Duloxetine effects on striatal resting‐state functional connectivity in patients with major depressive disorder

Reward deficits and associated striatal circuitry disturbances have been implicated in the onset and progression of major depressive disorder (MDD). However, no studies have been conducted to investigate how the striatal circuitry changes during standard antidepressant, which is important for development of novel and targeted treatments for MDD. We examined the seed‐to‐whole‐brain functional connectivity (FC) for six striatal subregions based on resting‐state fMRI data of 23 MDD patients before and after 8‐week duloxetine, a serotonin, and noradrenaline reuptake inhibitor. Twenty‐three healthy controls (HCs) were also scanned twice with an 8‐week interval. After the analysis of covariance, we observed significant group‐by‐time interaction on FC of the dorsal caudate (DC), ventral striatum (VS), and putamen seeds. Post hoc analyses revealed that the FC between several right striatal seeds and left superior frontal gyrus (SFG), between right DC and left precuneus, between right superior VS and left inferior parietal lobe, were significantly higher in MDD patients compared to HCs at baseline and were reduced after treatment. Conversely, the FC between right inferior VS and left cerebellum was lower in MDD patients and was increased after treatment. Patients with larger reduction in right superior VS—left SFG FC exhibited larger alleviation of rumination. These findings suggest that duloxetine modulates the striatal FC with dorsolateral prefrontal cortex, posterior default mode network, and cerebellum, and partly, these changes underlie symptomatic improvement. This study adds to our understanding of antidepressant mechanism and future therapeutic development might benefit from considering these striatal circuitry as potential targets.     

Overlapping and segregated resting‐state functional connectivity in patients with major depressive disorder with and without childhood neglect

Many studies have suggested that childhood maltreatment increase risk of adulthood major depressive disorder (MDD) and predict its unfavorable treatment outcome, yet the neural underpinnings associated with childhood maltreatment in MDD remain poorly understood. Here, we seek to investigate the whole‐brain functional connectivity patterns in MDD patients with childhood maltreatment. Resting‐state functional magnetic resonance imaging was used to explore intrinsic or spontaneous functional connectivity networks of 18 MDD patients with childhood neglect, 20 MDD patients without childhood neglect, and 20 healthy controls. Whole‐brain functional networks were constructed by measuring the temporal correlations of every pairs of brain voxels and were further analyzed by using graph‐theory approaches. Relative to the healthy control group, the two MDD patient groups showed overlapping reduced functional connectivity strength in bilateral ventral medial prefrontal cortex/ventral anterior cingulate cortex. However, compared with MDD patients without a history of childhood maltreatment, those patients with such a history displayed widespread reduction of functional connectivity strength primarily in brain regions within the prefrontal‐limbic‐thalamic‐cerebellar circuitry, and these reductions significantly correlated with measures of childhood neglect. Together, we showed that the MDD groups with and without childhood neglect exhibited overlapping and segregated functional connectivity patterns in the whole‐brain networks, providing empirical evidence for the contribution of early life stress to the pathophysiology of MDD. Hum Brain Mapp 35:1154–1166, 2014. © 2013 Wiley Periodicals, Inc.     

Alterations in amplitude of low frequency fluctuation in treatment‐naïve major depressive disorder measured with resting‐state fMRI

There are limited resting‐state functional magnetic resonance imaging (fMRI) studies in major depressive disorder (MDD). Of these studies, functional connectivity analyses are mostly used. However, a new method based on the magnitude of low frequency fluctuation (LFF) during resting‐state fMRI may provide important insight into MDD. In this study, we examined the amplitude of LFF (ALFF) within the whole brain during resting‐state fMRI in 30 treatment‐naïve MDD subjects and 30 healthy control (HC) subjects. When compared with HC, MDD subjects showed increased ALFF in the frontal cortex (including the bilateral ventral/dorsal anterior cingulate cortex, orbitofrontal cortex, premotor cortex, ventral prefrontal cortex, left dorsal lateral frontal cortex, left superior frontal cortex), basal ganglia (including the right putamen and left caudate nucleus), left insular cortex, right anterior entorhinal cortex and left inferior parietal cortex, together with decreased ALFF in the bilateral occipital cortex, cerebellum hemisphere, and right superior temporal cortex. These findings may relate to characteristics of MDD, such as excessive self‐referential processing and deficits in cognitive control of emotional processing, which may contribute to the persistent and recurrent nature of the disorder. Hum Brain Mapp 35:4979–4988, 2014. © 2014 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Large‐scale dynamic causal modeling of major depressive disorder based on resting‐state functional magnetic resonance imaging

