Inês Bernardino

A Direct Comparison of Local-Global Integration in Autism and other Developmental Disorders: Implications for the Central Coherence Hypothesis

The weak central coherence hypothesis represents one of the current explanatory models in Autism Spectrum Disorders (ASD). Several experimental paradigms based on hierarchical figures have been used to test this controversial account. We addressed this hypothesis by testing central coherence in ASD (n = 19 with intellectual disability and n = 20 without intellectual disability), Williams syndrome (WS, n = 18), matched controls with intellectual disability (n = 20) and chronological age-matched controls (n = 20). We predicted that central coherence should be most impaired in ASD for the weak central coherence account to hold true. An alternative account includes dorsal stream dysfunction which dominates in WS. Central coherence was first measured by requiring subjects to perform local/global preference judgments using hierarchical figures under 6 different experimental settings (memory and perception tasks with 3 distinct geometries with and without local/global manipulations). We replicated these experiments under 4 additional conditions (memory/perception*local/global) in which subjects reported the correct local or global configurations. Finally, we used a visuoconstructive task to measure local/global perceptual interference. WS participants were the most impaired in central coherence whereas ASD participants showed a pattern of coherence loss found in other studies only in four task conditions favoring local analysis but it tended to disappear when matching for intellectual disability. We conclude that abnormal central coherence does not provide a comprehensive explanation of ASD deficits and is more prominent in populations, namely WS, characterized by strongly impaired dorsal stream functioning and other phenotypic traits that contrast with the autistic phenotype. Taken together these findings suggest that other mechanisms such as dorsal stream deficits (largest in WS) may underlie impaired central coherence.

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.

Abnormal Brain Activation in Neurofibromatosis Type 1: A Link between Visual Processing and the Default Mode Network

Neurofibromatosis type 1 (NF1) is one of the most common single gene disorders affecting the human nervous system with a high incidence of cognitive deficits, particularly visuospatial. Nevertheless, neurophysiological alterations in low-level visual processing that could be relevant to explain the cognitive phenotype are poorly understood. Here we used functional magnetic resonance imaging (fMRI) to study early cortical visual pathways in children and adults with NF1. We employed two distinct stimulus types differing in contrast and spatial and temporal frequencies to evoke relatively different activation of the magnocellular (M) and parvocellular (P) pathways. Hemodynamic responses were investigated in retinotopically-defined regions V1, V2 and V3 and then over the acquired cortical volume. Relative to matched control subjects, patients with NF1 showed deficient activation of the low-level visual cortex to both stimulus types. Importantly, this finding was observed for children and adults with NF1, indicating that low-level visual processing deficits do not ameliorate with age. Moreover, only during M-biased stimulation patients with NF1 failed to deactivate or even activated anterior and posterior midline regions of the default mode network. The observation that the magnocellular visual pathway is impaired in NF1 in early visual processing and is specifically associated with a deficient deactivation of the default mode network may provide a neural explanation for high-order cognitive deficits present in NF1, particularly visuospatial and attentional. A link between magnocellular and default mode network processing may generalize to neuropsychiatric disorders where such deficits have been separately identified.

Abnormal relationship between GABA, neurophysiology and impulsive behavior in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a neurodevelopmental disorder characterized by a broad spectrum of cognitive deficits. In particular, executive dysfunction is recognized as a core deficit of NF1, including impairments in executive attention and inhibitory control. Yet, the neural mechanisms behind these important deficits are still unknown. Here, we studied inhibitory control in a visual go/no-go task in children and adolescents with NF1 and age- and gender-matched controls (n = 16 per group). We applied a multimodal approach using high-density electroencephalography (EEG), to study the evoked brain responses, and magnetic resonance spectroscopy (MRS) to measure the levels of GABA and glutamate + glutamine in the medial frontal cortex, a brain region that plays a pivotal role in inhibitory control, and also in a control region, the occipital cortex. Finally, we run correlation analyses to identify the relationship between inhibitory control, levels of neurotransmitters, and EEG markers of neural function. Individuals with NF1 showed impaired impulse control and reduced EEG correlates of early visual processing (parieto-occipital P1) and inhibitory control (frontal P3). MRS data revealed a reduction in medial frontal GABA+/tCr (total Creatine) levels in the NF1 group, in parallel with the already reported reduced occipital GABA levels. In contrast, glutamate + glutamine/tCr levels were normal, suggesting the existence of abnormal inhibition/excitation balance in this disorder. Notably, medial frontal but not occipital GABA levels correlated with general intellectual abilities (IQ) in NF1, and inhibitory control in both groups. Surprisingly, the relationship between inhibitory control and medial frontal GABA was reversed in NF1: higher GABA was associated with a faster response style whereas in controls it was related to a cautious strategy. Abnormal GABAergic physiology appears, thus, as an important factor underlying impaired cognition in NF1, in a level and region dependent manner.

