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).

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.

Structural and Functional Brain Patterns Predict Formal Thought Disorder's Severity and Its Persistence in Recent-Onset Psychosis: Results From the PRONIA Study.

BACKGROUND: Formal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level. METHODS: Two hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up. RESULTS: Cross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BACslow-5 = 73.2%, BACslow-4 = 72.9%, BACslow-3 = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%. CONCLUSIONS: We report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes.

A Positron Emission Tomography Study of Dopamine Transporter Density in Patients With Bipolar Disorder With Current Mania and Those With Recently Remitted Mania.

Importance: Although dopamine is implicated in the pathophysiology of bipolar disorder (BD), the precise alterations in the dopaminergic system remain unknown. Objective: To 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 Participants: This 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 Measures: DAT 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. Results: Of 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 < .001) as well as left putamen and caudate (MR = 24%; cluster level FWE-corrected P < .001). The reduction in BPND was more extensive and pronounced in patients with current mania, while patients with recently remitted mania had lower BPND in the left striatum but not the right. There was a significant negative correlation between YMRS scores and MP BPND in the right striatum in patients with current mania (ρ = -0.93; 95% CI, -0.99 to -0.69; P < .001) and those with recently remitted mania (ρ = 0.64; 95% CI, -0.86 to -0.23; P = .005) but not in the left striatum in either group. Conclusions and Relevance: These 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.

Trait related aberrant connectivity in clinically stable patients with schizophrenia: A seed based resting state fMRI study.

Aberrant resting-state connectivity within and between the Default Mode Network, the Executive Control Network, and the Salience Network is well-established in schizophrenia. Meta-analyses have identified that bilateral lingual gyrus is as the only region showing hyperactivity in schizophrenia and there are reports of increased connectivity between the lingual gyrus and other brain regions in schizophrenia. It is not clear whether these abnormalities represent state or trait markers of the illness, i.e., if they are only present during the acute phase of the illness (state) or if they reflect a predisposition to schizophrenia (trait). In this study, we used a seed-based functional connectivity analysis to investigate brain networks in schizophrenia patients who are in the stable phase of their illness and assess functional connectivity using seeds in the lingual gyrus, the posterior cingulate, the right dorsolateral prefrontal cortex (dlPFC), the right anterior insula (rAI) and the right orbital frontoinsula. Twenty patients with schizophrenia in a stable phase of their illness (as defined by the course of illness and Signs and Symptoms of Psychotic Illness (SSPI) scores) and 20 age and sex-matched healthy controls underwent resting-state functional Magnetic Resonance Imaging (rs-fMRI). Data was analysed using the Data Processing Assistant for Resting-State fMRI Advanced Edition (DPARSFA) V3.1 ( http://rfmri.org/DPARSF ) and the statistical parametric mapping software 8 (SPM8). Compared with healthy controls, patients with schizophrenia showed increased connectivity between the left lingual gyrus and the middle frontal gyrus, and the cingulate cortex. Lingual gyrus hyper-connectivity may be a stable trait neuroimaging marker for schizophrenia. Our findings suggest that aberrant connectivity in major resting-state networks may not be present after the acute illness has stabilised.

Cortical impoverishment in a stable subgroup of schizophrenia: Validation across various stages of psychosis.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Imprecise Predictive Coding Is at the Core of Classical Schizophrenia.

Current diagnostic criteria for schizophrenia place emphasis on delusions and hallucinations, whereas the classical descriptions of schizophrenia by Kraepelin and Bleuler emphasized disorganization and impoverishment of mental activity. Despite the availability of antipsychotic medication for treating delusions and hallucinations, many patients continue to experience persisting disability. Improving treatment requires a better understanding of the processes leading to persisting disability. We recently introduced the term classical schizophrenia to describe cases with disorganized and impoverished mental activity, cognitive impairment and predisposition to persisting disability. Recent evidence reveals that a polygenic score indicating risk for schizophrenia predicts severity of the features of classical schizophrenia: disorganization, and to a lesser extent, impoverishment of mental activity and cognitive impairment. Current understanding of brain function attributes a cardinal role to predictive coding: the process of generating models of the world that are successively updated in light of confirmation or contradiction by subsequent sensory information. It has been proposed that abnormalities of these predictive processes account for delusions and hallucinations. Here we examine the evidence provided by electrophysiology and fMRI indicating that imprecise predictive coding is the core pathological process in classical schizophrenia, accounting for disorganization, psychomotor poverty and cognitive impairment. Functional imaging reveals aberrant brain activity at network hubs engaged during encoding of predictions. We discuss the possibility that frequent prediction errors might promote excess release of the neurotransmitter, dopamine, thereby accounting for the occurrence of episodes of florid psychotic symptoms including delusions and hallucinations in classical schizophrenia. While the predictive coding hypotheses partially accounts for the time-course of classical schizophrenia, the overall body of evidence indicates that environmental factors also contribute. We discuss the evidence that chronic inflammation is a mechanism that might link diverse genetic and environmental etiological factors, and contribute to the proposed imprecision of predictive coding.

Connectivity-Guided Theta Burst Transcranial Magnetic Stimulation Versus Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Moderate to Severe Depression: Magnetic Resonance Imaging Protocol and SARS-CoV-2-Induced Changes for a Randomized Double-blind Controlled Trial.