Major depressive disorder (MDD) is a serious mental illness characterized by dysfunctional connectivity among distributed brain regions. Previous connectome studies based on functional magnetic resonance imaging (fMRI) have focused primarily on undirected functional connectivity and existing directed effective connectivity (EC) studies concerned mostly task‐based fMRI and incorporated only a few brain regions. To overcome these limitations and understand whether MDD is mediated by within‐network or between‐network connectivities, we applied spectral dynamic causal modeling to estimate EC of a large‐scale network with 27 regions of interests from four distributed functional brain networks (default mode, executive control, salience, and limbic networks), based on large sample‐size resting‐state fMRI consisting of 100 healthy subjects and 100 individuals with first‐episode drug‐naive MDD. We applied a newly developed parametric empirical Bayes (PEB) framework to test specific hypotheses. We showed that MDD altered EC both within and between high‐order functional networks. Specifically, MDD is associated with reduced excitatory connectivity mainly within the default mode network (DMN), and between the default mode and salience networks. In addition, the network‐averaged inhibitory EC within the DMN was found to be significantly elevated in the MDD. The coexistence of the reduced excitatory but increased inhibitory causal connections within the DMNs may underlie disrupted self‐recognition and emotional control in MDD. Overall, this study emphasizes that MDD could be associated with altered causal interactions among high‐order brain functional networks.     

Linking resting‐state networks and social cognition in schizophrenia and bipolar disorder

Individuals with schizophrenia and bipolar disorder show alterations in functional neural connectivity during rest. However, resting‐state network (RSN) disruptions have not been systematically compared between the two disorders. Further, the impact of RSN disruptions on social cognition, a key determinant of functional outcome, has not been studied. Forty‐eight individuals with schizophrenia, 46 with bipolar disorder, and 48 healthy controls completed resting‐state functional magnetic resonance imaging. An atlas‐based approach was used to examine functional connectivity within nine RSNs across the cortex. RSN connectivity was assessed via nonparametric permutation testing, and associations with performance on emotion perception, mentalizing, and emotion management tasks were examined. Group differences were observed in the medial and lateral visual networks and the sensorimotor network. Individuals with schizophrenia demonstrated reduced connectivity relative to healthy controls in all three networks. Individuals with bipolar disorder demonstrated reduced connectivity relative to controls in the medial visual network and connectivity within this network was significantly positively correlated with emotion management. In healthy controls, connectivity within the medial and lateral visual networks positively correlated with mentalizing. No significant correlations were found for either visual network in schizophrenia. Results highlight the role of altered early visual processing in social cognitive deficits in both schizophrenia and bipolar disorder. However, individuals with bipolar disorder appear to compensate for disrupted visual network connectivity on social cognitive tasks, whereas those with schizophrenia do not. The current study adds clarity on the neurophysiology underlying social cognitive deficits that result in impaired functioning in serious mental illness.     

Altered functional network architecture in orbitofronto‐striato‐thalamic circuit of unmedicated patients with obsessive‐compulsive disorder

