José Rebola

GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact.

Alterations in the balance between excitatory and inhibitory neurotransmission have been implicated in several neurodevelopmental disorders. Neurofibromatosis type 1 is one of the most common monogenic disorders causing cognitive deficits for which studies on a mouse model (Nfl(+/-)) proposed increased γ-aminobutyric acid-mediated inhibitory neurotransmission as the neural mechanism underlying these deficits. To test whether a similar mechanism translates to the human disorder, we used magnetic resonance spectroscopy to measure γ-aminobutyric acid levels in the visual cortex of children and adolescents with neurofibromatosis type 1 (n = 20) and matched control subjects (n = 26). We found that patients with neurofibromatosis type 1 have significantly lower γ-aminobutyric acid levels than control subjects, and that neurofibromatosis type 1 mutation type significantly predicted cortical γ-aminobutyric acid. Moreover, functional imaging of the visual cortex indicated that blood oxygen level-dependent signal was correlated with γ-aminobutyric acid levels both in patients and control subjects. Our results provide in vivo evidence of γ-aminobutyric acidergic dysfunction in neurofibromatosis type 1 by showing a reduction in γ-aminobutyric acid levels in human patients. This finding is relevant to understand the physiological profile of the disorder and has implications for the identification of targets for therapeutic strategies.

Functional parcellation of the operculo-insular cortex in perceptual decision making: An fMRI study

A current challenge in cognitive neuroscience is to provide an explicit separation of the neural correlates of abstract global decision variables from sensory and integrative ones. In particular, the insular cortex and the adjacent frontal operculum seem to have a crucial but still unclear role in evidence accumulation and decision signaling in perceptual decision-making tasks. Here, we have used a visual decision-making paradigm based on the detection of ambiguous two-tone (Mooney) face stimuli to assess the emergence of holistic percepts. These are constructed using global gestalt rules and not by gradual spatiotemporal increases in sensory evidence. Our paradigm (neurochronometric approach) enabled the experimental separation between multiple cognitive components in perceptual decision validated by both model-driven and data-driven analysis. This strategy allowed for the functional dissection of operculo-insular networks into task related complexes such as anterior (accumulator), middle (decision) and posterior (somatosensory/sensorimotor). We conclude that global perceptual integration based on holistic rules requires a distributed operculo-insular network.

To perceive or not perceive: the role of gamma-band activity in signaling object percepts.

The relation of gamma-band synchrony to holistic perception in which concerns the effects of sensory processing, high level perceptual gestalt formation, motor planning and response is still controversial. To provide a more direct link to emergent perceptual states we have used holistic EEG/ERP paradigms where the moment of perceptual “discovery” of a global pattern was variable. Using a rapid visual presentation of short-lived Mooney objects we found an increase of gamma-band activity locked to perceptual events. Additional experiments using dynamic Mooney stimuli showed that gamma activity increases well before the report of an emergent holistic percept. To confirm these findings in a data driven manner we have further used a support vector machine classification approach to distinguish between perceptual vs. non perceptual states, based on time-frequency features. Sensitivity, specificity and accuracy were all above 95%. Modulations in the 30–75 Hz range were larger for perception states. Interestingly, phase synchrony was larger for perception states for high frequency bands. By focusing on global gestalt mechanisms instead of local processing we conclude that gamma-band activity and synchrony provide a signature of holistic perceptual states of variable onset, which are separable from sensory and motor processing.

GABA deficiency in NF1 A multimodal [11C]-flumazenil and spectroscopy study

Objective: To provide a comprehensive investigation of the γ-aminobutyric acid (GABA) system in patients with neurofibromatosis type 1 (NF1) that allows understanding the nature of the GABA imbalance in humans at pre- and postsynaptic levels. Methods: In this cross-sectional study, we employed multimodal imaging and spectroscopy measures to investigate GABA type A (GABAA) receptor binding, using [11C]-flumazenil PET, and GABA concentration, using magnetic resonance spectroscopy (MRS). Fourteen adult patients with NF1 and 13 matched controls were included in the study. MRS was performed in the occipital cortex and in a frontal region centered in the functionally localized frontal eye fields. PET and MRS acquisitions were performed in the same day. Results: Patients with NF1 have reduced concentration of GABA+ in the occipital cortex (p = 0.004) and frontal eye fields (p = 0.026). PET results showed decreased binding of GABAA receptors in patients in the parieto-occipital cortex, midbrain, and thalamus, which are not explained by decreased gray matter levels. Conclusions: Abnormalities in the GABA system in NF1 involve both GABA concentration and GABAA receptor density suggestive of neurodevelopmental synaptopathy with both pre- and postsynaptic involvement.

Oscillations or synchrony? disruption of neural synchrony despite enhanced gamma oscillations in a model of disrupted perceptual coherence

It has been hypothesized that neural synchrony underlies perceptual coherence. The hypothesis of loss of central perceptual coherence has been proposed to be at the origin of abnormal cognition in autism spectrum disorders and Williams syndrome, a neurodevelopmental disorder linked with autism, and a clearcut model for impaired central coherence. We took advantage of this model of impaired holistic processing to test the hypothesis that loss of neural synchrony plays a separable role in visual integration using EEG and a set of experimental tasks requiring coherent integration of local elements leading to 3-D face perception. A profound reorganization of brain activity was identified. Neural synchrony was reduced across stimulus conditions, and this was associated with increased amplitude modulation at 25–45 Hz. This combination of a dramatic loss of synchrony despite increased oscillatory activity is strong evidence that synchrony underlies central coherence. This is the first time, to our knowledge, that dissociation between amplitude and synchrony is reported in a human model of impaired perceptual coherence, suggesting that loss of phase coherence is more directly related to disruption of holistic perception.

