Mapping the multimodal connectome: On the architects of brain network science.

Delineating the human brain network and analyzing its architecture is one of the major goals of modern neuroscience. Here, we commemorate a 2008 landmark structural connectome study in PLOS Biology and gauge how it shaped the field of brain network science.

Correction: Mapping the multimodal connectome: On the architects of brain network science.

[This corrects the article DOI: 10.1371/journal.pbio.3002043.].

Functional connectivity associated with improvement in emotion management after cognitive enhancement therapy in early-course schizophrenia.

BACKGROUND: The ability to manage emotions is an important social-cognitive domain impaired in schizophrenia and linked to functional outcome. The goal of our study was to examine the impact of cognitive enhancement therapy (CET) on the ability to manage emotions and brain functional connectivity in early-course schizophrenia. METHODS: Participants were randomly assigned to CET (n = 55) or an enriched supportive therapy (EST) control group (n = 45). The resting-state functional magnetic resonance imaging scans and measures of emotion management performances were collected at baseline, 9, and 18 months follow-up. The final sample consisted of 37 CET and 25 EST participants, including 19 CET and 12 EST participants with imaging data. Linear mixed-effects models investigated the impact of treatment on emotion management and functional connectivity from the amygdala to ventrolateral and dorsolateral prefrontal cortex (dlPFC). RESULTS: The CET group showed significant improvement over time in emotion management compared to EST. Neither functional connectivity changes nor main group differences were observed following treatment. However, a significant between-group interaction showed that improved emotion management ability was associated with increased functional connectivity between the left amygdala and the left dlPFC in the CET group exclusively. CONCLUSION: Our results replicate the previous work demonstrating that CET is effective at improving some aspects of social cognition in schizophrenia. We found evidence that improvement in emotion management may be associated with a change in amygdala-dlPFC connectivity. This fronto-limbic circuit may provide a mechanistic link between the biology of emotion management processes that can be enhanced in individuals with schizophrenia.

Functional connectome organization predicts conversion to psychosis in clinical high-risk youth from the SHARP program.

The emergence of prodromal symptoms of schizophrenia and their evolution into overt psychosis may stem from an aberrant functional reorganization of the brain during adolescence. To examine whether abnormalities in connectome organization precede psychosis onset, we performed a functional connectome analysis in a large cohort of medication-naive youth at risk for psychosis from the Shanghai At Risk for Psychosis (SHARP) study. The SHARP program is a longitudinal study of adolescents and young adults at Clinical High Risk (CHR) for psychosis, conducted at the Shanghai Mental Health Center in collaboration with neuroimaging laboratories at Harvard and MIT. Our study involved a total of 251 subjects, including 158 CHRs and 93 age-, sex-, and education-matched healthy controls. During 1-year follow-up, 23 CHRs developed psychosis. CHRs who would go on to develop psychosis were found to show abnormal modular connectome organization at baseline, while CHR non-converters did not. In all CHRs, abnormal modular connectome organization at baseline was associated with a threefold conversion rate. A region-specific analysis showed that brain regions implicated in early-course schizophrenia, including superior temporal gyrus and anterior cingulate cortex, were most abnormal in terms of modular assignment. Our results show that functional changes in brain network organization precede the onset of psychosis and may drive psychosis development in at-risk youth.

Brain network analysis reveals affected connectome structure in bipolar I disorder.

The notion that healthy brain function emerges from coordinated neural activity constrained by the brain's network of anatomical connections--i.e., the connectome--suggests that alterations in the connectome's wiring pattern may underlie brain disorders. Corroborating this hypothesis, studies in schizophrenia are indicative of altered connectome architecture including reduced communication efficiency, disruptions of central brain hubs, and affected "rich club" organization. Whether similar deficits are present in bipolar disorder is currently unknown. This study examines structural connectome topology in 216 bipolar I disorder patients as compared to 144 healthy controls, focusing in particular on central regions (i.e., brain hubs) and connections (i.e., rich club connections, interhemispheric connections) of the brain's network. We find that bipolar I disorder patients exhibit reduced global efficiency (-4.4%, P =0.002) and that this deficit relates (r = 0.56, P < 0.001) to reduced connectivity strength of interhemispheric connections (-13.0%, P = 0.001). Bipolar disorder patients were found not to show predominant alterations in the strength of brain hub connections in general, or of connections spanning brain hubs (i.e., "rich club" connections) in particular (all P > 0.1). These findings highlight a role for aberrant brain network architecture in bipolar I disorder with reduced global efficiency in association with disruptions in interhemispheric connectivity, while the central "rich club" system appears not to be particularly affected.