Dysfunction of corticostriatal loops has been proposed to underlie certain cognitive and behavioral problems associated with various neuropsychiatric disorders, such as obsessive‐compulsive disorder (OCD) characterized by repetitive, unwanted thoughts, and behaviors. Although functional abnormalities in the loops involving the orbitofronto‐striato‐thalamic (OFST) circuitry in patients with OCD have been reported, our understanding of a link between disruptions in the architecture of the intrinsic functional network of the OFST circuit and their symptoms remain incomplete. Using resting‐state functional MRI in conjunction with unsupervised clustering and multilevel functional connectivity (FC) techniques, FC of the OFST network and its topological organization in 61 OCD patients versus 61 matched controls were characterized. Patients exhibited disruptions in small‐world properties of the OFST circuit, which indicates an imbalance between functional integration and segregation. Patients also showed decreased FC between the central orbitofrontal cortex and dorsomedial striatum but increased FC between the medial thalamus and striatal areas. Using one of the largest samples of unmedicated OCD patients to date, our findings provide evidence supporting the OFST dysconnection hypothesis in OCD as a basic pathophysiological mechanism underlying the disorder, showing the disruption of FC between specific cortical, striatal, and thalamic clusters and aberrant topological patterns of the OFST circuit. Hum Brain Mapp 38:109–119, 2017. © 2016 Wiley Periodicals, Inc.     

Functionally linked resting‐state networks reflect the underlying structural connectivity architecture of the human brain

During rest, multiple cortical brain regions are functionally linked forming resting‐state networks. This high level of functional connectivity within resting‐state networks suggests the existence of direct neuroanatomical connections between these functionally linked brain regions to facilitate the ongoing interregional neuronal communication. White matter tracts are the structural highways of our brain, enabling information to travel quickly from one brain region to another region. In this study, we examined both the functional and structural connections of the human brain in a group of 26 healthy subjects, combining 3 Tesla resting‐state functional magnetic resonance imaging time‐series with diffusion tensor imaging scans. Nine consistently found functionally linked resting‐state networks were retrieved from the resting‐state data. The diffusion tensor imaging scans were used to reconstruct the white matter pathways between the functionally linked brain areas of these resting‐state networks. Our results show that well‐known anatomical white matter tracts interconnect at least eight of the nine commonly found resting‐state networks, including the default mode network, the core network, primary motor and visual network, and two lateralized parietal‐frontal networks. Our results suggest that the functionally linked resting‐state networks reflect the underlying structural connectivity architecture of the human brain. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Altered intra‐ and inter‐network functional coupling of resting‐state networks associated with motor dysfunction in stroke

Motor functions are supported through functional integration across the extended motor system network. Individuals following stroke often show deficits on motor performance requiring coordination of multiple brain networks; however, the assessment of connectivity patterns after stroke was still unclear. This study aimed to investigate the changes in intra‐ and inter‐network functional connectivity (FC) of multiple networks following stroke and further correlate FC with motor performance. Thirty‐three left subcortical chronic stroke patients and 34 healthy controls underwent resting‐state functional magnetic resonance imaging. Eleven resting‐state networks were identified via independent component analysis (ICA). Compared with healthy controls, the stroke group showed abnormal FC within the motor network (MN), visual network (VN), dorsal attention network (DAN), and executive control network (ECN). Additionally, the FC values of the ipsilesional inferior parietal lobule (IPL) within the ECN were negatively correlated with the Fugl‐Meyer Assessment (FMA) scores (hand + wrist). With respect to inter‐network interactions, the ipsilesional frontoparietal network (FPN) decreased FC with the MN and DAN; the contralesional FPN decreased FC with the ECN, but it increased FC with the default mode network (DMN); and the posterior DMN decreased FC with the VN. In sum, this study demonstrated the coexistence of intra‐ and inter‐network alterations associated with motor‐visual attention and high‐order cognitive control function in chronic stroke, which might provide insights into brain network plasticity following stroke.     

Altered resting‐state activity in seasonal affective disorder

At present, our knowledge about seasonal affective disorder (SAD) is based mainly up on clinical symptoms, epidemiology, behavioral characteristics and light therapy. Recently developed measures of resting‐state functional brain activity might provide neurobiological markers of brain disorders. Studying functional brain activity in SAD could enhance our understanding of its nature and possible treatment strategies. Functional network connectivity (measured using ICA‐dual regression), and amplitude of low‐frequency fluctuations (ALFF) were measured in 45 antidepressant‐free patients (39.78 ± 10.64, 30 ♀, 15 ♂) diagnosed with SAD and compared with age‐, gender‐ and ethnicity‐matched healthy controls (HCs) using resting‐state functional magnetic resonance imaging. After correcting for Type 1 error at high model orders (inter‐RSN correction), SAD patients showed significantly increased functional connectivity in 11 of the 47 identified RSNs. Increased functional connectivity involved RSNs such as visual, sensorimotor, and attentional networks. Moreover, our results revealed that SAD patients compared with HCs showed significant higher ALFF in the visual and right sensorimotor cortex. Abnormally altered functional activity detected in SAD supports previously reported attentional and psychomotor symptoms in patients suffering from SAD. Further studies, particularly under task conditions, are needed in order to specifically investigate cognitive deficits in SAD. Hum Brain Mapp 35:161–172, 2014. © 2012 Wiley Periodicals, Inc.     

