A demonstration of cone function plasticity after gene therapy in achromatopsia.

Recent advances in regenerative therapy have placed the treatment of previously incurable eye diseases within arms' reach. Achromatopsia is a severe monogenic heritable retinal disease that disrupts cone function from birth, leaving patients with complete colour blindness, low acuity, photosensitivity and nystagmus. While successful gene-replacement therapy in non-primate models of achromatopsia has raised widespread hopes for clinical treatment, it was yet to be determined if and how these therapies can induce new cone function in the human brain. Using a novel multimodal approach, we demonstrate for the first time that gene therapy can successfully activate dormant cone-mediated pathways in children with achromatopsia (CNGA3- and CNGB3-associated, 10-15 years). To test this, we combined functional MRI population receptive field mapping and psychophysics with stimuli that selectively measure cone photoreceptor signalling. We measured cortical and visual cone function before and after gene therapy in four paediatric patients, evaluating treatment-related change against benchmark data from untreated patients (n = 9) and normal-sighted participants (n = 28). After treatment, two of the four children displayed strong evidence for novel cone-mediated signals in visual cortex, with a retinotopic pattern that was not present in untreated achromatopsia and which is highly unlikely to emerge by chance. Importantly, this change was paired with a significant improvement in psychophysical measures of cone-mediated visual function. These improvements were specific to the treated eye, and provide strong evidence for successful read-out and use of new cone-mediated information. These data show for the first time that gene replacement therapy in achromatopsia within the plastic period of development can awaken dormant cone-signalling pathways after years of deprivation. This reveals unprecedented neural plasticity in the developing human nervous system and offers great promise for emerging regenerative therapies.

Visual Population Receptive Fields in People with Schizophrenia Have Reduced Inhibitory Surrounds.

People with schizophrenia (SZ) experience abnormal visual perception on a range of visual tasks, which have been linked to abnormal synaptic transmission and an imbalance between cortical excitation and inhibition. However, differences in the underlying architecture of visual cortex neurons, which might explain these visual anomalies, have yet to be reported in vivo Here, we probed the neural basis of these deficits using fMRI and population receptive field (pRF) mapping to infer properties of visually responsive neurons in people with SZ. We employed a difference-of-Gaussian model to capture the center-surround configuration of the pRF, providing critical information about the spatial scale of the pRFs inhibitory surround. Our analysis reveals that SZ is associated with reduced pRF size in early retinotopic visual cortex, as well as a reduction in size and depth of the inhibitory surround in V1, V2, and V4. We consider how reduced inhibition might explain the diverse range of visual deficits reported in SZ.SIGNIFICANCE STATEMENT People with schizophrenia (SZ) experience abnormal perception on a range of visual tasks, which has been linked to abnormal synaptic transmission and an imbalance between cortical excitation/inhibition. However, associated differences in the functional architecture of visual cortex neurons have yet to be reported in vivo We used fMRI and population receptive field (pRF) mapping to demonstrate that the fine-grained functional architecture of visual cortex in people with SZ differs from unaffected controls. SZ is associated with reduced pRF size in early retinotopic visual cortex largely due to reduced inhibitory surrounds. An imbalance between cortical excitation and inhibition could drive such a change in the center-surround pRF configuration and ultimately explain the range of visual deficits experienced in SZ.

Larger extrastriate population receptive fields in autism spectrum disorders.

Previous behavioral research suggests enhanced local visual processing in individuals with autism spectrum disorders (ASDs). Here we used functional MRI and population receptive field (pRF) analysis to test whether the response selectivity of human visual cortex is atypical in individuals with high-functioning ASDs compared with neurotypical, demographically matched controls. For each voxel, we fitted a pRF model to fMRI signals measured while participants viewed flickering bar stimuli traversing the visual field. In most extrastriate regions, perifoveal pRFs were larger in the ASD group than in controls. We observed no differences in V1 or V3A. Differences in the hemodynamic response function, eye movements, or increased measurement noise could not account for these results; individuals with ASDs showed stronger, more reliable responses to visual stimulation. Interestingly, pRF sizes also correlated with individual differences in autistic traits but there were no correlations with behavioral measures of visual processing. Our findings thus suggest that visual cortex in ASDs is not characterized by sharper spatial selectivity. Instead, we speculate that visual cortical function in ASDs may be characterized by extrastriate cortical hyperexcitability or differential attentional deployment.

fMRI and gene therapy in adults with CNGB3 mutation.