Structural and functional aspects relating to cost and benefit of rich club organization in the human cerebral cortex.

Recent findings have demonstrated that a small set of highly connected brain regions may play a central role in enabling efficient communication between cortical regions, together forming a densely interconnected "rich club." However, the density and spatial layout of the rich club also suggest that it constitutes a costly feature of brain architecture. Here, combining anatomical T1, diffusion tensor imaging, magnetic transfer imaging, and functional MRI, several aspects of structural and functional connectivity of the brain's rich club were examined. Our findings suggest that rich club regions and rich club connections exhibit high levels of wiring volume, high levels of white matter organization, high levels of metabolic energy usage, long maturational trajectories, more variable regional time series, and more inter-regional functional couplings. Taken together, these structural and functional measures extend the notion that rich club organization represents a high-cost feature of brain architecture that puts a significant strain on brain resources. The high cost of the rich club may, however, be offset by significant functional benefits that the rich club confers to the brain network as a whole.

Modular-Level Functional Connectome Alterations in Individuals With Hallucinations Across the Psychosis Continuum.

Functional connectome alterations, including modular network organization, have been related to the experience of hallucinations. It remains to be determined whether individuals with hallucinations across the psychosis continuum exhibit similar alterations in modular brain network organization. This study assessed functional connectivity matrices of 465 individuals with and without hallucinations, including patients with schizophrenia and bipolar disorder, nonclinical individuals with hallucinations, and healthy controls. Modular brain network organization was examined at different scales of network resolution, including (1) global modularity measured as Qmax and Normalised Mutual Information (NMI) scores, and (2) within- and between-module connectivity. Global modular organization was not significantly altered across groups. However, alterations in within- and between-module connectivity were observed for higher-order cognitive (e.g., central-executive salience, memory, default mode), and sensory modules in patients with schizophrenia and nonclinical individuals with hallucinations relative to controls. Dissimilar patterns of altered within- and between-module connectivity were found bipolar disorder patients with hallucinations relative to controls, including the visual, default mode, and memory network, while connectivity patterns between visual, salience, and cognitive control modules were unaltered. Bipolar disorder patients without hallucinations did not show significant alterations relative to controls. This study provides evidence for alterations in the modular organization of the functional connectome in individuals prone to hallucinations, with schizophrenia patients and nonclinical individuals showing similar alterations in sensory and higher-order cognitive modules. Other higher-order cognitive modules were found to relate to hallucinations in bipolar disorder patients, suggesting differential neural mechanisms may underlie hallucinations across the psychosis continuum.

Altered working memory-related brain activity in children at familial high risk for psychosis: A preliminary study.

BACKGROUND: Schizophrenia spectrum disorders are heritable illnesses that usually manifest in early adulthood but are increasingly viewed as neurodevelopmental disorders. Functional magnetic resonance imaging (fMRI) studies show altered brain activity during performance of working memory (WM) tasks in both individuals with schizophrenia and their first-degree relatives as compared to healthy controls (HC). This study examined whether similar changes are already present in pre-adolescent children at familial high-risk (FHR) for psychosis. METHODS: 37 children (17 FHR, 20 HC) between 7 and 12 years old participated in this study. WM performance was assessed using the Wechsler Intelligence Scale for Children-IV (WISC-IV). To assess brain activation during WM performance, participants completed a visual block-designed n-back task with 2 conditions (2-back and 0-back) during scanning. fMRI data was preprocessed and analyzed using FSL Feat. RESULTS: Compared to HC, FHR children showed significantly lower WISC-IV WM scores. In addition, FHR children exhibited hypoactivation in the 2-back (versus 0-back) condition in a cluster encompassing bilateral precuneus and cuneus and right posterior cingulate cortex. There were no significant group-differences in n-back task performance and brain activation. The precuneus cluster was not correlated with n-back performance or WISC WM scores. CONCLUSIONS: The current results provide preliminary evidence of impaired WM function and altered brain activity during WM performance in children with a familial predisposition for psychosis. Longitudinal studies are needed to determine whether these findings are related to abnormal brain development and predictive of cognitive deficits and psychosis later in life.

