Publications

1. Preprints
2. Journal articles
3. Conference proceedings
4. Book chapters

Preprints

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  Bayrak Ş, Khalil AA, Villringer K, Fiebach JB, Villringer A, Margulies DS, Ovadia-Caro S (2018)
  The impact of ischemic stroke on connectivity gradients
  bioRxiv
  
  

  Understanding the relationship between localized anatomical damage, reorganization, and functional deficits is a major challenge in stroke research. Previous work has shown that localized lesions cause widespread functional connectivity alterations in structurally intact areas, thereby affecting a whole network of interconnected regions. Recent advances suggest an alternative to discrete functional networks by describing a connectivity space based on a low-dimensional embedding of the full connectivity matrix. The dimensions of this space, described as connectivity gradients, capture the similarity of areas’ connections along a continuous space. Here, we defined a three-dimensional connectivity space template based on functional connectivity data from healthy controls. By projecting lesion locations into this space, we demonstrate that ischemic strokes resulted in dimension-specific alterations in functional connectivity over the first week after symptoms onset. Specifically, changes in functional connectivity were captured along connectivity Gradients 1 and 3. The degree of change in functional connectivity was determined by the distance from the lesion along these connectivity gradients regardless of the anatomical distance from the lesion. Together, these results provide a novel framework to study reorganization after stroke and suggest that, rather than only impacting on anatomically proximate areas, the indirect effects of ischemic strokes spread along the brain relative to the space defined by its connectivity.

  
  

Journal articles

2019

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  Turnbull A, Wang H-T, Schooler JW, Jefferies E, Margulies DS, Smallwood J (2019)
  The ebb and flow of attention: Between-subject variation in intrinsic connectivity and cognition associated with the dynamics of ongoing experience
  Neuroimage 185: 286–299
  
  

  Cognition is dynamic, allowing us the flexibility to shift focus from different aspects of the environment, or between internally- and externally-oriented trains of thought. Although we understand how individuals switch attention across different tasks, the neurocognitive processes that underpin the dynamics of less constrained elements of cognition are less well understood. To explore this issue, we developed a paradigm in which participants intermittently responded to external events across two conditions that systematically vary in their need for updating working memory based on information in the external environment. This paradigm distinguishes the influences on cognition that emerge because of demands placed by the task (sustained) from changes that result from the time elapsed since the last task response (transient). We used experience sampling to identify dynamic changes in ongoing cognition in this paradigm, and related between subject variation in these measures to variations in the intrinsic organisation of large-scale brain networks. We found systems important for attention were involved in the regulation of off-task thought. Coupling between the ventral attention network and regions of primary motor cortex was stronger for individuals who were able to regulate off-task thought in line with the demands of the task. This pattern of coupling was linked to greater task-related thought when environmental demands were high and elevated off-task thought when demands were low. In contrast, the coupling of the dorsal attention network with a region of lateral visual cortex was stronger for individuals for whom off-task thoughts transiently increased with the time since responding to the external world increased. This pattern is consistent with a role for this system in the time-limited top-down biasing of visual processing to increase behavioural efficiency. Unlike the attention networks, coupling between regions of the default mode network and dorsal occipital cortex was weaker for individuals for whom the level of detail decreased with the passage of time when the external task did not require continuous monitoring of external information. These data provide novel evidence for how neural systems vary across subjects and may underpin individual variation in the dynamics of thought, linking attention systems to the maintenance of task-relevant information, and the default mode network to supporting experiences with vivid detail.

  
  
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  Paquola C, Vos De Wael R, Wagstyl K, Bethlehem RAI, Hong S-J, Seidlitz J, Bullmore ET, Evans AC, Misic B, Margulies DS, Smallwood J, Bernhardt BC (2019)
  Microstructural and functional gradients are increasingly dissociated in transmodal cortices
  PLOS Biology 17(5): 1–28
  
  

  While the role of cortical microstructure in organising neural function is well established, it remains unclear how structural constraints can give rise to more flexible elements of cognition. While nonhuman primate research has demonstrated a close structure–function correspondence, the relationship between microstructure and function remains poorly understood in humans, in part because of the reliance on post mortem analyses, which cannot be directly related to functional data. To overcome this barrier, we developed a novel approach to model the similarity of microstructural profiles sampled in the direction of cortical columns. Our approach was initially formulated based on an ultra-high–resolution 3D histological reconstruction of an entire human brain and then translated to myelin-sensitive magnetic resonance imaging (MRI) data in a large cohort of healthy adults. This novel method identified a system-level gradient of microstructural differentiation traversing from primary sensory to limbic regions that followed shifts in laminar differentiation and cytoarchitectural complexity. Importantly, while microstructural and functional gradients described a similar hierarchy, they became increasingly dissociated in transmodal default mode and fronto–parietal networks. Meta-analytic decoding of these topographic dissociations highlighted involvement in higher-level aspects of cognition, such as cognitive control and social cognition. Our findings demonstrate a relative decoupling of macroscale functional from microstructural gradients in transmodal regions, which likely contributes to the flexible role these regions play in human cognition.

  
  
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  Hong S-J, de Wael RV, Bethlehem RAI, Lariviere S, Paquola C, Valk SL, Milham MP, Martino AD, Margulies DS, Smallwood J, Bernhardt BC (2019)
  Atypical functional connectome hierarchy in autism
  Nature Communications 10(1): 1022
  
  

  One paradox of autism is the co-occurrence of deficits in sensory and higher-order socio-cognitive processing. Here, we examined whether these phenotypical patterns may relate to an overarching system-level imbalance-specifically a disruption in macroscale hierarchy affecting integration and segregation of unimodal and transmodal networks. Combining connectome gradient and stepwise connectivity analysis based on task-free functional magnetic resonance imaging (fMRI), we demonstrated atypical connectivity transitions between sensory and higher-order default mode regions in a large cohort of individuals with autism relative to typically-developing controls. Further analyses indicated that reduced differentiation related to perturbed stepwise connectivity from sensory towards transmodal areas, as well as atypical long-range rich-club connectivity. Supervised pattern learning revealed that hierarchical features predicted deficits in social cognition and low-level behavioral symptoms, but not communication-related symptoms. Our findings provide new evidence for imbalances in network hierarchy in autism, which offers a parsimonious reference frame to consolidate its diverse features.

  
  
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  Oligschläger S, Xu T, Baczkowski BM, Falkiewicz M, Falchier A, Linn G, Margulies DS (2019)
  Gradients of connectivity distance in the cerebral cortex of the macaque monkey
  Brain Struct Funct 224(2): 925–935
  
  

  Cortical connectivity conforms to a series of organizing principles that are common across species. Spatial proximity, similar cortical type, and similar connectional profile all constitute factors for determining the connectivity between cortical regions. We previously demonstrated another principle of connectivity that is closely related to the spatial layout of the cerebral cortex. Using functional connectivity from resting-state fMRI in the human cortex, we found that the further a region is located from primary cortex, the more distant are its functional connections with the other areas of the cortex. However, it remains unknown whether this relationship between cortical layout and connectivity extends to other primate species. Here, we investigated this relationship using both resting-state functional connectivity as well as gold-standard tract-tracing connectivity in the macaque monkey cortex. For both measures of connectivity, we found a gradient of connectivity distance extending between primary and frontoparietal regions. In the human cortex, the further a region is located from primary areas, the stronger its connections to distant portions of the cortex, with connectivity distance highest in frontal and parietal regions. The similarity between the human and macaque findings provides evidence for a phylogenetically conserved relationship between the spatial layout of cortical areas and connectivity.

  
  
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  Mendes N, Oligschlaeger S, Lauckner ME, Golchert J, Huntenburg JM, Falkiewicz M, Ellamil M, Krause S, Baczkowski BM, Cozatl R, Osoianu A, Kumral D, Pool J, Golz L, Dreyer M, Haueis P, Jost R, Kramarenko Y, Engen H, Ohrnberger K, Gorgolewski KJ, Farrugia N, Babayan A, Reiter A, Schaare HL, Reinelt J, Roebbig J, Uhlig M, Erbey M, Gaebler M, Smallwood J, Villringer A, Margulies DS (2019)
  A functional connectome phenotyping dataset including cognitive state and personality measures
  Scientific data 6: 180307
  
  

  The dataset enables exploration of higher-order cognitive faculties, self-generated mental experience, and personality features in relation to the intrinsic functional architecture of the brain. We provide multimodal magnetic resonance imaging (MRI) data and a broad set of state and trait phenotypic assessments: mind-wandering, personality traits, and cognitive abilities. Specifically, 194 healthy participants (between 20 and 75 years of age) filled out 31 questionnaires, performed 7 tasks, and reported 4 probes of in-scanner mind-wandering. The scanning session included four 15.5-min resting-state functional MRI runs using a multiband EPI sequence and a high-resolution structural scan using a 3D MP2RAGE sequence. This dataset constitutes one part of the Leipzig Study for Mind-Body-Emotion Interactions database.

  
  
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  Babayan A, Erbey M, Kumral D, Reinelt JD, Reiter AMF, Röbbig J, Schaare HL, Uhlig M, Anwander A, Bazin P-L, Horstmann A, Lampe L, Nikulin VV, Okon-Singer H, Preusser S, Pampel A, Rohr CS, Sacher J, Thöne-Otto A, Trapp S, Nierhaus T, Altmann D, Arelin K, Blöchl M, Bongartz E, Breig P, Cesnaite E, Chen S, Cozatl R, Czerwonatis S, Dambrauskaite G, Dreyer M, Enders J, Engelhardt M, Fischer MM, Forschack N, Golchert J, Golz L, Guran CA, Hedrich S, Hentschel N, Hoffmann DI, Huntenburg JM, Jost R, Kosatschek A, Kunzendorf S, Lammers H, Lauckner ME, Mahjoory K, Kanaan AS, Mendes N, Menger R, Morino E, Näthe K, Neubauer J, Noyan H, Oligschläger S, Panczyszyn-Trzewik P, Poehlchen D, Putzke N, Roski S, Schaller M-C, Schieferbein A, Schlaak B, Schmidt R, Gorgolewski KJ, Schmidt HM, Schrimpf A, Stasch S, Voss M, Wiedemann A, Margulies DS, Gaebler M, Villringer A (2019)
  A mind-brain-body dataset of MRI, EEG, cognition, emotion, and peripheral physiology in young and old adults
  Scientific Data 6: 180308
  
  

  We present a publicly available dataset of 227 healthy participants comprising a young (N=153, 25.1±3.1 years, range 20-35 years, 45 female) and an elderly group (N=74, 67.6±4.7 years, range 59-77 years, 37 female) acquired cross-sectionally in Leipzig, Germany, between 2013 and 2015 to study mind-body-emotion interactions. During a two-day assessment, participants completed MRI at 3 Tesla (resting-state fMRI, quantitative T1 (MP2RAGE), T2-weighted, FLAIR, SWI/QSM, DWI) and a 62-channel EEG experiment at rest. During task-free resting-state fMRI, cardiovascular measures (blood pressure, heart rate, pulse, respiration) were continuously acquired. Anthropometrics, blood samples, and urine drug tests were obtained. Psychiatric symptoms were identified with Standardized Clinical Interview for DSM IV (SCID-I), Hamilton Depression Scale, and Borderline Symptoms List. Psychological assessment comprised 6 cognitive tests as well as 21 questionnaires related to emotional behavior, personality traits and tendencies, eating behavior, and addictive behavior. We provide information on study design, methods, and details of the data. This dataset is part of the larger MPI Leipzig Mind-Brain-Body database.

  
  
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  Schaare HL, Kharabian Masouleh S, Beyer F, Kumral D, Uhlig M, Reinelt JD, Reiter AMF, Lampe L, Babayan A, Erbey M, Roebbig J, Schroeter ML, Okon-Singer H, Müller K, Mendes N, Margulies DS, Witte AV, Gaebler M, Villringer A (2019)
  Association of peripheral blood pressure with gray matter volume in 19- to 40-year-old adults
  Neurology 92(8): e758–e773
  
  

  Objective To test whether elevated blood pressure (BP) relates to gray matter (GM) volume (GMV) changes in young adults who had not previously been diagnosed with hypertension (systolic BP [SBP]/diastolic BP [DBP] >=140/90 mm Hg).Methods We associated BP with GMV from structural 3T T1-weighted MRI of 423 healthy adults between 19 and 40 years of age (mean age 27.7 \textpm 5.3 years, 177 women, SBP/DBP 123.2/73.4 \textpm 12.2/8.5 mm Hg). Data originated from 4 previously unpublished cross-sectional studies conducted in Leipzig, Germany. We performed voxel-based morphometry on each study separately and combined results in image-based meta-analyses (IBMA) to assess cumulative effects across studies. Resting BP was assigned to 1 of 4 categories: (1) SBP <120 and DBP <80 mm Hg, (2) SBP 120–129 or DBP 80–84 mm Hg, (3) SBP 130–139 or DBP 85–89 mm Hg, (4) SBP >=140 or DBP >=90 mm Hg.Results IBMA yielded the following results: (1) lower regional GMV was correlated with higher peripheral BP; (2) lower GMV was found with higher BP when comparing individuals in subhypertensive categories 3 and 2, respectively, to those in category 1; (3) lower BP-related GMV was found in regions including hippocampus, amygdala, thalamus, frontal, and parietal structures (e.g., precuneus).Conclusion BP >=120/80 mm Hg was associated with lower GMV in regions that have previously been related to GM decline in older individuals with manifest hypertension. Our study shows that BP-associated GM alterations emerge continuously across the range of BP and earlier in adulthood than previously assumed. This suggests that treating hypertension or maintaining lower BP in early adulthood might be essential for preventing the pathophysiologic cascade of asymptomatic cerebrovascular disease to symptomatic end-organ damage, such as stroke or dementia.AD=Alzheimer disease; ANOVA=analysis of variance; BMI=body mass index; BP=blood pressure; CSFV=cerebrospinal fluid volume; CVD=cerebrovascular disease; DBP=diastolic blood pressure; FA=flip angle; FLAIR=fluid-attenuated inversion recovery; FOV=field of view; FWE=family-wise error; GM=gray matter; GMV=gray matter volume; HTN=hypertension; IBMA=image-based meta-analyses; LIFE Study=Leipzig Research Centre for Civilization Diseases Study; ROI=region of interest; SBP=systolic blood pressure; SDM=seed-based d mapping; TE=echo time; TI=inversion time; TIV=total intracranial volume; TR=repetition time; VBM=voxel-based morphometry; WM=white matter; WMH=white matter hyperintensities; WMV=white matter volume

  
  
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  Xu T, Sturgeon D, Ramirez JSB, Froudist-Walsh S, Margulies DS, Schroeder CE, Fair DA, Milham MP (2019)
  Inter-individual Variability of Functional Connectivity in Awake and Anesthetized Rhesus Monkeys
  Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
  
  

  Background Nonhuman primate models (NHP) are commonly used to advance our understanding of brain function and organization. However, to date, they have offered few insights into individual differences among NHPs. In large part, this is due to the logistical challenges of NHP research, which limit most studies to five subjects or fewer. Methods We leveraged the availability of a large-scale open NHP imaging resource to provide an initial examination of individual differences in the functional organization of the nonhuman primate brain. Specifically, we selected one awake fMRI dataset (Newcastle: n = 10) and two anesthetized fMRI data sets (Oxford: n = 19; UC-Davis: n = 19) to examine individual differences in functional connectivity characteristics across the cortex, as well as potential state dependencies. Results We noted significant individual variations of functional connectivity across the macaque cortex. Similar to the findings in human, during the awake state, the primary sensory and motor cortices showed lower variability than the high-order association regions. This variability pattern was significantly correlated with T1w/T2w map, the degree of long-distance connectivity, but not short-distance connectivity. However, the inter-individual variability under anesthesia exhibited a very distinct pattern, with lower variability in medial frontal cortex, precuneus and somatomotor regions and higher variability in the lateral ventral frontal and insular cortices. Conclusions This work has implications for our understanding of the evolutionary origins of individual variation in the human brain, as well as methodological implications that must be considered in any pursuit to study individual variation in NHP models.

  
  
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  Buckner RL, Margulies DS (2019)
  Macroscale Cortical Organization and a Default-Like Transmodal Apex Network in the Marmoset Monkey
  Nature Communications 10: 1976
  
  

  Networks of widely distributed regions populate human association cortex. One network, often called the default network, is positioned at the apex of a gradient of sequential networks that radiate outward from primary cortex. Here extensive anatomical data made available through the Marmoset Brain Architecture Project were explored to determine if a homologue exists in marmoset. Results revealed that a gradient of networks extend outward from primary cortex to progressively higher-order transmodal association cortex in both frontal and temporal cortex. The transmodal apex network comprises frontopolar and rostral temporal association cortex, parahippocampal areas TH / TF, the ventral posterior midline, and lateral parietal association cortex. The positioning of this network in the gradient and its composition of areas make it a candidate homologue to the human default network. That the marmoset, a physiologically- and genetically-accessible primate, might possess a default-network-like candidate creates opportunities for study of higher cognitive and social functions.

  
  
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  Goulas A, Margulies DS, Bezgin G, Hilgetag CC (In press)
  The architecture of mammalian cortical connectomes in light of the theory of the dual origin of the cerebral cortex
  Cortex
  
  

  Uncovering organizational principles of the cerebral cortex is essential for proper understanding of this prominent structure of the mammalian brain. The theory of the dual origin of the cerebral cortex offers such organizational principle. Here, we demonstrate that a duality pertains to the connectional architecture of the cerebral cortex of different mammals. This dual structure also constitutes a major axis of organization of the transcriptional architecture of the cortex and reflects the expression of different morphogens stemming from distinct patterning centers in the developing pallium. The duality of the cortex is also reflected in its spatial dimension, highlighting cortical areas as spatially ordered constellations that are centered around the paleocortex and archicortex, with the later primordial moieties reminiscent of antipodal points in the cortical sheet. The ontogeny of the uncovered dual connectional structure might be rooted in heterochronous neurodevelopmental gradients in the developing pallium, a suggestion corroborated by computational modeling. In all, the current results exemplify the duality of the cerebral cortex as an overarching organizational principle, reflected across the different levels of cortical architecture of different mammalian species, defining a natural axis of mammalian cortical organization.