Achromatopsia is an inherited retinal disease that affects 1 in 30,000-50,000 individuals and is characterised by an absence of functioning cone photoreceptors from birth. This results in severely reduced visual acuity, no colour vision, marked sensitivity to light and involuntary oscillations of the eyes (nystagmus). In most cases, a single gene mutation prevents normal development of cone photoreceptors, with mutations in the CNGB3 or CNGA3 gene being responsible for ∼80 % of all patients with achromatopsia. There are a growing number of studies investigating recovery of cone function after targeted gene therapy. These studies have provided some promise for patients with the CNGA3 mutation, but thus far have found limited or no recovery for patients with the CNGB3 mutation. Here, we developed colour-calibrated visual stimuli designed to isolate cone photoreceptor responses. We combined these with adapted fMRI techniques and pRF mapping to identify if cortical responses to cone-driven signals could be detected in 9 adult patients with the CNGB3 mutation after receiving gene therapy. We did not detect any change in brain activity after gene therapy when the 9 patients were analysed as a group. However, on an individual basis, one patient self-reported a change in colour perception, corroborated by improved performance on a psychophysical task designed to selectively identify cone function. This suggests a level of cone sensitivity that was lacking pre-treatment, further supported by a subtle but reliable change in cortical activity within their primary visual cortex.

Cortical network for gaze control in humans revealed using multimodal MRI.

Functional magnetic resonance imaging (fMRI) techniques allow definition of cortical nodes that are presumed to be components of large-scale distributed brain networks involved in cognitive processes. However, very few investigations examine whether such functionally defined areas are in fact structurally connected. Here, we used combined fMRI and diffusion MRI-based tractography to define the cortical network involved in saccadic eye movement control in humans. The results of this multimodal imaging approach demonstrate white matter pathways connecting the frontal eye fields and supplementary eye fields, consistent with the known connectivity of these regions in macaque monkeys. Importantly, however, these connections appeared to be more prominent in the right hemisphere of humans. In addition, there was evidence of a dorsal frontoparietal pathway connecting the frontal eye field and the inferior parietal lobe, also right hemisphere dominant, consistent with specialization of the right hemisphere for directed attention in humans. These findings demonstrate the utility and potential of using multimodal imaging techniques to define large-scale distributed brain networks, including those that demonstrate known hemispheric asymmetries in humans.

Expert cognitive control and individual differences associated with frontal and parietal white matter microstructure.

Although many functional imaging studies have reported frontal activity associated with "cognitive control" tasks, little is understood about factors underlying individual differences in performance. Here we compared the behavior and brain structure of healthy controls with fighter pilots, an expert group trained to make precision choices at speed in the presence of conflicting cues. Two different behavioral paradigms--Eriksen Flanker and change of plan tasks--were used to assess the influence of distractors and the ability to update ongoing action plans. Fighter pilots demonstrated superior cognitive control as indexed by accuracy and postconflict adaptation on the Flanker task, but also showed increased sensitivity to irrelevant, distracting choices. By contrast, when pilots were examined on their ability to inhibit a current action plan in favor of an alternative response, their performance was no better than the control group. Diffusion weighted imaging revealed differences in white matter radial diffusivity between pilots and controls not only in the right dorsomedial frontal region but also in the right parietal lobe. Moreover, analysis of individual differences in reaction time costs for conflict trials on the Flanker task demonstrated significant correlations with radial diffusivity at these locations, but in different directions. Postconflict adaptation effects, however, were confined to the dorsomedial frontal locus. The findings demonstrate that in humans expert cognitive control may surprisingly be mediated by enhanced response gain to both relevant and irrelevant stimuli, and is accompanied by structural alterations in the white matter of the frontal and parietal lobe.

