2) Binocular and monocular dipper functions superimposed in the good eye. (3) Monocular masking functions had a normal dipper shape in the good eye, but facilitation was diminished in the amblyopic eye. (4) A less consistent result was normal facilitation in dichoptic masking when testing the good eye, but a loss of this when testing the amblyopic eye. This pattern of amblyopic results was replicated in a normal observer by placing a neutral density filter in front of one eye. The two-stage model of binocular contrast gain control [Meese, T.S., Georgeson, M.A. & Baker, D.H. (2006). Binocular contrast vision at and above threshold. Journal of Vision 6, 1224--1243.] was `lesioned' in several ways to assess the form of the amblyopic deficit. The most successful model involves attenuation of signal and an increase in noise in the amblyopic eye, and intact stages of interocular suppression and binocular summation. This implies a behavioural influence from monocular noise in the amblyopic visual system as well as in normal observers with an ND filter over one eye.

Binocular contrast interactions:Dichoptic masking is not a single process

To decouple interocular suppression and binocular summation we varied the relative phase of mask and target in a 2IFC contrast-masking paradigm. In Experiment I, dichoptic mask gratings had the same orientation and spatial frequency as the target. For in-phase masking, suppression was strong (a log-log slope of ∼1) and there was weak facilitation at low mask contrasts. Anti-phase masking was weaker (a log-log slope of ∼0.7) and there was no facilitation. A two-stage model of contrast gain control [Meese, T.S., Georgeson, M.A. and Baker, D.H. (2006). Binocular contrast vision at and above threshold. Journal of Vision, 6: 1224-1243] provided a good fit to the in-phase results and fixed its free parameters. It made successful predictions (with no free parameters) for the anti-phase results when (A) interocular suppression was phase-indifferent but (B) binocular summation was phase sensitive. Experiments II and III showed that interocular suppression comprised two components: (i) a tuned effect with an orientation bandwidth of ∼±33° and a spatial frequency bandwidth of >3 octaves, and (ii) an untuned effect that elevated threshold by a factor of between 2 and 4. Operationally, binocular summation was more tightly tuned, having an orientation bandwidth of ∼±8°, and a spatial frequency bandwidth of ∼0.5 octaves. Our results replicate the unusual shapes of the in-phase dichoptic tuning functions reported by Legge [Legge, G.E. (1979). Spatial frequency masking in human vision: Binocular interactions. Journal of the Optical Society of America, 69: 838-847]. These can now be seen as the envelope of the direct effects from interocular suppression and the indirect effect from binocular summation, which contaminates the signal channel with a mask that has been suppressed by the target. © 2007 Elsevier Ltd. All rights reserved.

Suppression pathways saturate with contrast for parallel surrounds but not for superimposed cross-oriented masks

Contrast masking from parallel grating surrounds (doughnuts) and superimposed orthogonal masks have different characteristics. However, it is not known whether the saturation of the underlying suppression that has been found for parallel doughnut masks depends on (i) relative mask and target orientation, (ii) stimulus eccentricity or (iii) surround suppression. We measured contrast-masking functions for target patches of grating in the fovea and in the periphery for cross-oriented superimposed and doughnut masks and parallel doughnut masks. When suppression was evident, the factor that determined whether it accelerated or saturated was whether the mask stimulus was crossed or parallel. There are at least two interpretations of the asymptotic behaviour of the parallel surround mask. (1) Suppression arises from pathways that saturate with (mask) contrast. (2) The target is processed by a mechanism that is subject to surround suppression at low target contrasts, but a less sensitive mechanism that is immune from surround suppression ‘breaks through’ at higher target contrasts. If the mask can be made less potent, then masking functions should shift downwards, and sideways for the two accounts, respectively. We manipulated the potency of the mask by varying the size of the hole in a parallel doughnut mask. The results provided strong evidence for the first account but not the second. On the view that response compression becomes more severe progressing up the visual pathway, our results suggest that superimposed cross-orientation suppression precedes orientation tuned surround suppression. These results also reveal a previously unrecognized similarity between surround suppression and crowding (Pelli, Palomares, & Majaj, 2004).

