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.

ABSTRACT:The topic of functional connectivity in neuroimaging is expanding rapidly and many studies now focus on coupling between spatially separate brain regions. These studies show that a relatively small number of large scale networks exist within the brain, and that healthy function of these networks is disrupted in many clinical populations. To date, the vast majority of studies probing connectivity employ techniques that compute time averaged correlation over several minutes, and between specific pre-defined brain locations. However, increasing evidence suggests that functional connectivity is non-stationary in time. Further, electrophysiological measurements show that connectivity is dependent on the frequency band of neural oscillations. It is also conceivable that networks exhibit a degree of spatial inhomogeneity, i.e. the large scale networks that we observe may result from the time average of multiple transiently synchronised sub-networks, each with their own spatial signature. This means that the next generation of neuroimaging tools to compute functional connectivity must account for spatial inhomogeneity, spectral non-uniformity and temporal non-stationarity. Here, we present a means to achieve this via application of windowed canonical correlation analysis (CCA) to source space projected MEG data. We describe generation of time-frequency connectivity plots, showing the temporal and spectral distribution of coupling between brain regions. Moreover, CCA over voxels provides a means to assess spatial nonuniformity within short time-frequency windows. The feasibility of this technique is demonstrated in simulation and in a resting state MEG experiment where we elucidate multiple distinct spatiotemporal-spectral modes of covariation between the left and right sensorimotor areas. 3 1) INTRODUCTION:Traditional analysis of neuroimaging data has focussed on the identification of significant changes in some metric of interest that are time locked to a particular task. Such methodologies usually rely on knowledge of task timing, and in some cases accurate models of the temporal evolution of neuroimaging signals which are then compared to measured data. These techniques have proved effective in highlighting brain regions that are involved in sensory and cognitive tasks. However, the last decade has seen a 'paradigm shift' in functional brain imaging (Raichle, 2009), with traditional analyses increasingly complemented by analysis of functional connectivity (Biswal et al., 1995, Beckmann et al., 2005, Fox et al., 2005, Fox and Raichle, 2007, Deco and Corbetta, 2011. Here, researchers seek to elucidate spatial patterns of temporal covariation between brain regions.Significant statistical interdependency (e.g. assessed via temporal correlation (Biswal et al., 1995) or independent component analysis (Beckmann et al., 2005)) between signals originating in two or more spatially separate anatomical regions is usually taken to mean that those regions are 'connected'. Functional magnetic resonance imaging (fMRI) has...

In recent years functional neuroimaging techniques such as fMRI, MEG, EEG and PET have provided researchers with a wealth of information on human brain function. However none of these modalities can measure directly either the neuro-electrical or neuro-chemical processes that mediate brain function. This means that metrics directly reflecting brain 'activity' must be inferred from other metrics (e.g. magnetic fields (MEG) or haemodynamics (fMRI)). To overcome this limitation, many studies seek to combine multiple complementary modalities and an excellent example of this is the combination of MEG (which has high temporal resolution) with fMRI (which has high spatial resolution). However, the full potential of multi-modal approaches can only be truly realised in cases where the relationship between metrics is known. In this paper, we explore the relationship between measurements made using fMRI and MEG. We describe the origins of the two signals as well as their relationship to electrophysiology. We review multiple studies that have attempted to characterise the spatial relationship between fMRI and MEG, and we also describe studies that exploit the rich information content of MEG to explore differing relationships between MEG and fMRI across neural oscillatory frequency bands. Monitoring the brain at "rest" has become of significant recent interest to the neuroimaging community and we review recent evidence comparing MEG and fMRI metrics of functional connectivity. A brief discussion of the use of magnetic resonance spectroscopy (MRS) to probe the relationship between MEG/fMRI and neurochemistry is also given. Finally, we highlight future areas of interest and offer some recommendations for the parallel use of fMRI and MEG.

Network connectivity is an integral feature of human brain function, and characterising its maturational trajectory is a critical step towards understanding healthy and atypical neurodevelopment. Here, we used magnetoencephalography (MEG) to investigate both stationary (i.e. time averaged) and rapidly modulating (dynamic) electrophysiological connectivity, in participants aged from mid-childhood to early adulthood (youngest participant 9 years old; oldest participant 25 years old). Stationary functional connectivity (measured via inter-regional coordination of neural oscillations) increased with age in the alpha and beta frequency bands, particularly in bilateral parietal and temporo-parietal connections. Our dynamic analysis (also applied to alpha/beta oscillations) revealed the spatiotemporal signatures of 8 dynamic networks; these modulate on a ∼100 ms time scale, and temporal stability in attentional networks was found to increase with age. Significant overlap was found between age-modulated dynamic networks and inter-regional oscillatory coordination, implying that altered network dynamics underlie age related changes in functional connectivity. Our results provide novel insights into brain network electrophysiology, and lay a foundation for future work in childhood disorders.

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