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Background There is emerging evidence for abnormal beta oscillations in psychosis. Beta oscillations are likely to play a key role in the coordination of sensorimotor information that is crucial to healthy mental function. Growing evidence suggests that beta oscillations typically manifest as transient beta bursts that increase in probability following a motor response, observable as post-movement beta rebound. Evidence indicates that post-movement beta rebound is attenuated in psychosis, with greater attenuation associated with greater symptom severity and impairment. Delineating the functional role of beta bursts therefore may be key to understanding the mechanisms underlying persistent psychotic illness. Methods We used concurrent electroencephalography and functional magnetic resonance imaging to identify blood oxygen level–dependent correlates of beta bursts during the n-back working memory task and intervening rest periods in healthy participants (n = 30) and patients with psychosis (n = 48). Results During both task blocks and intervening rest periods, beta bursts phasically activated regions implicated in task-relevant content while suppressing currently tonically active regions. Patients showed attenuated post-movement beta rebound that was associated with persisting disorganization symptoms as well as impairments in cognition and role function. Patients also showed greater task-related reductions in overall beta burst rate and showed greater, more extensive, beta burst–related blood oxygen level–dependent activation. Conclusions Our evidence supports a model in which beta bursts reactivate latently maintained sensorimotor information and are dysregulated and inefficient in psychosis. We propose that abnormalities in the mechanisms by which beta bursts coordinate reactivation of contextually appropriate content can manifest as disorganization, working memory deficits, and inaccurate forward models and may underlie a core deficit associated with persisting symptoms and impairment.

Background Formal thought disorder (FTD) has been associated with more severe illness courses and functional deficits in patients with psychotic disorders. However, it remains unclear whether the presence of FTD characterises a specific subgroup of patients showing more prominent illness severity, neurocognitive and functional impairments. This study aimed to identify stable and generalizable FTD-subgroups of patients with recent-onset psychosis (ROP) by applying a comprehensive data-driven clustering approach and to test the validity of these subgroups by assessing associations between this FTD-related stratification, social and occupational functioning, and neurocognition. Methods 279 patients with ROP were recruited as part of the multi-site European PRONIA study (Personalised Prognostic Tools for Early Psychosis Management; www.pronia.eu). Five FTD-related symptoms (conceptual disorganization, poverty of content of speech, difficulty in abstract thinking, increased latency of response and poverty of speech) were assessed with Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). Results The results with two patient subgroups showing different levels of FTD were the most stable and generalizable clustering solution (predicted clustering strength value = 0.86). FTD-High subgroup had lower scores in social (pfdr < 0.001) and role (pfdr < 0.001) functioning, as well as worse neurocognitive performance in semantic (pfdr < 0.001) and phonological verbal fluency (pfdr < 0.001), short-term verbal memory (pfdr = 0.002) and abstract thinking (pfdr = 0.010), in comparison to FTD-Low group. Conclusions Clustering techniques allowed us to identify patients with more pronounced FTD showing more severe deficits in functioning and neurocognition, thus suggesting that FTD may be a relevant marker of illness severity in the early psychosis pathway.

Cortical thinning is a well-known feature in schizophrenia. The considerable variation in the spatial distribution of thickness changes has been used to parse heterogeneity. A 'cortical impoverishment' subgroup with a generalized reduction in thickness has been reported. However, it is unclear if this subgroup is recoverable irrespective of illness stage, and if it relates to the glutamate hypothesis of schizophrenia.We applied hierarchical cluster analysis to cortical thickness data from magnetic resonance imaging scans of three datasets in different stages of psychosis (n = 288; 160 patients; 128 healthy controls) and studied the cognitive and symptom profiles of the observed subgroups. In one of the samples, we also studied the subgroup differences in 7-Tesla magnetic resonance spectroscopy glutamate concentration in the dorsal anterior cingulate cortex.Our consensus-based clustering procedure consistently produced 2 subgroups of participants. Patients accounted for 75%-100% of participants in one subgroup that was characterized by significantly lower cortical thickness. Both subgroups were equally symptomatic in clinically unstable stages, but cortical impoverishment indicated a higher symptom burden in a clinically stable sample and higher glutamate levels in the first-episode sample. There were no subgroup differences in cognitive and functional outcome profiles or antipsychotic exposure across all stages.Cortical thinning does not vary with functioning or cognitive impairment, but it is more prevalent among patients, especially those with glutamate excess in early stages and higher residual symptom burden at later stages, providing an important mechanistic clue to one of the several possible pathways to the illness.