Neural correlates of spatial orienting in the human superior colliculus.

A natural visual scene contains more information than the visual system has the capacity to simultaneously process, requiring specific items to be selected for detailed analysis at the expense of others. Such selection and inhibition are fundamental in guiding search behavior, but the neural basis of these mechanisms remains unclear. Abruptly appearing visual items can automatically capture attention, but once attention has been directed away from the salient event, return to that same location is slowed. In non-human primates, signals associated with attentional capture (AC) and subsequent inhibition of return (IOR) have been recorded from the superior colliculus (SC)--a structure known to play a pivotal role in reflexive spatial orienting. Here, we sought to establish whether similar signals could be recorded from the human SC, as well as early retinotopic cortical visual areas, where signals associated with AC and IOR have yet to be investigated with respect to oculomotor responses. Using an optimized oculomotor paradigm together with high-field, high-spatial resolution functional magnetic resonance imaging and high-speed eye tracking, we demonstrate that BOLD signal changes recorded from the human SC correlate strongly with our saccadic measures of AC and IOR. A qualitatively similar pattern of responses was found for V1, but only the inhibitory response associated with IOR persisted through V2 and V3. Although the SC plays a role in mediating these automatic attentional biasing signals, the source of these signals is likely to lie in higher cortical areas.

Overlapping functional anatomy for working memory and visual search.

Recent behavioural findings using dual-task paradigms demonstrate the importance of both spatial and non-spatial working memory processes in inefficient visual search (Anderson et al. in Exp Psychol 55:301-312, 2008). Here, using functional magnetic resonance imaging (fMRI), we sought to determine whether brain areas recruited during visual search are also involved in working memory. Using visually matched spatial and non-spatial working memory tasks, we confirmed previous behavioural findings that show significant dual-task interference effects occur when inefficient visual search is performed concurrently with either working memory task. Furthermore, we find considerable overlap in the cortical network activated by inefficient search and both working memory tasks. Our findings suggest that the interference effects observed behaviourally may have arisen from competition for cortical processes subserved by these overlapping regions. Drawing on previous findings (Anderson et al. in Exp Brain Res 180:289-302, 2007), we propose that the most likely anatomical locus for these interference effects is the inferior and middle frontal cortex of the right hemisphere. These areas are associated with attentional selection from memory as well as manipulation of information in memory, and we propose that the visual search and working memory tasks used here compete for common processing resources underlying these mechanisms.

Monocular signals in human lateral geniculate nucleus reflect the Craik-Cornsweet-O'Brien effect.

The human visual system has a remarkable ability to accurately estimate the relative brightness of adjacent objects despite large variations in illumination. However, the lightness of two identical equiluminant gray regions can appear quite different when a light-dark luminance transition falls between them. This illusory brightness "filling-in" phenomenon, the Craik-Cornsweet-O'Brien (CCOB) illusion, exposes fundamental assumptions made by the visual system in estimating lightness, but its neural basis remains unclear. While the responses of high-level visual cortex can be correlated with perception of the CCOB, simple computational models suggest that the effect may originate from a much lower level, possibly subcortical. Here, we used high spatial resolution functional magnetic resonance imaging to show that the CCOB illusion is strongly correlated with signals recorded from the human lateral geniculate nucleus. Moreover, presenting the light and dark luminance transitions that induce the CCOB effect separately to each eye abolishes the illusion, suggesting that it depends on eye-specific signals. Our observations suggest that the CCOB effect arises from signals in populations of monocular neurons very early in the human geniculostriate visual pathway.

Correction: Local and Global Limits on Visual Processing in Schizophrenia.

[This corrects the article DOI: 10.1371/journal.pone.0117951.].

Correction: Reduced Crowding and Poor Contour Detection in Schizophrenia Are Consistent with Weak Surround Inhibition.

[This corrects the article DOI: 10.1371/journal.pone.0060951.].