  
  
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  Murphy C, Wang H-T, Konu D, Lowndes R, Margulies DS, Jefferies E, Smallwood J (2019)
  Modes of operation: A topographic neural gradient supporting stimulus dependent and independent cognition
  NeuroImage 186: 487–496
  
  

  Human cognition is flexible - drawing on both sensory input, and representations from memory, to successfully navigate complex environments. Contemporary accounts suggest this flexibility is possible because neural function is organized into a hierarchy. Neural regions are organized along a macroscale gradient, anchored at one end by unimodal systems involved with perception and action, and at the other by transmodal systems, including the default mode network, supporting cognition less directly tied to immediate stimulus input. The current study tested whether this cortical hierarchy captures modes of behaviour that depend on immediate input, as well as those that depend on representations from memory. Participants made decisions regarding the location or identity of shapes using information in the environment (0-back) or from a prior trial (1-back). Using task based imaging we established that, regardless of the nature of the decision, medial and lateral visual cortex were recruited when decisions rely on immediate input, while transmodal regions were recruited when judgments depend on information from the prior trial. Using principal components analysis, we demonstrated that shifting decision-making from perception to memory altered the focus of neural activity from unimodal to transmodal regions (and vice versa). Notably, the more pronounced these shifts in neural activity from unimodal to transmodal regions when decisions relied on memory, the more efficiently individuals performed this task. These data illustrate how the macroscale organization of neural function into a hierarchy allows cognition to rely on input, or information from memory, in a flexible and efficient manner.

  
  

2018

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  Vos de Wael R, Lariviere S, Caldairou B, Hong S-J, Margulies DS, Jefferies E, Bernasconi A, Smallwood J, Bernasconi N, Bernhardt BC (2018)
  Anatomical and microstructural determinants of hippocampal subfield functional connectome embedding
  Proc Natl Acad Sci U S A 115(40): 10154–10159
  
  

  The hippocampus plays key roles in cognition and affect and serves as a model system for structure/function studies in animals. So far, its complex anatomy has challenged investigations targeting its substructural organization in humans. State-of-the-art MRI offers the resolution and versatility to identify hippocampal subfields, assess its microstructure, and study topographical principles of its connectivity in vivo. We developed an approach to unfold the human hippocampus and examine spatial variations of intrinsic functional connectivity in a large cohort of healthy adults. In addition to mapping common and unique connections across subfields, we identified two main axes of subregional connectivity transitions. An anterior/posterior gradient followed long-axis landmarks and metaanalytical findings from task-based functional MRI, while a medial/lateral gradient followed hippocampal infolding and correlated with proxies of cortical myelin. Findings were consistent in an independent sample and highly stable across resting-state scans. Our results provide robust evidence for long-axis specialization in the resting human hippocampus and suggest an intriguing interplay between connectivity and microstructure.

  
  
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  Milham MP, Ai L, Koo B, Xu T, Amiez C, Balezeau F, Baxter MG, Blezer ELA, Brochier T, Chen A, Croxson PL, Damatac CG, Dehaene S, Everling S, Fair DA, Fleysher L, Freiwald W, Froudist-Walsh S, Griffiths TD, Guedj C, Hadj-Bouziane F, Ben Hamed S, Harel N, Hiba B, Jarraya B, Jung B, Kastner S, Klink PC, Kwok SC, Laland KN, Leopold DA, Lindenfors P, Mars RB, Menon RS, Messinger A, Meunier M, Mok K, Morrison JH, Nacef J, Nagy J, Rios MO, Petkov CI, Pinsk M, Poirier C, Procyk E, Rajimehr R, Reader SM, Roelfsema PR, Rudko DA, Rushworth MFS, Russ BE, Sallet J, Schmid MC, Schwiedrzik CM, Seidlitz J, Sein J, Shmuel A, Sullivan EL, Ungerleider L, Thiele A, Todorov OS, Tsao D, Wang Z, Wilson CRE, Yacoub E, Ye FQ, Zarco W, Zhou Y-di, Margulies DS, Schroeder CE (2018)
  An Open Resource for Non-human Primate Imaging
  Neuron (100)
  
  

  Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience. Unfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMatE Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design, and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 25 independent data collections aggregated across 22 sites (total = 217 non-human primates). We also outline the unique pitfalls and challenges that should be considered in the analysis of non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.

  
  
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  Sormaz M, Murphy C, Wang H-T, Hymers M, Karapanagiotidis T, Poerio G, Margulies DS, Jefferies E, Smallwood J (2018)
  Default mode network can support the level of detail in experience during active task states
  Proc Natl Acad Sci U S A 115(37): 9318–9323
  
  

  Regions of transmodal cortex, in particular the default mode network (DMN), have historically been argued to serve functions unrelated to task performance, in part because of associations with naturally occurring periods of off-task thought. In contrast, contemporary views of the DMN suggest it plays an integrative role in cognition that emerges from its location at the top of a cortical hierarchy and its relative isolation from systems directly involved in perception and action. The combination of these topographical features may allow the DMN to support abstract representations derived from lower levels in the hierarchy and so reflect the broader cognitive landscape. To investigate these contrasting views of DMN function, we sampled experience as participants performed tasks varying in their working-memory load while inside an fMRI scanner. We used self-report data to establish dimensions of thought that describe levels of detail, the relationship to a task, the modality of thought, and its emotional qualities. We used representational similarity analysis to examine correspondences between patterns of neural activity and each dimension of thought. Our results were inconsistent with a task-negative view of DMN function. Distinctions between on- and off-task thought were associated with patterns of consistent neural activity in regions adjacent to unimodal cortex, including motor and premotor cortex. Detail in ongoing thought was associated with patterns of activity within the DMN during periods of working-memory maintenance. These results demonstrate a contribution of the DMN to ongoing cognition extending beyond task-unrelated processing that can include detailed experiences occurring under active task conditions.

  
  
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  Medea B, Karapanagiotidis T, Konishi M, Ottaviani C, Margulies DS, Bernasconi A, Bernasconi N, Bernhardt BC, Jefferies E, Smallwood J (2018)
  How do we decide what to do? Resting-state connectivity patterns and components of self-generated thought linked to the development of more concrete personal goals
  Exp Brain Res 236(9): 2469–2481
  
  

  Human cognition is not limited to the available environmental input but can consider realities that are different to the here and now. We describe the cognitive states and neural processes linked to the refinement of descriptions of personal goals. When personal goals became concrete, participants reported greater thoughts about the self and the future during mind-wandering. This pattern was not observed for descriptions of TV programmes. Connectivity analysis of participants who underwent a resting-state functional magnetic resonance imaging scan revealed neural traits associated with this pattern. Strong hippocampal connectivity with ventromedial pre-frontal cortex was common to better-specified descriptions of goals and TV programmes, while connectivity between hippocampus and the pre-supplementary motor area was associated with individuals whose goals were initially abstract but became more concrete over the course of the experiment. We conclude that self-generated cognition that arises during the mind-wandering state can allow goals to be refined, and this depends on neural systems anchored in the hippocampus.

  
  
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  Wang H-T, Bzdok D, Margulies DS, Craddock C, Milham M, Jefferies E, Smallwood J (2018)
  Patterns of thought: Population variation in the associations between large-scale network organisation and self-reported experiences at rest
  Neuroimage 176: 518–527
  
  

  Contemporary cognitive neuroscience recognises unconstrained processing varies across individuals, describing variation in meaningful attributes, such as intelligence. It may also have links to patterns of on-going experience. This study examined whether dimensions of population variation in different modes of unconstrained processing can be described by the associations between patterns of neural activity and self-reports of experience during the same period. We selected 258 individuals from a publicly available data set who had measures of resting-state functional magnetic resonance imaging, and self-reports of experience during the scan. We used machine learning to determine patterns of association between the neural and self-reported data, finding variation along four dimensions. ’Purposeful’ experiences were associated with lower connectivity - in particular default mode and limbic networks were less correlated with attention and sensorimotor networks. ’Emotional’ experiences were associated with higher connectivity, especially between limbic and ventral attention networks. Experiences focused on themes of ’personal importance’ were associated with reduced functional connectivity within attention and control systems. Finally, visual experiences were associated with stronger connectivity between visual and other networks, in particular the limbic system. Some of these patterns had contrasting links with cognitive function as assessed in a separate laboratory session - purposeful thinking was linked to greater intelligence and better abstract reasoning, while a focus on personal importance had the opposite relationship. Together these findings are consistent with an emerging literature on unconstrained states and also underlines that these states are heterogeneous, with distinct modes of population variation reflecting the interplay of different large-scale networks.

  
  
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  Kipping JA, Margulies DS, Eickhoff SB, Lee A, Qiu A (2018)
  Trade-off of cerebello-cortical and cortico-cortical functional networks for planning in 6-year-old children
  Neuroimage 176: 510–517
  
  

  Childhood is a critical period for the development of cognitive planning. There is a lack of knowledge on its neural mechanisms in children. This study aimed to examine cerebello-cortical and cortico-cortical functional connectivity in association with planning skills in 6-year-olds (n=76). We identified the cerebello-cortical and cortico-cortical functional networks related to cognitive planning using activation likelihood estimation (ALE) meta-analysis on existing functional imaging studies on spatial planning, and data-driven independent component analysis (ICA) of children’s resting-state functional MRI (rs-fMRI). We investigated associations of cerebello-cortical and cortico-cortical functional connectivity with planning ability in 6-year-olds, as assessed using the Stockings of Cambridge task. Long-range functional connectivity of two cerebellar networks (lobules VI and lateral VIIa) with the prefrontal and premotor cortex were greater in children with poorer planning ability. In contrast, cortico-cortical association networks were not associated with the performance of planning in children. These results highlighted the key contribution of the lateral cerebello-frontal functional connectivity, but not cortico-cortical association functional connectivity, for planning ability in 6-year-olds. Our results suggested that brain adaptation to the acquisition of planning ability during childhood is partially achieved through the engagement of the cerebello-cortical functional connectivity.

  
  
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  Kernbach JM, Satterthwaite TD, Bassett DS, Smallwood J, Margulies DS, Krall S, Shaw P, Varoquaux G, Thirion B, Konrad K, Bzdok D (2018)
  Shared endo-phenotypes of default mode dsfunction in attention deficit/hyperactivity disorder and autism spectrum disorder
  Transl Psychiatry 8(1): 133
  
  

  Categorical diagnoses from the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) manuals are increasingly found to be incongruent with emerging neuroscientific evidence that points towards shared neurobiological dysfunction underlying attention deficit/hyperactivity disorder and autism spectrum disorder. Using resting-state functional magnetic resonance imaging data, functional connectivity of the default mode network, the dorsal attention and salience network was studied in 1305 typically developing and diagnosed participants. A transdiagnostic hierarchical Bayesian modeling framework combining Indian Buffet Processes and Latent Dirichlet Allocation was proposed to address the urgent need for objective brain-derived measures that can acknowledge shared brain network dysfunction in both disorders. We identified three main variation factors characterized by distinct coupling patterns of the temporoparietal cortices in the default mode network with the dorsal attention and salience network. The brain-derived factors were demonstrated to effectively capture the underlying neural dysfunction shared in both disorders more accurately, and to enable more reliable diagnoses of neurobiological dysfunction. The brain-derived phenotypes alone allowed for a classification accuracy reflecting an underlying neuropathology of 67.33% (+/-3.07) in new individuals, which significantly outperformed the 46.73% (+/-3.97) accuracy of categorical diagnoses. Our results provide initial evidence that shared neural dysfunction in ADHD and ASD can be derived from conventional brain recordings in a data-led fashion. Our work is encouraging to pursue a translational endeavor to find and further study brain-derived phenotypes, which could potentially be used to improve clinical decision-making and optimize treatment in the future.

  
  
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  Murphy C, Jefferies E, Rueschemeyer S-A, Sormaz M, Wang H-T, Margulies DS, Smallwood J (2018)
  Distant from input: Evidence of regions within the default mode network supporting perceptually-decoupled and conceptually-guided cognition
  Neuroimage 171: 393–401
  
  

  The default mode network supports a variety of mental operations such as semantic processing, episodic memory retrieval, mental time travel and mind-wandering, yet the commonalities between these functions remains unclear. One possibility is that this system supports cognition that is independent of the immediate environment; alternatively or additionally, it might support higher-order conceptual representations that draw together multiple features. We tested these accounts using a novel paradigm that separately manipulated the availability of perceptual information to guide decision-making and the representational complexity of this information. Using task based imaging we established regions that respond when cognition combines both stimulus independence with multi-modal information. These included left and right angular gyri and the left middle temporal gyrus. Although these sites were within the default mode network, they showed a stronger response to demanding memory judgements than to an easier perceptual task, contrary to the view that they support automatic aspects of cognition. In a subsequent analysis, we showed that these regions were located at the extreme end of a macroscale gradient, which describes gradual transitions from sensorimotor to transmodal cortex. This shift in the focus of neural activity towards transmodal, default mode, regions might reflect a process of where the functional distance from specific sensory enables conceptually rich and detailed cognitive states to be generated in the absence of input.

  
  
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  Hartwigsen G, Neef NE, Camilleri JA, Margulies DS, Eickhoff SB (2018)
  Functional Segregation of the Right Inferior Frontal Gyrus: Evidence From Coactivation-Based Parcellation
  Cereb Cortex
  
  

  Previous studies helped unraveling the functional architecture of the human cerebral cortex. However, a comprehensive functional segregation of right lateral prefrontal cortex is missing. Here, we delineated cortical clusters in right area 44 and 45 based on their task-constrained whole-brain activation patterns across neuroimaging experiments obtained from a large database. We identified 5 clusters that differed with respect to their coactivation patterns, which were consistent with resting-state functional connectivity patterns of an independent dataset. Two clusters in the posterior inferior frontal gyrus (IFG) were functionally associated with action inhibition and execution, while two anterior clusters were related to reasoning and social cognitive processes. A fifth cluster was associated with spatial attention. Strikingly, the functional organization of the right IFG can thus be characterized by a posterior-to-anterior axis with action-related functions on the posterior and cognition-related functions on the anterior end. We observed further subdivisions along a dorsal-to-ventral axis in posterior IFG between action execution and inhibition, and in anterior IFG between reasoning and social cognition. The different clusters were integrated in distinct large-scale networks for various cognitive processes. These results provide evidence for a general organization of cognitive processes along axes spanning from more automatic to more complex cognitive processes.

  
  
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  Jakobsen E, Liem F, Klados MA, Bayrak S, Petrides M, Margulies DS (2018)
  Automated individual-level parcellation of Broca’s region based on functional connectivity
  Neuroimage 170: 41–53
  
  

  Broca’s region can be subdivided into its constituent areas 44 and 45 based on established differences in connectivity to superior temporal and inferior parietal regions. The current study builds on our previous work manually parcellating Broca’s area on the individual-level by applying these anatomical criteria to functional connectivity data. Here we present an automated observer-independent and anatomy-informed parcellation pipeline with comparable precision to the manual labels at the individual-level. The method first extracts individualized connectivity templates of areas 44 and 45 by assigning to each surface vertex within the ventrolateral frontal cortex the partial correlation value of its functional connectivity to group-level templates of areas 44 and 45, accounting for other template connectivity patterns. To account for cross-subject variability in connectivity, the partial correlation procedure is then repeated using individual-level network templates, including individual-level connectivity from areas 44 and 45. Each node is finally labeled as area 44, 45, or neither, using a winner-take-all approach. The method also incorporates prior knowledge of anatomical location by weighting the results using spatial probability maps. The resulting area labels show a high degree of spatial overlap with the gold-standard manual labels, and group-average area maps are consistent with cytoarchitectonic probability maps of areas 44 and 45. To facilitate reproducibility and to demonstrate that the method can be applied to resting-state fMRI datasets with varying acquisition and preprocessing parameters, the labeling procedure is applied to two open-source datasets from the Human Connectome Project and the Nathan Kline Institute Rockland Sample. While the current study focuses on Broca’s region, the method is adaptable to parcellate other cortical regions with distinct connectivity profiles.

  
  
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  Villena-Gonzalez M, Wang H-T, Sormaz M, Mollo G, Margulies DS, Jefferies EA, Smallwood J (2018)
  Individual variation in the propensity for prospective thought is associated with functional integration between visual and retrosplenial cortex
  Cortex 99: 224–234
  
  

  It is well recognized that the default mode network (DMN) is involved in states of imagination, although the cognitive processes that this association reflects are not well understood. The DMN includes many regions that function as cortical "hubs", including the posterior cingulate/retrosplenial cortex, anterior temporal lobe and the hippocampus. This suggests that the role of the DMN in cognition may reflect a process of cortical integration. In the current study we tested whether functional connectivity from uni-modal regions of cortex into the DMN is linked to features of imaginative thought. We found that strong intrinsic communication between visual and retrosplenial cortex was correlated with the degree of social thoughts about the future. Using an independent dataset, we show that the same region of retrosplenial cortex is functionally coupled to regions of primary visual cortex as well as core regions that make up the DMN. Finally, we compared the functional connectivity of the retrosplenial cortex, with a region of medial prefrontal cortex implicated in the integration of information from regions of the temporal lobe associated with future thought in a prior study. This analysis shows that the retrosplenial cortex is preferentially coupled to medial occipital, temporal lobe regions and the angular gyrus, areas linked to episodic memory, scene construction and navigation. In contrast, the medial prefrontal cortex shows preferential connectivity with motor cortex and lateral temporal and prefrontal regions implicated in language, motor processes and working memory. Together these findings suggest that integrating neural information from visual cortex into retrosplenial cortex may be important for imagining the future and may do so by creating a mental scene in which prospective simulations play out. We speculate that the role of the DMN in imagination may emerge from its capacity to bind together distributed representations from across the cortex in a coherent manner.