Evaluation of the spatial variability in the major resting‐state networks across human brain functional atlases

The human brain is intrinsically organized into resting‐state networks (RSNs). Currently, several human brain functional atlases are used to define the spatial constituents of these RSNs. However, there are significant concerns about interatlas variability. In response, we undertook a quantitative comparison of the five major RSNs (default mode [DMN], salience, central executive, sensorimotor, and visual networks) across currently available brain functional atlases (n = 6) in which we demonstrated that (a) similarity between atlases was modest and positively linked to the size of the sample used to construct them; (b) across atlases, spatial overlap among major RSNs ranged between 17 and 76% (mean = 39%), which resulted in variability in their functional connectivity; (c) lower order RSNs were generally spatially conserved across atlases; (d) among higher order RSNs, the DMN was the most conserved across atlases; and (e) voxel‐wise flexibility (i.e., the likelihood of a voxel to change network assignment across atlases) was high for subcortical regions and low for the sensory, motor and medial prefrontal cortices, and the precuneus. In order to facilitate RSN reproducibility in future studies, we provide a new freely available Consensual Atlas of REsting‐state Networks, based on the most reliable atlases.     

Genetic influences on resting‐state functional networks: A twin study

Alterations in resting‐state networks (RSNs) are often associated with psychiatric and neurologic disorders. Given this critical linkage, it has been hypothesized that RSNs can potentially be used as endophenotypes for brain diseases. To validate this notion, a critical step is to show that RSNs exhibit heritability. However, the investigation of the genetic basis of RSNs has only been attempted in the default‐mode network at the region‐of‐interest level, while the genetic control on other RSNs has not been determined yet. Here, we examined the genetic and environmental influences on eight well‐characterized RSNs using a twin design. Resting‐state functional magnetic resonance imaging data in 56 pairs of twins were collected. The genetic and environmental effects on each RSN were estimated by fitting the functional connectivity covariance of each voxel in the RSN to the classic ACE twin model. The data showed that although environmental effects accounted for the majority of variance in wide‐spread areas, there were specific brain sites that showed significant genetic control for individual RSNs. These results suggest that part of the human brain functional connectome is shaped by genomic constraints. Importantly, this information can be useful for bridging genetic analysis and network‐level assessment of brain disorders. Hum Brain Mapp 36:3959–3972, 2015. © 2015 Wiley Periodicals, Inc.     

Improved correspondence of resting‐state networks after macroanatomical alignment

Resting state brain activity, as measured with functional magnetic resonance imaging (fMRI) in the absence of stimulation, is widely investigated in clinical, pharmacological, developmental and cross‐species neuroscience research. However, despite the general and broad interest in understating the nature of resting state networks (RSNs), there has not been a thorough investigation into the relationship between these functional networks and their adherence to underling brain anatomy. We acquired resting state fMRI data from 10 subjects and extracted individual and group RSN maps respectively using independent component analysis (ICA) and self organising group‐level ICA (sogICA). Cortex based alignment (CBA), an advanced surface based alignment technique which uses individual curvature information to align individual subjects' brains to a dynamic group average, was used to maximise anatomical correspondence across subjects. Cross subject spatial correlations of the RSN maps (independent components) were carried out with and without CBA. Seven RSNs, which are amongst the most reported and studied networks, were identified. We observed a systematic gain in the spatial correlation in all of them following CBA, although this gain was not uniform across RSNs. The observed increase in similarity of the functional RSNs after anatomical alignment illustrates that these functional networks are indeed related to underlying macroanatomical features. Moreover, our results demonstrate that by correcting for individual anatomical differences, advanced surface based alignment techniques increase the overlap of corresponding resting state networks across subjects, thereby providing a useful means to improve resting state group statistics with no need for substantial smoothing. Hum Brain Mapp 35:673–682, 2014. © 2012 Wiley Periodicals, Inc.     

