Measurement of brain glutathione with magnetic Resonance spectroscopy in Schizophrenia-Spectrum disorders - A systematic review and Meta-Analysis.

Oxidative stress may contribute to declining course and poor outcomes in psychosis. However, in vivo Magnetic Resonance Spectroscopy studies yield disparate results due to clinical stage, sample demographics, neuroanatomical focus, sample size, and acquisition method variations. We investigated glutathione in brain regions from participants with psychosis, and the relation of glutathione to clinical features and spectroscopy protocols. Meta-analysis comprised 21 studies. Glutathione levels did not differ between total psychosis patients (N = 639) and controls (N = 704) in the Medial Prefrontal region (k = 21, d = -0.09, CI = -0.28 to 0.10, p = 0.37). Patients with stable schizophrenia exhibited a small but significant glutathione reduction compared to controls (k = 14, d = -0.20, CI = -0.40 to -0.00, p = 0.05). Meta-regression showed older studies had greater glutathione reductions, possibly reflecting greater accuracy related to spectroscopy advancements in more recent studies. No significant effects of methodological variables, such as voxel size or echo time were found. Reduced glutathione in patients with stable established schizophrenia may provide novel targets for precision medicine. Standardizing MRS acquisition methods in future studies may help address discrepancies in glutathione levels.

Glutathione and glutamate in schizophrenia: a 7T MRS study.

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.

Aberrant myelination of the cingulum and Schneiderian delusions in schizophrenia: a 7T magnetization transfer study.

BACKGROUND: The structural integrity of the anterior cingulum has been repeatedly observed to be abnormal in patients with schizophrenia. More recently, aberrant myelination of frontal fasciculi, especially, cingulum has been proposed to underlie delayed corollary discharges that can affect sense of agency and contribute to delusions of control (Schneiderian delusions). Using the magnetization transfer phenomenon at an ultra-high field 7T MRI, we investigated the putative myelin content of cingulum bundle in patients with schizophrenia. METHODS: Seventeen clinically stable patients with schizophrenia and 20 controls were recruited for this 7T MRI study. We used a region-of-interest method and extracted magnetization transfer ratio (MTR) from left and right dorsal cingulum bundles and estimated patients v. controls differences. We also related the cingulum MTR values to the severity of Schneiderian delusions. RESULTS: Patients had a significant reduction in the MTR, indicating reduced myelin content, in the cingulum bundle (right cingulum Hedges' g = 0.91; left cingulum g = 0.03). The reduced MTR of left cingulum was associated with higher severity of Schneiderian delusions (τ = -0.45, p = 0.026) but no such relationship was seen for the right cingulum MTR (τ = -0.136, p = 0.50) among patients. The association between the left cingulum MTR and Schneiderian delusions was not explained by the presence of other delusions, hallucinations, disorganization or negative symptoms. CONCLUSIONS: Dysmyelination of the cingulum bundle is seen in a subgroup of patients with schizophrenia and may be involved in the mechanism of Schneiderian delusions.

The Core Deficit of Classical Schizophrenia: Implications for Predicting the Functional Outcome of Psychotic Illness and Developing Effective Treatments.

Many people suffering from psychotic illnesses experience persisting impairment of occupational and social function. Evidence assembled since the classical description of schizophrenia over a century ago indicates that both disorganization and impoverishment of mental activity are associated with persisting impairment. Longitudinal studies of young people at risk of schizophrenia reveal that both mental impoverishment and disorganization predict poor long-term outcome. These clinical features are related to cognitive impairments. Evidence from brain imaging indicates overlap in the brain abnormalities implicated in these phenomena, including impaired function of long-range connections between sensory cortex and the salience network, a network engaged in recruiting cerebral systems for processing of information salient to current circumstances. The evidence suggests that the common features underlying these two groups of symptoms might reflect a core pathological process distinguishing nonaffective from affective psychosis. This pathological process might therefore justifiably be designated the "core deficit" of classical schizophrenia. To develop more effective treatments to prevent persisting disability, we require the ability to identify individuals at risk at an early stage. Recent studies provide pointers toward effective strategies for identifying cases at risk of poor outcome. Accumulating evidence confirms that appreciable potential for neuroplastic change in the brain persists into adult life. Furthermore, brain function can be enhanced by targeted neuromodulation treatments. We now have promising tools not only for investigating the psychological and neural mechanisms that underlie persisting functional impairment but also for identifying individuals at risk and for harnessing brain plasticity to improve treatment.