Common and distinct neural bases of Schizophrenia (SZ) and bipolar disorder (BP) have been explored using resting-state fMRI (rs-fMRI) functional connectivity (FC). However, fMRI is an indirect measure of neural activity, which is a convolution of the hemodynamic response function (HRF) and latent neural activity. The HRF, which models neurovascular coupling, varies across the brain within and across individuals, and is altered in many psychiatric disorders. Given this background, this study had three aims: quantifying HRF aberrations in SZ and BP, measuring the impact of such HRF aberrations on FC group differences, and exploring the genetic basis of HRF aberrations. We estimated voxel-level HRFs by deconvolving rs-fMRI data obtained from SZ (N = 38), BP (N = 19), and matched healthy controls (N = 35). We identified HRF group differences (P < .05, FDR corrected) in many regions previously implicated in SZ/BP, with mediodorsal, habenular, and central lateral nuclei of the thalamus exhibiting HRF differences in all pairwise group comparisons. Thalamus seed-based FC analysis revealed that ignoring HRF variability results in false-positive and false-negative FC group differences, especially in insula, superior frontal, and lingual gyri. HRF was associated with DRD2 gene expression (P < .05, 1.62 < |Z| < 2.0), as well as with medication dose (P < .05, 1.75 < |Z| < 3.25). In this first study to report HRF aberrations in SZ and BP, we report the possible modulatory effect of dopaminergic signalling on HRF, and the impact that HRF variability can have on FC studies in clinical samples. To mitigate the impact of HRF variability on FC group differences, we suggest deconvolution during data preprocessing.

ImportanceAlthough dopamine is implicated in the pathophysiology of bipolar disorder (BD), the precise alterations in the dopaminergic system remain unknown.ObjectiveTo assess dopamine transporter (DAT) density in the striatum in patients with BD with current and recently remitted mania in comparison to healthy control individuals and its correlation with severity of manic symptoms.Design, Setting, and ParticipantsThis cross-sectional study conducted in a tertiary care referral center for mood disorders in Vancouver, British Columbia, Canada, recruited 26 patients with BD (9 with current mania; 17 with recently remitted mania) and 21 matched healthy control individuals. DAT density was measured using positron emission tomography with [11C]d-threo-methylphenidate (MP). The differences between the groups in nondisplaceable binding potential (BPND) for DAT was assessed using statistical parametric mapping. The study was conducted from November 2001 to February 2007 and the data were analyzed from November 2020 to December 2021.Main Outcomes and MeasuresDAT density as indexed by BPND for MP across groups; manic symptom severity as measured with the Young Mania Rating Scale (YMRS) and correlated with BPND values in patients with BD.ResultsOf 47 total participants (mean [SD] age, 37.8 [14.4] years), 27 (57.4%) were female; 26 individuals had BD (9 with current mania and 17 with recently remitted mania) and there were 21 healthy control individuals. MP BPND was significantly lower in patients with BD in the right putamen and nucleus accumbens (mean reduction [MR] = 22%; cluster level familywise error [FWE]–corrected P P P P = .005) but not in the left striatum in either group.Conclusions and RelevanceThese findings indicate that mania was associated with reduced DAT density and remitted mania was associated with DAT levels that approximated those present in individuals without BD. These results have potential implications for drug development for mania.

Virtual human technologies are now being widely explored as therapy tools for mental health disorders including depression and anxiety. These technologies leverage the ability of the virtual agents to engage in naturalistic social interactions with a user to elicit behavioural expressions which are indicative of depression and anxiety. Research efforts have focused on optimising the human-like expressive capabilities of the virtual human, but less attention has been given to investigating the effect of virtual human mediation on the expressivity of the user. In addition, it is still not clear what an optimal task is or what task characteristics are likely to sustain long term user engagement. To this end, this paper describes the design and evaluation of virtual human-mediated tasks in a user study of 56 participants. Half the participants complete tasks guided by a virtual human, while the other half are guided by text on screen. Self-reported PHQ9 scores, biosignals and participants' ratings of tasks are collected. Findings show that virtual-human mediation influences behavioural expressiveness and this observation differs for different depression severity levels. It further shows that virtual human mediation improves users' disposition towards tasks.

