SummaryFor effective information processing, two large-scale distributed neural networks appear to be critical: a multimodal executive system anchored on the dorsolateral prefrontal cortex (DLPFC) and a salience system anchored on the anterior insula. Aberrant interaction among distributed networks is a feature of psychiatric disorders such as schizophrenia. We used whole-brain Granger causal modeling using resting fMRI and observed a significant failure of both the feedforward and reciprocal influence between the insula and the DLPFC in schizophrenia. Further, a significant failure of directed influence from bilateral visual cortices to the insula was also seen in patients. These findings provide compelling evidence for a breakdown of the salience-execution loop in the clinical expression of psychosis. In addition, this offers a parsimonious explanation for the often-observed “frontal inefficiency,” the failure to recruit prefrontal system when salient or novel information becomes available in patients with schizophrenia.

Background: Deficits characteristic of attention deficit/hyperactivity disorder (ADHD), including poor attention and inhibitory control, are at least partially alleviated by factors that increase engagement of attention, suggesting a hypodopaminergic reward deficit. Lapses of attention are associated with attenuated deactivation of the default mode network (DMN), a distributed brain system normally deactivated during tasks requiring attention to the external world. Task-related DMN deactivation has been shown to be attenuated in ADHD relative to controls. We hypothesised that motivational incentives to balance speed against restraint would increase task engagement during an inhibitory control task, enhancing DMN deactivation in ADHD. We also hypothesised that methylphenidate, an indirect dopamine agonist, would tend to normalise abnormal patterns of DMN deactivation. Method: We obtained functional magnetic resonance images from 18 methylphenidate-responsive children with ADHD (DSM-IV combined subtype) and 18 pairwise-matched typically developing children aged 9-15 years while they performed a paced Go/No-go task. We manipulated motivational incentive to balance response speed against inhibitory control, and tested children with ADHD both on and off methylphenidate. Results: When children with ADHD were off-methylphenidate and task incentive was low, event-related DMN deactivation was significantly attenuated compared to controls, but the two groups did not differ under high motivational incentives. The modulation of DMN deactivation by incentive in the children with ADHD, off-methylphenidate, was statistically significant, and significantly greater than in typically developing children. When children with ADHD were on-methylphenidate, motivational modulation of event-related DMN deactivation was abolished, and no attenuation relative to their typically developing peers was apparent in either motivational condition. Conclusions: During an inhibitory control task, children with ADHD exhibit a raised motivational threshold at which taskrelevant stimuli become sufficiently salient to deactivate the DMN. Treatment with methylphenidate normalises this threshold, rendering their pattern of task-related DMN deactivation indistinguishable from that of typically developing children.

Recent years have shown the critical importance of inter-regional neural network connectivity in supporting healthy brain function. Such connectivity is measurable using neuroimaging techniques such as MEG, however the richness of the electrophysiological signal makes gaining a complete picture challenging. Specifically, connectivity can be calculated as statistical interdependencies between neural oscillations within a large range of different frequency bands. Further, connectivity can be computed between frequency bands. This pan-spectral network hierarchy likely helps to mediate simultaneous formation of multiple brain networks, which support ongoing task demand. However, to date it has been largely overlooked, with many electrophysiological functional connectivity studies treating individual frequency bands in isolation. Here, we combine oscillatory envelope based functional connectivity metrics with a multi-layer network framework in order to derive a more complete picture of connectivity within and between frequencies. We test this methodology using MEG data recorded during a visuomotor task, highlighting simultaneous and transient formation of motor networks in the beta band, visual networks in the gamma band and a beta to gamma interaction. Having tested our method, we use it to demonstrate differences in occipital alpha band connectivity in patients with schizophrenia compared to healthy controls. We further show that these connectivity differences are predictive of the severity of persistent symptoms of the disease, highlighting their clinical relevance. Our findings demonstrate the unique potential of MEG to characterise neural network formation and dissolution. Further, we add weight to the argument that dysconnectivity is a core feature of the neuropathology underlying schizophrenia.

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.