Induced gamma activity in primary visual cortex is related to luminance and not color contrast: an MEG study

Gamma activity in the visual cortex has been reported in numerous EEG studies of coherent and illusory figures. A dominant theme of many such findings has been that temporal synchronization in the gamma band in response to these identifiable percepts is related to perceptual binding of the common features of the stimulus. In two recent studies using magnetoencephalography (MEG) and the beamformer analysis technique, we have shown that the magnitude of induced gamma activity in visual cortex is dependent upon independent stimulus features such as spatial frequency and contrast. In particular, we showed that induced gamma activity is maximal in response to gratings of 3 cycles per degree (3 cpd) of high luminance contrast. In this work, we set out to examine stimulus contrast further by using isoluminant red/green gratings that possess color but not luminance contrast using the same cohort of subjects. We found no induced gamma activity in V1 or visual cortex in response to the isoluminant gratings in these subjects who had previously shown strong induced gamma activity in V1 for luminance contrast gratings.

The influence of fixation points on contrast detection and discrimination of patches of grating: Masking and facilitation

The use of fixation points (FPs) in visual psychophysics is common practice, though the costs and benefits of different fixation regimens have not been compared. Here we investigate the influence of several different types of FP configurations on the contrast detection of patches of sine-wave gratings. We find that for small targets (1°), the addition of a superimposed central FP can increase thresholds by a factor of 1.3 (2.5 dB) in comparison with no FP, and a factor of 1.5 (3.6 dB) in comparison with FPs that surround the target. These results are consistent with (i) a suppressive influence on the central region of the target from a central FP, and (ii) facilitatory influences from surrounding FPs. Our analysis of the slope of the psychometric function suggests that the facilitatory influence is not due to reduction of uncertainty. Plausible candidate causes for the facilitation are: (i) sensory interactions, (ii) aids to ocular accommodation and convergence, (iii) a reduction in eye-movements and (iv) more accurate placement of the observer’s window of attention. Masking by a central FP is not found for the suprathreshold task of contrast discrimination, suggesting that the masking effects of pedestal and FP do not combine linearly. This means that estimates of the level of masking produced by a contrast pedestal can depend on the details of the fixation point.

Neuronal convergence in early contrast vision: binocular summation is followed by response nonlinearity and area summation

We assessed summation of contrast across eyes and area at detection threshold ( C t). Stimuli were sine-wave gratings (2.5 c/deg) spatially modulated by cosine- and anticosine-phase raised plaids (0.5 c/deg components oriented at ±45°). When presented dichoptically the signal regions were interdigitated across eyes but produced a smooth continuous grating following their linear binocular sum. The average summation ratio ( C t1/([ C t1+2]) for this stimulus pair was 1.64 (4.3 dB). This was only slightly less than the binocular summation found for the same patch type presented to both eyes, and the area summation found for the two different patch types presented to the same eye. We considered 192 model architectures containing each of the following four elements in all possible orders: (i) linear summation or a MAX operator across eyes, (ii) linear summation or a MAX operator across area, (iii) linear or accelerating contrast transduction, and (iv) additive Gaussian, stochastic noise. Formal equivalences reduced this to 62 different models. The most successful four-element model was: linear summation across eyes followed by nonlinear contrast transduction, linear summation across area, and late noise. Model performance was enhanced when additional nonlinearities were placed before binocular summation and after area summation. The implications for models of probability summation and uncertainty are discussed.

A common contrast pooling rule for suppression within and between the eyes

Recent work has revealed multiple pathways for cross-orientation suppression in cat and human vision. In particular, ipsiocular and interocular pathways appear to assert their influence before binocular summation in human but have different (1) spatial tuning, (2) temporal dependencies, and (3) adaptation after-effects. Here we use mask components that fall outside the excitatory passband of the detecting mechanism to investigate the rules for pooling multiple mask components within these pathways. We measured psychophysical contrast masking functions for vertical 1 cycle/deg sine-wave gratings in the presence of left or right oblique (645 deg) 3 cycles/deg mask gratings with contrast C%, or a plaid made from their sum, where each component (i) had contrast 0.5Ci%. Masks and targets were presented to two eyes (binocular), one eye (monoptic), or different eyes (dichoptic). Binocular-masking functions superimposed when plotted against C, but in the monoptic and dichoptic conditions, the grating produced slightly more suppression than the plaid when Ci $ 16%. We tested contrast gain control models involving two types of contrast combination on the denominator: (1) spatial pooling of the mask after a local nonlinearity (to calculate either root mean square contrast or energy) and (2) "linear suppression" (Holmes & Meese, 2004, Journal of Vision 4, 1080–1089), involving the linear sum of the mask component contrasts. Monoptic and dichoptic masking were typically better fit by the spatial pooling models, but binocular masking was not: it demanded strict linear summation of the Michelson contrast across mask orientation. Another scheme, in which suppressive pooling followed compressive contrast responses to the mask components (e.g., oriented cortical cells), was ruled out by all of our data. We conclude that the different processes that underlie monoptic and dichoptic masking use the same type of contrast pooling within their respective suppressive fields, but the effects do not sum to predict the binocular case.