BACKGROUND Depression is a substantial health and economic burden. In approximately one-third of patients, depression is resistant to first-line treatment; therefore, it is essential to find alternative treatments. Transcranial magnetic stimulation (TMS) is a neuromodulatory treatment involving the application of magnetic pulses to the brain that is approved in the United Kingdom and the United States in treatment-resistant depression. This trial aims to compare the clinical effectiveness, cost-effectiveness, and mechanism of action of standard treatment repetitive TMS (rTMS) targeted at the F3 electroencephalogram site with a newer treatment—a type of TMS called theta burst stimulation (TBS) targeted based on measures of functional brain connectivity. This protocol outlines brain imaging acquisition and analysis for the Brain Imaging Guided Transcranial Magnetic Stimulation in Depression (BRIGhTMIND) study trial that is used to create personalized TMS targets and answer the proposed mechanistic hypotheses. OBJECTIVE The aims of the imaging arm of the BRIGhTMIND study are to identify functional and neurochemical brain signatures indexing the treatment mechanisms of rTMS and connectivity-guided intermittent theta burst TMS and to identify imaging-based markers predicting response to treatment. METHODS The study is a randomized double-blind controlled trial with 1:1 allocation to either 20 sessions of TBS or standard rTMS. Multimodal magnetic resonance imaging (MRI) is acquired for each participant at baseline (before TMS treatment) with T1-weighted and task-free functional MRI during rest used to estimate TMS targets. For participants enrolled in the mechanistic substudy, additional diffusion-weighted sequences are acquired at baseline and at posttreatment follow-up 16 weeks after treatment randomization. Core data sets of T1-weighted and task-free functional MRI during rest are acquired for all participants and are used to estimate TMS targets. Additional sequences of arterial spin labeling, magnetic resonance spectroscopy, and diffusion-weighted images are acquired depending on the recruitment site for mechanistic evaluation. Standard rTMS treatment is targeted at the F3 electrode site over the left dorsolateral prefrontal cortex, whereas TBS treatment is guided using the coordinate of peak effective connectivity from the right anterior insula to the left dorsolateral prefrontal cortex. Both treatment targets benefit from the level of MRI guidance, but only TBS is provided with precision targeting based on functional brain connectivity. RESULTS Recruitment began in January 2019 and is ongoing. Data collection is expected to continue until January 2023. CONCLUSIONS This trial will determine the impact of precision MRI guidance on rTMS treatment and assess the neural mechanisms underlying this treatment in treatment-resistant depressed patients. CLINICALTRIAL ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644 INTERNATIONAL REGISTERED REPORT DERR1-10.2196/31925

Background: A longstanding notion in the concept of psychosis is the prominence of loosened associative links in thought processes. Assessment of such subtle aspects of thought disorders has proved to be a challenging task in clinical practice and to date no surrogate markers exist that can reliably track the physiological effects of treatments that could reduce thought disorders. Recently, automated speech graph analysis has emerged as a promising means to reliably quantify structural speech disorganization. Methods: Using structural and functional imaging, we investigated the neural basis and the functional relevance of the structural connectedness of speech samples obtained from 56 patients with psychosis (22 with bipolar disorder, 34 with schizophrenia). Speech structure was assessed by non-semantic graph analysis. Results: We found a canonical correlation linking speech connectedness and i) functional as well as developmentally relevant structural brain markers (degree centrality from resting state functional imaging and cortical gyrification index) ii) psychometric evaluation of thought disorder iii) aspects of cognitive performance (processing speed deficits) and iv) functional outcome in patients. Of various clinical metrics, only speech connectedness was correlated with biological markers. Speech connectedness filled the dynamic range of responses better than psychometric measurements of thought disorder. Conclusions: The results provide novel evidence that speech dysconnectivity could emerge from neurodevelopmental deficits and associated dysconnectivity in psychosis.