  
  
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  Lefort-Besnard J, Bassett DS, Smallwood J, Margulies DS, Derntl B, Gruber O, Aleman A, Jardri R, Varoquaux G, Thirion B, Eickhoff SB, Bzdok D (2018)
  Different shades of default mode disturbance in schizophrenia: Subnodal covariance estimation in structure and function
  Hum Brain Mapp 39(2): 644–661
  
  

  Schizophrenia is a devastating mental disease with an apparent disruption in the highly associative default mode network (DMN). Interplay between this canonical network and others probably contributes to goal-directed behavior so its disturbance is a candidate neural fingerprint underlying schizophrenia psychopathology. Previous research has reported both hyperconnectivity and hypoconnectivity within the DMN, and both increased and decreased DMN coupling with the multimodal saliency network (SN) and dorsal attention network (DAN). This study systematically revisited network disruption in patients with schizophrenia using data-derived network atlases and multivariate pattern-learning algorithms in a multisite dataset (n = 325). Resting-state fluctuations in unconstrained brain states were used to estimate functional connectivity, and local volume differences between individuals were used to estimate structural co-occurrence within and between the DMN, SN, and DAN. In brain structure and function, sparse inverse covariance estimates of network coupling were used to characterize healthy participants and patients with schizophrenia, and to identify statistically significant group differences. Evidence did not confirm that the backbone of the DMN was the primary driver of brain dysfunction in schizophrenia. Instead, functional and structural aberrations were frequently located outside of the DMN core, such as in the anterior temporoparietal junction and precuneus. Additionally, functional covariation analyses highlighted dysfunctional DMN-DAN coupling, while structural covariation results highlighted aberrant DMN-SN coupling. Our findings reframe the role of the DMN core and its relation to canonical networks in schizophrenia. We thus underline the importance of large-scale neural interactions as effective biomarkers and indicators of how to tailor psychiatric care to single patients.

  
  
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  Huntenburg JM, Bazin P-L, Margulies DS (2018)
  Large-Scale Gradients in Human Cortical Organization
  Trends Cogn Sci 22(1): 21–31
  
  

  Recent advances in mapping cortical areas in the human brain provide a basis for investigating the significance of their spatial arrangement. Here we describe a dominant gradient in cortical features that spans between sensorimotor and transmodal areas. We propose that this gradient constitutes a core organizing axis of the human cerebral cortex, and describe an intrinsic coordinate system on its basis. Studying the cortex with respect to these intrinsic dimensions can inform our understanding of how the spectrum of cortical function emerges from structural constraints.

  
  
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  Tang R, Ketcha M, Badea A, Calabrese ED, Margulies DS, Vogelstein JT, Priebe CE, Sussman DL (2018)
  Connectome Smoothing via Low-rank Approximations
  IEEE Transactions on Medical Imaging
  
  

  In brain imaging and connectomics, the study of brain networks, estimating the mean of a population of graphs based on a sample is a core problem. Often, this problem is especially difficult because the sample or cohort size is relatively small, sometimes even a single subject, while the number of nodes can be very large with noisy estimates of connectivity. While the element-wise sample mean of the adjacency matrices is a common approach, this method does not exploit underlying structural properties of the graphs. We propose using a low-rank method which incorporates dimension selection and diagonal augmentation to smooth the estimates and improve performance over the naäve methodology for small sample sizes. Theoretical results for the stochastic blockmodel show that this method offers major improvements when there are many vertices. Similarly, we demonstrate that the low-rank methods outperform the standard sample mean for a variety of independent edge distributions as well as human connectome data derived from magnetic resonance imaging, especially when sample sizes are small. Moreover, the low-rank methods yield “eigen-connectomes”, which correlate with the lobe-structure of the human brain and superstructures of the mouse brain. These results indicate that low-rank methods are an important part of the toolbox for researchers studying populations of graphs in general, and statistical connectomics in particular.

  
  
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  Kernbach JM, Yeo BTT, Smallwood J, Margulies DS, Thiebaut de Schotten M, Walter H, Sabuncu MR, Holmes AJ, Gramfort A, Varoquaux G, Thirion B, Bzdok D (2018)
  Subspecialization within default mode nodes characterized in 10,000 UK Biobank participants
  Proceedings of the National Academy of Sciences U S A
  
  

  The default mode network (DMN) encompasses supramodal association areas involved in higher-order cognition. One speculation is that this neural system is important for brain-wide information flow. We tested this account by exploring whether DMN patterns are informative about functional coupling or structural associations in the rest of the brain. Our multimodal pattern analysis findings highlight how the DMN nodes are fractionated: In specific subnodes, gray-matter morphology was linked to fiber tracts from the hippocampus in the medial temporal limbic system. In adjacent subnodes, fluctuations in neural activity were linked to between-network connectivity shifts. Such a mosaic architecture may be a prerequisite for many of the roles the DMN may play in advanced cognitive processes.The human default mode network (DMN) is implicated in several unique mental capacities. In this study, we tested whether brain-wide interregional communication in the DMN can be derived from population variability in intrinsic activity fluctuations, gray-matter morphology, and fiber tract anatomy. In a sample of 10,000 UK Biobank participants, pattern-learning algorithms revealed functional coupling states in the DMN that are linked to connectivity profiles between other macroscopical brain networks. In addition, DMN gray matter volume was covaried with white matter microstructure of the fornix. Collectively, functional and structural patterns unmasked a possible division of labor within major DMN nodes: Subregions most critical for cortical network interplay were adjacent to subregions most predictive of fornix fibers from the hippocampus that processes memories and places.

  
  

2017

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  Margulies DS, Smallwood J (2017)
  Converging evidence for the role of transmodal cortex in cognition
  Proc Natl Acad Sci U S A 114(48): 12641–12643
  
  

  
  
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  Ho TC, Sacchet MD, Connolly CG, Margulies DS, Tymofiyeva O, Paulus MP, Simmons AN, Gotlib IH, Yang TT (2017)
  Inflexible Functional Connectivity of the Dorsal Anterior Cingulate Cortex in Adolescent Major Depressive Disorder
  Neuropsychopharmacology 42(12): 2434–2445
  
  

  Recent evidence suggests that anterior cingulate cortex (ACC) maturation during adolescence contributes to or underlies the development of major depressive disorder (MDD) during this sensitive period. The ACC is a structure that sits at the intersection of several task-positive networks (eg, central executive network, CEN), which are still developing during adolescence. While recent work using seed-based approaches indicate that depressed adolescents show limited task-evoked vs resting-state connectivity (termed ’inflexibility’) between the ACC and task-negative networks, no study has used network-based approaches to investigate inflexibility of the ACC in task-positive networks to understand adolescent MDD. Here, we used graph theory to compare flexibility of network-level topology in eight subregions of the ACC (spanning three task-positive networks) in 42 unmedicated adolescents with MDD and 53 well-matched healthy controls. All participants underwent fMRI scanning during resting state and a response inhibition task that robustly engages task-positive networks. Relative to controls, depressed adolescents were characterized by inflexibility in local efficiency of a key ACC node in the CEN: right dorsal anterior cingulate cortex/medial frontal gyrus (R dACC/MFG). Furthermore, individual differences in flexibility of local efficiency of R dACC/MFG significantly predicted inhibition performance, consistent with current literature demonstrating that flexible network organization affords successful cognitive control. Finally, reduced local efficiency of dACC/MFG during the task was significantly associated with an earlier age of depression onset, consistent with prior work suggesting that MDD may alter functional network development. Our results support a neurodevelopmental hypothesis of MDD wherein dysfunctional self-regulation is potentially reflected by altered ACC maturation.

  
  
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  Margulies DS (2017)
  Unraveling the Complex Tapestry of Association Networks
  Neuron 95(2): 239–241
  
  

  Prior group-level studies have described several large-scale distributed networks within association cortex. In this issue of Neuron, Braga and Buckner (2017) attend to the individual brain, revealing a challenging new portrait of its fine-grained organization.

  
  
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  Poerio GL, Sormaz M, Wang H-T, Margulies DS, Jefferies E, Smallwood J (2017)
  The role of the default mode network in component processes underlying the wandering mind
  Soc Cogn Affect Neurosci 12(7): 1047–1062
  
  

  Experiences such as mind-wandering illustrate that cognition is not always tethered to events in the here-and-now. Although converging evidence emphasises the default mode network (DMN) in mind-wandering, its precise contribution remains unclear. The DMN comprises cortical regions that are maximally distant from primary sensory and motor cortex, a topological location that may support the stimulus-independence of mind-wandering. The DMN is functionally heterogeneous, comprising regions engaged by memory, social cognition and planning; processes relevant to mind-wandering content. Our study examined the relationships between: (i) individual differences in resting-state DMN connectivity, (ii) performance on memory, social and planning tasks and (iii) variability in spontaneous thought, to investigate whether the DMN is critical to mind-wandering because it supports stimulus-independent cognition, memory retrieval, or both. Individual variation in task performance modulated the functional organization of the DMN: poor external engagement was linked to stronger coupling between medial and dorsal subsystems, while decoupling of the core from the cerebellum predicted reports of detailed memory retrieval. Both patterns predicted off-task future thoughts. Consistent with predictions from component process accounts of mind-wandering, our study suggests a 2-fold involvement of the DMN: (i) it supports experiences that are unrelated to the environment through strong coupling between its sub-systems; (ii) it allows memory representations to form the basis of conscious experience.

  
  
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  Kuehn E, Dinse J, Jakobsen E, Long X, Schafer A, Bazin P-L, Villringer A, Sereno MI, Margulies DS (2017)
  Body Topography Parcellates Human Sensory and Motor Cortex
  Cereb Cortex 27(7): 3790–3805
  
  

  The cytoarchitectonic map as proposed by Brodmann currently dominates models of human sensorimotor cortical structure, function, and plasticity. According to this model, primary motor cortex, area 4, and primary somatosensory cortex, area 3b, are homogenous areas, with the major division lying between the two. Accumulating empirical and theoretical evidence, however, has begun to question the validity of the Brodmann map for various cortical areas. Here, we combined in vivo cortical myelin mapping with functional connectivity analyses and topographic mapping techniques to reassess the validity of the Brodmann map in human primary sensorimotor cortex. We provide empirical evidence that area 4 and area 3b are not homogenous, but are subdivided into distinct cortical fields, each representing a major body part (the hand and the face). Myelin reductions at the hand-face borders are cortical layer-specific, and coincide with intrinsic functional connectivity borders as defined using large-scale resting state analyses. Our data extend the Brodmann model in human sensorimotor cortex and suggest that body parts are an important organizing principle, similar to the distinction between sensory and motor processing.

  
  
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  Oligschlager S, Huntenburg JM, Golchert J, Lauckner ME, Bonnen T, Margulies DS (2017)
  Gradients of connectivity distance are anchored in primary cortex
  Brain Struct Funct 222(5): 2173–2182
  
  

  Brain Structure & Function’s inaugural Editors’ Choice Award as the best paper published in BS&F in 2017

  Connectivity between distant cortical areas is a valuable, yet costly feature of cortical organization and is predominantly found between regions of heteromodal association cortex. The recently proposed ’tethering hypothesis’ describes the emergence of long-distance connections in association cortex as a function of their spatial separation from primary cortical regions. Here, we investigate this possibility by characterizing the distance between functionally connected areas along the cortical surface. We found a systematic relationship between an area’s characteristic connectivity distance and its distance from primary cortical areas. Specifically, the further a region is located from primary sensorimotor regions, the more distant are its functional connections with other areas of the cortex. The measure of connectivity distance also captured major functional subdivisions of the cerebral cortex: unimodal, attention, and higher-order association regions. Our findings provide evidence for the anchoring role of primary cortical regions in establishing the spatial distribution of cortical properties that are related to functional specialization and differentiation.

  
  
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  de Caso I, Karapanagiotidis T, Aggius-Vella E, Konishi M, Margulies DS, Jefferies E, Smallwood J (2017)
  Knowing me, knowing you: Resting-state functional connectivity of ventromedial prefrontal cortex dissociates memory related to self from a familiar other
  Brain Cogn 113: 65–75
  
  

  Material related to the self, as well as to significant others, often displays mnemonic superiority through its associations with highly organised and elaborate representations. Neuroimaging studies suggest this effect is related to activation in regions of medial prefrontal cortex (mPFC). Incidental memory scores for trait adjectives, processed in relation to the self, a good friend and David Cameron were collected. Scores for each referent were used as regressors in seed-based analyses of resting state fMRI data performed in ventral, middle and dorsal mPFC seeds, as well as hippocampal formation. Stronger memory for self-processed items was predicted by functional connnectivity between ventral mPFC, angular gyrus and middle temporal gyri. These regions are within the default mode network, linked to relatively automatic aspects of memory retrieval. In contrast, memory for items processed in relation to best friends, was better in individuals whose ventral mPFC showed relatively weak connectivity with paracingulate gyrus as well as positive connectivity with lateral prefrontal and parietal regions associated with controlled retrieval. These results suggest that mechanisms responsible for memory related to ourselves and personally-familiar people are partially dissociable and reflect connections between ventral mPFC, implicated in schema-based memory, and regions implicated in more automatic and controlled aspects of retrieval.

  
  
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  Goulas A, Stiers P, Hutchison RM, Everling S, Petrides M, Margulies DS (2017)
  Intrinsic functional architecture of the macaque dorsal and ventral lateral frontal cortex
  J Neurophysiol 117(3): 1084–1099
  
  

  Investigations of the cellular and connectional organization of the lateral frontal cortex (LFC) of the macaque monkey provide indispensable knowledge for generating hypotheses about the human LFC. However, despite numerous investigations, there are still debates on the organization of this brain region. In vivo neuroimaging techniques such as resting-state functional magnetic resonance imaging (fMRI) can be used to define the functional circuitry of brain areas, producing results largely consistent with gold-standard invasive tract-tracing techniques and offering the opportunity for cross-species comparisons within the same modality. Our results using resting-state fMRI from macaque monkeys to uncover the intrinsic functional architecture of the LFC corroborate previous findings and inform current debates. Specifically, within the dorsal LFC, we show that 1) the region along the midline and anterior to the superior arcuate sulcus is divided in two areas separated by the posterior supraprincipal dimple, 2) the cytoarchitectonically defined area 6DC/F2 contains two connectional divisions, and 3) a distinct area occupies the cortex around the spur of the arcuate sulcus, updating what was previously proposed to be the border between dorsal and ventral motor/premotor areas. Within the ventral LFC, the derived parcellation clearly suggests the presence of distinct areas: 1) an area with a somatomotor/orofacial connectional signature (putative area 44), 2) an area with an oculomotor connectional signature (putative frontal eye fields), and 3) premotor areas possibly hosting laryngeal and arm representations. Our results illustrate in detail the intrinsic functional architecture of the macaque LFC, thus providing valuable evidence for debates on its organization.NEW & NOTEWORTHY Resting-state functional MRI is used as a complementary method to invasive techniques to inform current debates on the organization of the macaque lateral frontal cortex. Given that the macaque cortex serves as a model for the human cortex, our results help generate more fine-tuned hypothesis for the organization of the human lateral frontal cortex.

  
  
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  Liem F, Varoquaux G, Kynast J, Beyer F, Kharabian Masouleh S, Huntenburg JM, Lampe L, Rahim M, Abraham A, Craddock RC, Riedel-Heller S, Luck T, Loeffler M, Schroeter ML, Witte AV, Villringer A, Margulies DS (2017)
  Predicting brain-age from multimodal imaging data captures cognitive impairment
  Neuroimage 148: 179–188
  
  

  The disparity between the chronological age of an individual and their brain-age measured based on biological information has the potential to offer clinically relevant biomarkers of neurological syndromes that emerge late in the lifespan. While prior brain-age prediction studies have relied exclusively on either structural or functional brain data, here we investigate how multimodal brain-imaging data improves age prediction. Using cortical anatomy and whole-brain functional connectivity on a large adult lifespan sample (N=2354, age 19-82), we found that multimodal data improves brain-based age prediction, resulting in a mean absolute prediction error of 4.29 years. Furthermore, we found that the discrepancy between predicted age and chronological age captures cognitive impairment. Importantly, the brain-age measure was robust to confounding effects: head motion did not drive brain-based age prediction and our models generalized reasonably to an independent dataset acquired at a different site (N=475). Generalization performance was increased by training models on a larger and more heterogeneous dataset. The robustness of multimodal brain-age prediction to confounds, generalizability across sites, and sensitivity to clinically-relevant impairments, suggests promising future application to the early prediction of neurocognitive disorders.

