Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound.

After natalizumab (NAT) cessation, some multiple sclerosis (MS) patients experience a severe disease rebound. The rebound pathophysiology is still unclear; however, it has been linked to interleukin-17-producing T-helper (Th17) cells. We demonstrate that during NAT treatment, MCAM+CCR6+Th17 cells gradually acquire a pathogenic profile, including proinflammatory cytokine production, pathogenic transcriptional signatures, brain endothelial barrier impairment, and oligodendrocyte damage via induction of apoptotic pathways. This is accompanied by an increase in Th17 cell frequencies in the cerebrospinal fluid of NAT-treated patients. Notably, Th17 cells derived from NAT-treated patients, who later developed a disease rebound upon treatment cessation, displayed a distinct transcriptional pathogenicity profile associated with altered migratory properties. Accordingly, increased brain infiltration of patient Th17 cells was illustrated in a humanized mouse model and brain histology from a rebound patient. Therefore, peripheral blood-accumulated MCAM+CCR6+Th17 cells might be involved in rebound pathophysiology, and monitoring of changes in Th17 cell pathogenicity in patients before/during NAT treatment cessation might enable rebound risk assessment in the future.

White matter diffusion estimates in obsessive-compulsive disorder across 1653 individuals: machine learning findings from the ENIGMA OCD Working Group.

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research.

The functional connectome in obsessive-compulsive disorder: resting-state mega-analysis and machine learning classification for the ENIGMA-OCD consortium.

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level.

Endurance Exercise Attenuates Established Progressive Experimental Autoimmune Encephalomyelitis and Is Associated with an Amelioration of Innate Immune Responses in NOD Mice.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease causing axonal degeneration and demyelination. Exercise in mice with active monophasic experimental autoimmune encephalomyelitis (EAE) attenuates disease severity associated with diverse impacts on T cell-mediated immunity. However, studies have so far focused on preventive approaches. In this study, we investigated the impact of endurance exercise on established EAE disease in a model of secondary progressive MS. When the exercise program on motorized running wheels was started at disease manifestation, the disease course was significantly ameliorated. This was associated with a significant decrease in B cell, dendritic cell, and neutrophil cell counts in the central nervous system (CNS). Furthermore, we observed an increased expression of major histocompatibility complex class II (MHC-II) as well as alterations in costimulatory molecule expression in CNS B cells and dendritic cells. In contrast, T cell responses were not altered in the CNS or periphery. Thus, exercise training is capable of attenuating the disease course even in established secondary progressive EAE, potentially via modulation of the innate immune compartment. Further studies are warranted to corroborate our findings and assess the potential of this lifestyle intervention as a complementary therapeutic strategy in secondary progressive MS patients.

Neuronal efficiency following n-back training task is accompanied by a higher cerebral glucose metabolism.

Recent functional magnetic resonance imaging (fMRI) studies revealed lower neural activation during processing of an n-back task following working memory training, indicating a training-related increase in neural efficiency. In the present study, we asked if the training induced regional neural activation is accompanied by changes in glucose consumption. An active control and an experimental group of healthy middle-aged volunteers conducted 32 sessions of visual and verbal n-back trainings over 8 weeks. We analyzed data of 52 subjects (25 experimental and 27 control group) for practice effects underlying verbal working memory task and 50 subjects (24 experimental and 26 control group) for practice effects underlying visual WM task. The samples of these two tasks were nearly identical (data of 47 subjects were available for both verbal and visual tasks). Both groups completed neuroimaging sessions at a hybrid PET/MR system before and after training. Each session included criterion task fMRI and resting state positron emission tomography with FDG (FDG-PET). As reported previously, lower neural activation following n-back training was found in regions of the fronto-parieto-cerebellar circuitry during a verbal n-back task. Notably, these changes co-occurred spatially with a higher relative FDG-uptake. Decreased neural activation within regions of the fronto-parietal network during visual n-back task did not show co-occurring changes in relative FDG-uptake. There was no direct association between neuroimaging and behavioral measures, which could be due to the inter-subjects' variability in reaching capacity limits. Our findings provide new details for working memory training induced neural efficiency on a molecular level by integrating FDG-PET and fMRI measures.

An overview of the first 5 years of the ENIGMA obsessive-compulsive disorder working group: The power of worldwide collaboration.

Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive-compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA.

Dietary conjugated linoleic acid links reduced intestinal inflammation to amelioration of CNS autoimmunity.