Size matters, but not for everyone:Individual differences for contrast discrimination

It is very well known that contrast detection thresholds improve with the size of a grating-type stimulus, but it is thought that the benefit of size is abolished for contrast discriminations well above threshold (e.g., Legge, G. E., & Foley, J. M. (1980)]. Here we challenge the generality of this view. We performed contrast detection and contrast discrimination for circular patches of sine wave grating as a function of stimulus size. We confirm that sensitivity improves with approximately the fourth-root of stimulus area at detection threshold (a log-log slope of -0.25) but find individual differences (IDs) for the suprathreshold discrimination task. For several observers, performance was largely unaffected by area, but for others performance first improved (by as much as a log-log slope of -0.5) and then reached a plateau. We replicated these different results several times on the same observers. All of these results were described in the context of a recent gain control model of area summation [Meese, T. S. (2004)], extended to accommodate the multiple stimulus sizes used here. In this model, (i) excitation increased with the fourth-root of stimulus area for all observers, and (ii) IDs in the discrimination data were described by IDs in the relation between suppression and area. This means that empirical summation in the contrast discrimination task can be attributed to growth in suppression with stimulus size that does not keep pace with the growth in excitation. © 2005 ARVO.

Grating and plaid masks indicate linear summation in a contrast gain pool

In human vision, the response to luminance contrast at each small region in the image is controlled by a more global process where suppressive signals are pooled over spatial frequency and orientation bands. But what rules govern summation among stimulus components within the suppressive pool? We addressed this question by extending a pedestal plus pattern mask paradigm to use a stimulus with up to three mask components: a vertical 1 c/deg pedestal, plus pattern masks made from either a grating (orientation = -45°) or a plaid (orientation = ±45°), with component spatial frequency of 3 c/deg. The overall contrast of both types of pattern mask was fixed at 20% (i.e., plaid component contrasts were 10%). We found that both of these masks transformed conventional dipper functions (threshold vs. pedestal contrast with no pattern mask) in exactly the same way: The dipper region was raised and shifted to the right, but the dipper handles superimposed. This equivalence of the two pattern masks indicates that contrast summation between the plaid components was perfectly linear prior to the masking stage. Furthermore, the pattern masks did not drive the detecting mechanism above its detection threshold because they did not abolish facilitation by the pedestal (Foley, 1994). Therefore, the pattern masking could not be attributed to within-channel masking, suggesting that linear summation of contrast signals takes place within a suppressive contrast gain pool. We present a quantitative model of the effects and discuss the implications for neurophysiological models of the process. © 2004 ARVO.

Spatial coherence does not affect contrast discrimination for multiple Gabor stimuli

Gestalt grouping rules imply a process or mechanism for grouping together local features of an object into a perceptual whole. Several psychophysical experiments have been interpreted as evidence for constrained interactions between nearby spatial filter elements and this has led to the hypothesis that element linking might be mediated by these interactions. A common tacit assumption is that these interactions result in response modulation which disturbs a local contrast code. We addressed this possibility by performing contrast discrimination experiments using two-dimensional arrays of multiple Gabor patches arranged either (i) vertically, (ii) in circles (coherent conditions), or (iii) randomly (incoherent condition), as well as for a single Gabor patch. In each condition, contrast increments were applied to either the entire test stimulus (experiment 1) or a single patch whose position was cued (experiment 2). In experiment 3, the texture stimuli were reduced to a single contour by displaying only the central vertical strip. Performance was better for the multiple-patch conditions than for the single-patch condition, but whether the multiple-patch stimulus was coherent or not had no systematic effect on the results in any of the experiments. We conclude that constrained local interactions do not interfere with a local contrast code for our suprathreshold stimuli, suggesting that, in general, this is not the way in which element linking is achieved. The possibility that interactions are involved in enhancing the detectability of contour elements at threshold remains unchallenged by our experiments.