Altered temporal stability in dynamic neural networks underlies connectivity changes in neurodevelopment.

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.

Development of human electrophysiological brain networks.

Functional activity in the human brain is intrinsically organized into independently active, connected brain regions. These networks include sensorimotor systems, as well as higher-order cognitive networks such as the default mode network (DMN), which dominates activity when the brain is at rest, and the frontoparietal (FPN) and salience (SN) networks, which are often engaged during demanding tasks. Evidence from functional magnetic resonance imaging (fMRI) suggests that although sensory systems are mature by the end of childhood, the integrity of the FPN and SN develops throughout adolescence. There has been little work to corroborate these findings with electrophysiology. Using magnetoencephalography (MEG) recordings of 48 participants (aged 9-25 yr) at rest, we find that beta-band functional connectivity within the FPN, SN, and DMN continues to increase through adolescence, whereas connectivity in the visual system is mature by late childhood. In contrast to fMRI results, but replicating the MEG findings of Schäfer et al. (Schäfer CB, Morgan BR, Ye AX, Taylor MJ, Doesburg SM. Hum Brain Mapp 35: 5249-5261, 2014), we also see that connectivity between networks increases rather than decreases with age. This suggests that the development of coordinated beta-band oscillations within and between higher-order cognitive networks through adolescence might contribute to the developing abilities of adolescents to focus their attention and coordinate diverse aspects of mental activity. NEW & NOTEWORTHY Using magnetoencephalography to assess beta frequency oscillations, we show that functional connectivity within higher-order cognitive networks increases from childhood, reaching adult values by age 20 yr. In contrast, connectivity within a primary sensory (visual) network reaches adult values by age 14 yr. In contrast to functional MRI findings, connectivity between cognitive networks matures at a rate similar to within-network connectivity, suggesting that coordination of beta oscillations both within and between networks is associated with maturation of cognitive skills.

Targeted transcranial theta-burst stimulation alters fronto-insular network and prefrontal GABA.

Repetitive transcranial magnetic stimulation (rTMS) has been used worldwide to treat depression. However, the exact physiological effects are not well understood. Pathophysiology of depression involves crucial limbic structures (e.g. insula), and it is still not clear if these structures can be modulated through neurostimulation of surface regions (e.g. dorsolateral prefrontal cortex, DLPFC), and whether rTMS-induced excitatory/inhibitory transmission alterations relate to fronto-limbic connectivity changes. Therefore, we sought proof-of-concept for neuromodulation of insula via prefrontal intermittent theta-burst stimulation (iTBS), and how these effects relate to GABAergic and glutamatergic systems. In 27 healthy controls, we employed a single-blind crossover randomised-controlled trial comparing placebo and real iTBS using resting-state functional MRI and magnetic resonance spectroscopy. Granger causal analysis was seeded from right anterior insula (rAI) to locate individualized left DLPFC rTMS targets. Effective connectivity coefficients within rAI and DLPFC were calculated, and levels of GABA/Glx, GABA/Cr and Glx/Cr in DLPFC and anterior cingulate voxels were also measured. ITBS significantly dampened fronto-insular connectivity and reduced GABA/Glx in both voxels. GABA/Glx had a significant mediating effect on iTBS-induced changes in DLPFC-to-rAI connectivity. We demonstrate modulation of the rAI using targeted iTBS through alterations of excitatory/inhibitory interactions, which may underlie therapeutic effects of rTMS, offering promise for rTMS treatment optimization.

A multi-layer network approach to MEG connectivity analysis.

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.

Abnormal salience signaling in schizophrenia: The role of integrative beta oscillations.

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 evidence implicates beta band oscillations in long-range integrative processes. We used magnetoencephalography and a task designed to disambiguate responses to relevant from irrelevant stimuli to investigate 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 synchronization to behaviorally relevant, as compared to irrelevant, stimuli, while patients with schizophrenia showed the reverse pattern: a greater beta synchronization 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.

