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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 postinflammatory response, and that this reduction would be most marked in patients with residual schizophrenia an early stage with positive psychotic symptoms has progressed to a late stage characterised 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 excito-toxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Subtle disturbances of visual and motor function are known features of schizophrenia and can greatly impact quality of life; however, few studies investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event-related beta desynchronisation (ERBD)), then increase above baseline for a short time after the movement (post movement beta rebound (PMBR)); while in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a selfpaced visuomotor paradigm and magnetoencephalography (MEG) to contrast these responses in patients with schizophrenia and control volunteers. We found significant reductions in the peak-to-peak change in amplitude from ERBD to PMBR in schizophrenia compared with controls. This effect was strongest in patients who made fewer movements, whereas beta was not modulated by movement in controls. There was no significant difference in the amplitude of visual gamma between patients and controls. These data demonstrate that clear abnormalities in basic sensorimotor processing in schizophrenia can be observed using a very simple MEG paradigm

Aberrant salience attribution and cerebral dysconnectivity both have strong evidential support as core dysfunctions in schizophrenia. Aberrant salience arising from an excess of dopamine activity has been implicated in delusions and hallucinations, exaggerating the significance of everyday occurrences and thus leading to perceptual distortions and delusional causal inferences. Meanwhile, abnormalities in key nodes of a salience brain network have been implicated in other characteristic symptoms, including the disorganization and impoverishment of mental activity. A substantial body of literature reports disruption to brain network connectivity in schizophrenia. Electrical oscillations likely play a key role in the coordination of brain activity at spatially remote sites, and recent, evidence implicates beta band oscillations in long-range integrative processes. We used magnetoencephalography (MEG) and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigated beta oscillations in nodes of a network implicated in salience detection and previously shown to be structurally and functionally abnormal in schizophrenia. Healthy participants, as expected, produced an enhanced beta synchronisation to behaviourally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronisation in response to irrelevant than to relevant stimuli. These findings not only support both the aberrant salience and disconnectivity hypotheses, but indicate a common mechanism that allows us to integrate them into a single framework for understanding schizophrenia in terms of disrupted recruitment of contextually appropriate brain networks.

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.

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 postinflammatory response, and that this reduction would be most marked in patients with residual schizophrenia an early stage with positive psychotic symptoms has progressed to a late stage characterised 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 excito-toxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Multiple sclerosis (MS) is a debilitating disease commonly attributed to degradation of white matter myelin. Symptoms include fatigue, as well as problems associated with vision and movement. Although areas of demyelination in white matter are observed routinely in patients undergoing MRI scans, such measures are often a poor predictor of disease severity. For this reason, it is instructive to measure associated changes in brain function. Widespread white-matter demyelination may lead to delays of propagation of neuronal activity, and with its excellent temporal resolution, magnetoencephalography can be used to probe such delays in controlled conditions (e.g., during a task). In healthy subjects, responses to visuomotor tasks are well documented: in motor cortex, movement elicits a localised decrease in the power of beta band oscillations (event-related beta desynchronisation) followed by an increase above baseline on movement cessation (post-movement beta rebound (PMBR)). In visual cortex, visual stimulation generates increased gamma oscillations. In this study, we use a visuomotor paradigm to measure these responses in MS patients and compare them to age- and gender-matched healthy controls. We show a significant increase in the time-to-peak of the PMBR in patients which correlates significantly with the symbol digit modalities test: a measure of information processing speed. A significant decrease in the amplitude of visual gamma oscillations in patients is also seen. These findings highlight the potential value of electrophysiological imaging in generating a new understanding of visual disturbances and abnormal motor control in MS patients.

Subtle disturbances of visual and motor function are known features of schizophrenia and can greatly impact quality of life; however, few studies investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event-related beta desynchronisation (ERBD)), then increase above baseline for a short time after the movement (post movement beta rebound (PMBR)); while in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a selfpaced visuomotor paradigm and magnetoencephalography (MEG) to contrast these responses in patients with schizophrenia and control volunteers. We found significant reductions in the peak-to-peak change in amplitude from ERBD to PMBR in schizophrenia compared with controls. This effect was strongest in patients who made fewer movements, whereas beta was not modulated by movement in controls. There was no significant difference in the amplitude of visual gamma between patients and controls. These data demonstrate that clear abnormalities in basic sensorimotor processing in schizophrenia can be observed using a very simple MEG paradigm