  
  
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  Kharabian Masouleh S, Herzig S, Klose L, Roggenhofer E, Tenckhoff H, Kaiser T, Thone-Otto A, Wiese M, Berg T, Schroeter ML, Margulies DS, Villringer A (2017)
  Functional connectivity alterations in patients with chronic hepatitis C virus infection: A multimodal MRI study
  J Viral Hepat 24(3): 216–225
  
  

  Chronic hepatitis C virus (HCV) infection is associated with fatigue and depression. Cognitive impairments are also reported in a smaller number of HCV-positive patients. Recent studies linked HCV to low-grade inflammation in brain. Here, we test the hypothesis that chronic HCV is associated with 3T-neuroimaging-derived grey matter volume (GMV) and functional connectivity alterations in a sample of chronic HCV (1b), without severe liver disease. Regional GMV and resting-state fMRI-derived eigenvector centrality (EC) were compared between 19 HCV-positive patients and 23 healthy controls (all females, 50-69 and 52-64 years, respectively), controlling for white matter hyperintensities and age. Standard tests were used to assess fatigue, depression and cognitive performance. Also, liver fibrosis stage and viral load were quantified among patients. In comparison with controls, HCV-positive patients had higher scores in fatigue and depression, and worse alertness scores. The groups performed similarly in other cognitive domains. We report higher EC in a cluster in the right anterior superior parietal lobule in patients, while no differences are found in GMV. Post hoc functional connectivity analysis showed increased connectivity of this cluster with primary and secondary somatosensory cortex, and temporal and occipital lobes in patients. Higher mean EC in the superior parietal cluster, adjusted for mean framewise displacement, was associated with better memory and attention performance, but not with fatigue, depression, viral load or level of liver fibrosis, among patients. These results suggest a compensatory mechanism in chronic hepatitis C and explain equivocal results in the literature about cognitive deficits in infected persons. Further studies should define the relation of these connectivity changes to the brain’s inflammatory activity.

  
  
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  Huntenburg JM, Bazin P-L, Goulas A, Tardif CL, Villringer A, Margulies DS (2017)
  A Systematic Relationship Between Functional Connectivity and Intracortical Myelin in the Human Cerebral Cortex
  Cereb Cortex 27(2): 981–997
  
  

  Research in the macaque monkey suggests that cortical areas with similar microstructure are more likely to be connected. Here, we examine this link in the human cerebral cortex using 2 magnetic resonance imaging (MRI) measures: quantitative T1 maps, which are sensitive to intracortical myelin content and provide an in vivo proxy for cortical microstructure, and resting-state functional connectivity. Using ultrahigh-resolution MRI at 7 T and dedicated image processing tools, we demonstrate a systematic relationship between T1-based intracortical myelin content and functional connectivity. This effect is independent of the proximity of areas. We employ nonlinear dimensionality reduction to characterize connectivity components and identify specific aspects of functional connectivity that are linked to myelin content. Our results reveal a consistent spatial pattern throughout different analytic approaches. While functional connectivity and myelin content are closely linked in unimodal areas, the correspondence is lower in transmodal areas, especially in posteromedial cortex and the angular gyrus. Our findings are in agreement with comprehensive reports linking histologically assessed microstructure and connectivity in different mammalian species and extend them to the human cerebral cortex in vivo.

  
  
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  Golchert J, Smallwood J, Jefferies E, Liem F, Huntenburg JM, Falkiewicz M, Lauckner ME, Oligschlager S, Villringer A, Margulies DS (2017)
  In need of constraint: Understanding the role of the cingulate cortex in the impulsive mind
  Neuroimage 146: 804–813
  
  

  Impulsive behavior often occurs without forethought and can be driven by strong emotions or sudden impulses, leading to problems in cognition and behavior across a wide range of situations. Although neuroimaging studies have explored the neurocognitive indicators of impulsivity, the large-scale functional networks that contribute to different aspects of impulsive cognition remain unclear. In particular, we lack a coherent account of why impulsivity is associated with such a broad range of different psychological features. Here, we use resting state functional connectivity, acquired in two independent samples, to investigate the neural substrates underlying different aspects of self-reported impulsivity. Based on the involvement of the anterior cingulate cortex (ACC) in cognitive but also affective processes, five seed regions were placed along the caudal to rostral gradient of the ACC. We found that positive urgency was related to functional connectivity between subgenual ACC and bilateral parietal regions such as retrosplenial cortex potentially highlighting this connection as being important in the modulation of the non-prospective, hastiness - related aspects of impulsivity. Further, two impulsivity dimensions were associated with significant alterations in functional connectivity of the supragenual ACC: (i) lack of perseverance was positively correlated to connectivity with the bilateral dorsolateral prefrontal cortex and right inferior frontal gyrus and (ii) lack of premeditation was inversely associated with functional connectivity with clusters within bilateral occipital cortex. Further analysis revealed that these connectivity patterns overlapped with bilateral dorsolateral prefrontal and bilateral occipital regions of the multiple demand network, a large-scale neural system implicated in the general control of thought and action. Together these results demonstrate that different forms of impulsivity have different neural correlates, which are linked to the functional connectivity of a region of anterior cingulate cortex. This suggests that poor perseveration and premeditation might be linked to dysfunctions in how the rostral zone of the ACC interacts with the multiple demand network that allows cognition to proceed in a controlled way.

  
  
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  Golchert J, Smallwood J, Jefferies E, Seli P, Huntenburg JM, Liem F, Lauckner ME, Oligschlager S, Bernhardt BC, Villringer A, Margulies DS (2017)
  Individual variation in intentionality in the mind-wandering state is reflected in the integration of the default-mode, fronto-parietal, and limbic networks
  Neuroimage 146: 226–235
  
  

  Mind-wandering has a controversial relationship with cognitive control. Existing psychological evidence supports the hypothesis that episodes of mind-wandering reflect a failure to constrain thinking to task-relevant material, as well the apparently alternative view that control can facilitate the expression of self-generated mental content. We assessed whether this apparent contradiction arises because of a failure to consider differences in the types of thoughts that occur during mind-wandering, and in particular, the associated level of intentionality. Using multi-modal magnetic resonance imaging (MRI) analysis, we examined the cortical organisation that underlies inter-individual differences in descriptions of the spontaneous or deliberate nature of mind-wandering. Cortical thickness, as well as functional connectivity analyses, implicated regions relevant to cognitive control and regions of the default-mode network for individuals who reported high rates of deliberate mind-wandering. In contrast, higher reports of spontaneous mind-wandering were associated with cortical thinning in parietal and posterior temporal regions in the left hemisphere (which are important in the control of cognition and attention) as well as heightened connectivity between the intraparietal sulcus and a region that spanned limbic and default-mode regions in the ventral inferior frontal gyrus. Finally, we observed a dissociation in the thickness of the retrosplenial cortex/lingual gyrus, with higher reports of spontaneous mind-wandering being associated with thickening in the left hemisphere, and higher repots of deliberate mind-wandering with thinning in the right hemisphere. These results suggest that the intentionality of the mind-wandering state depends on integration between the control and default-mode networks, with more deliberation being associated with greater integration between these systems. We conclude that one reason why mind-wandering has a controversial relationship with control is because it depends on whether the thoughts emerge in a deliberate or spontaneous fashion.

  
  
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  Bellec P, Chu C, Chouinard-Decorte F, Benhajali Y, Margulies DS, Craddock RC (2017)
  The Neuro Bureau ADHD-200 Preprocessed repository
  Neuroimage 144(Pt B): 275–286
  
  

  In 2011, the "ADHD-200 Global Competition" was held with the aim of identifying biomarkers of attention-deficit/hyperactivity disorder from resting-state functional magnetic resonance imaging (rs-fMRI) and structural MRI (s-MRI) data collected on 973 individuals. Statisticians and computer scientists were potentially the most qualified for the machine learning aspect of the competition, but generally lacked the specialized skills to implement the necessary steps of data preparation for rs-fMRI. Realizing this barrier to entry, the Neuro Bureau prospectively collaborated with all competitors by preprocessing the data and sharing these results at the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) (http://www.nitrc.org/frs/?group_id=383). This "ADHD-200 Preprocessed" release included multiple analytical pipelines to cater to different philosophies of data analysis. The processed derivatives included denoised and registered 4D fMRI volumes, regional time series extracted from brain parcellations, maps of 10 intrinsic connectivity networks, fractional amplitude of low frequency fluctuation, and regional homogeneity, along with grey matter density maps. The data was used by several teams who competed in the ADHD-200 Global Competition, including the winning entry by a group of biostaticians. To the best of our knowledge, the ADHD-200 Preprocessed release was the first large public resource of preprocessed resting-state fMRI and structural MRI data, and remains to this day the only resource featuring a battery of alternative processing paths.

  
  
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  Sarzynska J, Falkiewicz M, Riegel M, Babula J, Margulies DS, Necka E, Grabowska A, Szatkowska I (2017)
  More intelligent extraverts are more likely to deceive
  PLoS One 12(4): e0176591
  
  

  The tendency to lie is a part of personality. But are personality traits the only factors that make some people lie more often than others? We propose that cognitive abilities have equal importance. People with higher cognitive abilities are better, and thus more effective liars. This might reinforce using lies to solve problems. Yet, there is no empirical research that shows this relationship in healthy adults. Here we present three studies in which the participants had free choice about their honesty. We related differences in cognitive abilities and personality to the odds of lying. Results show that personality and intelligence are both important. People low on agreeableness and intelligent extraverts are most likely to lie. This suggests that intelligence might mediate the relationship between personality traits and lying frequency. While personality traits set general behavioral tendencies, intelligence and environment set boundaries.

  
  

2016

•  PDF |  SI |  Link |  Code |  Data | Abstract
  
  Margulies DS, Ghosh SS, Goulas A, Falkiewicz M, Huntenburg JM, Langs G, Bezgin G, Eickhoff SB, Castellanos FX, Petrides M, Jefferies E, Smallwood J (2016)
  Situating the default-mode network along a principal gradient of macroscale cortical organization
  Proc Natl Acad Sci U S A 113(44): 12574–12579
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  Understanding how the structure of cognition arises from the topographical organization of the cortex is a primary goal in neuroscience. Previous work has described local functional gradients extending from perceptual and motor regions to cortical areas representing more abstract functions, but an overarching framework for the association between structure and function is still lacking. Here, we show that the principal gradient revealed by the decomposition of connectivity data in humans and the macaque monkey is anchored by, at one end, regions serving primary sensory/motor functions and at the other end, transmodal regions that, in humans, are known as the default-mode network (DMN). These DMN regions exhibit the greatest geodesic distance along the cortical surface-and are precisely equidistant-from primary sensory/motor morphological landmarks. The principal gradient also provides an organizing spatial framework for multiple large-scale networks and characterizes a spectrum from unimodal to heteromodal activity in a functional metaanalysis. Together, these observations provide a characterization of the topographical organization of cortex and indicate that the role of the DMN in cognition might arise from its position at one extreme of a hierarchy, allowing it to process transmodal information that is unrelated to immediate sensory input.

  
  
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  Alderson-Day B, Diederen K, Fernyhough C, Ford JM, Horga G, Margulies DS, McCarthy-Jones S, Northoff G, Shine JM, Turner J, van de Ven V, van Lutterveld R, Waters F, Jardri R (2016)
  Auditory Hallucinations and the Brain’s Resting-State Networks: Findings and Methodological Observations
  Schizophr Bull 42(5): 1110–1123
  
  

  In recent years, there has been increasing interest in the potential for alterations to the brain’s resting-state networks (RSNs) to explain various kinds of psychopathology. RSNs provide an intriguing new explanatory framework for hallucinations, which can occur in different modalities and population groups, but which remain poorly understood. This collaboration from the International Consortium on Hallucination Research (ICHR) reports on the evidence linking resting-state alterations to auditory hallucinations (AH) and provides a critical appraisal of the methodological approaches used in this area. In the report, we describe findings from resting connectivity fMRI in AH (in schizophrenia and nonclinical individuals) and compare them with findings from neurophysiological research, structural MRI, and research on visual hallucinations (VH). In AH, various studies show resting connectivity differences in left-hemisphere auditory and language regions, as well as atypical interaction of the default mode network and RSNs linked to cognitive control and salience. As the latter are also evident in studies of VH, this points to a domain-general mechanism for hallucinations alongside modality-specific changes to RSNs in different sensory regions. However, we also observed high methodological heterogeneity in the current literature, affecting the ability to make clear comparisons between studies. To address this, we provide some methodological recommendations and options for future research on the resting state and hallucinations.

  
  
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  Tzouma A, Margulies DS, Triarhou LC (2016)
  Commentary on "The Cerebellar System and What it Signifies from a Biological Perspective: A Communication by Christofredo Jakob (1866-1956) Before the Society of Neurology and Psychiatry of Buenos Aires, December 1938"
  Cerebellum 15(4): 417–424
  
  

  This commentary highlights a "cerebellar classic" by a pioneer of neurobiology, Christfried Jakob. Jakob discussed the connectivity between the cerebellum and mesencephalic, diencephalic, and telencephalic structures in an evolutionary, developmental, and histophysiological perspective. He proposed three evolutionary morphofunctional stages, the archicerebellar, paleocerebellar, and neocerebellar; he attributed the reduced cerebellospinal connections in humans, compared to other primates, to the perfection of the rubrolenticular and thalamocortical systems and the intense ascending pathways to the red nucleus in exchange for the more elementary descending efferent pathways. Jakob hypothesized the convergence of cerebellar pathways in associative cortical regions, insisting on the intimate collaboration of the cerebellum with the frontal lobe. The extensive lines of communication between regions throughout the association cortex substantiate Jakob’s intuition and begin to outline the mechanisms for substantial cerebellar involvement in functions beyond the purely motor domain. Atop a foundation of anatomical and phylogenetic mastery, Jakob conceived ideas that were noteworthy, timely, and have much relevance to our current thinking on cerebellar structure and function.

  
  
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  Hove MJ, Stelzer J, Nierhaus T, Thiel SD, Gundlach C, Margulies DS, Van Dijk KRA, Turner R, Keller PE, Merker B (2016)
  Brain Network Reconfiguration and Perceptual Decoupling During an Absorptive State of Consciousness
  Cereb Cortex 26(7): 3116–3124
  
  

  Trance is an absorptive state of consciousness characterized by narrowed awareness of external surroundings and has long been used-for example, by shamans-to gain insight. Shamans across cultures often induce trance by listening to rhythmic drumming. Using functional magnetic resonance imaging (fMRI), we examined the brain-network configuration associated with trance. Experienced shamanic practitioners (n = 15) listened to rhythmic drumming, and either entered a trance state or remained in a nontrance state during 8-min scans. We analyzed changes in network connectivity. Trance was associated with higher eigenvector centrality (i.e., stronger hubs) in 3 regions: posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (dACC), and left insula/operculum. Seed-based analysis revealed increased coactivation of the PCC (a default network hub involved in internally oriented cognitive states) with the dACC and insula (control-network regions involved in maintaining relevant neural streams). This coactivation suggests that an internally oriented neural stream was amplified by the modulatory control network. Additionally, during trance, seeds within the auditory pathway were less connected, possibly indicating perceptual decoupling and suppression of the repetitive auditory stimuli. In sum, trance involved coactive default and control networks, and decoupled sensory processing. This network reconfiguration may promote an extended internal train of thought wherein integration and insight can occur.

  
  
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  Rohr CS, Villringer A, Solms-Baruth C, van der Meer E, Margulies DS, Okon-Singer H (2016)
  The neural networks of subjectively evaluated emotional conflicts
  Hum Brain Mapp 37(6): 2234–2246
  
  

  Previous work on the neural underpinnings of emotional conflict processing has largely focused on designs that instruct participants to ignore a distracter which conflicts with a target. In contrast, this study investigated the noninstructed experience and evaluation of an emotional conflict, where positive or negative cues can be subjectively prioritized. To this end, healthy participants freely watched short film scenes that evoked emotional conflicts while their BOLD responses were measured. Participants’ individual ratings of conflict and valence perception during the film scenes were collected immediately afterwards, and the individual ratings were regressed against the BOLD data. Our analyses revealed that (a) amygdala and medial prefrontal cortex were significantly involved in prioritizing positive or negative cues, but not in subjective evaluations of conflict per se, and (b) superior temporal sulcus (STS) and inferior parietal lobule (IPL), which have been implicated in social cognition and emotion control, were involved in both prioritizing positive or negative cues and subjectively evaluating conflict, and may thus constitute "hubs" or "switches" in emotional conflict processing. Psychophysiological interaction (PPI) analyses further revealed stronger functional connectivity between IPL and ventral prefrontal-medial parietal areas in prioritizing negative cues, and stronger connectivity between STS and dorsal-rostral prefrontal-medial parietal areas in prioritizing positive cues. In sum, our results suggest that IPL and STS are important in the subjective evaluation of complex conflicts and influence valence prioritization via prefrontal and parietal control centers. Hum Brain Mapp 37:2234-2246, 2016. (c) 2016 Wiley Periodicals, Inc.

  
  
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  Meshi D, Mamerow L, Kirilina E, Morawetz C, Margulies DS, Heekeren HR (2016)
  Sharing self-related information is associated with intrinsic functional connectivity of cortical midline brain regions
  Sci Rep 6: 22491
  
  

  Human beings are social animals and they vary in the degree to which they share information about themselves with others. Although brain networks involved in self-related cognition have been identified, especially via the use of resting-state experiments, the neural circuitry underlying individual differences in the sharing of self-related information is currently unknown. Therefore, we investigated the intrinsic functional organization of the brain with respect to participants’ degree of self-related information sharing using resting state functional magnetic resonance imaging and self-reported social media use. We conducted seed-based correlation analyses in cortical midline regions previously shown in meta-analyses to be involved in self-referential cognition: the medial prefrontal cortex (MPFC), central precuneus (CP), and caudal anterior cingulate cortex (CACC). We examined whether and how functional connectivity between these regions and the rest of the brain was associated with participants’ degree of self-related information sharing. Analyses revealed associations between the MPFC and right dorsolateral prefrontal cortex (DLPFC), as well as the CP with the right DLPFC, the left lateral orbitofrontal cortex and left anterior temporal pole. These findings extend our present knowledge of functional brain connectivity, specifically demonstrating how the brain’s intrinsic functional organization relates to individual differences in the sharing of self-related information.