Structural connectivity of the salience-executive loop in schizophrenia.

Previously, differences have been shown in effective connectivity of the salience network between healthy controls and patients with schizophrenia. Specifically, the right anterior insula (rAI) fails to modulate the dorsolateral prefrontal cortex (DLPFC). In 35 controls and 31 patients with schizophrenia, we extended these findings by investigating the white matter connectivity of this pathway using tractography, and its relationship with the disrupted effective connectivity. We showed increased fractional anisotropy in the pathway connecting the rAI with the DLPFC, which related to reduced effective connectivity. This may be due to either secondary changes in white matter or a primary defect in structural integrity resulting from deficient axonal pruning. This novel finding warrants further investigation of white matter connectivity in schizophrenia and the mechanisms underlying this pathophysiology.

The mechanisms of persisting disability in schizophrenia: imprecise predictive coding via cortico-striatal-thalamo-cortical loop dysfunction.

Persisting symptoms and disability remain a problem for an appreciable proportion of people with schizophrenia despite treatment with antipsychotic medication. Improving outcomes requires an understanding of the nature and mechanisms of the pathological processes underlying persistence. Classical features of schizophrenia, which include disorganization and impoverishment of mental activity, are well recognised early clinical features that predict poor long-term outcome. Substantial evidence indicates that these features reflect imprecise predictive coding. Predictive coding provides an over-arching framework for understanding efficient function of the nervous system. Imprecise predictive coding also has the potential to precipitate acute psychosis characterised by reality distortion (delusions and hallucinations) at times of stress. On the other hand, substantial evidence indicates that persistent reality distortion itself gives rise to poor occupational and social function in the long term. Furthermore, abuse of psychotomimetic drugs, which exacerbate reality distortion, contributes to poor long-term outcome in schizophrenia. Neural circuits involved in modulating volitional acts are well understood to be implicated in addiction. Plastic changes in these circuits may account for the association between psychotomimetic drug abuse and poor outcomes in schizophrenia. We propose a mechanistic model according to which unbalanced inputs to the corpus striatum disturb the precision of sub-cortical modulation of cortical activity supporting volitional action. This model accounts for the evidence that early classical symptoms predict poor outcome, while in some circumstances, persistent reality distortion also predicts poor outcome. This model has implications for the development of novel treatments that address the risk of persisting symptoms and disabilities in schizophrenia.

Connectivity-guided intermittent theta burst versus repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled trial.

Disruption in reciprocal connectivity between the right anterior insula and the left dorsolateral prefrontal cortex is associated with depression and may be a target for neuromodulation. In a five-center, parallel, double-blind, randomized controlled trial we personalized resting-state functional magnetic resonance imaging neuronavigated connectivity-guided intermittent theta burst stimulation (cgiTBS) at a site based on effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. We tested its efficacy in reducing the primary outcome depression symptoms measured by the GRID Hamilton Depression Rating Scale 17-item over 8, 16 and 26 weeks, compared with structural magnetic resonance imaging (MRI) neuronavigated repetitive transcranial magnetic stimulation (rTMS) delivered at the standard stimulation site (F3) in patients with 'treatment-resistant depression'. Participants were randomly assigned to 20 sessions over 4-6 weeks of either cgiTBS (n = 128) or rTMS (n = 127) with resting-state functional MRI at baseline and 16 weeks. Persistent decreases in depressive symptoms were seen over 26 weeks, with no differences between arms on the primary outcome GRID Hamilton Depression Rating Scale 17-item score (intention-to-treat adjusted mean, -0.31, 95% confidence interval (CI) -1.87, 1.24, P = 0.689). Two serious adverse events were possibly related to TMS (mania and psychosis). MRI-neuronavigated cgiTBS and rTMS were equally effective in patients with treatment-resistant depression over 26 weeks (trial registration no. ISRCTN19674644).

Theta power during encoding predicts subsequent-memory performance and default mode network deactivation.