Aberrant salience attribution and cerebral dysconnectivity both have strong evidential support as core dysfunctions in schizophrenia. Aberrant salience arising from an excess of dopamine activity has been implicated in delusions and hallucinations, exaggerating the significance of everyday occurrences and thus leading to perceptual distortions and delusional causal inferences. Meanwhile, abnormalities in key nodes of a salience brain network have been implicated in other characteristic symptoms, including the disorganization and impoverishment of mental activity. A substantial body of literature reports disruption to brain network connectivity in schizophrenia. Electrical oscillations likely play a key role in the coordination of brain activity at spatially remote sites, and recent, evidence implicates beta band oscillations in long-range integrative processes. We used magnetoencephalography (MEG) and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigated beta oscillations in nodes of a network implicated in salience detection and previously shown to be structurally and functionally abnormal in schizophrenia. Healthy participants, as expected, produced an enhanced beta synchronisation to behaviourally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronisation in response to irrelevant than to relevant stimuli. These findings not only support both the aberrant salience and disconnectivity hypotheses, but indicate a common mechanism that allows us to integrate them into a single framework for understanding schizophrenia in terms of disrupted recruitment of contextually appropriate brain networks.

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.

The physiological effect of hyperoxia has been poorly characterised, with studies reporting conflicting results on the role of hyperoxia as a vasoconstrictor. It is not clear whether hyperoxia is the primary contributor to vasoconstriction or whether induced changes in CO2 that commonly accompany hyperoxia are a factor. As calibrated BOLD fMRI based on hyperoxia becomes more widely used, it is essential to understand the effects of oxygen on resting cerebral physiology. This study used a RespirActTM system to deliver a repeatable isocapnic hyperoxia stimulus to investigate the independent effect of O2 on cerebral physiology, removing any potential confounds related to altered CO2. T1-independent Phase Contrast MRI was used to demonstrate that isocapnic hyperoxia has no significant effect on carotid blood flow (normoxia 201 ± 11 ml/min, -0.3 ± 0.8 % change during hyperoxia, p = 0.8), whilst Look Locker ASL was used to demonstrate that there is no significant change in arterial cerebral blood volume (normoxia 1.3 ± 0.4 %, -0.5 ± 5 % change during hyperoxia). These are in contrast to significant changes in blood flow observed for hypercapnia (6.8 ± 1.5 %/mmHg CO2). In addition, magnetoencephalography provided a method to monitor the effect of isocapnic hyperoxia on neuronal oscillatory power. In response to hyperoxia, a significant focal decrease in oscillatory power was observed across the alpha, beta and low gamma bands in the occipital lobe, compared to a more global significant decrease on hypercapnia. This work suggests that isocapnic hyperoxia provides a more reliable stimulus than hypercapnia for calibrated BOLD, and that previous reports of vasoconstriction during hyperoxia probably reflect the effects of hyperoxia-induced changes in CO2. However, hyperoxia does induce changes in oscillatory power consistent with an increase in vigilance, but these changes are smaller than those observed under hypercapnia. The effect of this change in neural activity on calibra

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 the 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 non-uniformity 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 spatio-temporal-spectral modes of covariation between the left and right sensorimotor areas.

Calibration of the BOLD signal is potentially of great value in providing a closer measure of the underlying changes in brain function related to neuronal activity than the BOLD signal alone, but current approaches rely on an assumed relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF). This is poorly characterised in humans and does not reflect the predominantly venous nature of BOLD contrast, whilst this relationship may vary across brain regions and depend on the structure of the local vascular bed. This work demonstrates a new approach to BOLD calibration which does not require an assumption about the relationship between cerebral blood volume and cerebral blood flow. This method involves repeating the same stimulus both at normoxia and hyperoxia, using hyperoxic BOLD contrast to estimate the relative changes in venous blood oxygenation and venous CBV. To do this the effect of hyperoxia on venous blood oxygenation has to be calculated, which requires an estimate of basal oxygen extraction fraction, and this can be estimated from the phase as an alternative to using a literature estimate. Additional measurement of the relative change in CBF, combined with the blood oxygenation change can be used to calculate the relative change in CMRO2 due to the stimulus. CMRO2 changes of 18 ± 8% in response to a motor task were measured without requiring the assumption of a CBV/CBF coupling relationship, and are in agreement with previous approaches.

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.