  
  
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  Xiao Y, Friederici AD, Margulies DS, Brauer J (2016)
  Longitudinal changes in resting-state fMRI from age 5 to age 6years covary with language development
  Neuroimage 128: 116–124
  
  

  Resting-state functional magnetic resonance imaging is a powerful technique to study the whole-brain neural connectivity that underlies cognitive systems. The present study aimed to define the changes in neural connectivity in their relation to language development. Longitudinal resting-state functional data were acquired from a cohort of preschool children at age 5 and one year later, and changes in functional connectivity were correlated with language performance in sentence comprehension. For this, degree centrality, a voxel-based network measure, was used to assess age-related differences in connectivity at the whole-brain level. Increases in connectivity with age were found selectively in a cluster within the left posterior superior temporal gyrus and sulcus (STG/STS). In order to further specify the connection changes, a secondary seed-based functional connectivity analysis on this very cluster was performed. The correlations between resting-state functional connectivity (RSFC) and language performance revealed developmental effects with age and, importantly, also dependent on the advancement in sentence comprehension ability over time. In children with greater advancement in language abilities, the behavioral improvement was positively correlated with RSFC increase between left posterior STG/STS and other regions of the language network, i.e., left and right inferior frontal cortex. The age-related changes observed in this study provide evidence for alterations in the language network as language develops and demonstrates the viability of this approach for the investigation of normal and aberrant language development.

  
  
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  Xiao Y, Friederici AD, Margulies DS, Brauer J (2016)
  Development of a selective left-hemispheric fronto-temporal network for processing syntactic complexity in language comprehension
  Neuropsychologia 83: 274–282
  
  

  The development of language comprehension abilities in childhood is closely related to the maturation of the brain, especially the ability to process syntactically complex sentences. Recent studies proposed that the fronto-temporal connection within left perisylvian regions, supporting the processing of syntactically complex sentences, is still immature at preschool age. In the current study, resting state functional magnetic resonance imaging data were acquired from typically developing 5-year-old children and adults to shed further light on the brain functional development. Children additionally performed a behavioral syntactic comprehension test outside the scanner. The amplitude of low-frequency fluctuations was analyzed in order to identify the functional correlation networks of language-relevant brain regions. Results showed an intrahemispheric correlation between left inferior frontal gyrus (IFG) and left posterior superior temporal sulcus (pSTS) in adults, whereas an interhemispheric correlation between left IFG and its right-hemispheric homolog was predominant in children. Correlation analysis between resting-state functional connectivity and sentence processing performance in 5-year-olds revealed that local connectivity within the left IFG is associated with competence of processing syntactically simple canonical sentences, while long-range connectivity between IFG and pSTS in left hemisphere is associated with competence of processing syntactically relatively more complex non-canonical sentences. The present developmental data suggest that a selective left fronto-temporal connectivity network for processing complex syntax is already in functional connection at the age of 5 years when measured in a non-task situation. The correlational findings provide new insight into the relationship between intrinsic functional connectivity and syntactic language abilities in preschool children.

  
  
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  Jakobsen E, Bottger J, Bellec P, Geyer S, Rubsamen R, Petrides M, Margulies DS (2016)
  Subdivision of Broca’s region based on individual-level functional connectivity
  Eur J Neurosci 43(4): 561–571
  
  

  Broca’s region is composed of two adjacent cytoarchitectonic areas, 44 and 45, which have distinct connectivity to superior temporal and inferior parietal regions in both macaque monkeys and humans. The current study aimed to make use of prior knowledge of sulcal anatomy and resting-state functional connectivity, together with a novel visualization technique, to manually parcellate areas 44 and 45 in individual brains in vivo. One hundred and one resting-state functional magnetic resonance imaging datasets from the Human Connectome Project were used. Left-hemisphere surface-based correlation matrices were computed and visualized in brainGL. By observation of differences in the connectivity patterns of neighbouring nodes, areas 44 and 45 were manually parcellated in individual brains, and then compared at the group-level. Additionally, the manual labelling approach was compared with parcellation results based on several data-driven clustering techniques. Areas 44 and 45 could be clearly distinguished from each other in all individuals, and the manual segmentation method showed high test-retest reliability. Group-level probability maps of areas 44 and 45 showed spatial consistency across individuals, and corresponded well to cytoarchitectonic probability maps. Group-level connectivity maps were consistent with previous studies showing distinct connectivity patterns of areas 44 and 45. Data-driven parcellation techniques produced clusters with varying degrees of spatial overlap with the manual labels, indicating the need for further investigation and validation of machine learning cortical segmentation approaches. The current study provides a reliable method for individual-level cortical parcellation that could be applied to regions distinguishable by even the most subtle differences in patterns of functional connectivity.

  
  
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  Cohen N, Margulies DS, Ashkenazi S, Schaefer A, Taubert M, Henik A, Villringer A, Okon-Singer H (2016)
  Using executive control training to suppress amygdala reactivity to aversive information
  Neuroimage 125: 1022–1031
  
  

  The ability to regulate emotions is essential for adaptive behavior. This ability is suggested to be mediated by the connectivity between prefrontal brain regions and the amygdala. Yet, it is still unknown whether the ability to regulate emotions can be trained by using a non-emotional procedure, such as the recruitment of executive control (EC). Participants who were trained using a high-frequent executive control (EC) task (80% incongruent trials) showed reduced amygdala reactivity and behavioral interference of aversive pictures. These effects were observed only following multiple-session training and not following one training session. In addition, they were not observed for participants exposed to low-frequent EC training (20% incongruent trials). Resting-state functional connectivity analysis revealed a marginally significant interaction between training group and change in the connectivity between the amygdala and the right inferior frontal gyrus (IFG). Amygdala-IFG connectivity was significantly increased following the training only in the high-frequent EC training group. These findings are the first to show that non-emotional training can induce changes in amygdala reactivity to aversive information and alter amygdala-prefrontal connectivity.

  
  
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  Gorgolewski KJ, Varoquaux G, Rivera G, Schwartz Y, Sochat VV, Ghosh SS, Maumet C, Nichols TE, Poline J-B, Yarkoni T, Margulies DS, Poldrack RA (2016)
  NeuroVaultorg: A repository for sharing unthresholded statistical maps, parcellations, and atlases of the human brain
  Neuroimage 124(Pt B): 1242–1244
  
  

  NeuroVault.org is dedicated to storing outputs of analyses in the form of statistical maps, parcellations and atlases, a unique strategy that contrasts with most neuroimaging repositories that store raw acquisition data or stereotaxic coordinates. Such maps are indispensable for performing meta-analyses, validating novel methodology, and deciding on precise outlines for regions of interest (ROIs). NeuroVault is open to maps derived from both healthy and clinical populations, as well as from various imaging modalities (sMRI, fMRI, EEG, MEG, PET, etc.). The repository uses modern web technologies such as interactive web-based visualization, cognitive decoding, and comparison with other maps to provide researchers with efficient, intuitive tools to improve the understanding of their results. Each dataset and map is assigned a permanent Universal Resource Locator (URL), and all of the data is accessible through a REST Application Programming Interface (API). Additionally, the repository supports the NIDM-Results standard and has the ability to parse outputs from popular FSL and SPM software packages to automatically extract relevant metadata. This ease of use, modern web-integration, and pioneering functionality holds promise to improve the workflow for making inferences about and sharing whole-brain statistical maps.

  
  
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  Ellamil M, Berson J, Margulies DS (2016)
  Influences on and Measures of Unintentional Group Synchrony
  Front Psychol 7: 1744
  
  

  Many instances of large-scale coordination occur in real-life social situations without the explicit awareness of the individuals involved. While the majority of research to date has examined dyadic interactions - those between two individuals - during intentional or deliberate coordination, the present review surveys the handful of recent studies investigating behavioral and physiological synchrony across groups of more than two people when coordination was not an explicit goal. Both minimal (e.g., visual information, shared location) and naturalistic (e.g., choir voice section, family relationship) group interactions appear to promote unintentional group synchrony although they have so far only been studied separately. State differences in unintentional group synchrony, or the relative presence of coordination in various conditions, have tended to be assessed differently, such as using correlation-type relationships, compared to its temporal dynamics, or changes over time in the degree of coordination, which appear to be best captured using phase differences. Simultaneously evaluating behavioral, physiological, and social responses as well systematically comparing different synchrony measures could further our understanding of the influences on and measures of group synchrony, allowing us to move away from studying individual persons responding to static laboratory stimuli and toward investigating collective experiences in natural, dynamic social interactions.

  
  
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  Xiao Y, Brauer J, Lauckner M, Zhai H, Jia F, Margulies DS, Friederici AD (2016)
  Development of the Intrinsic Language Network in Preschool Children from Ages 3 to 5 Years
  PLoS One 11(11): e0165802
  
  

  Resting state studies of spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) blood oxygen level dependent signal have shown great potential in mapping the intrinsic functional connectivity of the human brain underlying cognitive functions. The aim of the present study was to explore the developmental changes in functional networks of the developing human brain exemplified with the language network in typically developing preschool children. To this end, resting-sate fMRI data were obtained from native Chinese children at ages of 3 and 5 years, 15 in each age group. Resting-state functional connectivity (RSFC) was analyzed for four regions of interest; these are the left and right anterior superior temporal gyrus (aSTG), left posterior superior temporal gyrus (pSTG), and left inferior frontal gyrus (IFG). The comparison of these RSFC maps between 3- and 5-year-olds revealed that RSFC decreases in the right aSTG and increases in the left hemisphere between aSTG seed and IFG, between pSTG seed and IFG, as well as between IFG seed and posterior superior temporal sulcus. In a subsequent analysis, functional asymmetry of the language network seeding in aSTG, pSTG and IFG was further investigated. The results showed an increase of left lateralization in both RSFC of pSTG and of IFG from ages 3 to 5 years. The IFG showed a leftward lateralized trend in 3-year-olds, while pSTG demonstrated rightward asymmetry in 5-year-olds. These findings suggest clear developmental trajectories of the language network between 3- and 5-year-olds revealed as a function of age, characterized by increasing long-range connections and dynamic hemispheric lateralization with age. Our study provides new insights into the developmental changes of a well-established functional network in young children and also offers a basis for future cross-culture and cross-age studies of the resting-state language network.

  
  
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  Ellamil M, Berson J, Wong J, Buckley L, Margulies DS (2016)
  One in the Dance: Musical Correlates of Group Synchrony in a Real-World Club Environment
  PLoS One 11(10): e0164783
  
  

  Previous research on interpersonal synchrony has mainly investigated small groups in isolated laboratory settings, which may not fully reflect the complex and dynamic interactions of real-life social situations. The present study expands on this by examining group synchrony across a large number of individuals in a naturalistic environment. Smartphone acceleration measures were recorded from participants during a music set in a dance club and assessed to identify how group movement synchrony covaried with various features of the music. In an evaluation of different preprocessing and analysis methods, giving more weight to front-back movement provided the most sensitive and reliable measure of group synchrony. During the club music set, group synchrony of torso movement was most strongly associated with pulsations that approximate walking rhythm (100-150 beats per minute). Songs with higher real-world play counts were also correlated with greater group synchrony. Group synchrony thus appears to be constrained by familiarity of the movement (walking action and rhythm) and of the music (song popularity). These findings from a real-world, large-scale social and musical setting can guide the development of methods for capturing and examining collective experiences in the laboratory and for effectively linking them to synchrony across people in daily life.

  
  
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  Lohmann G, Stelzer J, Zuber V, Buschmann T, Margulies DS, Bartels A, Scheffler K (2016)
  Task-Related Edge Density (TED)-A New Method for Revealing Dynamic Network Formation in fMRI Data of the Human Brain
  PLoS One 11(6): e0158185
  
  

  The formation of transient networks in response to external stimuli or as a reflection of internal cognitive processes is a hallmark of human brain function. However, its identification in fMRI data of the human brain is notoriously difficult. Here we propose a new method of fMRI data analysis that tackles this problem by considering large-scale, task-related synchronisation networks. Networks consist of nodes and edges connecting them, where nodes correspond to voxels in fMRI data, and the weight of an edge is determined via task-related changes in dynamic synchronisation between their respective times series. Based on these definitions, we developed a new data analysis algorithm that identifies edges that show differing levels of synchrony between two distinct task conditions and that occur in dense packs with similar characteristics. Hence, we call this approach "Task-related Edge Density" (TED). TED proved to be a very strong marker for dynamic network formation that easily lends itself to statistical analysis using large scale statistical inference. A major advantage of TED compared to other methods is that it does not depend on any specific hemodynamic response model, and it also does not require a presegmentation of the data for dimensionality reduction as it can handle large networks consisting of tens of thousands of voxels. We applied TED to fMRI data of a fingertapping and an emotion processing task provided by the Human Connectome Project. TED revealed network-based involvement of a large number of brain areas that evaded detection using traditional GLM-based analysis. We show that our proposed method provides an entirely new window into the immense complexity of human brain function.

  
  
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  Smallwood J, Karapanagiotidis T, Ruby F, Medea B, de Caso I, Konishi M, Wang H-T, Hallam G, Margulies DS, Jefferies E (2016)
  Representing Representation: Integration between the Temporal Lobe and the Posterior Cingulate Influences the Content and Form of Spontaneous Thought
  PLoS One 11(4): e0152272
  
  

  When not engaged in the moment, we often spontaneously represent people, places and events that are not present in the environment. Although this capacity has been linked to the default mode network (DMN), it remains unclear how interactions between the nodes of this network give rise to particular mental experiences during spontaneous thought. One hypothesis is that the core of the DMN integrates information from medial and lateral temporal lobe memory systems, which represent different aspects of knowledge. Individual differences in the connectivity between temporal lobe regions and the default mode network core would then predict differences in the content and form of people’s spontaneous thoughts. This study tested this hypothesis by examining the relationship between seed-based functional connectivity and the contents of spontaneous thought recorded in a laboratory study several days later. Variations in connectivity from both medial and lateral temporal lobe regions was associated with different patterns of spontaneous thought and these effects converged on an overlapping region in the posterior cingulate cortex. We propose that the posterior core of the DMN acts as a representational hub that integrates information represented in medial and lateral temporal lobe and this process is important in determining the content and form of spontaneous thought.

  
  
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  Barnhofer T, Huntenburg JM, Lifshitz M, Wild J, Antonova E, Margulies DS (2016)
  How Mindfulness Training May Help to Reduce Vulnerability for Recurrent Depression: A Neuroscientific Perspective
  Clinical Psychological Science 4(2): 328–343
  
  

  This review investigates how recent neuroimaging findings on vulnerability for depression and the mechanisms of mindfulness may serve to inform and enhance the understanding that is guiding the use of mindfulness training in the prevention and treatment of recurrent and chronic depression. In particular, we review evidence suggesting that alterations in default-mode-network activity and connectivity represent a fundamental deficit underlying cognitive vulnerability for depression and explore the ways in which mindfulness meditation may reverse such alterations. Furthermore, we discuss findings from studies that have investigated the effects of mindfulness on emotion-regulatory capacities. These findings suggest mindful emotion regulation has a characteristic neural signature that is particularly conducive to therapeutic learning. We conclude that training in mindfulness has unique strengths for addressing neural mechanisms associated with cognitive vulnerabilities for recurrent and chronic depression and propose future lines of research to more effectively harness this potential.

  
  
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  Craddock RC, Margulies DS, Bellec P, Nichols BN, Alcauter S, Barrios FA, Burnod Y, Cannistraci CJ, Cohen-Adad J, De Leener B, Dery S, Downar J, Dunlop K, Franco AR, Seligman Froehlich C, Gerber AJ, Ghosh SS, Grabowski TJ, Hill S, Sólon Heinsfeld A, Hutchison RM, Kundu P, Laird AR, Liew S-L, Lurie DJ, McLaren DG, Meneguzzi F, Mennes M, Mesmoudi S, O’Connor D, Pasaye EH, Peltier S, Poline J-B, Prasad G, Fraga Pereira R, Quirion P-O, Rokem A, Saad ZS, Shi Y, Strother SC, Toro R, Uddin LQ, Van Horn JD, Van Meter JW, Welsh RC, Xu T (2016)
  Brainhack: a collaborative workshop for the open neuroscience community
  GigaScience 5(1): s13742–016-0121-x
  
  

  Brainhack events offer a novel workshop format with participant-generated content that caters to the rapidly growing open neuroscience community. Including components from hackathons and unconferences, as well as parallel educational sessions, Brainhack fosters novel collaborations around the interests of its attendees. Here we provide an overview of its structure, past events, and example projects. Additionally, we outline current innovations such as regional events and post-conference publications. Through introducing Brainhack to the wider neuroscience community, we hope to provide a unique conference format that promotes the features of collaborative, open science.

  
  

2015

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  Joel D, Berman Z, Tavor I, Wexler N, Gaber O, Stein Y, Shefi N, Pool J, Urchs S, Margulies DS, Liem F, Hanggi J, Jancke L, Assaf Y (2015)
  Sex beyond the genitalia: The human brain mosaic
  Proc Natl Acad Sci U S A 112(50): 15468–15473
  
  

  Whereas a categorical difference in the genitals has always been acknowledged, the question of how far these categories extend into human biology is still not resolved. Documented sex/gender differences in the brain are often taken as support of a sexually dimorphic view of human brains ("female brain" or "male brain"). However, such a distinction would be possible only if sex/gender differences in brain features were highly dimorphic (i.e., little overlap between the forms of these features in males and females) and internally consistent (i.e., a brain has only "male" or only "female" features). Here, analysis of MRIs of more than 1,400 human brains from four datasets reveals extensive overlap between the distributions of females and males for all gray matter, white matter, and connections assessed. Moreover, analyses of internal consistency reveal that brains with features that are consistently at one end of the "maleness-femaleness" continuum are rare. Rather, most brains are comprised of unique "mosaics" of features, some more common in females compared with males, some more common in males compared with females, and some common in both females and males. Our findings are robust across sample, age, type of MRI, and method of analysis. These findings are corroborated by a similar analysis of personality traits, attitudes, interests, and behaviors of more than 5,500 individuals, which reveals that internal consistency is extremely rare. Our study demonstrates that, although there are sex/gender differences in the brain, human brains do not belong to one of two distinct categories: male brain/female brain.