A close interaction between gut immune responses and distant organ-specific autoimmunity including the CNS in multiple sclerosis has been established in recent years. This so-called gut-CNS axis can be shaped by dietary factors, either directly or via indirect modulation of the gut microbiome and its metabolites. Here, we report that dietary supplementation with conjugated linoleic acid, a mixture of linoleic acid isomers, ameliorates CNS autoimmunity in a spontaneous mouse model of multiple sclerosis, accompanied by an attenuation of intestinal barrier dysfunction and inflammation as well as an increase in intestinal myeloid-derived suppressor-like cells. Protective effects of dietary supplementation with conjugated linoleic acid were not abrogated upon microbiota eradication, indicating that the microbiome is dispensable for these conjugated linoleic acid-mediated effects. Instead, we observed a range of direct anti-inflammatory effects of conjugated linoleic acid on murine myeloid cells including an enhanced IL10 production and the capacity to suppress T-cell proliferation. Finally, in a human pilot study in patients with multiple sclerosis (n = 15, under first-line disease-modifying treatment), dietary conjugated linoleic acid-supplementation for 6 months significantly enhanced the anti-inflammatory profiles as well as functional signatures of circulating myeloid cells. Together, our results identify conjugated linoleic acid as a potent modulator of the gut-CNS axis by targeting myeloid cells in the intestine, which in turn control encephalitogenic T-cell responses.

CNS Pericytes Modulate Local T Cell Infiltration in EAE.

Pericytes at the blood-brain barrier (BBB) are located between the tight endothelial cell layer of the blood vessels and astrocytic endfeet. They contribute to central nervous system (CNS) homeostasis by regulating BBB development and maintenance. Loss of pericytes results in increased numbers of infiltrating immune cells in the CNS in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis (MS). However, little is known about their competence to modulate immune cell activation or function in CNS autoimmunity. To evaluate the capacity of pericytes to directly interact with T cells in an antigen-specific fashion and potentially (re)shape their function, we depleted major histocompatibility complex (MHC) class II from pericytes in a cell type-specific fashion and performed T cell-pericyte cocultures and EAE experiments. We found that pericytes present antigen in vitro to induce T cell activation and proliferation. In an adoptive transfer EAE experiment, pericyte-specific MHC II KO resulted in locally enhanced T cell infiltration in the CNS; even though, overall disease course of mice was not affected. Thus, pericytes may serve as non-professional antigen-presenting cells affecting states of T cell activation, thereby locally shaping lesion formation in CNS inflammation but without modulating disease severity.

Working memory task induced neural activation: A simultaneous PET/fMRI study.

PURPOSE: Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) is a powerful method for mapping cerebral glucose metabolism as a proxy of neural activity, assuming a steady-state during the recording interval. We asked if a clinical FDG-PET imaging protocol might also capture changes in neural activity associated with performance of a working memory (WM) task. METHODS: To test this concept, we examined hybrid PET/MR data for FDG-PET and simultaneous functional magnetic resonance imaging (fMRI) in a sample of healthy volunteers. The PET image acquisition started 30 min after a bolus injection of approximately 100 MBq FDG, and the WM task was undertaken starting at approximately 60 min post-injection. We reconstructed FDG-PET sum images corresponding to baseline (44-60 min p.i.) and WM tasks (63- 71 min p.i.), each with intensity scaling to the corresponding global mean. RESULTS: Compared to the baseline resting condition, relative FDG uptake increased during WM task performance in brain regions previously associated with WM. Furthermore, these metabolically active regions partly overlapped with the regions showing task-dependent increases in BOLD signal in simultaneous fMRI. CONCLUSION: We find evidence for WM task-induced neural activation using a clinical FDG-PET imaging protocol. These findings encourage the development of dedicated protocols for tracking neural correlates of cognitive function.

Cortical and subcortical responsiveness to intensive adaptive working memory training: An MRI surface-based analysis.

Working memory training (WMT) has been shown to have effects on cognitive performance, the precise effects and the underlying neurobiological mechanisms are, however, still a matter of debate. In particular, the impact of WMT on gray matter morphology is still rather unclear. In the present study, 59 healthy middle-aged participants (age range 50-65 years) were pseudo-randomly single-blinded allocated to an 8-week adaptive WMT or an 8-week nonadaptive intervention. Before and after the intervention, high resolution magnetic resonance imaging (MRI) was performed and cognitive test performance was assessed in all participants. Vertex-wise cortical volume, thickness, surface area, and cortical folding was calculated. Seven subcortical volumes of interest and global mean cortical thickness were also measured. Comparisons of symmetrized percent change (SPC) between groups were conducted to identify group by time interactions. Greater increases in cortical gyrification in bilateral parietal regions, including superior parietal cortex and inferior parietal lobule as well as precuneus, greater increases in cortical volume and thickness in bilateral primary motor cortex, and changes in surface area in bilateral occipital cortex (medial and lateral occipital cortex) were detected in WMT group after training compared to active controls. Structural training-induced changes in WM-related regions, especially parietal regions, might provide a better brain processing environment for higher WM load.

Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions.

Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity.

T cells critically depend on reprogramming of metabolic signatures to meet the bioenergetic demands during activation and clonal expansion. Here we identify the transcription factor Nur77 as a cell-intrinsic modulator of T cell activation. Nur77-deficient T cells are highly proliferative, and lack of Nur77 is associated with enhanced T cell activation and increased susceptibility for T cell-mediated inflammatory diseases, such as CNS autoimmunity, allergic contact dermatitis and collagen-induced arthritis. Importantly, Nur77 serves as key regulator of energy metabolism in T cells, restricting mitochondrial respiration and glycolysis and controlling switching between different energy pathways. Transcriptional network analysis revealed that Nur77 modulates the expression of metabolic genes, most likely in close interaction with other transcription factors, especially estrogen-related receptor α. In summary, we identify Nur77 as a transcriptional regulator of T cell metabolism, which elevates the threshold for T cell activation and confers protection in different T cell-mediated inflammatory diseases.

Frontoparietal and salience network alterations in obsessive­compulsive disorder: insights from independent component and sliding time window analyses

Background: Resting-state functional MRI (fMRI) studies commonly report alterations in 3 core networks in obsessive­compulsive disorder (OCD) ­ the frontoparietal network, the default mode network and the salience network ­ defined by functionally connected infraslow oscillations in ongoing brain activity. However, most of these studies observed static functional connectivity in the brains of patients with OCD. Methods: To investigate dynamic functional connectivity alterations and widen the evidence base toward the triple network model in OCD, we performed group-based independent component and sliding time window analyses in 49 patients with OCD and 41 healthy controls. Results: The traditional independent component analysis showed alterations in the left frontoparietal network as well as between the left and right frontoparietal networks in patients with OCD compared with healthy controls. For dynamic functional connectivity, the sliding time window approach revealed peak dysconnectivity between the left and right frontoparietal networks and between the left frontoparietal network and the salience network. Limitations: The number of independent components, noise in the resting-state fMRI images, the heterogeneity of the OCD sample, and comorbidities and medication status in the patients could have biased the results. Conclusion: Disrupted modulation of these intrinsic brain networks may contribute to the pathophysiology of OCD.

Evolutionary modifications in human brain connectivity associated with schizophrenia.

The genetic basis and human-specific character of schizophrenia has led to the hypothesis that human brain evolution may have played a role in the development of the disorder. We examined schizophrenia-related changes in brain connectivity in the context of evolutionary changes in human brain wiring by comparing in vivo neuroimaging data from humans and chimpanzees, one of our closest living evolutionary relatives and a species with which we share a very recent common ancestor. We contrasted the connectome layout between the chimpanzee and human brain and compared differences with the pattern of schizophrenia-related changes in brain connectivity as observed in patients. We show evidence of evolutionary modifications of human brain connectivity to significantly overlap with the cortical pattern of schizophrenia-related dysconnectivity (P < 0.001, permutation testing). We validated these effects in three additional, independent schizophrenia datasets. We further assessed the specificity of effects by examining brain dysconnectivity patterns in seven other psychiatric and neurological brain disorders (including, among others, major depressive disorder and obsessive-compulsive disorder, arguably characterized by behavioural symptoms that are less specific to humans), which showed no such associations with modifications of human brain connectivity. Comparisons of brain connectivity across humans, chimpanzee and macaques further suggest that features of connectivity that evolved in the human lineage showed the strongest association to the disorder, that is, brain circuits potentially related to human evolutionary specializations. Taken together, our findings suggest that human-specific features of connectome organization may be enriched for changes in brain connectivity related to schizophrenia. Modifications in human brain connectivity in service of higher order brain functions may have potentially also rendered the brain vulnerable to brain dysfunction.

Regulation of human inducible nitric oxide synthase expression by an upstream open reading frame.

The human inducible nitric oxide synthase (iNOS) gene contains an upstream open reading frame (uORF) in its 5'-untranslated region (5'-UTR) implying a translational regulation of iNOS expression. Transfection experiments in human DLD-1 cells revealed that the uORF although translatable seems not to inhibit the translation start at the bona fide ATG. Our data clearly show that human iNOS translation is cap-dependent and that the 5'-UTR of the iNOS mRNA contains no internal ribosome entry site. Translation of the bona fide coding sequence is most likely mediated by a leaky scanning mechanism. The 5'-UTR is encoded by exon 1 and exon 2 of the iNOS gene with the uORF stop codon located in front of the first intron indicating an involvement of the nonsense mediated RNA decay (NMD) in iNOS regulation. SiRNA-mediated down-regulation of Upf1 resulted in enhanced endogenous cytokine iNOS expression in human DLD-1 cells. Transfection of constructs containing iNOS exon 1, intron 1 and exon 2 in front of a luciferase gene showed a clear effect of the mutation of the uORF-ATG on luciferase reportergene expression. Our data indicate that the uORF in the 5'-UTR sequence of human iNOS gene reduces its expression via the NMD mechanism.