Diffusion MRI derived free-water imaging measures in patients with schizophrenia and their non-psychotic siblings.

Free-water imaging is a diffusion MRI technique that separately models water diffusion hindered by fiber tissue and water that disperses freely in the extracellular space. Studies using this technique have shown that schizophrenia is characterized by a lower level of fractional anisotropy of the tissue compartment (FAt) and higher free-water fractional volume (FW). It is unknown, however, whether such abnormalities are an expression of pre-existing (genetic) risk for schizophrenia or a manifestation of the illness. To investigate the contribution of familial risk factors to white matter abnormalities, we used the free-water imaging technique to assess FAt and FW in a large cohort of 471 participants including 161 patients with schizophrenia, 182 non-psychotic siblings, and 128 healthy controls. In this sample, patients did not show significant differences in FAt as compared to controls, but did exhibit a higher level of FW relative to both controls and siblings in the left uncinate fasciculus, superior corona radiata and fornix / stria terminalis. This increase in FW was found to be related to, though not solely explained by, ventricular enlargement. Siblings did not show significant FW abnormalities. However, siblings did show a higher level of FAt as compared to controls and patients, in line with results of a previous study on the same data using conventional DTI. Taken together, our findings suggest that extracellular free-water accumulation in patients is likely a manifestation of established disease rather than an expression of familial risk for schizophrenia and that super-normal levels of FAt in unaffected siblings may reflect a compensatory process.

Hyperactivation of Posterior Default Mode Network During Self-Referential Processing in Children at Familial High-Risk for Psychosis.

Patients with schizophrenia spectrum disorders show disturbances in self-referential processing and associated neural circuits including the default mode network (DMN). These disturbances may precede the onset of psychosis and may underlie early social and emotional problems. In this study, we examined self-referential processing in a group of children (7-12 years) at familial high risk (FHR) for psychosis (N = 17), compared to an age and sex-matched group of healthy control (HC) children (N = 20). The participants were presented with a list of adjectives and asked to indicate whether or not the adjectives described them (self-reference condition) and whether the adjectives described a good or bad trait (semantic condition). Three participants were excluded due to chance-level performance on the semantic task, leaving N = 15 FHR and N = 19 HC for final analysis. Functional MRI (fMRI) was used to measure brain activation during self-referential vs. semantic processing. Internalizing and externalizing problems were assessed with the Child Behavior Checklist (CBCL). Evaluating main effects of task (self > semantic) showed activation of medial prefrontal cortex in HC and precuneus/posterior cingulate cortex (PCC) in FHR. Group-comparison yielded significant results for the FHR > HC contrast, showing two clusters of hyperactivation in precuneus/ PCC (p = 0.004) and anterior cerebellum / temporo-occipital cortex (p = 0.009). Greater precuneus/PCC activation was found to correlate with greater CBCL internalizing (r = 0.60, p = 0.032) and total (r = 0.69, p = 0.009) problems. In all, this study shows hyperactivity of posterior DMN during self-referential processing in pre-adolescent FHR children. This finding posits DMN-related disturbances in self-processing as a developmental brain abnormality associated with familial risk factors that predates not just psychosis, but also the prodromal stage. Moreover, our results suggest that early disturbances in self-referential processing may be related to internalizing problems in at-risk children.

The effects of antipsychotics on interactions of dynamic functional connectivity in the triple-network in first episode schizophrenia.