  
  
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  Rohr CS, Dreyer FR, Aderka IM, Margulies DS, Frisch S, Villringer A, Okon-Singer H (2015)
  Individual differences in common factors of emotional traits and executive functions predict functional connectivity of the amygdala
  Neuroimage 120: 154–163
  
  

  Evidence suggests that individual differences in emotion control are associated with frontoparietal-limbic networks and linked to emotional traits and executive functions. In a first attempt to directly target the link between emotional traits and executive functions using resting-state fMRI analysis, 43 healthy adults completed a test battery including executive tasks and emotional trait self-assessments that were subjected to a principal component analysis. Of the three factors detected, two explained 40.4% of the variance and were further investigated. Both factors suggest a relation between emotional traits and executive functions. Specifically, the first factor consisted of measures related to inhibitory control and negative affect, and the second factor was related to reward and positive affect. To investigate whether this interplay between emotional traits and executive functions is reflected in neural connectivity, we used resting-state fMRI to explore the functional connectivity of the amygdala as a starting point, and progressed to other seed-based analyses based on the initial findings. We found that the first factor predicted the strength of connectivity between brain regions known to be involved in the cognitive control of emotion, including the amygdala and the dorsolateral prefrontal cortex, whereas the second factor predicted the strength of connectivity between brain regions known to be involved in reward and attention, including the amygdala, the caudate and the thalamus. These findings suggest that individual differences in the ability to inhibit negative affect are mediated by prefrontal-limbic pathways, while the ability to be positive and use rewarding information is mediated by a network that includes the amygdala and thalamostriatal regions.

  
  
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  Garcia-Garcia I, Jurado MA, Garolera M, Marques-Iturria I, Horstmann A, Segura B, Pueyo R, Sender-Palacios MJ, Vernet-Vernet M, Villringer A, Junque C, Margulies DS, Neumann J (2015)
  Functional network centrality in obesity: A resting-state and task fMRI study
  Psychiatry Res 233(3): 331–338
  
  

  Obesity is associated with structural and functional alterations in brain areas that are often functionally distinct and anatomically distant. This suggests that obesity is associated with differences in functional connectivity of regions distributed across the brain. However, studies addressing whole brain functional connectivity in obesity remain scarce. Here, we compared voxel-wise degree centrality and eigenvector centrality between participants with obesity (n=20) and normal-weight controls (n=21). We analyzed resting state and task-related fMRI data acquired from the same individuals. Relative to normal-weight controls, participants with obesity exhibited reduced degree centrality in the right middle frontal gyrus in the resting-state condition. During the task fMRI condition, obese participants exhibited less degree centrality in the left middle frontal gyrus and the lateral occipital cortex along with reduced eigenvector centrality in the lateral occipital cortex and occipital pole. Our results highlight the central role of the middle frontal gyrus in the pathophysiology of obesity, a structure involved in several brain circuits signaling attention, executive functions and motor functions. Additionally, our analysis suggests the existence of task-dependent reduced centrality in occipital areas; regions with a role in perceptual processes and that are profoundly modulated by attention.

  
  
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  Goulas A, Schaefer A, Margulies DS (2015)
  The strength of weak connections in the macaque cortico-cortical network
  Brain Struct Funct 220(5): 2939–2951
  
  

  Examination of the cortico-cortical network of mammals has unraveled key topological features and their role in the function of the healthy and diseased brain. Recent findings from social and biological networks pinpoint the significant role of weak connections in network coherence and mediation of information from segregated parts of the network. In the current study, inspired by such findings and proposed architectures pertaining to social networks, we examine the structure of weak connections in the macaque cortico-cortical network by employing a tract-tracing dataset. We demonstrate that the cortico-cortical connections as a whole, as well as connections between segregated communities of brain areas, comply with the architecture suggested by the so-called strength-of-weak-ties hypothesis. However, we find that the wiring of these connections is not optimal with respect to the aforementioned architecture. This configuration is not attributable to a trade-off with factors known to constrain brain wiring, i.e., wiring cost and efficiency. Lastly, weak connections, but not strong ones, appear important for network cohesion. Our findings relate a topological property to the strength of cortico-cortical connections, highlight the prominent role of weak connections in the cortico-cortical structural network and pinpoint their potential functional significance. These findings suggest that certain neuroimaging studies, despite methodological challenges, should explicitly take them into account and not treat them as negligible.

  
  
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  Striem-Amit E, Ovadia-Caro S, Caramazza A, Margulies DS, Villringer A, Amedi A (2015)
  Functional connectivity of visual cortex in the blind follows retinotopic organization principles
  Brain 138(Pt 6): 1679–1695
  
  

  Is visual input during critical periods of development crucial for the emergence of the fundamental topographical mapping of the visual cortex? And would this structure be retained throughout life-long blindness or would it fade as a result of plastic, use-based reorganization? We used functional connectivity magnetic resonance imaging based on intrinsic blood oxygen level-dependent fluctuations to investigate whether significant traces of topographical mapping of the visual scene in the form of retinotopic organization, could be found in congenitally blind adults. A group of 11 fully and congenitally blind subjects and 18 sighted controls were studied. The blind demonstrated an intact functional connectivity network structural organization of the three main retinotopic mapping axes: eccentricity (centre-periphery), laterality (left-right), and elevation (upper-lower) throughout the retinotopic cortex extending to high-level ventral and dorsal streams, including characteristic eccentricity biases in face- and house-selective areas. Functional connectivity-based topographic organization in the visual cortex was indistinguishable from the normally sighted retinotopic functional connectivity structure as indicated by clustering analysis, and was found even in participants who did not have a typical retinal development in utero (microphthalmics). While the internal structural organization of the visual cortex was strikingly similar, the blind exhibited profound differences in functional connectivity to other (non-visual) brain regions as compared to the sighted, which were specific to portions of V1. Central V1 was more connected to language areas but peripheral V1 to spatial attention and control networks. These findings suggest that current accounts of critical periods and experience-dependent development should be revisited even for primary sensory areas, in that the connectivity basis for visual cortex large-scale topographical organization can develop without any visual experience and be retained through life-long experience-dependent plasticity. Furthermore, retinotopic divisions of labour, such as that between the visual cortex regions normally representing the fovea and periphery, also form the basis for topographically-unique plastic changes in the blind.

  
  
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  Nierhaus T, Forschack N, Piper SK, Holtze S, Krause T, Taskin B, Long X, Stelzer J, Margulies DS, Steinbrink J, Villringer A (2015)
  Imperceptible somatosensory stimulation alters sensorimotor background rhythm and connectivity
  J Neurosci 35(15): 5917–5925
  
  

  Most sensory input to our body is not consciously perceived. Nevertheless, it may reach the cortex and influence our behavior. In this study, we investigated noninvasive neural signatures of unconscious cortical stimulus processing to understand mechanisms, which (1) prevent low-intensity somatosensory stimuli from getting access to conscious experience and which (2) can explain the associated impediment of conscious perception for additional stimuli. Stimulation of digit 2 in humans far below the detection threshold elicited a cortical evoked potential (P1) at 60 ms, but no further somatosensory evoked potential components. No event-related desynchronization was detected; rather, there was a transient synchronization in the alpha frequency range. Using the same stimulation during fMRI, a reduced centrality of contralateral primary somatosensory cortex (SI) was found, which appeared to be mainly driven by reduced functional connectivity to frontoparietal areas. We conclude that after subthreshold stimulation the (excitatory) feedforward sweep of bottom-up processing terminates in SI preventing access to conscious experience. We speculate that this interruption is due to a predominance of inhibitory processing in SI. The increase in alpha activity and the disconnection of SI from frontoparietal areas are likely correlates of an elevated perception threshold and may thus serve as a gating mechanism for the access to conscious experience.

  
  
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  Gorgolewski KJ, Mendes N, Wilfling D, Wladimirow E, Gauthier CJ, Bonnen T, Ruby FJM, Trampel R, Bazin P-L, Cozatl R, Smallwood J, Margulies DS (2015)
  A high resolution 7-Tesla resting-state fMRI test-retest dataset with cognitive and physiological measures
  Sci Data 2: 140054
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  Here we present a test-retest dataset of functional magnetic resonance imaging (fMRI) data acquired at rest. 22 participants were scanned during two sessions spaced one week apart. Each session includes two 1.5 mm isotropic whole-brain scans and one 0.75 mm isotropic scan of the prefrontal cortex, giving a total of six time-points. Additionally, the dataset includes measures of mood, sustained attention, blood pressure, respiration, pulse, and the content of self-generated thoughts (mind wandering). This data enables the investigation of sources of both intra- and inter-session variability not only limited to physiological changes, but also including alterations in cognitive and affective states, at high spatial resolution. The dataset is accompanied by a detailed experimental protocol and source code of all stimuli used.

  
  
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  Gorgolewski KJ, Varoquaux G, Rivera G, Schwarz Y, Ghosh SS, Maumet C, Sochat VV, Nichols TE, Poldrack RA, Poline J-B, Yarkoni T, Margulies DS (2015)
  NeuroVaultorg: a web-based repository for collecting and sharing unthresholded statistical maps of the human brain
  Front Neuroinform 9: 8
  
  

  Here we present NeuroVault-a web based repository that allows researchers to store, share, visualize, and decode statistical maps of the human brain. NeuroVault is easy to use and employs modern web technologies to provide informative visualization of data without the need to install additional software. In addition, it leverages the power of the Neurosynth database to provide cognitive decoding of deposited maps. The data are exposed through a public REST API enabling other services and tools to take advantage of it. NeuroVault is a new resource for researchers interested in conducting meta- and coactivation analyses.

  
  

2014

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  Garcia-Garcia I, Horstmann A, Jurado MA, Garolera M, Chaudhry SJ, Margulies DS, Villringer A, Neumann J (2014)
  Reward processing in obesity, substance addiction and non-substance addiction
  Obes Rev 15(11): 853–869
  
  

  Similarities and differences between obesity and addiction are a prominent topic of ongoing research. We conducted an activation likelihood estimation meta-analysis on 87 studies in order to map the functional magnetic resonance imaging (fMRI) response to reward in participants with obesity, substance addiction and non-substance (or behavioural) addiction, and to identify commonalities and differences between them. Our study confirms the existence of alterations during reward processing in obesity, non-substance addiction and substance addiction. Specifically, participants with obesity or with addictions differed from controls in several brain regions including prefrontal areas, subcortical structures and sensory areas. Additionally, participants with obesity and substance addictions exhibited similar blood-oxygen-level-dependent fMRI hyperactivity in the amygdala and striatum when processing either general rewarding stimuli or the problematic stimuli (food and drug-related stimuli, respectively). We propose that these similarities may be associated with an enhanced focus on reward–especially with regard to food or drug-related stimuli–in obesity and substance addiction. Ultimately, this enhancement of reward processes may facilitate the presence of compulsive-like behaviour in some individuals or under some specific circumstances. We hope that increasing knowledge about the neurobehavioural correlates of obesity and addictions will lead to practical strategies that target the high prevalence of these central public health challenges.

  
  
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  Schaefer A, Burmann I, Regenthal R, Arelin K, Barth C, Pampel A, Villringer A, Margulies DS, Sacher J (2014)
  Serotonergic modulation of intrinsic functional connectivity
  Curr Biol 24(19): 2314–2318
  
  

  Serotonin functions as an essential neuromodulator that serves a multitude of roles, most prominently balancing mood. Serotonergic challenge has been observed to reduce intrinsic functional connectivity in brain regions implicated in mood regulation. However, the full scope of serotonergic action on functional connectivity in the human brain has not been explored. Here, we show evidence that a single dose of a serotonin reuptake inhibitor dramatically alters functional connectivity throughout the whole brain in healthy subjects (n = 22). Our network-centrality analysis reveals a widespread decrease in connectivity in most cortical and subcortical areas. In the cerebellum and thalamus, however, we find localized increases. These rapid and brain-encompassing connectivity changes linked to acute serotonin transporter blockade suggest a key role for the serotonin transporter in the modulation of the functional macroscale connectome.

  
  
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  Ovadia-Caro S, Margulies DS, Villringer A (2014)
  The value of resting-state functional magnetic resonance imaging in stroke
  Stroke 45(9): 2818–2824
  
  

  
  
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  Witte AV, Kerti L, Margulies DS, Floel A (2014)
  Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults
  J Neurosci 34(23): 7862–7870
  
  

  Dietary habits such as caloric restriction or nutrients that mimic these effects may exert beneficial effects on brain aging. The plant-derived polyphenol resveratrol has been shown to increase memory performance in primates; however, interventional studies in older humans are lacking. Here, we tested whether supplementation of resveratrol would enhance memory performance in older adults and addressed potential mechanisms underlying this effect. Twenty-three healthy overweight older individuals that successfully completed 26 weeks of resveratrol intake (200 mg/d) were pairwise matched to 23 participants that received placebo (total n = 46, 18 females, 50-75 years). Before and after the intervention/control period, subjects underwent memory tasks and neuroimaging to assess volume, microstructure, and functional connectivity (FC) of the hippocampus, a key region implicated in memory functions. In addition, anthropometry, glucose and lipid metabolism, inflammation, neurotrophic factors, and vascular parameters were assayed. We observed a significant effect of resveratrol on retention of words over 30 min compared with placebo (p = 0.038). In addition, resveratrol led to significant increases in hippocampal FC, decreases in glycated hemoglobin (HbA1c) and body fat, and increases in leptin compared with placebo (all p < 0.05). Increases in FC between the left posterior hippocampus and the medial prefrontal cortex correlated with increases in retention scores and with decreases in HbA1c (all p < 0.05). This study provides initial evidence that supplementary resveratrol improves memory performance in association with improved glucose metabolism and increased hippocampal FC in older adults. Our findings offer the basis for novel strategies to maintain brain health during aging.

  
  
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  Yang Z, Craddock RC, Margulies DS, Yan C-G, Milham MP (2014)
  Common intrinsic connectivity states among posteromedial cortex subdivisions: Insights from analysis of temporal dynamics
  Neuroimage 93 Pt 1: 124–137
  
  

  Perspectives of human brain functional connectivity continue to evolve. Static representations of functional interactions between brain regions are rapidly giving way to dynamic perspectives, which emphasize non-random temporal variations in intrinsic functional connectivity (iFC) patterns. Here, we bring this dynamic perspective to our understanding of iFC patterns for posteromedial cortex (PMC), a cortical hub known for its functional diversity. Previous work has consistently differentiated iFC patterns among PMC subregions, though assumed static iFC over time. Here, we assessed iFC as a function of time utilizing a sliding-window correlation approach, and applied hierarchical clustering to detect representative iFC states from the windowed iFC. Across subregions, five iFC states were detected over time. Although with differing frequencies, each subregion was associated with each of the states, suggesting that these iFC states are "common" to PMC subregions. Importantly, each subregion possessed a unique preferred state(s) and distinct transition patterns, explaining previously observed iFC differentiations. These results resonate with task-based fMRI studies suggesting that large-scale functional networks can be flexibly reconfigured in response to changing task-demands. Additionally, we used retest scans ( 1week later) to demonstrate the reproducibility of the iFC states identified, and establish moderate to high test-retest reliability for various metrics used to quantify switching behaviors. We also demonstrate the ability of dynamic properties in the visual PMC subregion to index inter-individual differences in a measure of concept formation and mental flexibility. These findings suggest functional relevance of dynamic iFC and its potential utility in biomarker identification over time, as d-iFC methodologies are refined and mature.

  
  
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  Long X, Goltz D, Margulies DS, Nierhaus T, Villringer A (2014)
  Functional connectivity-based parcellation of the human sensorimotor cortex
  Eur J Neurosci 39(8): 1332–1342
  
  

  Task-based functional magnetic resonance imaging (fMRI) has been successfully employed to obtain somatotopic maps of the human sensorimotor cortex. Here, we showed through direct comparison that a similar functional map can be obtained, independently of a task, by performing a connectivity-based parcellation of the sensorimotor cortex based on resting-state fMRI. Cortex corresponding to two adjacent Brodmann areas (BA 3 and BA 4) was selected as the sensorimotor area. Parcellation was obtained along a medial-lateral axis, which was confirmed to be somatotopic (corresponding roughly to an upper, middle and lower limb, respectively) by comparing it with maps obtained using motoric task-based fMRI in the same participants. Interestingly, the resting-state parcellation map demonstrated higher correspondence to the task-based divisions after individuals performed the motor task. Using the resting-state fMRI data, we also observed higher functional correlations between the centrally located hand region and the other two regions, than between the foot and tongue. The functional relevance of these somatosensory parcellation results indicates the feasibility of a wide range of potential applications to brain mapping.

  
  
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  Rojas GM, Galvez M, Vega Potler N, Craddock RC, Margulies DS, Castellanos FX, Milham MP (2014)
  Stereoscopic three-dimensional visualization applied to multimodal brain images: clinical applications and a functional connectivity atlas
  Front Neurosci 8: 328
  
  

  Effective visualization is central to the exploration and comprehension of brain imaging data. While MRI data are acquired in three-dimensional space, the methods for visualizing such data have rarely taken advantage of three-dimensional stereoscopic technologies. We present here results of stereoscopic visualization of clinical data, as well as an atlas of whole-brain functional connectivity. In comparison with traditional 3D rendering techniques, we demonstrate the utility of stereoscopic visualizations to provide an intuitive description of the exact location and the relative sizes of various brain landmarks, structures and lesions. In the case of resting state fMRI, stereoscopic 3D visualization facilitated comprehension of the anatomical position of complex large-scale functional connectivity patterns. Overall, stereoscopic visualization improves the intuitive visual comprehension of image contents, and brings increased dimensionality to visualization of traditional MRI data, as well as patterns of functional connectivity.