Corrigendum: Visual surround suppression in schizophrenia.

[This corrects the article DOI: 10.3389/fpsyg.2013.00088.].

Binocular Therapy for Childhood Amblyopia Improves Vision Without Breaking Interocular Suppression.

Purpose: Amblyopia is a common developmental visual impairment characterized by a substantial difference in acuity between the two eyes. Current monocular treatments, which promote use of the affected eye by occluding or blurring the fellow eye, improve acuity, but are hindered by poor compliance. Recently developed binocular treatments can produce rapid gains in visual function, thought to be as a result of reduced interocular suppression. We set out to develop an effective home-based binocular treatment system for amblyopia that would engage high levels of compliance but that would also allow us to assess the role of suppression in children's response to binocular treatment. Methods: Balanced binocular viewing therapy (BBV) involves daily viewing of dichoptic movies (with "visibility" matched across the two eyes) and gameplay (to monitor compliance and suppression). Twenty-two children (3-11 years) with anisometropic (n = 7; group 1) and strabismic or combined mechanism amblyopia (group 2; n = 6 and 9, respectively) completed the study. Groups 1 and 2 were treated for a maximum of 8 or 24 weeks, respectively. Results: The treatment elicited high levels of compliance (on average, 89.4% ± 24.2% of daily dose in 68.23% ± 12.2% of days on treatment) and led to a mean improvement in acuity of 0.27 logMAR (SD 0.22) for the amblyopic eye. Importantly, acuity gains were not correlated with a reduction in suppression. Conclusions: BBV is a binocular treatment for amblyopia that can be self-administered at home (with remote monitoring), producing rapid and substantial benefits that cannot be solely mediated by a reduction in interocular suppression.

Temporal dynamics of parietal cortex involvement in visual search.

The functional-neuroanatomic relationship that describes the involvement of the parietal cortex in visual search was investigated using repetitive transcranial magnetic stimulation (rTMS; 10 Hz, 500 ms in duration). Twelve adult participants performed feature-based visual search for a unique letter-without eye movements-under conditions that involved manipulations of search efficiency (efficient versus inefficient) and target-selection demands (set-size: 4 versus 10). rTMS was applied over the right posterior parietal cortex at the onset of the search array for all factorial conditions (0-500 ms); stimulation was additionally administered at 500 ms post-array onset (500-1000 ms) during inefficient search (set-size 10). Stimulation over the primary sensorimotor cortex served as a within-subjects control condition, and eye movements were monitored continuously. Significant increases in reaction time were restricted to parietal stimulation during inefficient search (set-size 10), with interference observed when rTMS was administered at the onset of the search array and at 500 ms post-array onset. The early effect was confined to target-present trials and the late effect was confined to target-absent trials, which may indicate temporally dissociable parietal involvement in target detection and response-based selection and/or search termination, respectively. Error rates did not vary significantly as a function of any of the independent variables. Taken together, these results are consistent with evidence from functional magnetic resonance studies indicating that inefficient feature-based visual search requires an intact parietal cortex, and also indicate that the parietal cortex is involved in inefficient search later than has been previously reported.

Local and global limits on visual processing in schizophrenia.

Schizophrenia has been linked to impaired performance on a range of visual processing tasks (e.g. detection of coherent motion and contour detection). It has been proposed that this is due to a general inability to integrate visual information at a global level. To test this theory, we assessed the performance of people with schizophrenia on a battery of tasks designed to probe voluntary averaging in different visual domains. Twenty-three outpatients with schizophrenia (mean age: 40±8 years; 3 female) and 20 age-matched control participants (mean age 39±9 years; 3 female) performed a motion coherence task and three equivalent noise (averaging) tasks, the latter allowing independent quantification of local and global limits on visual processing of motion, orientation and size. All performance measures were indistinguishable between the two groups (ps>0.05, one-way ANCOVAs), with one exception: participants with schizophrenia pooled fewer estimates of local orientation than controls when estimating average orientation (p = 0.01, one-way ANCOVA). These data do not support the notion of a generalised visual integration deficit in schizophrenia. Instead, they suggest that distinct visual dimensions are differentially affected in schizophrenia, with a specific impairment in the integration of visual orientation information.