BACKGROUND: Brain dynamics abnormalities in the triple-network, which involves the salience network (SN), the default mode network (DMN) and the central executive network (CEN), have been reported in schizophrenia. However, it remains to be clarified how antipsychotics affect dynamic functional connectivity (DFC) within the triple-network and whether differences in clinical outcomes are associated with varying levels of network model dysfunction. METHODS: Resting-state functional magnetic resonance imaging scans were obtained from 64 first-episode schizophrenia patients (SZ) and 67 healthy controls (HC). All patients were scanned before and after 12-week antipsychotic treatment and the HC were scanned only at baseline. RESULTS: At baseline, SZ participants showed significantly reduced dynamic functional interactions across the triple-network compared to HC. The SZ group displayed a pattern of reduction in resting-state DFC among the triple-network compared with HC. After medication, the mean dynamic network interaction index (dNII) value was improved. A significant quadratic relation was observed between longitudinal change of mean dNII and the reduction ratio of PANSS total score within the SZ group. The DFC within inter-network (between DMN and SN, and between DMN and CEN) and intra-network connections of DMN were significantly higher relative to baseline. Intra-SN DFC, intra-DMN DFC and DFC between SN and DMN were found to be predictive of clinical features at baseline. Intra-CEN DFC and DFC between DMN and CEN were predictive of treatment response. CONCLUSIONS: Aberrant brain dynamics in the triple-network could be regulated with medication. DFC organization in the triple network was found to predict the clinical outcome.

Abnormal Function in Dentate Nuclei Precedes the Onset of Psychosis: A Resting-State fMRI Study in High-Risk Individuals.

OBJECTIVE: The cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions. We recently developed a new parcellation of the dentate nuclei (DN), the major output nuclei of the cerebellum, which optimally divides the structure into 3 functional territories that contribute uniquely to default-mode, motor-salience, and visual processing networks as indexed by resting-state functional connectivity (RsFc). Here we test for the first time whether RsFc differences in the DN, precede the onset of psychosis in individuals at risk of developing schizophrenia. METHODS: We used the magnetic resonance imaging (MRI) dataset from the Shanghai At Risk for Psychosis study that included subjects at high risk to develop schizophrenia (N = 144), with longitudinal follow-up to determine which subjects developed a psychotic episode within 1 year of their functional magnetic resonance imaging (fMRI) scan (converters N = 23). Analysis used the 3 functional parcels (default-mode, salience-motor, and visual territory) from the DN as seed regions of interest for whole-brain RsFc analysis. RESULTS: RsFc analysis revealed abnormalities at baseline in high-risk individuals who developed psychosis, compared to high-risk individuals who did not develop psychosis. The nature of the observed abnormalities was found to be anatomically specific such that abnormal RsFc was localized predominantly in cerebral cortical networks that matched the 3 functional territories of the DN that were evaluated. CONCLUSIONS: We show for the first time that abnormal RsFc of the DN may precede the onset of psychosis. This new evidence highlights the role of the cerebellum as a potential target for psychosis prediction and prevention.

Functional connectome differences in individuals with hallucinations across the psychosis continuum.

Hallucinations may arise from an imbalance between sensory and higher cognitive brain regions, reflected by alterations in functional connectivity. It is unknown whether hallucinations across the psychosis continuum exhibit similar alterations in functional connectivity, suggesting a common neural mechanism, or whether different mechanisms link to hallucinations across phenotypes. We acquired resting-state functional MRI scans of 483 participants, including 40 non-clinical individuals with hallucinations, 99 schizophrenia patients with hallucinations, 74 bipolar-I disorder patients with hallucinations, 42 bipolar-I disorder patients without hallucinations, and 228 healthy controls. The weighted connectivity matrices were compared using network-based statistics. Non-clinical individuals with hallucinations and schizophrenia patients with hallucinations exhibited increased connectivity, mainly among fronto-temporal and fronto-insula/cingulate areas compared to controls (P < 0.001 adjusted). Differential effects were observed for bipolar-I disorder patients with hallucinations versus controls, mainly characterized by decreased connectivity between fronto-temporal and fronto-striatal areas (P = 0.012 adjusted). No connectivity alterations were found between bipolar-I disorder patients without hallucinations and controls. Our results support the notion that hallucinations in non-clinical individuals and schizophrenia patients are related to altered interactions between sensory and higher-order cognitive brain regions. However, a different dysconnectivity pattern was observed for bipolar-I disorder patients with hallucinations, which implies a different neural mechanism across the psychosis continuum.

Neuroimaging in Schizophrenia.