Liposomes:Formulation and characterisation as contrast agents and as vaccine delivery systems

Liposome systems are well reported for their activity as vaccine adjuvants; however novel lipid-based microbubbles have also been reported to enhance the targeting of antigens into dendritic cells (DCs) in cancer immunotherapy (Suzuki et al 2009). This research initially focused on the formulation of gas-filled lipid coated microbubbles and their potential activation of macrophages using in vitro models. Further studies in the thesis concentrated on aqueous-filled liposomes as vaccine delivery systems. Initial work involved formulating and characterising four different methods of producing lipid-coated microbubbles (sometimes referred to as gas-filled liposomes), by homogenisation, sonication, a gas-releasing chemical reaction and agitation/pressurisation in terms of stability and physico-chemical characteristics. Two of the preparations were tested as pressure probes in MRI studies. The first preparation composed of a standard phospholipid (DSPC) filled with air or nitrogen (N2), whilst in the second method the microbubbles were composed of a fluorinated phospholipid (F-GPC) filled with a fluorocarbon saturated gas. The studies showed that whilst maintaining high sensitivity, a novel contrast agent which allows stable MRI measurements of fluid pressure over time, could be produced using lipid-coated microbubbles. The F-GPC microbubbles were found to withstand pressures up to 2.6 bar with minimal damage as opposed to the DSPC microbubbles, which were damaged at above 1.3 bar. However, it was also found that DSPC-filled with N2 microbubbles were also extremely robust to pressure and their performance was similar to that of F-GPC based microbubbles. Following on from the MRI studies, the DSPC-air and N2 filled lipid-based microbubbles were assessed for their potential activation of macrophages using in vitro models and compared to equivalent aqueous-filled liposomes. The microbubble formulations did not stimulate macrophage uptake, so studies thereafter focused on aqueous-filled liposomes. Further studies concentrated on formulating and characterising, both physico-chemically and immunologically, cationic liposomes based on the potent adjuvant dimethyldioctadecylammonium (DDA) and immunomodulatory trehalose dibehenate (TDB) with the addition of polyethylene glycol (PEG). One of the proposed hypotheses for the mechanism behind the immunostimulatory effect obtained with DDA:TDB is the ‘depot effect’ in which the liposomal carrier helps to retain the antigen at the injection site thereby increasing the time of vaccine exposure to the immune cells. The depot effect has been suggested to be primarily due to their cationic nature. Results reported within this thesis demonstrate that higher levels of PEG i.e. 25 % were able to significantly inhibit the formation of a liposome depot at the injection site and also severely limit the retention of antigen at the site. This therefore resulted in a faster drainage of the liposomes from the site of injection. The versatility of cationic liposomes based on DDA:TDB in combination with different immunostimulatory ligands including, polyinosinic-polycytidylic acid (poly (I:C), TLR 3 ligand), and CpG (TLR 9 ligand) either entrapped within the vesicles or adsorbed onto the liposome surface was investigated for immunogenic capacity as vaccine adjuvants. Small unilamellar (SUV) DDA:TDB vesicles (20-100 nm native size) with protein antigen adsorbed to the vesicle surface were the most potent in inducing both T cell (7-fold increase) and antibody (up to 2 log increase) antigen specific responses. The addition of TLR agonists poly(I:C) and CpG to SUV liposomes had small or no effect on their adjuvanticity. Finally, threitol ceramide (ThrCer), a new mmunostimulatory agent, was incorporated into the bilayers of liposomes composed of DDA or DSPC to investigate the uptake of ThrCer, by dendritic cells (DCs), and presentation on CD1d molecules to invariant natural killer T cells. These systems were prepared both as multilamellar vesicles (MLV) and Small unilamellar (SUV). It was demonstrated that the IFN-g secretion was higher for DDA SUV liposome formulation (p<0.05), suggesting that ThrCer encapsulation in this liposome formulation resulted in a higher uptake by DCs.

