Deficits in the interpretation of others' intentions from gaze-direction or other social attention cues are well-recognized in ASD. Here we investigated whether an EEG brain computer interface (BCI) can be used to train social cognition skills in ASD patients. We performed a single-arm feasibility clinical trial and enrolled 15 participants (mean age 22y 2m) with high-functioning ASD (mean full-scale IQ 103). Participants were submitted to a BCI training paradigm using a virtual reality interface over seven sessions spread over 4 months. The first four sessions occurred weekly, and the remainder monthly. In each session, the subject was asked to identify objects of interest based on the gaze direction of an avatar. Attentional responses were extracted from the EEG P300 component. A final follow-up assessment was performed 6-months after the last session. To analyze responses to joint attention cues participants were assessed pre and post intervention and in the follow-up, using an ecologic “Joint-attention task.” We used eye-tracking to identify the number of social attention items that a patient could accurately identify from an avatar's action cues (e.g., looking, pointing at). As secondary outcome measures we used the Autism Treatment Evaluation Checklist (ATEC) and the Vineland Adaptive Behavior Scale (VABS). Neuropsychological measures related to mood and depression were also assessed. In sum, we observed a decrease in total ATEC and rated autism symptoms (Sociability; Sensory/Cognitive Awareness; Health/Physical/Behavior); an evident improvement in Adapted Behavior Composite and in the DLS subarea from VABS; a decrease in Depression (from POMS) and in mood disturbance/depression (BDI). BCI online performance and tolerance were stable along the intervention. Average P300 amplitude and alpha power were also preserved across sessions. We have demonstrated the feasibility of BCI in this kind of intervention in ASD. Participants engage successfully and consistently in the task. Although the primary outcome (rate of automatic responses to joint attention cues) did not show changes, most secondary neuropsychological outcome measures showed improvement, yielding promise for a future efficacy trial. (clinical-trial ID: NCT02445625—clinicaltrials.gov).

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.

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.

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 (GABA_A) 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 GABA_A 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 GABA_A receptor density suggestive of neurodevelopmental synaptopathy with both pre- and postsynaptic involvement.

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.