Schizophrenia is a chronic psychotic disorder with a lifetime prevalence of about 1%. Onset is typically in adolescence or early adulthood; characteristic symptoms include positive symptoms, negative symptoms, and impairments in cognition. Neuroimaging studies have shown substantive evidence of brain structural, functional, and neurochemical alterations that are more pronounced in the association cortex and subcortical regions. These abnormalities are not sufficiently specific to be of diagnostic value, but there may be a role for imaging techniques to provide predictions of outcome. Incorporating multimodal imaging datasets using machine learning approaches may offer better diagnostic and predictive value in schizophrenia.

Altered resting-state functional connectivity in young children at familial high risk for psychotic illness: A preliminary study.

Multiple lines of evidence suggest that illness development in schizophrenia and other psychotic disorders predates the first psychotic episode by many years. In this study, we examined a sample of 15 pre-adolescent children, ages 7 through 12 years, who are at familial high-risk (FHR) because they have a parent or sibling with a history of schizophrenia or related psychotic disorder. Using multi-voxel pattern analysis (MVPA), a data-driven fMRI analysis, we assessed whole-brain differences in functional connectivity in the FHR sample as compared to an age- and sex-matched control (CON) group of 15 children without a family history of psychosis. MVPA analysis yielded a single cluster in right posterior superior temporal gyrus (pSTG/BA 22) showing significant group-differences in functional connectivity. Post-hoc characterization of this cluster through seed-to-voxel analysis revealed mostly reduced functional connectivity of the pSTG seed to a set of language and default mode network (DMN) associated brain regions including Heschl's gyrus, inferior temporal gyrus extending into fusiform gyrus, (para)hippocampus, thalamus, and a cerebellar cluster encompassing mainly Crus I/II. A height-threshold of whole-brain p < .001 (two-sided), and FDR-corrected cluster-threshold of p < .05 (non-parametric statistics) was used for post-hoc characterization. These findings suggest that abnormalities in functional communication in a network encompassing right STG and associated brain regions are present before adolescence in at-risk children and may be a risk marker for psychosis. Subsequent changes in this functional network across development may contribute to either disease manifestation or resilience in children with a familial vulnerability for psychosis.

Brain functional connectivity data enhance prediction of clinical outcome in youth at risk for psychosis.

The first episode of psychosis is typically preceded by a prodromal phase with subthreshold symptoms and functional decline. Improved outcome prediction in this stage is needed to allow targeted early intervention. This study assesses a combined clinical and resting-state fMRI prediction model in 137 adolescents and young adults at Clinical High Risk (CHR) for psychosis from the Shanghai At Risk for Psychosis (SHARP) program. Based on outcome at one-year follow-up, participants were separated into three outcome categories including good outcome (symptom remission, N = 71), intermediate outcome (ongoing CHR symptoms, N = 30), and poor outcome (conversion to psychosis or treatment-refractory, N = 36). Validated clinical predictors from the psychosis-risk calculator were combined with measures of resting-state functional connectivity. Using multinomial logistic regression analysis and leave-one-out cross-validation, a clinical-only prediction model did not achieve a significant level of outcome prediction (F1 = 0.32, p = .154). An imaging-only model yielded a significant prediction model (F1 = 0.41, p = .016), but a combined model including both clinical and connectivity measures showed the best performance (F1 = 0.46, p < .001). Influential predictors in this model included functional decline, verbal learning performance, a family history of psychosis, default-mode and frontoparietal within-network connectivity, and between-network connectivity among language, salience, dorsal attention, sensorimotor, and cerebellar networks. These findings suggest that brain changes reflected by alterations in functional connectivity may be useful for outcome prediction in the prodromal stage.

Interhemispheric connectivity and hemispheric specialization in schizophrenia patients and their unaffected siblings.

Hemispheric integration and specialization are two prominent organizational principles for macroscopic brain function. Impairments of interhemispheric cooperation have been reported in schizophrenia patients, but whether such abnormalities should be attributed to effects of illness or familial risk remains inconclusive. Moreover, it is unclear how abnormalities in interhemispheric connectivity impact hemispheric specialization. To address these questions, we performed magnetic resonance imaging (MRI) in a large cohort of 253 participants, including 84 schizophrenia patients, 106 of their unaffected siblings and 63 healthy controls. Interhemispheric connectivity and hemispheric specialization were calculated from resting-state functional connectivity, and compared across groups. Results showed that schizophrenia patients exhibit lower interhemispheric connectivity as compared to controls and siblings. In addition, patients showed higher levels of hemispheric specialization as compared to siblings. Level of interhemispheric connectivity and hemispheric specialization correlated with duration of illness in patients. No significant alterations were identified in siblings relative to controls on both measurements. Furthermore, alterations in interhemispheric connectivity correlated with changes in hemispheric specialization in patients relative to controls and siblings. Taken together, these results suggest that lower interhemispheric connectivity and associated abnormalities in hemispheric specialization are features of established illness, rather than an expression of preexistent familial risk for schizophrenia.