Apolipoprotein E ε4 modulates functional brain connectome in Alzheimer's disease

The apolipoprotein E (APOE) ?4 allele is a well‐established genetic risk factor for Alzheimer's disease (AD). Recent research has demonstrated an APOE ?4‐mediated modulation of intrinsic functional brain networks in cognitively normal individuals. However, it remains largely unknown whether and how APOE ?4 affects the brain's functional network architecture in patients with AD. Using resting‐state functional MRI and graph‐theory approaches, we systematically investigated the topological organization of whole‐brain functional networks in 16 APOE ?4 carriers and 26 matched noncarriers with AD at three levels: global whole‐brain, intermediate module, and regional node/connection. Neuropsychological analysis showed that the APOE ?4 carriers performed worse on delayed memory but better on a late item generation of a verbal fluency task (associated with executive function) than noncarriers. Whole‐brain graph analyses revealed that APOE ?4 significantly disrupted whole‐brain topological organization as characterized by (i) reduced parallel information transformation efficiency; (ii) decreased intramodular connectivity within the posterior default mode network (pDMN) and intermodular connectivity of the pDMN and executive control network (ECN) with other neuroanatomical systems; and (iii) impaired functional hubs and their rich‐club connectivities that primarily involve the pDMN, ECN, and sensorimotor systems. Further simulation analysis indicated that these altered connectivity profiles of the pDMN and ECN largely accounted for the abnormal global network topology. Finally, the changes in network topology exhibited significant correlations with the patients' cognitive performances. Together, our findings suggest that the APOE genotype modulates large‐scale brain networks in AD and shed new light on the gene‐connectome interaction in this disease. Hum Brain Mapp 36:1828–1846, 2015. © 2015 Wiley Periodicals, Inc .     

Preprocessing strategy influences graph‐based exploration of altered functional networks in major depression

Resting‐state fMRI studies have gained widespread use in exploratory studies of neuropsychiatric disorders. Graph metrics derived from whole brain functional connectivity studies have been used to reveal disease‐related variations in many neuropsychiatric disorders including major depression (MDD). These techniques show promise in developing diagnostics for these often difficult to identify disorders. However, the analysis of resting‐state datasets is increasingly beset by a myriad of approaches and methods, each with underlying assumptions. Choosing the most appropriate preprocessing parameters a priori is difficult. Nevertheless, the specific methodological choice influences graph‐theoretical network topologies as well as regional metrics. The aim of this study was to systematically compare different preprocessing strategies by evaluating their influence on group differences between healthy participants (HC) and depressive patients. We thus investigated the effects of common preprocessing variants, including global mean‐signal regression (GMR), temporal filtering, detrending, and network sparsity on group differences between brain networks of HC and MDD patients measured by global and nodal graph theoretical metrics. Occurrence of group differences in global metrics was absent in the majority of tested preprocessing variants, but in local graph metrics it is sparse, variable, and highly dependent on the combination of preprocessing variant and sparsity threshold. Sparsity thresholds between 16 and 22% were shown to have the greatest potential to reveal differences between HC and MDD patients in global and local network metrics. Our study offers an overview of consequences of methodological decisions and which neurobiological characteristics of MDD they implicate, adding further caution to this rapidly growing field. Hum Brain Mapp 37:1422‐1442, 2016. © 2016 Wiley Periodicals, Inc.     