The subsequent memory paradigm, according to which cerebral activity for later remembered (LR) and later forgotten (LF) items is contrasted, can be used to characterize the processes necessary for successful memory encoding. Previous simultaneous electroencephalography/functional magnetic resonance imaging (EEG/fMRI) memory studies suggest an inverse relationship between frontal theta band power and the blood oxygenation level dependent (BOLD) signal in the default mode network (DMN). The principal aim of this EEG/fMRI study was to test the hypothesis that this putative theta-DMN relationship is less evident in LF compared with LR trials. Fourteen healthy participants performed an episodic memory task in which pictorial stimuli were presented during encoding, and categorized (as LR or LF) by subsequent memory performance. For each encoding trial, the mean of the Hilbert envelope of the theta signal from 400 to 800 ms after stimulus presentation was calculated. To integrate the EEG and fMRI data, general linear models (GLMs) were used to assess the extent to which these single-trial theta values (as modulators of the main effect of stimulus) predicted DMN BOLD signal change, using: (i) whole-head univariate GLMs and (ii) GLMs in which the outcome variable was the time-course of a DMN component derived from spatial independent component analysis of the fMRI data. Theta was significantly greater for LR than LF stimuli. Furthermore, the inverse relationship between theta and BOLD in the DMN was consistently stronger for LR than LF pictures. These findings imply that theta oscillations are key to attenuating processes which may otherwise impair memory encoding.

Tardive dyskinesia in schizophrenia.

Sarró et al report grey matter deficits associated with tardive dyskinesia in schizophrenia. Much evidence suggests that the intrinsic pathophysiology of schizophrenia contributes to predisposition to tardive dyskinesia. The possibility that antipsychotics might play a causal role in the grey matter deficits cannot be excluded, but the evidence is tenuous.

Motivational incentives and methylphenidate enhance electrophysiological correlates of error monitoring in children with attention deficit/hyperactivity disorder.

BACKGROUND: Children with attention deficit hyperactivity disorder (ADHD) are characterised by developmentally inappropriate levels of hyperactivity, impulsivity and/or inattention and are particularly impaired when performing tasks that require a high level of cognitive control. Methylphenidate (MPH) and motivational incentives may help improve cognitive control by enhancing the ability to monitor response accuracy and regulate performance accordingly. METHODS: Twenty-eight children with DSM-IV ADHD (combined type) aged 9-15 years and pairwise-matched typically developing children (CTRL) performed a go/no-go task in which the incentives attached to performance on no-go trials were manipulated. The ADHD group performed the task off and on their usual dose of MPH. CTRL children performed the task twice but were never medicated. EEG data were recorded simultaneously and two electrophysiological indices of error monitoring, the error-related negativity (ERN) and error positivity (Pe) were measured. Amplitudes of each ERP were compared between diagnostic groups (CTRL, ADHD), medication days (Off MPH, On MPH) and motivational conditions (baseline - low incentive, reward, response cost). RESULTS: Error rates were lower in the reward and response cost conditions compared with baseline across diagnostic groups and medication days. ERN and Pe amplitudes were significantly reduced in ADHD compared with CTRL, and were significantly enhanced by MPH. Incentives significantly increased ERN and Pe amplitudes in the ADHD group but had no effect in CTRL. The effects of incentives did not interact with the effects of MPH on either ERP. Effect sizes were computed and revealed larger effects of MPH than incentives on ERN and Pe amplitudes. CONCLUSIONS: The findings reveal independent effects of motivational incentives and MPH on two electrophysiological markers of error monitoring in children with ADHD, suggesting that each may be important tools for enhancing or restoring cognitive control in these children.

Olanzapine and food craving: a case control study.

BACKGROUND: Antipsychotic-induced weight gain is a problematic side effect. The mechanism is still not fully understood. Carbohydrate (and possibly other food) cravings have been suggested in literature, but not been systematically investigated. OBJECTIVES: To investigate the hypothesis that food cravings, especially for carbohydrate, are responsible for olanzapine-induced weight gain. METHOD: A case control design was used to measure general and specific food cravings using Food Craving Inventory (White et al., 2002) in three groups: patients with a diagnosis of schizophrenia taking olanzapine (Number = 20) or typical antipsychotics (Number = 20) and in a healthy control group (Number = 20). RESULTS: No statistically significant differences were found between the three groups in the craving scores. There was a trend in the typical group to show more cravings than other groups. CONCLUSION: Our study failed to prove the hypothesis that carbohydrate craving is responsible for olanzapine-induced weight gain. This conclusion is limited by the small number of the subjects included.