Altered reward-related effective connectivity in obsessive-compulsive disorder: an fMRI study

Background: Obsessive­compulsive disorder (OCD) is characterized by anxiety-provoking, obsessive thoughts. Patients usually react to these thoughts with repetitive behaviours that reduce anxiety and are perceived as rewarding. Hence, reward plays a major role in the psychopathology of OCD. Previous studies showed altered activation in frontostriatal networks, among others, in association with the processing of reward in patients with OCD. Potential alterations in connectivity within these networks have, however, barely been explored. Methods: We investigated a sample of patients with OCD and healthy controls using functional MRI and a reward learning task presented in an event-related design. Dynamic causal modelling (DCM) was used to estimate effective connectivity. Results: Our sample included 37 patients with OCD and 39 healthy controls. Analyses of task-related changes in connectivity showed a significantly altered effective connectivity between the ventromedial prefrontal cortex (vmPFC) and the orbitofrontal cortex (OFC), among others, both in terms of endogenous connectivity as well as modulatory effects under positive feedback. Clinical measures of compulsion correlated with the effect of feedback input on visual sensory areas. Limitations: The reported alterations should be interpreted within the context of the task and the a priori­defined network considered in the analysis. Conclusion: This disrupted connectivity in parts of the default mode network and the frontostriatal network may indicate increased rumination and self-related processing impairing the responsiveness toward external rewards. This, in turn, may underlie the general urge for reinforcement accompanying compulsive behaviours.

Network-based decoupling of local gyrification in obsessive-compulsive disorder.

Gyrification is associated with cortical maturation and closely linked to neurodevelopmental processes. Obsessive-compulsive disorder has previously been associated with neurodevelopmental risk factors. Using graph theoretical modeling we examined structural covariance patterns to assess potential disruptions in processes associated with neurodevelopment in OCD. In total 97 patients and 92 healthy controls underwent magnetic resonance imaging. Structural covariance networks based on local gyrification indices were constructed using an atlas-based parcellation scheme. Network properties were assessed using the network-based statistic as well as global and local graph theoretical measures. Correlations between gyrification and symptom severity as well as age of disease onset were examined. Network-based statistic analysis revealed one cluster with significantly decreased structural covariance in patients comprising mainly ventral brain regions (p = .041). Normalized characteristic path length was found to be impaired in patients (p = .051). On a nodal level, left middle frontal sulcus displayed a significantly decreased local clustering coefficient (p < .001). Finally, gyrification in several inferior frontal nodes significantly correlated with age of onset but not symptom severity. The decrease in a gyrification-based covariance network in OCD appears to be mostly confined to ventral areas in which gyrification starts the latest during development. This pattern may indicate that alterations taking place during development are potentially time locked to specific periods. Correlations between gyrification in inferio-frontal nodes and age of onset potentially indicate a structural trait rather than state marker for OCD. Finally, a trend in impaired global integration capabilities may point towards potentially widespread global alterations during neurodevelopment in patients.

Changes in extra-striatal functional connectivity in patients with schizophrenia in a psychotic episode.

BACKGROUND: In patients with schizophrenia in a psychotic episode, intra-striatal intrinsic connectivity is increased in the putamen but not ventral striatum. Furthermore, multimodal changes have been observed in the anterior insula that interact extensively with the putamen. AIMS: We hypothesised that during psychosis, putamen extra-striatal functional connectivity is altered with both the anterior insula and areas normally connected with the ventral striatum (i.e. altered functional connectivity distinctiveness of putamen and ventral striatum). METHOD: We acquired resting-state functional magnetic resonance images from 21 patients with schizophrenia in a psychotic episode and 42 controls. RESULTS: Patients had decreased functional connectivity: the putamen with right anterior insula and dorsal prefrontal cortex, the ventral striatum with left anterior insula. Decreased functional connectivity between putamen and right anterior insula was specifically associated with patients' hallucinations. Functional connectivity distinctiveness was impaired only for the putamen. CONCLUSIONS: Results indicate aberrant extra-striatal connectivity during psychosis and a relationship between reduced putamen-right anterior insula connectivity and hallucinations. Data suggest that altered intrinsic connectivity links striatal and insular pathophysiology in psychosis.