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 postinflammatory response, and that this reduction would be most marked in patients with residual schizophrenia an early stage with positive psychotic symptoms has progressed to a late stage characterised 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 excito-toxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Multiple sclerosis (MS) is a debilitating disease commonly attributed to degradation of white matter myelin. Symptoms include fatigue, as well as problems associated with vision and movement. Although areas of demyelination in white matter are observed routinely in patients undergoing MRI scans, such measures are often a poor predictor of disease severity. For this reason, it is instructive to measure associated changes in brain function. Widespread white-matter demyelination may lead to delays of propagation of neuronal activity, and with its excellent temporal resolution, magnetoencephalography can be used to probe such delays in controlled conditions (e.g., during a task). In healthy subjects, responses to visuomotor tasks are well documented: in motor cortex, movement elicits a localised decrease in the power of beta band oscillations (event-related beta desynchronisation) followed by an increase above baseline on movement cessation (post-movement beta rebound (PMBR)). In visual cortex, visual stimulation generates increased gamma oscillations. In this study, we use a visuomotor paradigm to measure these responses in MS patients and compare them to age- and gender-matched healthy controls. We show a significant increase in the time-to-peak of the PMBR in patients which correlates significantly with the symbol digit modalities test: a measure of information processing speed. A significant decrease in the amplitude of visual gamma oscillations in patients is also seen. These findings highlight the potential value of electrophysiological imaging in generating a new understanding of visual disturbances and abnormal motor control in MS patients.

Aberrant salience attribution and cerebral dysconnectivity both have strong evidential support as core dysfunctions in schizophrenia. Aberrant salience arising from an excess of dopamine activity has been implicated in delusions and hallucinations, exaggerating the significance of everyday occurrences and thus leading to perceptual distortions and delusional causal inferences. Meanwhile, abnormalities in key nodes of a salience brain network have been implicated in other characteristic symptoms, including the disorganization and impoverishment of mental activity. A substantial body of literature reports disruption to brain network connectivity in schizophrenia. Electrical oscillations likely play a key role in the coordination of brain activity at spatially remote sites, and recent, evidence implicates beta band oscillations in long-range integrative processes. We used magnetoencephalography (MEG) and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigated beta oscillations in nodes of a network implicated in salience detection and previously shown to be structurally and functionally abnormal in schizophrenia. Healthy participants, as expected, produced an enhanced beta synchronisation to behaviourally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronisation in response to irrelevant than to relevant stimuli. These findings not only support both the aberrant salience and disconnectivity hypotheses, but indicate a common mechanism that allows us to integrate them into a single framework for understanding schizophrenia in terms of disrupted recruitment of contextually appropriate brain networks.

Subtle disturbances of visual and motor function are known features of schizophrenia and can greatly impact quality of life; however, few studies investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event-related beta desynchronisation (ERBD)), then increase above baseline for a short time after the movement (post movement beta rebound (PMBR)); while in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a selfpaced visuomotor paradigm and magnetoencephalography (MEG) to contrast these responses in patients with schizophrenia and control volunteers. We found significant reductions in the peak-to-peak change in amplitude from ERBD to PMBR in schizophrenia compared with controls. This effect was strongest in patients who made fewer movements, whereas beta was not modulated by movement in controls. There was no significant difference in the amplitude of visual gamma between patients and controls. These data demonstrate that clear abnormalities in basic sensorimotor processing in schizophrenia can be observed using a very simple MEG paradigm

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.

The physiological effect of hyperoxia has been poorly characterised, with studies reporting conflicting results on the role of hyperoxia as a vasoconstrictor. It is not clear whether hyperoxia is the primary contributor to vasoconstriction or whether induced changes in CO2 that commonly accompany hyperoxia are a factor. As calibrated BOLD fMRI based on hyperoxia becomes more widely used, it is essential to understand the effects of oxygen on resting cerebral physiology. This study used a RespirActTM system to deliver a repeatable isocapnic hyperoxia stimulus to investigate the independent effect of O2 on cerebral physiology, removing any potential confounds related to altered CO2. T1-independent Phase Contrast MRI was used to demonstrate that isocapnic hyperoxia has no significant effect on carotid blood flow (normoxia 201 ± 11 ml/min, -0.3 ± 0.8 % change during hyperoxia, p = 0.8), whilst Look Locker ASL was used to demonstrate that there is no significant change in arterial cerebral blood volume (normoxia 1.3 ± 0.4 %, -0.5 ± 5 % change during hyperoxia). These are in contrast to significant changes in blood flow observed for hypercapnia (6.8 ± 1.5 %/mmHg CO2). In addition, magnetoencephalography provided a method to monitor the effect of isocapnic hyperoxia on neuronal oscillatory power. In response to hyperoxia, a significant focal decrease in oscillatory power was observed across the alpha, beta and low gamma bands in the occipital lobe, compared to a more global significant decrease on hypercapnia. This work suggests that isocapnic hyperoxia provides a more reliable stimulus than hypercapnia for calibrated BOLD, and that previous reports of vasoconstriction during hyperoxia probably reflect the effects of hyperoxia-induced changes in CO2. However, hyperoxia does induce changes in oscillatory power consistent with an increase in vigilance, but these changes are smaller than those observed under hypercapnia. The effect of this change in neural activity on calibra

