Neural substrates of psychosis revealed by altered dependencies between brain activity and white-matter architecture in individuals with 22q11 deletion syndrome

Background: Dysconnectivity has been consistently proposed as a major key mechanism in psychosis. Indeed, disruptions in large-scale structural and functional brain networks have been associated with psychotic symptoms. However, brain activity is largely constrained by underlying white matter pathways and the study of function-structure dependency, compared to conventional unimodal analysis, allows a biologically relevant assessment of neural mechanisms. The 22q11.2 deletion syndrome (22q11DS) constitutes a remarkable opportunity to study the pathophysiological processes of psychosis. Methods: 58 healthy controls and 57 deletion carriers, aged from 16 to 32 years old, underwent resting-state functional and diffusion-weighted magnetic resonance imaging. Deletion carriers were additionally fully assessed for psychotic symptoms. Firstly, we used a graph signal processing method to combine brain activity and structural connectivity measures to obtain regional structural decoupling indexes (SDIs). We use SDI to assess the differences of functional structural dependency (FSD) across the groups. Subsequently we investigated how alterations in FSDs are associated with the severity of positive psychotic symptoms in participants with 22q11DS. Results: In line with previous findings, participants in both groups showed a spatial gradient of FSD ranging from sensory-motor regions (stronger FSD) to regions involved in higher-order function (weaker FSD). Compared to controls, in participants with 22q11DS, and further in deletion carriers with more severe positive psychotic symptoms, the functional activity was more strongly dependent on the structure in parahippocampal gyrus and subcortical dopaminergic regions, while it was less dependent within the cingulate cortex. This analysis revealed group differences not otherwise detected when assessing the structural and functional nodal measures separately. Conclusions: Our findings point toward a disrupted modulation of functional activity on the underlying structure, which was further associated to psychopathology for candidate critical regions in 22q11DS. This study provides the first evidence for the clinical relevance of function-structure dependency and its contribution to the emergence of psychosis.

Altered structural network architecture is predictive of the presence of psychotic symptoms in patients with 22q11.2 deletion syndrome

Maria Carmela Padula, Marie Schaer, Maude Schneider, Dimitri Nestor Alice Van De Ville

22q11.2 deletion syndrome (22q11DS) represents a homogeneous model of schizophrenia particularly suitable for the search of neural biomarkers of psychosis. Impairments in structural connectivity related to the presence of psychotic symptoms have been reported in patients with 22q11DS. However, the relationships between connectivity changes in patients with different symptomatic profiles are still largely unknown and warrant further investigations. In this study, we used structural connectivity to discriminate patients with 22q11DS with (N = 31) and without (N = 31) attenuated positive psychotic symptoms. Different structural connectivity measures were used, including the number of streamlines connecting pairs of brain regions, graph theoretical measures, and diffusion measures. We used univariate group comparisons as well as predictive multivariate approaches. The univariate comparison of connectivity measures between patients with or without attenuated positive psychotic symptoms did not give significant results. However, the multivariate prediction revealed that altered structural network architecture discriminates patient subtypes (accuracy = 67.7%). Among the regions contributing to the classification we found the anterior cingulate cortex, which is known to be associated to the presence of psychotic symptoms in patients with 22q11DS. Furthermore, a significant discrimination (accuracy = 64%) was obtained with fractional anisotropy and radial diffusivity in the left inferior longitudinal fasciculus and the right cingulate gyrus. Our results point to alterations in structural network architecture and white matter microstructure in patients with 22q11DS with attenuated positive symptoms, mainly involving connections of the limbic system. These alterations may therefore represent a potential biomarker for an increased risk of psychosis that should be further tested in longitudinal studies.