Psychosis is a major mental illness with first onset in young adults. The prognosis is poor in around half of the people affected, and difficult to predict. The few tools available to predict prognosis have major weaknesses which limit their use in clinical practice. We aimed to develop and validate a risk prediction model of symptom nonremission in first-episode psychosis. Our development cohort consisted of 1027 patients with first-episode psychosis recruited between 2005 and 2010 from 14 early intervention services across the National Health Service in England. Our validation cohort consisted of 399 patients with first-episode psychosis recruited between 2006 and 2009 from a further 11 English early intervention services. The one-year nonremission rate was 52% and 54% in the development and validation cohorts, respectively. Multivariable logistic regression was used to develop a risk prediction model for nonremission, which was externally validated. The prediction model showed good discrimination C-statistic of 0.73 (0.64, 0.81) and adequate calibration with intercept alpha of –0.014 (–0.34, 0.31) and slope beta of 0.85 (0.42, 1.27). Our model improved the net-benefit by 16% at a risk threshold of 50% compared to the strategy of treating all, equivalent to 16 more detected nonremitted first-episode psychosis individuals per 100 without incorrectly classifying remitted cases. Once prospectively validated, our first episode psychosis prediction model could help identify patients at increased risk of nonremission at initial clinical contact.

Given the emerging evidence in support of parietal brain stimulation to treat speech disorder in psychosis, we investigated structural and functional parietal dysconnectivity in schizophrenia (n = 34) and bipolar disorder with psychotic symptoms (n = 16). We found that both patient groups demonstrated reduced left parietal structural connectivity compared to healthy controls (n = 32). The three groups also differed significantly on the variability of left and right parietal dynamic functional connectivity. In patients with schizophrenia, parietal dysconnectivity predicted the severity of disorganisation symptoms. These findings suggest that dysconnectivity between the parietal lobe and the rest of the brain plays a key role in disorganisation symptoms of schizophrenia.

Background Persistent formal thought disorder (FTD) is a core feature of schizophrenia. Recent cognitive and neuroimaging studies indicate a distinct mechanistic pathway underlying the persistent positive FTD (pFTD or disorganized thinking), though its structural determinants are still elusive. Using network-based cortical thickness estimates from ultra-high field 7-Tesla Magnetic Resonance Imaging (7T MRI), we investigated the structural correlates of pFTD. Methods We obtained speech samples and 7T MRI anatomical scans from medicated clinically stable patients with schizophrenia (n = 19) and healthy controls (n = 20). Network-based morphometry was used to estimate the mean cortical thickness of 17 functional networks covering the entire cortical surface from each subject. We also quantified the vertexwise variability of thickness within each network to quantify the spatial coherence of the 17 networks, estimated patients vs. controls differences, and related the thickness of the affected networks to the severity of pFTD. Results Patients had reduced thickness of the frontoparietal and default mode networks, and reduced spatial coherence affecting the salience and the frontoparietal control network. A higher burden of positive FTD related to reduced frontoparietal thickness and reduced spatial coherence of the salience network. The presence of positive FTD, but not its severity, related to the reduced thickness of the language network comprising of the superior temporal cortex. Conclusions These results suggest that cortical thickness of both cognitive control and language networks underlie the positive FTD in schizophrenia. The structural integrity of cognitive control networks is a critical determinant of the expressed severity of persistent FTD in schizophrenia.

In the classical descriptions of schizophrenia, Kraepelin and Bleuler recognized disorganization and impoverishment of mental activity as fundamental symptoms. Their classical descriptions also included a tendency to persisting disability. The psychopathological processes underlying persisting disability in schizophrenia remain poorly understood. The delineation of a core deficit underlying persisting disability would be of value in predicting outcome and enhancing treatment. We tested the hypothesis that mental disorganization and impoverishment are associated with persisting impairments of cognition and role function, and together reflect a latent core deficit that is discernible in cases diagnosed by modern criteria. We used Confirmatory Factor Analysis to determine whether measures of disorganization, mental impoverishment, impaired cognition, and role functioning in 40 patients with schizophrenia represent a single latent variable. Disorganization scores were computed from the variance shared between disorganization measures from 3 commonly used symptom scales. Mental impoverishment scores were computed similarly. A single factor model exhibited a good fit, supporting the hypothesis that these measures reflect a core deficit. Persisting brain disorders are associated with a reduction in post-movement beta rebound (PMBR), the characteristic increase in electrophysiological beta amplitude that follows a motor response. Patients had significantly reduced PMBR compared with healthy controls. PMBR was negatively correlated with core deficit score. While the symptoms constituting impoverished and disorganized mental activity are dissociable in schizophrenia, nonetheless, the variance that these 2 symptom domains share with impaired cognition and role function, appears to reflect a pathophysiological process that might be described as the core deficit of classical schizophrenia.