Neural correlates of visual integration in Williams syndrome: Gamma oscillation patterns in a model of impaired coherence

Williams syndrome (WS) is a clinical model of dorsal stream vulnerability and impaired visual integration. However, little is still known about the neurophysiological correlates of perceptual integration in this condition. We have used a 3D structure-from-motion (SFM) integrative task to characterize the neuronal underpinnings of 3D perception in WS and to probe whether gamma oscillatory patterns reflect changed holistic perception. Coherent faces were parametrically modulated in 3D depth (three different depth levels) to vary levels of stimulus ambiguity. We have found that the electrophysiological (EEG/ERP) correlates of such holistic percepts were distinct across groups. Independent component analysis demonstrated the presence of a novel component with a late positivity around 200 ms that was absent in controls. Source localization analysis of ERP signals showed a posterior occipital shift in WS and reduced parietal dorsal stream sources. Interestingly, low gamma-band oscillations (20-40 Hz) induced by this 3D perceptual integration task were significantly stronger and sustained during the stimulus presentation in WS whereas high gamma-band oscillations (60-90 Hz) were reduced in this clinical model of impaired visual coherence, as compared to controls. These observations suggest that dorsal stream processing of 3D SFM stimuli has distinct neural correlates in WS and different cognitive strategies are employed by these patients to reach visual coherence. Importantly, we found evidence for the presence of different sub-bands (20-40 Hz/60-90 Hz) within the gamma range which can be dissociated concerning the respective role on the coherent percept formation, both in typical and atypical development.

Egocentric and allocentric spatial representations in Williams syndrome.

Williams syndrome (WS) is a neurodevelopmental disorder characterized by severe visuospatial deficits, particularly affecting spatial navigation and wayfinding. Creating egocentric (viewer-dependent) and allocentric (viewer-independent) representations of space is essential for the development of these abilities. However, it remains unclear whether egocentric and allocentric representations are impaired in WS. In this study, we investigate egocentric and allocentric frames of reference in this disorder. A WS group (n = 18), as well as a chronological age-matched control group (n = 20), a non-verbal mental age-matched control group (n = 20) and a control group with intellectual disability (n = 17), was tested with a computerized and a 3D spatial judgment task. The results showed that WS participants are impaired when performing both egocentric and allocentric spatial judgments even when compared with mental age-matched control participants. This indicates that a substantial deficit affecting both spatial representations is present in WS. The egocentric impairment is in line with the dorsal visual pathway deficit previously reported in WS. Interestingly, the difficulties found in performing allocentric spatial judgments give important cues to better understand the ventral visual functioning in WS.

Abnormal Achromatic and Chromatic Contrast Sensitivity in Neurofibromatosis Type 1

PURPOSE Neurofibromatosis type 1 (NF1) is a monogenic disorder with the majority of patients presenting subtle to moderate cognitive impairments. Visuospatial deficits are considered to be one of the hallmark characteristics of their cognitive profile. However, low-level visual processing has not been previously investigated. Our aim was to study contrast perception in these patients to assess the function of early visual areas. METHODS Contrast sensitivity was tested in 19 children and adolescents with NF1 and 33 control children and adolescents and 12 adults with NF1 and 24 control adults. The tasks used probed two achromatic spatiotemporal frequency channels and chromatic red-green and blue-yellow pathways. RESULTS Individuals with NF1 showed significant contrast sensitivity deficits for the achromatic higher spatial frequency channel [F(₁,₈₃) = 36.1, P < 0.001] and for the achromatic low spatial high temporal (magnocellular) frequency channel [F(₁,₇₂) = 8.0, P < 0.01]. Furthermore, individuals with NF1 presented a significant deficit in chromatic red-green (parvocellular) contrast sensitivity (P < 0.01) but not in blue-yellow (koniocelular) sensitivity. The decrease in achromatic sensitivity for higher spatial frequency was observed throughout the visual field, in both central and peripheral locations. In contrast, central contrast sensitivity for the magnocellular-biased condition was relatively preserved and only peripheral sensitivity was affected. Interestingly, the same pattern of deficits was found in both age groups tested. CONCLUSIONS These findings showed that contrast sensitivity is impaired in patients with NF1, associating for the first time abnormal low-level vision to the cognitive profile of this disorder.

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.