Perceptual load affects spatial tuning of neuronal populations in human early visual cortex.

Withdrawal of attention from a visual scene as a result of perceptual load modulates overall levels of activity in human visual cortex [1], but its effects on cortical spatial tuning properties are unknown. Here we show attentional load at fixation affects the spatial tuning of population receptive fields (pRFs) in early visual cortex (V1-3) using functional magnetic resonance imaging (fMRI). We found that, compared to low perceptual load, high perceptual load yielded a 'blurrier' representation of the visual field surrounding the attended location and a centrifugal 'repulsion' of pRFs. Additional data and control analyses confirmed that these effects were neither due to changes in overall activity levels nor to eye movements. These findings suggest neural 'tunnel vision' as a form of distractor suppression under high perceptual load.

White matter microstructure and cognitive function.

In recent years, diffusion-weighted magnetic resonance imaging (DW-MRI) has been increasingly used to explore the relationship between white matter structure and cognitive function. This technique uses the passive diffusion of water molecules to infer properties of the surrounding tissue. DW-MRI has been extensively employed to investigate how individual differences in behavior are related to variability in white matter microstructure on a range of different cognitive tasks and also to examine the effect experiential learning might have on brain structural connectivity. Using diffusion tensor tractography, large white matter pathways have been traced in vivo and used to explore patterns of white matter projections between different brain regions. Recent findings suggest that diffusion-weighted imaging might even be used to measure functional differences in water diffusion during task performance. This review describes some research highlights in diffusion-weighted imaging and how this technique can be employed to further our understanding of cognitive function.

Visual surround suppression in schizophrenia.

Compared to unaffected observers patients with schizophrenia (SZ) show characteristic differences in visual perception, including a reduced susceptibility to the influence of context on judgments of contrast - a manifestation of weaker surround suppression (SS). To examine the generality of this phenomenon we measured the ability of 24 individuals with SZ to judge the luminance, contrast, orientation, and size of targets embedded in contextual surrounds that would typically influence the target's appearance. Individuals with SZ demonstrated weaker SS compared to matched controls for stimuli defined by contrast or size, but not for those defined by luminance or orientation. As perceived luminance is thought to be regulated at the earliest stages of visual processing our findings are consistent with a suppression deficit that is predominantly cortical in origin. In addition, we propose that preserved orientation SS in SZ may reflect the sparing of broadly tuned mechanisms of suppression. We attempt to reconcile these data with findings from previous studies.

Reduced crowding and poor contour detection in schizophrenia are consistent with weak surround inhibition.

BACKGROUND: Detection of visual contours (strings of small oriented elements) is markedly poor in schizophrenia. This has previously been attributed to an inability to group local information across space into a global percept. Here, we show that this failure actually originates from a combination of poor encoding of local orientation and abnormal processing of visual context. METHODS: We measured the ability of observers with schizophrenia to localise contours embedded in backgrounds of differently oriented elements (either randomly oriented, near-parallel or near-perpendicular to the contour). In addition, we measured patients' ability to process local orientation information (i.e., report the orientation of an individual element) for both isolated and crowded elements (i.e., presented with nearby distractors). RESULTS: While patients are poor at detecting contours amongst randomly oriented elements, they are proportionally less disrupted (compared to unaffected controls) when contour and surrounding elements have similar orientations (near-parallel condition). In addition, patients are poor at reporting the orientation of an individual element but, again, are less prone to interference from nearby distractors, a phenomenon known as visual crowding. CONCLUSIONS: We suggest that patients' poor performance at contour perception arises not as a consequence of an "integration deficit" but from a combination of reduced sensitivity to local orientation and abnormalities in contextual processing. We propose that this is a consequence of abnormal gain control, a phenomenon that has been implicated in orientation-selectivity as well as surround suppression.