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.

BackgroundThe 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.MethodsSeventeen 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.ResultsPatients 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.ConclusionsDysmyelination of the cingulum bundle is seen in a subgroup of patients with schizophrenia and may be involved in the mechanism of Schneiderian delusions.

Background Whether there are distinct subtypes of schizophrenia is an important issue to advance understanding and treatment of schizophrenia. Aims To understand and treat individuals with schizophrenia, the aim was to advance understanding of differences between individuals, whether there are discrete subtypes, and how first-episode patients (FEP) may differ from multiple episode patients (MEP). Method These issues were analysed in 687 FEP and 1880 MEP with schizophrenia using the Positive and Negative Syndrome Scale for (PANSS) schizophrenia before and after antipsychotic medication for 6 weeks. Results The seven Negative Symptoms were correlated with each other and with P2 (conceptual disorganisation), G13 (disturbance of volition), and G7 (motor retardation). The main difference between individuals was in the cluster of seven negative symptoms, which had a continuous unimodal distribution. Medication decreased the PANSS scores for all the symptoms, which were similar in the FEP and MEP groups. Conclusions The negative symptoms are a major source of individual differences, and there are potential implications for treatment. Declaration of interests L.P. received speaker fees from Otsuka Canada and educational grant from Janssen Canada in 2017. Copyright and usage © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Background Formal thought disorder (FThD) has been associated with more severe illness courses and functional deficits in psychosis patients. Given these associations, it remains unclear whether the presence of FThD accounts for the heterogeneous presentation of psychoses, and whether it characterises a specific subgroup of patients showing prominent differential illness severity, neurocognitive and functional impairments already in the early stages of psychosis. Thus, our aim is 1) to evaluate whether there are stable subtypes of patients with Recent-Onset Psychosis (ROP) that are characterized by distinct FThD patterns, 2) to investigate whether this FThD-related stratification is associated with clinical, and neurocognitive phenotypes at an early stage of the disease, and 3) to explore correlation patterns among the FThD-related symptoms, functioning and neurocognition through network analysis. Methods 279 individuals experiencing ROP were recruited for this project as part of multi-site European PRONIA study. In the present study, FThD was assessed with conceptual disorganization, difficulty in abstract thinking, poverty of content of speech, increased latency of response and poverty of speech items from the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). We first applied a multi-step clustering protocol comparing three clustering algorithms: (i) k-means, (ii) hierarchical clustering, and (iii) partitioning around medoids with the number of clusters ranging from 2 to 10. Our protocol runs following four checkpoints; (i) validity [ClValid package], (ii) re-evaluation of validity results and unbiased determination of the winning algorithm [NbClust package], (iii) stability test [ClusterStability package] and (iv) generalizability [predict.strength package] testing for the most optimal clustering solution. Thereafter, we investigated whether the identified FThD subgrouping solution was associated with neurocognitive performance, social and occupational functioning by using Welch’s two-sample t-test or Mann-Whitney-U test based on the distribution of data, and explored the interrelation of these domains with network analysis by using qgraph package with the spearman correlation matrix among variables. All analyses and univariate statistical comparisons were conducted with R version 3.5.2. We used the False Discovery Rate (FDR)37 to correct all P-values for the multiple comparisons. Results The k-means algorithm-based on two-cluster solution (FThD high vs. low) surviving these validity, stability and generalizability tests was chosen for further association tests and network analysis with core disease phenotypes. Patients in FThD high subgroup had lower scores in global (pfdr = 0.0001), social (pfdr < 0.0001) and role (pfdr < 0.0001) functioning, in semantic (pfdr < 0.0001) and phonological verbal fluency (pfdr = 0.0004), verbal short-term memory (pfdr = 0.0018) and abstract thinking (pfdr = 0.0099). Cluster assignment was not informed by the global disease severity (pfdr = 0.7786) but was associated with more pronounced negative symptoms (pfdr = 0.0001) in the FThD high subgroup. Discussion Our findings highlight how the combination of unsupervised machine learning algorithms with network analysis techniques may provide novel insight about the mappings between psychopathology, neurocognition and functioning. Furthermore, they point how FThD may represent a target variable for individualized psycho-, socio-, logotherapeutic interventions aimed at improving neurocognition abilities and functioning. Prospective studies should further test this promising perspective.