  
  
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  Callard F, Margulies DS (2014)
  What we talk about when we talk about the default mode network
  Front Hum Neurosci 8: 619
  
  

  The default mode network (DMN) has been widely defined as a set of brain regions that are engaged when people are in a "resting state" (left to themselves in a scanner, with no explicit task instruction). The network emerged as a scientific object in the early twenty-first century, and in just over a decade has become the focus of intense empirical and conceptual neuroscientific inquiry. In this Perspective, we contribute to the work of critical neuroscience by providing brief reflections on the birth, working life, and future of the DMN. We consider: how the DMN emerged through the convergence of distinct lines of scientific investigation; controversies surrounding the definition, function and localization of the DMN; and the lines of interdisciplinary investigation that the DMN has helped to enable. We conclude by arguing that one of the most pressing issues in the field in 2014 is to understand how the mechanisms of thought are related to the function of brain dynamics. While the DMN has been central in allowing the field to reach this point, it is not inevitable that the DMN itself will remain at the heart of future investigations of this complex problem.

  
  
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  Schaefer A, Margulies DS, Lohmann G, Gorgolewski KJ, Smallwood J, Kiebel SJ, Villringer A (2014)
  Dynamic network participation of functional connectivity hubs assessed by resting-state fMRI
  Front Hum Neurosci 8: 195
  
  

  Network studies of large-scale brain connectivity have demonstrated that highly connected areas, or "hubs," are a key feature of human functional and structural brain organization. We use resting-state functional MRI data and connectivity clustering to identify multi-network hubs and show that while hubs can belong to multiple networks their degree of integration into these different networks varies dynamically over time. The extent of the network variation was related to the connectedness of the hub. In addition, we found that these network dynamics were inversely related to positive self-generated thoughts reported by individuals and were further decreased with older age. Moreover, the left caudate varied its degree of participation between a default mode subnetwork and a limbic network. This variation was predictive of individual differences in the reports of past-related thoughts. These results support an association between ongoing thought processes and network dynamics and offer a new approach to investigate the brain dynamics underlying mental experience.

  
  
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  Gorgolewski KJ, Lurie D, Urchs S, Kipping JA, Craddock RC, Milham MP, Margulies DS, Smallwood J (2014)
  A correspondence between individual differences in the brain’s intrinsic functional architecture and the content and form of self-generated thoughts
  PLoS One 9(5): e97176
  
  

  Although neural activity often reflects the processing of external inputs, intrinsic fluctuations in activity have been observed throughout the brain. These may relate to patterns of self-generated thought that can occur while not performing goal-driven tasks. To understand the relationship between self-generated mental activity and intrinsic neural fluctuations, we developed the New York Cognition Questionnaire (NYC-Q) to assess the content and form of an individual’s experiences during the acquisition of resting-state fMRI data. The data were collected as a part of the Nathan Kline Rockland Enhanced sample. We decomposed NYC-Q scores using exploratory factor analysis and found that self-reported thoughts clustered into distinct dimensions of content (future related, past related, positive, negative, and social) and form (words, images, and specificity). We used these components to perform an individual difference analysis exploring how differences in the types of self-generated thoughts relate to whole brain measures of intrinsic brain activity (fractional amplitude of low frequency fluctuations, regional homogeneity, and degree centrality). We found patterns of self-generated thoughts related to changes that were distributed across a wide range of cortical areas. For example, individuals who reported greater imagery exhibited greater low frequency fluctuations in a region of perigenual cingulate cortex, a region that is known to participate in the so-called default-mode network. We also found certain forms of thought were associated with other areas, such as primary visual cortex, the insula, and the cerebellum. For example, individuals who reported greater future thought exhibited less homogeneous neural fluctuations in a region of lateral occipital cortex, a result that is consistent with the claim that particular types of self-generated thought depend on processes that are decoupled from sensory processes. These data provide evidence that self-generated thought is a heterogeneous category of experience and that studying its content can be helpful in understanding brain dynamics.

  
  
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  Stelzer J, Buschmann T, Lohmann G, Margulies DS, Trampel R, Turner R (2014)
  Prioritizing spatial accuracy in high-resolution fMRI data using multivariate feature weight mapping
  Front Neurosci 8: 66
  
  

  Although ultra-high-field fMRI at field strengths of 7T or above provides substantial gains in BOLD contrast-to-noise ratio, when very high-resolution fMRI is required such gains are inevitably reduced. The improvement in sensitivity provided by multivariate analysis techniques, as compared with univariate methods, then becomes especially welcome. Information mapping approaches are commonly used, such as the searchlight technique, which take into account the spatially distributed patterns of activation in order to predict stimulus conditions. However, the popular searchlight decoding technique, in particular, has been found to be prone to spatial inaccuracies. For instance, the spatial extent of informative areas is generally exaggerated, and their spatial configuration is distorted. We propose the combination of a non-parametric and permutation-based statistical framework with linear classifiers. We term this new combined method Feature Weight Mapping (FWM). The main goal of the proposed method is to map the specific contribution of each voxel to the classification decision while including a correction for the multiple comparisons problem. Next, we compare this new method to the searchlight approach using a simulation and ultra-high-field 7T experimental data. We found that the searchlight method led to spatial inaccuracies that are especially noticeable in high-resolution fMRI data. In contrast, FWM was more spatially precise, revealing both informative anatomical structures as well as the direction by which voxels contribute to the classification. By maximizing the spatial accuracy of ultra-high-field fMRI results, global multivariate methods provide a substantial improvement for characterizing structure-function relationships.

  
  
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  Bottger J, Schurade R, Jakobsen E, Schaefer A, Margulies DS (2014)
  Connexel visualization: a software implementation of glyphs and edge-bundling for dense connectivity data using brainGL
  Front Neurosci 8: 15
  
  

  The visualization of brain connectivity becomes progressively more challenging as analytic and computational advances begin to facilitate connexel-wise analyses, which include all connections between pairs of voxels. Drawing full connectivity graphs can result in depictions that, rather than illustrating connectivity patterns in more detail, obfuscate patterns owing to the data density. In an effort to expand the possibilities for visualization, we describe two approaches for presenting connexels: edge-bundling, which clarifies structure by grouping geometrically similar connections; and, connectivity glyphs, which depict a condensed connectivity map at each point on the cortical surface. These approaches can be applied in the native brain space, facilitating interpretation of the relation of connexels to brain anatomy. The tools have been implemented as part of brainGL, an extensive open-source software for the interactive exploration of structural and functional brain data.

  
  
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  Zuo X-N, Anderson JS, Bellec P, Birn RM, Biswal BB, Blautzik J, Breitner JCS, Buckner RL, Calhoun VD, Castellanos FX, Chen A, Chen B, Chen J, Chen X, Colcombe SJ, Courtney W, Craddock RC, Di Martino A, Dong H-M, Fu X, Gong Q, Gorgolewski KJ, Han Y, He Y, He Y, Ho E, Holmes A, Hou X-H, Huckins J, Jiang T, Jiang Y, Kelley W, Kelly C, King M, LaConte SM, Lainhart JE, Lei X, Li H-J, Li K, Li K, Lin Q, Liu D, Liu J, Liu X, Liu Y, Lu G, Lu J, Luna B, Luo J, Lurie D, Mao Y, Margulies DS, Mayer AR, Meindl T, Meyerand ME, Nan W, Nielsen JA, O’Connor D, Paulsen D, Prabhakaran V, Qi Z, Qiu J, Shao C, Shehzad Z, Tang W, Villringer A, Wang H, Wang K, Wei D, Wei G-X, Weng X-C, Wu X, Xu T, Yang N, Yang Z, Zang Y-F, Zhang L, Zhang Q, Zhang Z, Zhang Z, Zhao K, Zhen Z, Zhou Y, Zhu X-T, Milham MP (2014)
  An open science resource for establishing reliability and reproducibility in functional connectomics
  Sci Data 1: 140049
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  Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals’ resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included.

  
  

2013

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  Kipping JA, Grodd W, Kumar V, Taubert M, Villringer A, Margulies DS (2013)
  Overlapping and parallel cerebello-cerebral networks contributing to sensorimotor control: an intrinsic functional connectivity study
  Neuroimage 83: 837–848
  
  

  In concert with sensorimotor control areas of the cerebrum, the cerebellum shows differential activation patterns during a variety of sensorimotor-related tasks. However, the spatial details and extent of the complex and heterogeneous cerebello-cerebral systems involved in action control remain uncertain. In this study, we use intrinsic functional connectivity (iFC) to examine cerebello-cerebral networks of five cerebellar lobules (I-IV, V, VI, and VIIIa/b) that have been empirically identified to form the functional basis of sensorimotor processes. A refined cerebellar seed-region selection allowed us to identify a network of primary sensorimotor and supplementary motor areas (I-V), a network of prefrontal, premotor, occipito-temporal and inferior-parietal regions (VI), and two largely overlapping networks involving premotor and superior parietal regions, the temporo-parietal junction as well as occipito-temporal regions (VIIIa/b). All networks involved the medial prefrontal/cingulate cortex. These cerebral clusters were used in a partial correlation analysis to systematically map cerebral connectivity throughout the entire cerebellum. We discuss these findings in the framework of affective and cognitive control, sensorimotor, multisensory systems, and executive/language systems. Within the cerebellum we found that cerebro-cerebellar systems seem to run in parallel, as indicated by distinct sublobular functional topography of prefrontal, parietal, sensorimotor, cingulate, and occipito-temporal regions. However, all areas showed overlapping connectivity to various degrees in both hemispheres. The results of both analyses demonstrate that different sublobular parts of the cerebellar lobules may dominate in different aspects of primary or higher-order sensorimotor processing. This systems-level cerebellar organization provides a more detailed structure for cerebello-cerebral interaction which contributes to our understanding of complex motor behavior.

  
  
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  Margulies DS, Petrides M (2013)
  Distinct parietal and temporal connectivity profiles of ventrolateral frontal areas involved in language production
  J Neurosci 33(42): 16846–16852
  
  

  Broca’s region, which in the language-dominant hemisphere of the human brain plays a major role in language production, includes two distinct cytoarchitectonic areas: 44 and 45. The unique connectivity patterns of these two areas have not been well established. In a resting-state functional connectivity study, we tested predictions about these areas from invasive tract-tracing studies of the connectivity of their homologs in the macaque monkey. We demonstrated their distinct connectivity profiles as well as their differences from the caudally adjacent ventral parts of the premotor cortex and the primary motor cortical region that represent the orofacial musculature. Area 45 is strongly connected with the superior temporal sulcus and the cortex on the adjacent superior and middle temporal gyri. In the parietal region, area 45 is connected with the angular gyrus, whereas area 44 is connected with the supramarginal gyrus. The primary motor cortical region in the caudal precentral gyrus is not connected with the posterior parietal region, which lies outside the confines of the postcentral gyrus, whereas the ventrorostral premotor cortical area 6VR, in the most anterior part of the precentral gyrus, has strong connections with the rostral supramarginal gyrus. Thus, area 44, which has stronger connections to the posterior supramarginal gyrus, can be distinguished from both the adjacent area 6VR and area 45. These findings provide a major improvement in understanding the connectivity of the areas in the ventrolateral frontal region that are involved in language production.

  
  
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  Baird B, Smallwood J, Gorgolewski KJ, Margulies DS (2013)
  Medial and lateral networks in anterior prefrontal cortex support metacognitive ability for memory and perception
  J Neurosci 33(42): 16657–16665
  
  

  Convergent evidence indicates that frontopolar Brodmann area 10, and more generally the anterior prefrontal cortex (aPFC), supports the human capacity to monitor and reflect on cognition and experience. An important unanswered question, however, is whether aPFC is a homogeneous region that supports a general-purpose metacognitive ability or whether there could be regional specialization within aPFC with respect to specific types of metacognitive processes. Previous studies suggest that the lateral and medial subdivisions within aPFC may support metacognitive judgments of moment-to-moment perceptual processes and assessments of information from memory stored over longer time scales, respectively. Here we directly compared intraindividual variability in metacognitive capacity for perceptual decisions and memorial judgments and used resting-state functional connectivity (rs-fcMRI) to relate this variability to the connectivity of the medial and lateral regions of aPFC. We found a behavioral dissociation in metacognitive ability for perceptual and memorial judgments. Furthermore, functional connectivity analysis revealed distinct patterns of connectivity that correlated with individual differences in each domain. Metacognitive ability for perceptual decisions was associated with greater connectivity between lateral regions of aPFC and right dorsal anterior cingulate cortex, bilateral putamen, right caudate, and thalamus, whereas metacognitive ability for memory retrieval predicted greater connectivity between medial aPFC and the right central precuneus and intraparietal sulcus/inferior parietal lobule. Together, these results suggest that an individual’s capacity for accurate introspection in the domains of perception and memory is related to the functional integrity of unique neural networks anchored in the medial and lateral regions of the aPFC.

  
  
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  Margulies DS, Bottger J, Watanabe A, Gorgolewski KJ (2013)
  Visualizing the human connectome
  Neuroimage 80: 445–461
  
  

  Innovations in data visualization punctuate the landmark advances in human connectome research since its beginnings. From tensor glyphs for diffusion-weighted imaging, to advanced rendering of anatomical tracts, to more recent graph-based representations of functional connectivity data, many of the ways we have come to understand the human connectome are through the intuitive insight these visualizations enable. Nonetheless, several unresolved problems persist. For example, probabilistic tractography lacks the visual appeal of its deterministic equivalent, multimodal representations require extreme levels of data reduction, and rendering the full connectome within an anatomical space makes the contents cluttered and unreadable. In part, these challenges require compromises between several tensions that determine connectome visualization practice, such as prioritizing anatomic or connectomic information, aesthetic appeal or information content, and thoroughness or readability. To illustrate the ongoing negotiation between these priorities, we provide an overview of various visualization methods that have evolved for anatomical and functional connectivity data. We then describe interactive visualization tools currently available for use in research, and we conclude with concerns and developments in the presentation of connectivity results.

  
  
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  Ovadia-Caro S, Villringer K, Fiebach J, Jungehulsing GJ, van der Meer E, Margulies DS, Villringer A (2013)
  Longitudinal effects of lesions on functional networks after stroke
  J Cereb Blood Flow Metab 33(8): 1279–1285
  
  

  While ischemic stroke reflects focal damage determined by the affected vascular territory, clinical symptoms are often more complex and may be better explained by additional indirect effects of the focal lesion. Assumed to be structurally underpinned by anatomical connections, supporting evidence has been found using alterations in the functional connectivity of resting-state functional magnetic resonance imaging (fMRI) data in both sensorimotor and attention networks. To assess the generalizability of this phenomenon in a stroke population with heterogeneous lesions, we investigated the distal effects of lesions on a global level. Longitudinal resting-state fMRI scans were acquired at three consecutive time points, beginning during the acute phase (days 1, 7, and 90 post-stroke) in 12 patients after ischemic stroke. We found a preferential functional change in affected networks (i.e., networks containing lesions changed more during recovery when compared with unaffected networks). This change in connectivity was significantly correlated with clinical changes assessed with the National Institute of Health Stroke Scale. Our results provide evidence that the functional architecture of large-scale networks is critical to understanding the clinical effect and trajectory of post-stroke recovery.

  
  
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  Lv Y, Margulies DS, Cameron Craddock R, Long X, Winter B, Gierhake D, Endres M, Villringer K, Fiebach J, Villringer A (2013)
  Identifying the perfusion deficit in acute stroke with resting-state functional magnetic resonance imaging
  Ann Neurol 73(1): 136–140
  
  

  Temporal delay in blood oxygenation level-dependent (BOLD) signals may be sensitive to perfusion deficits in acute stroke. Resting-state functional magnetic resonance imaging (rsfMRI) was added to a standard stroke MRI protocol. We calculated the time delay between the BOLD signal at each voxel and the whole-brain signal using time-lagged correlation and compared the results to mean transit time derived using bolus tracking. In all 11 patients, areas exhibiting significant delay in BOLD signal corresponded to areas of hypoperfusion identified by contrast-based perfusion MRI. Time delay analysis of rsfMRI provides information comparable to that of conventional perfusion MRI without the need for contrast agents.

  
  
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  Callard F, Smallwood J, Golchert J, Margulies DS (2013)
  The era of the wandering mind? Twenty-first century research on self-generated mental activity
  Front Psychol 4: 891
  
  

  The first decade of the twenty-first century was characterized by renewed scientific interest in self-generated mental activity (activity largely generated by the individual, rather than in direct response to experimenters’ instructions or specific external sensory inputs). To understand this renewal of interest, we interrogated the peer-reviewed literature from 2003 to 2012 (i) to explore recent changes in use of terms for self-generated mental activity; (ii) to investigate changes in the topics on which mind wandering research, specifically, focuses; and (iii) to visualize co-citation communities amongst researchers working on self-generated mental activity. Our analyses demonstrated that there has been a dramatic increase in the term "mind wandering" from 2006, and a significant crossing-over of psychological investigations of mind wandering into cognitive neuroscience (particularly in relation to research on the default mode and default mode network). If our article concludes that this might, indeed, be the "era of the wandering mind," it also calls for more explicit reflection to be given by researchers in this field to the terms they use, the topics and brain regions they focus on, and the research literatures that they implicitly foreground or ignore.