Connectome development and a novel extension to the neurodevelopmental model of schizophrenia.

The brain is the ultimate adaptive system, a complex network organized across multiple levels of spatial and temporal resolution that is sculpted over several decades via its interactions with the environment. This review sets out to examine how fundamental biological processes in early and late neurodevelopment, in interaction with environmental inputs, guide the formation of the brain's network and its ongoing reorganization throughout the course of development. Moreover, we explore how disruptions in these processes could lead to abnormal brain network architecture and organization and thereby give rise to schizophrenia. Arguing that the neurodevelopmental trajectory leading up to the manifestation of psychosis may best be understood from the sequential trajectory of connectome formation and maturation, we propose a novel extension to the neurodevelopmental model of the illness that posits that schizophrenia is a disorder of connectome development.

El cerebro es el útimo sistema de adaptación, una red compleja organizada en múltiples niveles de resolución espacial y temporal que se ha esculpido durante varias décadas a través de sus interacciones con el medio ambiente. Esta revisión se propone examinar cómo los procesos biológicos fundamentales en el neurodesarrollo precoz y tardío, al interactuar con los estímulos ambientales, guían la formación de la red cerebral y su reorganización permanente a lo largo del curso del desarrollo. Además, se explora la forma cómo las alteraciones en estos procesos podrían llevar a una anomalía en la arquitectura y en la organización de la red cerebral, y así facilitar la aparición de la esquizofrenia. Se argumenta que la trayectoria del neurodesarrollo que conduce a la manifestación de la psicosis se puede entender mejor a partir de la trayectoria secuencial de la formación y maduración del conectoma, y se propone una nueva extensión para el modelo del neurodesarrollo de la enferme-dad, que postula que la esquizofrenia es un trastorno del desarrollo del conectoma.

Le cerveau est le système adaptatif par excellence, un réseau complexe organisé en plusieurs niveaux de résolution temporelle et spatiale, sculpté au fil des décennies par ses interactions avec l'environnement. Cet article examine comment les processus biologiques fondamentaux guident la formation du réseau cérébral et sa réorganisation continue au cours de l'évolution, dans le développement neuronal précoce et tardif, en interaction avec des aspects environnementaux. De plus, nous analysons comment des perturbations de ces processus peuvent conduire à une organisation et une architecture anormales du réseau cérébral et ainsi conduire à la schizophrénie. Nous proposons une extension nouvelle au modèle neurodéveloppemental de la maladie qui stipule que la schizophrénie est un trouble de développement du connectome, en soutenant que la trajectoire neurodéveloppementale conduisant à la manifestation de la psychose peut être mieux comprise à partir de la trajectoire séquentielle de formation et de maturation du connectome.

Cortical magnetization transfer abnormalities and connectome dysconnectivity in schizophrenia.

Macroscale dysconnectivity in schizophrenia is associated with neuropathological abnormalities. The extent to which alterations in cortical myelination as revealed in vivo by magnetization transfer ratio (MTR) are related to macroscale dysconnectivity remains unknown. We acquired magnetization transfer imaging (MTI) data and diffusion weighted imaging (DWI) data from 78 schizophrenia patients and 93 healthy controls for MTR extraction and connectome reconstruction to examine the possible link between cortical myelination and macroscale dysconnectivity. Our findings showed significant cortical MTR disruptions in several prefrontal areas in schizophrenia patients, including bilateral rostral middle frontal areas, right pars orbitalis, and right frontal pole. Furthermore, cortical MTR alterations between patients and controls were significantly correlated with the level of regional disconnectivity. Together, our findings provide evidence that microstructural neuropathological abnormalities in schizophrenia are predominately present in prefrontal areas of the cortex and are associated with alterations in structural connectome architecture at the whole brain network level.