BackgroundPersistent formal thought disorder (FTD) is a core feature of schizophrenia. Recent cognitive and neuroimaging studies indicate a distinct mechanistic pathway underlying the persistent positive FTD (pFTD or disorganized thinking), though its structural determinants are still elusive. Using network-based cortical thickness estimates from ultra-high field 7-Tesla Magnetic Resonance Imaging (7T MRI), we investigated the structural correlates of pFTD.MethodsWe obtained speech samples and 7T MRI anatomical scans from medicated clinically stable patients with schizophrenia (n=19) and healthy controls (n=20). Network-based morphometry was used to estimate the mean cortical thickness of 17 functional networks covering the entire cortical surface from each subject. We also quantified the vertexwise variability of thickness within each network to quantify the spatial coherence of the 17 networks, estimated patients vs. controls differences, and related the thickness of the affected networks to the severity of pFTD.ResultsPatients had reduced thickness of the frontoparietal and default mode networks, and reduced spatial coherence affecting the salience and the frontoparietal control network. A higher burden of positive FTD related to reduced frontoparietal thickness and reduced spatial coherence of the salience network. The presence of positive FTD, but not its severity, related to the reduced thickness of the language network comprising of the superior temporal cortex.ConclusionsThese results suggest that cortical thickness of both cognitive control and language networks underlie the positive FTD in schizophrenia. The structural integrity of cognitive control networks is a critical determinant of the expressed severity of persistent FTD in schizophrenia.

Objective Schizophrenia spectrum disorders (SSD) and psychotic bipolar disorder share a number of genetic and neurobiological features, despite a divergence in clinical course and outcome trajectories. We studied the diagnostic classification potential that can be achieved on the basis of the structure and connectivity within a triple network system (the default mode, salience and central executive network) in patients with SSD and psychotic bipolar disorder. Methods Directed static connectivity and its dynamic variance was estimated among 8 nodes of the three large-scale networks. Multivariate autoregressive models of deconvolved resting state functional magnetic resonance imaging time series were obtained from 57 patients (38 with SSD and 19 with bipolar disorder and psychosis). We used 2/3 of the patients for training and validation of the classifier and the remaining 1/3 as an independent hold-out test data for performance estimation. Results A high level of discrimination between bipolar disorder with psychosis and SSD (combined balanced accuracy = 96.2%; class accuracies 100% for bipolar and 92.3% for SSD) was achieved when effective connectivity and morphometry of the triple network nodes was combined with symptom scores. Patients with SSD were discriminated from patients with bipolar disorder and psychosis as showing higher clinical severity of disorganization and higher variability in the effective connectivity between salience and executive networks. Conclusions Our results support the view that the study of network-level connectivity patterns can not only clarify the pathophysiology of SSD but also provide a measure of excellent clinical utility to identify discrete diagnostic/prognostic groups among individuals with psychosis.