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 the 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 non-uniformity 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 spatio-temporal-spectral modes of covariation between the left and right sensorimotor areas.

Calibration of the BOLD signal is potentially of great value in providing a closer measure of the underlying changes in brain function related to neuronal activity than the BOLD signal alone, but current approaches rely on an assumed relationship between cerebral blood volume (CBV) and cerebral blood flow (CBF). This is poorly characterised in humans and does not reflect the predominantly venous nature of BOLD contrast, whilst this relationship may vary across brain regions and depend on the structure of the local vascular bed. This work demonstrates a new approach to BOLD calibration which does not require an assumption about the relationship between cerebral blood volume and cerebral blood flow. This method involves repeating the same stimulus both at normoxia and hyperoxia, using hyperoxic BOLD contrast to estimate the relative changes in venous blood oxygenation and venous CBV. To do this the effect of hyperoxia on venous blood oxygenation has to be calculated, which requires an estimate of basal oxygen extraction fraction, and this can be estimated from the phase as an alternative to using a literature estimate. Additional measurement of the relative change in CBF, combined with the blood oxygenation change can be used to calculate the relative change in CMRO2 due to the stimulus. CMRO2 changes of 18 ± 8% in response to a motor task were measured without requiring the assumption of a CBV/CBF coupling relationship, and are in agreement with previous approaches.

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.

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 postinflammatory response, and that this reduction would be most marked in patients with residual schizophrenia an early stage with positive psychotic symptoms has progressed to a late stage characterised 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 excito-toxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Multiple sclerosis (MS) is a debilitating disease commonly attributed to degradation of white matter myelin. Symptoms include fatigue, as well as problems associated with vision and movement. Although areas of demyelination in white matter are observed routinely in patients undergoing MRI scans, such measures are often a poor predictor of disease severity. For this reason, it is instructive to measure associated changes in brain function. Widespread white-matter demyelination may lead to delays of propagation of neuronal activity, and with its excellent temporal resolution, magnetoencephalography can be used to probe such delays in controlled conditions (e.g., during a task). In healthy subjects, responses to visuomotor tasks are well documented: in motor cortex, movement elicits a localised decrease in the power of beta band oscillations (event-related beta desynchronisation) followed by an increase above baseline on movement cessation (post-movement beta rebound (PMBR)). In visual cortex, visual stimulation generates increased gamma oscillations. In this study, we use a visuomotor paradigm to measure these responses in MS patients and compare them to age- and gender-matched healthy controls. We show a significant increase in the time-to-peak of the PMBR in patients which correlates significantly with the symbol digit modalities test: a measure of information processing speed. A significant decrease in the amplitude of visual gamma oscillations in patients is also seen. These findings highlight the potential value of electrophysiological imaging in generating a new understanding of visual disturbances and abnormal motor control in MS patients.

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 postinflammatory response, and that this reduction would be most marked in patients with residual schizophrenia an early stage with positive psychotic symptoms has progressed to a late stage characterised 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 excito-toxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

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.

Subtle disturbances of visual and motor function are known features of schizophrenia and can greatly impact quality of life; however, few studies investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event-related beta desynchronisation (ERBD)), then increase above baseline for a short time after the movement (post movement beta rebound (PMBR)); while in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a selfpaced visuomotor paradigm and magnetoencephalography (MEG) to contrast these responses in patients with schizophrenia and control volunteers. We found significant reductions in the peak-to-peak change in amplitude from ERBD to PMBR in schizophrenia compared with controls. This effect was strongest in patients who made fewer movements, whereas beta was not modulated by movement in controls. There was no significant difference in the amplitude of visual gamma between patients and controls. These data demonstrate that clear abnormalities in basic sensorimotor processing in schizophrenia can be observed using a very simple MEG paradigm