Differential effects of surface area, gyrification and cortical thickness on voxel based morphometric deficits in schizophrenia.

Voxel Based Morphometry (VBM) and Surface Based Morphometry (SBM) are the two most commonly used methods to study the structure of gray matter in various disease states such as schizophrenia. Though overlapping changes have been observed in same datasets using the two procedures, the proportional contribution of the anatomical properties of the cortical mantle such as thickness, surface area and gyrification to the group differences in gray matter volume (GMV) observed using VBM is unknown. In the present study, we investigate the relationship between the GMV and the anatomical properties of the cortical mantle in regions showing significant VBM changes in schizophrenia using a sample of 57 patients and 41 healthy controls. To this end, we obtained significant clusters showing VBM changes in schizophrenia and studied the contribution of the three anatomical properties derived from SBM to the observed group differences in the GMV using a multiple mediation analysis. Our results suggest that while SBM measures make distinct but regionally variable contribution to the VBM differences, a large proportion of the group difference observed using VBM is not explained by the individual surface anatomical properties. While VBM may be more sensitive in identifying the regions with gray matter abnormalities, studies investigating the pathophysiology of illnesses such as schizophrenia are better informed when both SBM and VBM analyses are performed concurrently.

Motion-related artefacts in EEG predict neuronally plausible patterns of activation in fMRI data.

The simultaneous acquisition and subsequent analysis of EEG and fMRI data is challenging owing to increased noise levels in the EEG data. A common method to integrate data from these two modalities is to use aspects of the EEG data, such as the amplitudes of event-related potentials (ERP) or oscillatory EEG activity, to predict fluctuations in the fMRI data. However, this relies on the acquisition of high quality datasets to ensure that only the correlates of neuronal activity are being studied. In this study, we investigate the effects of head-motion-related artefacts in the EEG signal on the predicted T2*-weighted signal variation. We apply our analyses to two independent datasets: 1) four participants were asked to move their feet in the scanner to generate small head movements, and 2) four participants performed an episodic memory task. We created T2*-weighted signal predictors from indicators of abrupt head motion using derivatives of the realignment parameters, from visually detected artefacts in the EEG as well as from three EEG frequency bands (theta, alpha and beta). In both datasets, we found little correlation between the T2*-weighted signal and EEG predictors that were not convolved with the canonical haemodynamic response function (cHRF). However, all convolved EEG predictors strongly correlated with the T2*-weighted signal variation in various regions including the bilateral superior temporal cortex, supplementary motor area, medial parietal cortex and cerebellum. The finding that movement onset spikes in the EEG predict T2*-weighted signal intensity only when the time course of movements is convolved with the cHRF, suggests that the correlated signal might reflect a BOLD response to neural activity associated with head movement. Furthermore, the observation that broad-spectral EEG spikes tend to occur at the same time as abrupt head movements, together with the finding that abrupt movements and EEG spikes show similar correlations with the T2*-weighted signal, indicates that the EEG spikes are produced by abrupt movement and that continuous regressors of EEG oscillations contain motion-related noise even after stringent correction of the EEG data. If not properly removed, these artefacts complicate the use of EEG data as a predictor of T2*-weighted signal variation.

Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction.

The insular cortex is one of the brain regions that show consistent abnormalities in both structural and functional neuroimaging studies of schizophrenia. In healthy individuals, the insula has been implicated in a myriad of physiologic functions. The anterior cingulate cortex (ACC) and insula together constitute the salience network, an intrinsic large-scale network showing strong functional connectivity. Considering the insula as a functional unit along with the ACC provides an integrated understanding of the role of the insula in information processing. In this review, we bring together evidence from imaging studies to understand the role of the salience network in schizophrenia and propose a model of insular dysfunction in psychosis.