Elsevier Sci Ltd2017

Motor and cognitive brain circuits of brain-machine interactions

Silvia Marchesotti

Brain-machine interfaces (BMIs) allow the user to control an external device such as a robotic arm, a cursor, or an avatar in a virtual world through the real-time decoding of brain signals and without the involvement of the musculoskeletal system. Although BMIs hold great promise for providing motor-impaired patients with means of control and interaction with the external world, the neurocognitive mechanisms that are involved in the use of a BMI remain poorly understood. In addition, BMIs allow researchers to investigate and separate the brain processes underlying cognitive functions from those related to motor control and afferent sensory signals that reliably accompany movements. Thus, BMIs are powerful tools for basic and applied neuroscience research. The present work investigates different stages of a BMI-mediated action and targets the subjective, behavioral, and neural signals of BMI control based on electroencephalography (EEG) signals. More specifically, the main study of this thesis has focused on the development of a multimodal imaging platform that allows EEG-based BMI control inside the magnetic resonance imaging (MRI) scanner and during the acquisition of functional MRI (fMRI). This platform has enabled us to exploit both the high temporal resolution of EEG and the high spatial resolution of fMRI to precisely identify the brain mechanisms underlying BMI control and those reflecting the subjective feeling of being in control over a BMI-action (i.e., the sense of agency, SoA). In this study we found an extended cortico-subcortical network involved in operating a motor-imagery BMI. Overall BMI performance was associated with activity in a set of regions including contralateral premotor cortex and the posterior cingulate cortex. Finally, cortical midline regions and the basal ganglia were involved in the subjective sense of controlling the BMI. In a second study, we further investigated whether the ability to control a BMI relates to the ability to perform motor imagery. Despite decades of technical advances, effective BMI-control remains limited to a subset of users. We show that inter-subject variability in BMI proficiency is associated with differences in motor imagery accuracy as captured by subjective and behavioral measurements, pointing to a prominent role of kinesthetic rather than visual imagery. We also identified enhanced lateralized ÎŒ-band oscillations over sensorimotor cortices during motor imagery in high- versus low-aptitude BMI users. Finally, we developed a novel paradigm for joint BMI actions, allowing two users to be jointly engaged in BMI control; our preliminary data provide evidence in support of the hypothesis that joint actions yield BMI-performance improvement even in absence of a physical connection. Our findings also show that during joint BMI-control the SoA over the imagery-mediated actions is significantly enhanced, and is affected by BMI abilities. This work show the potential of applying a multimodal imaging approach to the field of BMI: exploiting our EEG-BMI-fMRI platform we were able to identify, the neural mechanisms involved in motor and cognitive aspects of imagery-mediated BMI. Furthermore, our results enable us to better understand the subjective and behavioral aspects of BMI-actions, and reveal strategies that could potentially reinforce BMI control. Our findings can ultimately be of relevance for the field of neuroprosthetics and make BMI more accessible to a broader range of users.

EPFL2016

Disentangling resting-state BOLD variability and PCC functional connectivity in 22q11.2 deletion syndrome

Maria Carmela Padula, Marie Schaer, Dimitri Nestor Alice Van De Ville, Daniela Maria Zöller

Although often ignored in fMRI studies, moment-to-moment variability of blood oxygenation level dependent (BOLD) signals reveals important information about brain function. Indeed, higher brain signal variability has been associated with better cognitive performance in young adults compared to children and elderly adults. Functional connectivity, a very, common approach in resting-state fMRI analysis, is scaled for variance. Thus, alterations might be confounded or driven by BOLD signal variance alterations. Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurodevelopmental disorder that is associated with a vast cognitive and clinical phenotype. To date, several resting-state fMRI studies reported altered functional connectivity in 22q11.2DS, however BOLD signal variance has not yet been analyzed. Here, we employed PLS correlation analysis to reveal multivariate patterns of diagnosis-related alterations and age-relationship throughout the cortex of 50 patients between 9 and 25 years old and 50 healthy controls in the same age range. To address how functional connectivity in the default mode network is influenced by BOLD signal fluctuations, we conducted the same analysis on seed-to-voxel connectivity of the posterior cingulate cortex (PCC) and compared resulting brain patterns. BOLD signal variance was lower mainly in regions of the default mode network and in the dorsolateral prefrontal cortex, but higher in large parts of the temporal lobes. In those regions, BOLD signal variance was correlated with age in healthy controls, but not in patients, suggesting deviant developmental trajectories from child- to adulthood. Positive connectivity of the PCC within the default mode network as well as negative connectivity towards the frontoparietal network were weaker in patients with 22q11.2DS. We furthermore showed that lower functional connectivity of the PCC was not driven by higher BOLD signal variability. Our results confirm the strong implication of BOLD variance in aging and give an initial insight in its relationship with functional connectivity in the DMN.

Elsevier2017