Background: \ud Outcomes for people with first-episode psychosis are highly heterogeneous. Few reliable validated methods are available to predict the outcome for individual patients in the first clinical contact. In this study, we aimed to build multivariable prediction models of 1-year remission and recovery outcomes using baseline clinical variables in people with first-episode psychosis.\ud \ud Methods: \ud In this machine learning approach, we applied supervised machine learning, using regularised regression and nested leave-one-site-out cross-validation, to baseline clinical data from the English Evaluating the Development and Impact of Early Intervention Services (EDEN) study (n=1027), to develop and internally validate prediction models at 1-year follow-up. We assessed four binary outcomes that were recorded at 1 year: symptom remission, social recovery, vocational recovery, and quality of life (QoL). We externally validated the prediction models by selecting from the top predictor variables identified in the internal validation models the variables shared with the external validation datasets comprised of two Scottish longitudinal cohort studies (n=162) and the OPUS trial, a randomised controlled trial of specialised assertive intervention versus standard treatment (n=578).\ud \ud Findings: \ud The performance of prediction models was robust for the four 1-year outcomes of symptom remission (area under the receiver operating characteristic curve [AUC] 0·703, 95% CI 0·664–0·742), social recovery (0·731, 0·697–0·765), vocational recovery (0·736, 0·702–0·771), and QoL (0·704, 0·667–0·742; p

Patients with schizophrenia demonstrate robust abnormalities of the synchronisation of beta oscillations that occur in diverse brain regions following sensory, motor or mental events. A prominent abnormality seen in primary motor cortex is a reduction in amplitude of so-called beta-rebound. Here a sharp decrease in neural oscillatory power in the beta band is observed during movement (MRBD) followed by an increase above baseline on movement cessation (PMBR). An understanding of how neural circuits give rise to MRBD and PMBR is clinically relevant to the pathophysiology of schizophrenia. Here we survey a very recent neural mass model for movement-induced changes in the beta rhythm and show that it is an ideal candidate for use in a clinical setting. The model arises as an exact mean-field reduction of a spiking network, has a realistic model of synaptic processing and is able to describe the dynamic changes in population synchrony that can underlie event-related desynchronisation/synchronisation for MRBD/PMBR. A lengthening of the synaptic response time to sensory drive, modelling NMDA receptor hypofunction, shows a reduction in beta-rebound consistent with that seen in schizophrenia.

AimsTo derive scores for mental disorganization and impoverishment from commonly used rating scales, and test the hypothesis that disorganization and impoverishment, along with impaired cognition and role-function reflect a latent variable that is a plausible candidate for the putative core deficit.BackgroundFor more than 100 years, disorganization and impoverishment of mental activity have been recognised as fundamental symptoms of schizophrenia. These symptoms may reflect a core brain process underlying persisting disability. Delusions and hallucinations have been regarded as accessory features. The psychopathological processes predisposing to persisting disability in schizophrenia are poorly understood. The delineation of a core deficit underlying persisting disability would be potentially of great value in predicting outcome and developing improved treatment.MethodPatients aged 18–55 years were included if: they satisfied DSM IV criteria for schizophrenia or schizoaffective disorder. Healthy controls were recruited by public advertisement and selected to match the patient group in age and sex. Study sample included 39 participants with schizophrenia, 1 with schizoaffective disorder and 44 matched healthy controls. We derived disorganization and impoverishment scores from three symptom scales: PANSS, SSPI and CASH. We computed composite scores for disorganization and for impoverishment and employed Confirmatory Factor Analysis to test the hypothesis that a single factor accounts for the relationships between disorganization, impoverishment, cognitive impairment and impaired role function. We assessed the relationship between this latent “core deficit” and diminished Post Movement Beta Rebound (PMBR), an electrophysiological measure from Magnetoencephalography (MEG), associated with persisting brain disorders.ResultFit indices for the single factor model from CFA indicated a good fit: χ2(2) = 1.817, p = .403; RMSEA ConclusionOur findings demonstrate that the shared variance between impoverishment (psychomotor poverty); disorganization; cognitive impairment; and impaired role function can be accounted for by a latent variable that can reasonably be described as the core deficit of classical schizophrenia. The demonstration that the severity of the putative core deficit is correlated with the reduction in PMBR provides evidence that the core deficit is associated with an identifiable abnormality of brain dysfunction.