Development of a novel magnetic resonance imaging contrast agent for pressure measurements using lipid-coated microbubbles

The aim of this study was to prepare gas-filled lipid-coated microbubbles as potential MRI contrast agents for imaging of fluid pressure. Air-filled microbubbles were produced with phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in the presence or absence of cholesterol and/or polyethylene-glycol distearate (PEG-distearate). Microbubbles were also prepared containing a fluorinated phospholipid, perfluoroalkylated glycerol-phosphatidylcholine, F-GPC shells encompassing perfluorohexane-saturated nitrogen gas. These microbubbles were evaluated in terms of physico-chemical characteristics such as size and stability. In parallel to these studies, DSPC microbubbles were also formulated containing nitrogen (N2) gas and compared to air-filled microbubbles. By preventing advection, signal drifts were used to assess their stability. DSPC microbubbles were found to have a drift of 20% signal change per bar of applied pressure in contrast to the F-GPC microbubbles which are considerably more stable with a lower drift of 5% signal change per bar of applied pressure. By increasing the pressure of the system and monitoring the MR signal intensity, the point at which the majority of the microbubbles have been damaged was determined. For the DSPC microbubbles this occurs at 1.3 bar whilst the F-GPC microbubbles withstand pressures up to 2.6 bar. For the comparison between air-filled and N2-filled microbubbles, the MRI sensitivity is assessed by cycling the pressure of the system and monitoring the MR signal intensity. It was found that the sensitivity exhibited by the N2-filled microbubbles remained constant, whilst the air-filled microbubbles demonstrated a continuous drop in sensitivity due to continuous bubble damage.

Differential impact of posterior lesions in the left and right hemisphere on visual category learning and generalization to contrast reversal

Hemispheric differences in the learning and generalization of pattern categories were explored in two experiments involving sixteen patients with unilateral posterior, cerebral lesions in the left (LH) or right (RH) hemisphere. In each experiment participants were first trained to criterion in a supervised learning paradigm to categorize a set of patterns that either consisted of simple geometric forms (Experiment 1) or unfamiliar grey-level images (Experiment 2). They were then tested for their ability to generalize acquired categorical knowledge to contrast-reversed versions of the learning patterns. The results showed that RH lesions impeded category learning of unfamiliar grey-level images more severely than LH lesions, whereas this relationship appeared reversed for categories defined by simple geometric forms. With regard to generalization to contrast reversal, categorization performance of LH and RH patients was unaffected in the case of simple geometric forms. However, generalization to of contrast-reversed grey-level images distinctly deteriorated for patients with LH lesions relative to those with RH lesions, with the latter (but not the former) being consistently unable to identify the pattern manipulation. These findings suggest a differential use of contrast information in the representation of pattern categories in the two hemispheres. Such specialization appears in line with previous distinctions between a predominantly lefthemispheric, abstract-analytical and a righthemispheric, specific-holistic representation of object categories, and their prediction of a mandatory representation of contrast polarity in the RH. Some implications for the well-established dissociation of visual disorders for the recognition of faces and letters are discussed.

The effect of interocular phase difference on perceived contrast

Binocular vision is traditionally treated as two processes: the fusion of similar images, and the interocular suppression of dissimilar images (e.g. binocular rivalry). Recent work has demonstrated that interocular suppression is phase-insensitive, whereas binocular summation occurs only when stimuli are in phase. But how do these processes affect our perception of binocular contrast? We measured perceived contrast using a matching paradigm for a wide range of interocular phase offsets (0–180°) and matching contrasts (2–32%). Our results revealed a complex interaction between contrast and interocular phase. At low contrasts, perceived contrast reduced monotonically with increasing phase offset, by up to a factor of 1.6. At higher contrasts the pattern was non-monotonic: perceived contrast was veridical for in-phase and antiphase conditions, and monocular presentation, but increased a little at intermediate phase angles. These findings challenge a recent model in which contrast perception is phase-invariant. The results were predicted by a binocular contrast gain control model. The model involves monocular gain controls with interocular suppression from positive and negative phase channels, followed by summation across eyes and then across space. Importantly, this model—applied to conditions with vertical disparity—has only a single (zero) disparity channel and embodies both fusion and suppression processes within a single framework.