Aberrant salience attribution and cerebral dysconnectivity both have strong evidential support as core dysfunctions in schizophrenia. Aberrant salience arising from an excess of dopamine activity has been implicated in delusions and hallucinations, exaggerating the significance of everyday occurrences and thus leading to perceptual distortions and delusional causal inferences. Meanwhile, abnormalities in key nodes of a salience brain network have been implicated in other characteristic symptoms, including the disorganization and impoverishment of mental activity. A substantial body of literature reports disruption to brain network connectivity in schizophrenia. Electrical oscillations likely play a key role in the coordination of brain activity at spatially remote sites, and recent, evidence implicates beta band oscillations in long-range integrative processes. We used magnetoencephalography (MEG) and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigated beta oscillations in nodes of a network implicated in salience detection and previously shown to be structurally and functionally abnormal in schizophrenia. Healthy participants, as expected, produced an enhanced beta synchronisation to behaviourally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronisation in response to irrelevant than to relevant stimuli. These findings not only support both the aberrant salience and disconnectivity hypotheses, but indicate a common mechanism that allows us to integrate them into a single framework for understanding schizophrenia in terms of disrupted recruitment of contextually appropriate brain networks.

The physiological effect of hyperoxia has been poorly characterised, with studies reporting conflicting results on the role of hyperoxia as a vasoconstrictor. It is not clear whether hyperoxia is the primary contributor to vasoconstriction or whether induced changes in CO2 that commonly accompany hyperoxia are a factor. As calibrated BOLD fMRI based on hyperoxia becomes more widely used, it is essential to understand the effects of oxygen on resting cerebral physiology. This study used a RespirActTM system to deliver a repeatable isocapnic hyperoxia stimulus to investigate the independent effect of O2 on cerebral physiology, removing any potential confounds related to altered CO2. T1-independent Phase Contrast MRI was used to demonstrate that isocapnic hyperoxia has no significant effect on carotid blood flow (normoxia 201 ± 11 ml/min, -0.3 ± 0.8 % change during hyperoxia, p = 0.8), whilst Look Locker ASL was used to demonstrate that there is no significant change in arterial cerebral blood volume (normoxia 1.3 ± 0.4 %, -0.5 ± 5 % change during hyperoxia). These are in contrast to significant changes in blood flow observed for hypercapnia (6.8 ± 1.5 %/mmHg CO2). In addition, magnetoencephalography provided a method to monitor the effect of isocapnic hyperoxia on neuronal oscillatory power. In response to hyperoxia, a significant focal decrease in oscillatory power was observed across the alpha, beta and low gamma bands in the occipital lobe, compared to a more global significant decrease on hypercapnia. This work suggests that isocapnic hyperoxia provides a more reliable stimulus than hypercapnia for calibrated BOLD, and that previous reports of vasoconstriction during hyperoxia probably reflect the effects of hyperoxia-induced changes in CO2. However, hyperoxia does induce changes in oscillatory power consistent with an increase in vigilance, but these changes are smaller than those observed under hypercapnia. The effect of this change in neural activity on calibra

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 the 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 non-uniformity 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 spatio-temporal-spectral modes of covariation between the left and right sensorimotor areas.

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.

Multiple sclerosis (MS) is a debilitating disease commonly attributed to degradation of white matter myelin. Symptoms include fatigue, as well as problems associated with vision and movement. Although areas of demyelination in white matter are observed routinely in patients undergoing MRI scans, such measures are often a poor predictor of disease severity. For this reason, it is instructive to measure associated changes in brain function. Widespread white-matter demyelination may lead to delays of propagation of neuronal activity, and with its excellent temporal resolution, magnetoencephalography can be used to probe such delays in controlled conditions (e.g., during a task). In healthy subjects, responses to visuomotor tasks are well documented: in motor cortex, movement elicits a localised decrease in the power of beta band oscillations (event-related beta desynchronisation) followed by an increase above baseline on movement cessation (post-movement beta rebound (PMBR)). In visual cortex, visual stimulation generates increased gamma oscillations. In this study, we use a visuomotor paradigm to measure these responses in MS patients and compare them to age- and gender-matched healthy controls. We show a significant increase in the time-to-peak of the PMBR in patients which correlates significantly with the symbol digit modalities test: a measure of information processing speed. A significant decrease in the amplitude of visual gamma oscillations in patients is also seen. These findings highlight the potential value of electrophysiological imaging in generating a new understanding of visual disturbances and abnormal motor control in MS patients.