Functional reorganization of the visual dorsal stream as probed by 3-d visual coherence in williams syndrome

Object and depth perception from motion cues involves the recruitment of visual dorsal stream brain areas. In 3-D structure-from-motion (SFM) perception, motion and depth information are first extracted in this visual stream to allow object categorization, which is in turn mediated by the ventral visual stream. Such interplay justifies the use of SFM paradigms to understand dorsal–ventral integration of visual information. The nature of such processing is particularly interesting to be investigated in a neurological model of cognitive dissociation between dorsal (impaired) and ventral stream (relatively preserved) processing, Williams syndrome (WS). In the current fMRI study, we assessed dorsal versus ventral stream processing by using a performance-matched 3-D SFM object categorization task. We found evidence for substantial reorganization of the dorsal stream in WS as assessed by whole-brain ANOVA random effects analysis, with subtle differences in ventral activation. Dorsal reorganization was expressed by larger medial recruitment in WS (cuneus, precuneus, and retrosplenial cortex) in contrast with controls, which showed the expected dorsolateral pattern (caudal intraparietal sulcus and lateral occipital cortex). In summary, we found a substantial reorganization of dorsal stream regions in WS in response to simple visual categories and 3-D SFM perception, with less affected ventral stream. Our results corroborate the existence of a medial dorsal pathway that provides the substrate for information rerouting and reorganization in the presence of lateral dorsal stream vulnerability. This interpretation is consistent with recent findings suggesting parallel routing of information in medial and lateral parts of dorsal stream.

Visual Perception and Reading: New Clues to Patterns of Dysfunction Across Multiple Visual Channels in Developmental Dyslexia

Purpose The specificity of visual channel impairment in dyslexia has been the subject of much controversy. The purpose of this study was to determine if a differential pattern of impairment can be verified between visual channels in children with developmental dyslexia, and in particular, if the pattern of deficits is more conspicuous in tasks where the magnocellular-dorsal system recruitment prevails. Additionally, we also aimed at investigating the association between visual perception thresholds and reading. Methods In the present case-control study, we compared perception thresholds of 33 children diagnosed with developmental dyslexia and 34 controls in a speed discrimination task, an achromatic contrast sensitivity task, and a chromatic contrast sensitivity task. Moreover, we addressed the correlation between the different perception thresholds and reading performance, as assessed by means of a standardized reading test (accuracy and fluency). Group comparisons were performed by the Mann-Whitney U test, and Spearmans rho was used as a measure of correlation. Results Results showed that, when compared to controls, children with dyslexia were more impaired in the speed discrimination task, followed by the achromatic contrast sensitivity task, with no impairment in the chromatic contrast sensitivity task. These results are also consistent with the magnocellular theory since the impairment profile of children with dyslexia in the visual threshold tasks reflected the amount of magnocellular-dorsal stream involvement. Moreover, both speed and achromatic thresholds were significantly correlated with reading performance, in terms of accuracy and fluency. Notably, chromatic contrast sensitivity thresholds did not correlate with any of the reading measures. Conclusions Our evidence stands in favor of a differential visual channel deficit in children with developmental dyslexia and contributes to the debate on the pathophysiology of reading impairments.

Visual areas PPA and pSTS diverge from other processing modules during perceptual closure: functional dichotomies within category selective networks.

The nature of neural processing within category-preferring visual networks remains an open topic in human neuroscience. Although the topography of face, scene, and object-preferring modules in the human brain is well established, the functional characterization, in terms of dynamic selectivity across their nodes is still elusive. Here, we use long trials of perceptually impoverished images of faces and objects to assess the dynamics of BOLD activity and selectivity induced by perceptual closure within these regions of interest. Departing from paradigms involving immediate percepts, we used ambiguous images favoring holistic search and independence from low level stimulus properties. By assessing the neural responses to images that go beyond the preferred category of the studied ROIs we could dissect the specificity of these processes as a function of the timing of perceptual closure and contribute to the debate regarding specialization of these modules. We found that pSTS is a notable exception to the observation that category selective high-level visual areas also participate on the perceptual closure of their non-preferred category. A similar observation was found for PPA responses to faces. Most importantly, these observations directly link the pSTS region with the social processing network, which cannot be engaged by object stimuli.

Evidence for a differential interference of noise in sub-lexical and lexical reading routes in healthy participants and dyslexics

ABSTRACT The ineffective exclusion of surrounding noise has been proposed to underlie the reading deficits in developmental dyslexia. However, previous studies supporting this hypothesis focused on low-level visual tasks, providing only an indirect link of noise interference on reading processes. In this study, we investigated the effect of noise on regular, irregular, and pseudoword reading in 23 dyslexic children and 26 age- and IQ-matched controls, by applying the white noise displays typically used to validate this theory to a lexical decision task. Reading performance and eye movements were measured. Results showed that white noise did not consistently affect dyslexic readers more than typical readers. Noise affected more dyslexic than typical readers in terms of reading accuracy, but it affected more typical than dyslexic readers in terms of response time and eye movements (number of fixations and regressions). Furthermore, in typical readers, noise affected more the speed of reading of pseudowords than real words. These results suggest a particular impact of noise on the sub-lexical reading route where attention has to be deployed to individual letters. The use of a lexical route would reduce the effect of noise. A differential impact of noise between words and pseudowords may therefore not be evident in dyslexic children if they are not yet proficient in using the lexical route. These findings indicate that the type of reading stimuli and consequent reading strategies play an important role in determining the effects of noise interference in reading processing and should be taken into account by further studies.