Highlights • Beta rebound (PMBR) is reduced in recent-onset and established schizophrenia cases • In established cases, PMBR is negatively correlated with disorganisation symptoms • Hidden Markov model shows different transient pan-spectral bursts underlying PMBR., Magnetoencephalography (MEG) measures magnetic fields generated by synchronised neural current flow and provides direct inference on brain electrophysiology and connectivity, with high spatial and temporal resolution. The movement-related beta decrease (MRBD) and the post-movement beta rebound (PMBR) are well-characterised effects in magnetoencephalography (MEG), with the latter having been shown to relate to long-range network integrity. Our previous work has shown that the PMBR is diminished (relative to controls) in a group of schizophrenia patients. However, little is known about how this effect might differ in patients at different stages of illness and degrees of clinical severity. Here, we extend our previous findings showing that the MEG derived PMBR abnormality in schizophrenia exists in 29 recent-onset and 35 established cases (i.e., chronic patients), compared to 42 control cases. In established cases, PMBR is negatively correlated with severity of disorganization symptoms. Further, using a hidden Markov model analysis, we show that transient pan-spectral oscillatory ”bursts”, which underlie the PMBR, differ between healthy controls and patients. Results corroborate that PMBR is associated with disorganization of mental activity in schizophrenia.

Introduction: Schizophrenia and Schizotypal Personality Disorder (SPD) lie on a single spectrum of mental illness and converging evidence suggests similarities in the etiology of the two conditions. However, schizotypy is a heterogeneous facet of personality in the healthy population and so may be seen as a bridge between health and mental illness. Neural evidence for such a continuity would have implications for the characterization and treatment of schizophrenia. Based on our previous work identifying a relationship between symptomology in Schizophrenia and abnormal movement-induced electrophysiological response (the post-movement beta rebound (PMBR)), we predicted that if subclinical schizotypy arises from similar neural mechanisms to schizophrenia, schizotypy in healthy individuals would be associated with reduced PMBR.\ud Methods: 116 participants completed a visuomotor task whilst their neural activity was recorded by magnetoencephalography. Partial correlations were computed between a measure of PMBR extracted from left primary motor cortex and scores on the Schizotypal Personality Questionnaire (SPQ), a self-report measure of schizotypal personality. Correlations between PMBR and SPQ factor scores measuring Cognitive-Perceptual, Interpersonal and Disorganization dimensions of schizotypy were also computed. Effects of site, age, and sex were controlled for.\ud Results: We found a significant negative correlation between total SPQ score and PMBR. This was most strongly mediated by variance shared between Interpersonal and Disorganization factor scores.\ud Conclusion: These findings indicate a continuum of neural deficit between schizotypy and schizophrenia, with diminution of PMBR, previously reported in schizophrenia, also measurable in individuals with schizotypal features, particularly disorganization and impaired interpersonal relations.

BackgroundIn patients with schizophrenia, distributed abnormalities are observed in grey matter volume. A recent hypothesis posits that these distributed changes are indicative of a plastic reorganisation process occurring in response to a functional defect in neuronal information transmission. We investigated the structural covariance across various brain regions in early-stage schizophrenia to determine if indeed the observed patterns of volumetric loss conform to a coordinated pattern of structural reorganisation.MethodsStructural magnetic resonance imaging scans were obtained from 40 healthy adults and 41 age, gender and parental socioeconomic status matched patients with schizophrenia. Volumes of grey matter tissue were estimated at the regional level across 90 atlas-based parcellations. Group-level structural covariance was studied using a graph theoretical framework.ResultsPatients had distributed reduction in grey matter volume, with high degree of localised covariance (clustering) compared with controls. Patients with schizophrenia had reduced centrality of anterior cingulate and insula but increased centrality of the fusiform cortex, compared with controls. Simulating targeted removal of highly central nodes resulted in significant loss of the overall covariance patterns in patients compared with controls.ConclusionRegional volumetric deficits in schizophrenia are not a result of random, mutually independent processes. Our observations support the occurrence of a spatially interconnected reorganisation with the systematic de-escalation of conventional ‘hub’ regions. This raises the question of whether the morphological architecture in schizophrenia is primed for compensatory functions, albeit with a high risk of inefficiency.

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)); whilst in visual cortex, gamma oscillations are increased throughout stimulus presentation. In this study, we used a self-paced 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., Highlights • Visual and motor deficits in schizophrenia are rarely investigated. • We use MEG to non-invasively assess the neural basis of these deficits. • Patients showed abnormalities in neuronal oscillations in motor cortex. • Beta band power, reflecting cortical inhibition, was reduced after movements. • Increased movement frequency may be a behavioural compensation for this reduction.