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. TRIAL REGISTRATION: ISRCTN Registry ISRCTN19674644; https://www.isrctn.com/ISRCTN19674644. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31925.

Characterization of Hemodynamic Alterations in Schizophrenia and Bipolar Disorder and Their Effect on Resting-State fMRI Functional Connectivity.

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.

The clinical relevance of formal thought disorder in the early stages of psychosis: results from the PRONIA study.

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.

Development and Validation of a Nonremission Risk Prediction Model in First-Episode Psychosis: An Analysis of 2 Longitudinal Studies.

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 (0.71, 0.75) and adequate calibration with intercept alpha of 0.12 (0.02, 0.22) and slope beta of 0.98 (0.85, 1.11). Our model improved the net-benefit by 15% at a risk threshold of 50% compared to the strategy of treating all, equivalent to 15 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.

Oxidative Stress and the Pathophysiology and Symptom Profile of Schizophrenia Spectrum Disorders.

Schizophrenia is associated with increased levels of oxidative stress, as reflected by an increase in the concentrations of damaging reactive species and a reduction in anti-oxidant defences to combat them. Evidence has suggested that whilst not the likely primary cause of schizophrenia, increased oxidative stress may contribute to declining course and poor outcomes associated with schizophrenia. Here we discuss how oxidative stress may be implicated in the aetiology of schizophrenia and examine how current understanding relates associations with symptoms, potentially via lipid peroxidation induced neuronal damage. We argue that oxidative stress may be a good target for future pharmacotherapy in schizophrenia and suggest a multi-step model of illness progression with oxidative stress involved at each stage.

Regional Brain Correlates of Beta Bursts in Health and Psychosis: A Concurrent Electroencephalography and Functional Magnetic Resonance Imaging Study.

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 control 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.

Motor-related oscillatory activity in schizophrenia according to phase of illness and clinical symptom severity.

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.

Effective connectivity of the right anterior insula in schizophrenia: The salience network and task-negative to task-positive transition.

Triple network dysfunction theory of schizophrenia postulates that the interaction between the default-mode and the fronto-parietal executive network is disrupted by aberrant salience signals from the right anterior insula (rAI). To date, it is not clear how the proposed resting-state disruption translates to task-processing inefficiency in subjects with schizophrenia. Using a contiguous resting and 2-back task performance fMRI paradigm, we quantified the change in effective connectivity that accompanies rest-to-task state transition in 29 clinically stable patients with schizophrenia and 31 matched healthy controls. We found an aberrant task-evoked increase in the influence of the rAI to both executive (Cohen's d = 1.35, p = 2.8 × 10-6) and default-mode (Cohen's d = 1.22, p = 1.5 × 10-5) network regions occur in patients when compared to controls. In addition, the effective connectivity from middle occipital gyrus (dorsal visual cortex) to insula is also increased in patients as compared with healthy controls. Aberrant insula to executive network influence is pronounced in patients with more severe negative symptom burden. These findings suggest that control signals from rAI are abnormally elevated and directed towards both task-positive and task-negative brain regions, when task-related demands arise in schizophrenia. This aberrant, undiscriminating surge in salience signalling may disrupt contextually appropriate allocation of resources in the neuronal workspace in patients with schizophrenia.

Quantifying the Core Deficit in Classical 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.

Connectivity guided theta burst transcranial magnetic stimulation versus repetitive transcranial magnetic stimulation for treatment-resistant moderate to severe depression: study protocol for a randomised double-blind controlled trial (BRIGhTMIND).

INTRODUCTION: The BRIGhTMIND study aims to determine the clinical effectiveness, cost-effectiveness and mechanism of action of connectivity guided intermittent theta burst stimulation (cgiTBS) versus standard repetitive transcranial magnetic stimulation (rTMS) in adults with moderate to severe treatment resistant depression. METHODS AND ANALYSIS: The study is a randomised double-blind controlled trial with 1:1 allocation to either 20 sessions of (1) cgiTBS or (2) neuronavigated rTMS not using connectivity guidance. A total of 368 eligible participants with a diagnosis of current unipolar major depressive disorder that is both treatment resistant (defined as scoring 2 or more on the Massachusetts General Hospital Staging Score) and moderate to severe (scoring >16 on the 17-item Hamilton Depression Rating Scale (HDRS-17)), will be recruited from primary and secondary care settings at four treatment centres in the UK. The primary outcome is depression response at 16 weeks (50% or greater reduction in HDRS-17 score from baseline). Secondary outcomes include assessments of self-rated depression, anxiety, psychosocial functioning, cognition and quality of life at 8, 16 and 26 weeks postrandomisation. Cost-effectiveness, patient acceptability, safety, mechanism of action and predictors of response will also be examined. ETHICS AND DISSEMINATION: Ethical approval was granted by East Midlands Leicester Central Research Ethics Committee (ref: 18/EM/0232) on 30 August 2018. The results of the study will be published in relevant peer-reviewed journals, and then through professional and public conferences and media. Further publications will explore patient experience, moderators and mediators of outcome and mechanism of action. TRIAL REGISTRATION NUMBER: ISRCTN19674644.

Parietal lobe and disorganisation syndrome in schizophrenia and psychotic bipolar disorder: A bimodal connectivity study.

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.