Sex‐related differences in resting‐state brain activity and connectivity in the orbital frontal cortex and insula in patients with functional constipation

Functional magnetic resonance imaging (fMRI) has been used to investigate sex‐related differences in brain abnormalities in patients with irritable bowel syndrome (IBS). Like IBS, women with functional constipation (FC) are 2.1 times as many as men. No study has been performed yet to examine sex‐related differences in brain activity and connectivity in patients with FC. Here, we employed resting‐state fMRI with amplitude of low‐frequency fluctuation (ALFF) to investigate brain functional differences in 51 patients with FC (34 females) and 52 healthy controls (34 females). Results showed abdominal pain and abdominal distension correlated with trait (TAI) and state (SAI) anxiety ratings in the female FC group, and abdominal distension correlated with sensation of incomplete evacuation in the male FC group. Two‐way ANOVA revealed sex effects on ALFF in precentral gyrus, thalamus, insula (INS), and orbital frontal cortex (OFC, P_FWE < 0.05). Post hoc test showed that the female FC group had lower ALFF than males in these brain regions (P < 0.01), and ALFF in INS and OFC was correlated with abdominal pain and difficulty of defecation, respectively. Seed voxel correlation analysis showed that the female FC group had weaker connectivity than males between INS and lateral OFC (lOFC). INS‐lOFC connectivity was negatively correlated with the anxiety score in the female FC group and was negatively correlated with abdominal distension in the male FC group. These findings provide the first insight into sex‐related differences in patients with FC and highlight that INS and OFC play an important role in modulating the intrinsic functional connectivity of the resting brain network showing that this role is influenced by sex.     

Corticostriatal connectivity fingerprints: Probability maps based on resting‐state functional connectivity

Over the last decade, structure–function relationships have begun to encompass networks of brain areas rather than individual structures. For example, corticostriatal circuits have been associated with sensorimotor, limbic, and cognitive information processing, and damage to these circuits has been shown to produce unique behavioral outcomes in Autism, Parkinson's Disease, Schizophrenia and healthy ageing. However, it remains an open question how abnormal or absent connectivity can be detected at the individual level. Here, we provide a method for clustering gross morphological structures into subregions with unique functional connectivity fingerprints, and generate network probability maps usable as a baseline to compare individual cases against. We used connectivity metrics derived from resting‐state fMRI (N = 100), in conjunction with hierarchical clustering methods, to parcellate the striatum into functionally distinct clusters. We identified three highly reproducible striatal subregions, across both hemispheres and in an independent replication dataset (N = 100) (dice‐similarity values 0.40–1.00). Each striatal seed region resulted in a highly reproducible distinct connectivity fingerprint: the putamen showed predominant connectivity with cortical and cerebellar sensorimotor and language processing areas; the ventromedial striatum cluster had a distinct limbic connectivity pattern; the caudate showed predominant connectivity with the thalamus, frontal and occipital areas, and the cerebellum. Our corticostriatal probability maps agree with existing connectivity data in humans and non‐human primates, and showed a high degree of replication. We believe that these maps offer an efficient tool to further advance hypothesis driven research and provide important guidance when investigating deviant connectivity in neurological patient populations suffering from e.g., stroke or cerebral palsy. Hum Brain Mapp 38:1478–1491, 2017. © 2016 Wiley Periodicals, Inc.     

Changes in resting‐state functionally connected parietofrontal networks after videogame practice

Neuroimaging studies provide evidence for organized intrinsic activity under task‐free conditions. This activity serves functionally relevant brain systems supporting cognition. Here, we analyze changes in resting‐state functional connectivity after videogame practice applying a test–retest design. Twenty young females were selected from a group of 100 participants tested on four standardized cognitive ability tests. The practice and control groups were carefully matched on their ability scores. The practice group played during two sessions per week across 4 weeks (16 h total) under strict supervision in the laboratory, showing systematic performance improvements in the game. A group independent component analysis (GICA) applying multisession temporal concatenation on test–retest resting‐state fMRI, jointly with a dual‐regression approach, was computed. Supporting the main hypothesis, the key finding reveals an increased correlated activity during rest in certain predefined resting state networks (albeit using uncorrected statistics) attributable to practice with the cognitively demanding tasks of the videogame. Observed changes were mainly concentrated on parietofrontal networks involved in heterogeneous cognitive functions. Hum Brain Mapp 34:3143–3157, 2013. © 2012 Wiley Periodicals, Inc.