  
  
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  Koehler S, Ovadia-Caro S, van der Meer E, Villringer A, Heinz A, Romanczuk-Seiferth N, Margulies DS (2013)
  Increased functional connectivity between prefrontal cortex and reward system in pathological gambling
  PLoS One 8(12): e84565
  
  

  Pathological gambling (PG) shares clinical characteristics with substance-use disorders and is thus discussed as a behavioral addiction. Recent neuroimaging studies on PG report functional changes in prefrontal structures and the mesolimbic reward system. While an imbalance between these structures has been related to addictive behavior, whether their dysfunction in PG is reflected in the interaction between them remains unclear. We addressed this question using functional connectivity resting-state fMRI in male subjects with PG and controls. Seed-based functional connectivity was computed using two regions-of-interest, based on the results of a previous voxel-based morphometry study, located in the prefrontal cortex and the mesolimbic reward system (right middle frontal gyrus and right ventral striatum). PG patients demonstrated increased connectivity from the right middle frontal gyrus to the right striatum as compared to controls, which was also positively correlated with nonplanning aspect of impulsiveness, smoking and craving scores in the PG group. Moreover, PG patients demonstrated decreased connectivity from the right middle frontal gyrus to other prefrontal areas as compared to controls. The right ventral striatum demonstrated increased connectivity to the right superior and middle frontal gyrus and left cerebellum in PG patients as compared to controls. The increased connectivity to the cerebellum was positively correlated with smoking in the PG group. Our results provide further evidence for alterations in functional connectivity in PG with increased connectivity between prefrontal regions and the reward system, similar to connectivity changes reported in substance use disorder.

  
  
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  Smallwood J, Gorgolewski KJ, Golchert J, Ruby FJM, Engen H, Baird B, Vinski MT, Schooler JW, Margulies DS (2013)
  The default modes of reading: modulation of posterior cingulate and medial prefrontal cortex connectivity associated with comprehension and task focus while reading
  Front Hum Neurosci 7: 734
  
  

  Reading is a fundamental human capacity and yet it can easily be derailed by the simple act of mind-wandering. A large-scale brain network, referred to as the default mode network (DMN), has been shown to be involved in both mind-wandering and reading, raising the question as to how the same neural system could be implicated in processes with both costs and benefits to narrative comprehension. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to explore whether the intrinsic functional connectivity of the two key midline hubs of the DMN-the posterior cingulate cortex (PCC) and anterior medial prefrontal cortex (aMPFC)-was predictive of individual differences in reading comprehension and task focus recorded outside of the scanner. Worse comprehension was associated with greater functional connectivity between the PCC and a region of the ventral striatum. Better comprehension was associated with greater functional connectivity with a region of the right insula. By contrast reports of increasing task focus were associated with functional connectivity from the aMPFC to clusters in the PCC, the left parietal and temporal cortex, and the cerebellum. Our results suggest that the DMN has both costs (such as poor comprehension) and benefits to reading (such as an on-task focus) because its midline core can couple its activity with other regions to form distinct functional communities that allow seemingly opposing mental states to occur. This flexible coupling allows the DMN to participate in cognitive states that complement the act of reading as well as others that do not.

  
  
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  Rohr CS, Okon-Singer H, Craddock RC, Villringer A, Margulies DS (2013)
  Affect and the brain’s functional organization: a resting-state connectivity approach
  PLoS One 8(7): e68015
  
  

  The question of how affective processing is organized in the brain is still a matter of controversial discussions. Based on previous initial evidence, several suggestions have been put forward regarding the involved brain areas: (a) right-lateralized dominance in emotional processing, (b) hemispheric dominance according to positive or negative valence, (c) one network for all emotional processing and (d) region-specific discrete emotion matching. We examined these hypotheses by investigating intrinsic functional connectivity patterns that covary with results of the Positive and Negative Affective Schedule (PANAS) from 65 participants. This approach has the advantage of being able to test connectivity rather than activation, and not requiring a potentially confounding task. Voxelwise functional connectivity from 200 regions-of-interest covering the whole brain was assessed. Positive and negative affect covaried with functional connectivity involving a shared set of regions, including the medial prefrontal cortex, the anterior cingulate, the visual cortex and the cerebellum. In addition, each affective domain had unique connectivity patterns, and the lateralization index showed a right hemispheric dominance for negative affect. Therefore, our results suggest a predominantly right-hemispheric network with affect-specific elements as the underlying organization of emotional processes.

  
  
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  Lv Y, Margulies DS, Villringer A, Zang Y-F (2013)
  Effects of finger tapping frequency on regional homogeneity of sensorimotor cortex
  PLoS One 8(5): e64115
  
  

  Resting-state functional magnetic resonance imaging (RS-fMRI) has been widely used to investigate temporally correlated fluctuations between distributed brain areas, as well as to characterize local synchronization of low frequency (<0.1 Hz) spontaneous fMRI signal. Regional homogeneity (ReHo) was proposed as a voxel-wise measure of the synchronization of the timecourses of neighboring voxels and has been used in many studies of brain disorders. However, the interpretation of ReHo remains challenging because the effect of high frequency task on ReHo is still not clear. In order to investigate the effect of a high-frequency task on the modulation of local synchronization of resting-state activity, we employed three right-finger movement scanning sessions: slow-event related (’Slow’), fast-event related (’Fast’), and continuous finger pressure (’Tonic’), from 21 healthy participants and compared the ReHo of the three task states with that of resting-state (’Rest’). In the contralateral sensorimotor cortex, ’Slow’ task state showed greater ReHo than ’Rest’ in low frequency band (0-0.08Hz) fMRI signal, but lower ReHo in high frequency band (0.08-1.67 Hz); ’Fast’ task state showed lower ReHo than ’Rest’ in both the low and high frequency band; ’Tonic’ state did not show any significant difference compared to ’Rest’. The results in the contralateral sensorimotor cortex suggest that local synchronization of BOLD signal varies with different finger tapping speed. In the ipsilateral sensorimotor cortex, all the three task states had lower ReHo than the ’Rest’ state both in the low and high frequency, suggesting a similar effect of fast and slow finger tapping frequencies on local synchronization of BOLD signal in the ipsilateral motor cortex.

  
  
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  Gorgolewski KJ, Margulies DS, Milham MP (2013)
  Making data sharing count: a publication-based solution
  Front Neurosci 7: 9
  
  

  The neuroimaging community has been increasingly called up to openly share data. Although data sharing has been a cornerstone of large-scale data consortia, the incentive for the individual researcher remains unclear. Other fields have benefited from embracing a data publication form - the data paper - that allows researchers to publish their datasets as a citable scientific publication. Such publishing mechanisms both give credit that is recognizable within the scientific ecosystem, and also ensure the quality of the published data and metadata through the peer review process. We discuss the specific challenges of adapting data papers to the needs of the neuroimaging community, and we propose guidelines for the structure as well as review process.

  
  

2012

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  Sehm B, Schafer A, Kipping J, Margulies DS, Conde V, Taubert M, Villringer A, Ragert P (2012)
  Dynamic modulation of intrinsic functional connectivity by transcranial direct current stimulation
  J Neurophysiol 108(12): 3253–3263
  
  

  Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique capable of modulating cortical excitability and thereby influencing behavior and learning. Recent evidence suggests that bilateral tDCS over both primary sensorimotor cortices (SM1) yields more prominent effects on motor performance in both healthy subjects and chronic stroke patients than unilateral tDCS over SM1. To better characterize the underlying neural mechanisms of this effect, we aimed to explore changes in resting-state functional connectivity during both stimulation types. In a randomized single-blind crossover design, 12 healthy subjects underwent functional magnetic resonance imaging at rest before, during, and after 20 min of unilateral, bilateral, and sham tDCS stimulation over SM1. Eigenvector centrality mapping (ECM) was used to investigate tDCS-induced changes in functional connectivity patterns across the whole brain. Uni- and bilateral tDCS over SM1 resulted in functional connectivity changes in widespread brain areas compared with sham stimulation both during and after stimulation. Whereas bilateral tDCS predominantly modulated changes in primary and secondary motor as well as prefrontal regions, unilateral tDCS affected prefrontal, parietal, and cerebellar areas. No direct effect was seen under the stimulating electrode in the unilateral condition. The time course of changes in functional connectivity in the respective brain areas was nonlinear and temporally dispersed. These findings provide evidence toward a network-based understanding regarding the underpinnings of specific tDCS interventions.

  
  
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  Callard F, Smallwood J, Margulies DS (2012)
  Default Positions: How Neuroscience’s Historical Legacy has Hampered Investigation of the Resting Mind
  Front Psychol 3: 321
  
  

  The puzzle of the brain and mind at rest - their so-called default state - is strongly influenced by the historical precedents that led to its emergence as a scientific question. What eventually became the default-mode network (DMN) was inaugurated via meta-analysis to explain the observation that the baseline "at rest" condition was concealing a pattern of neural activations in anterior and posterior midline brain regions that were not commonly seen in external-task-driven experiments. One reason why these activations have puzzled scientists is because psychology and cognitive neuroscience have historically been focused on paradigms built around external tasks, and so lacked the scientific and theoretical tools to interpret the cognitive functions of the DMN. This externally-focused bias led to the erroneous assumption that the DMN is the primary neural system active at rest, as well as the assumption that this network serves non-goal-directed functions. Although cognitive neuroscience now embraces the need to decode the meaning of self-generated neural activity, a more deliberate and comprehensive framework will be needed before the puzzle of the wandering mind can be laid to rest.

  
  
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  Lohmann G, Ovadia-Caro S, Jungehulsing GJ, Margulies DS, Villringer A, Turner R (2012)
  Connectivity concordance mapping: a new tool for model-free analysis of FMRI data of the human brain
  Front Syst Neurosci 6: 13
  
  

  Functional magnetic resonance data acquired in a task-absent condition ("resting state") require new data analysis techniques that do not depend on an activation model. Here, we propose a new analysis method called Connectivity Concordance Mapping (CCM). The main idea is to assign a label to each voxel based on the reproducibility of its whole-brain pattern of connectivity. Specifically, we compute the correlations of time courses of each voxel with every other voxel for each measurement. Voxels whose correlation pattern is consistent across measurements receive high values. The result of a CCM analysis is thus a voxel-wise map of concordance values. Regions of high inter-subject concordance can be assumed to be functionally consistent, and may thus be of specific interest for further analysis. Here we present two fMRI studies to demonstrate the possible applications of the algorithm. The first is a eyes-open/eyes-closed paradigm designed to highlight the potential of the method in a relatively simple domain. The second study is a longitudinal repeated measurement of a patient following stroke. Longitudinal clinical studies such as this may represent the most interesting domain of applications for this algorithm.

  
  

2011

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  Callard F, Margulies DS (2011)
  The Subject at Rest: Novel conceptualizations of self and brain from cognitive neuroscience’s study of the ‘resting state’
  Subjectivity 4(3): 227–257
  
  

  The neuroscientific field of ‘resting state’ research has been described as heralding a paradigm shift in functional neuroimaging. As this new field has been central to the development of a cognitive neuroscientific theory of inner mental life, we here map and analyse its emergence and potential implications for conceptualizations of brain, self and subjectivity within and beyond the neurosciences. The article traces how the ‘resting state’ and ‘default mode’ became visible as objects of scientific enquiry through the yoking together of what were initially separate research endeavours addressing different neurophysiological and neuropsychological questions. In the process, ‘rest’ – as signifying the cessation of movement or labour – has been transformed: the brain, inner mental life – and potentially the self – are conceptualized by researchers in this field as perpetually productive and oriented towards the future.

  
  
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  Taubert M, Lohmann G, Margulies DS, Villringer A, Ragert P (2011)
  Long-term effects of motor training on resting-state networks and underlying brain structure
  Neuroimage 57(4): 1492–1498
  
  

  Acquired motor skills are coded in fronto-parietal brain networks, but how these networks evolve through motor training is unclear. On the one hand, increased functional connectivity has been shown immediately after a training session; on the other hand, training-induced structural changes are visible only after several weeks. Based on known associations between functional and structural network development during human ontogeny, we hypothesised that learning a challenging motor task leads to long-lasting changes in functional resting-state networks and the corresponding cortical and sub-cortical brain structures. Using longitudinal functional and structural MRI at multiple time points, we demonstrate increased fronto-parietal network connectivity one week after two brief motor training sessions in a dynamic balancing task, although subjects were engaged in their regular daily activities during the week. Repeated training sessions over six consecutive weeks progressively modulate these changes in accordance with individual performance improvements. Multimodal correlation analyses showed an association between structural grey matter alterations and functional connectivity changes in prefrontal and supplementary-motor areas. These coincident changes were most prominent in the first three weeks of training. In contrast, changes in fronto-parietal functional connectivity and the underlying white matter fibre structure developed gradually during the six weeks. Our results demonstrate a tight correlation between training-induced functional and structural brain plasticity on the systems level and suggest a functional relevance of intrinsic brain activity for morphological adaptation in the human brain.

  
  
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  Bottger J, Margulies DS, Horn P, Thomale UW, Podlipsky I, Shapira-Lichter I, Chaudhry SJ, Szkudlarek C, Mueller K, Lohmann G, Hendler T, Bohner G, Fiebach JB, Villringer A, Vajkoczy P, Abbushi A (2011)
  A software tool for interactive exploration of intrinsic functional connectivity opens new perspectives for brain surgery
  Acta Neurochir (Wien) 153(8): 1561–1572
  
  

  BACKGROUND: Functional connectivity analysis of resting-state functional magnetic resonance imaging data (fcrs-fMRI) has been shown to be a robust non-invasive method for localization of functional networks (without using specific tasks) and to be promising for presurgical planning. However, in order to transfer the approach to everyday clinical practice, fcrs-fMRI needs to be further validated and made easily accessible to neurosurgeons. This paper addresses the latter by presenting a software tool designed for neurosurgeons for analyzing and visualizing fcrs-fMRI data. METHODS: A prototypical interactive visualization tool was developed to enable neurosurgeons to explore functional connectivity data and evaluate its usability. The implementation builds upon LIPSIA, an established software package for the assessment of functional neuroimaging data, and integrates the selection of a region-of-interest with the computation and visualization of functionally connected areas. The tool was used to explore data from a healthy participant and eight brain lesion patients. The usability of the software was evaluated with four neurosurgeons previously unacquainted with the methodology, who were asked to identify prominent, large-scale cortical networks. FINDINGS: With this novel tool, previously published findings, such as tumor displacement of the sensorimotor cortex and other disturbances of functional networks, were reproduced. The neurosurgeons were able to consistently obtain results similar to the results of an expert, with the exception of the language network. Immediate feedback helped to pinpoint functional networks quickly and intuitively, with even inexperienced users requiring less than 3 min per network. CONCLUSIONS: Although fcrs-fMRI is a nascent method still undergoing evaluation with respect to established standards, the interactive software is nonetheless a promising tool for non-invasive exploration of individual functional connectivity networks in neurosurgical practice, both for well-known networks and for those less typically addressed.

  
  
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  Gee DG, Biswal BB, Kelly C, Stark DE, Margulies DS, Shehzad Z, Uddin LQ, Klein DF, Banich MT, Castellanos FX, Milham MP (2011)
  Low frequency fluctuations reveal integrated and segregated processing among the cerebral hemispheres
  Neuroimage 54(1): 517–527
  
  

  Resting-state functional magnetic resonance imaging (fMRI) has provided a novel approach for examining interhemispheric interaction, demonstrating a high degree of functional connectivity between homotopic regions in opposite hemispheres. However, heterotopic resting-state functional connectivity (RSFC) remains relatively uncharacterized. In the present study, we examine non-homotopic regions, characterizing heterotopic RSFC and comparing it to intrahemispheric RSFC, to examine the impact of hemispheric separation on the integration and segregation of processing in the brain. Resting-state fMRI scans were acquired from 59 healthy participants to examine inter-regional correlations in spontaneous low frequency fluctuations in BOLD signal. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions (56 per hemisphere) distributed throughout the entire cerebrum. We compared RSFC for pairings of non-homologous regions located in different hemispheres (heterotopic connectivity) to RSFC for the same pairings when located within hemisphere (intrahemispheric connectivity). For positive connections, connectivity strength was greater within each hemisphere, consistent with integrated intrahemispheric processing. However, for negative connections, RSFC strength was greater between the hemispheres, consistent with segregated interhemispheric processing. These patterns were particularly notable for connections involving frontal and heteromodal regions. The distribution of positive and negative connectivity was nearly identical within and between the hemispheres, though we demonstrated detailed regional variation in distribution. We discuss implications for leading models of interhemispheric interaction. The future application of our analyses may provide important insight into impaired interhemispheric processing in clinical and aging populations.

  
  
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  Adelstein JS, Shehzad Z, Mennes M, Deyoung CG, Zuo X-N, Kelly C, Margulies DS, Bloomfield A, Gray JR, Castellanos FX, Milham MP (2011)
  Personality is reflected in the brain’s intrinsic functional architecture
  PLoS One 6(11): e27633
  
  

  Personality describes persistent human behavioral responses to broad classes of environmental stimuli. Investigating how personality traits are reflected in the brain’s functional architecture is challenging, in part due to the difficulty of designing appropriate task probes. Resting-state functional connectivity (RSFC) can detect intrinsic activation patterns without relying on any specific task. Here we use RSFC to investigate the neural correlates of the five-factor personality domains. Based on seed regions placed within two cognitive and affective ’hubs’ in the brain–the anterior cingulate and precuneus–each domain of personality predicted RSFC with a unique pattern of brain regions. These patterns corresponded with functional subdivisions responsible for cognitive and affective processing such as motivation, empathy and future-oriented thinking. Neuroticism and Extraversion, the two most widely studied of the five constructs, predicted connectivity between seed regions and the dorsomedial prefrontal cortex and lateral paralimbic regions, respectively. These areas are associated with emotional regulation, self-evaluation and reward, consistent with the trait qualities. Personality traits were mostly associated with functional connections that were inconsistently present across participants. This suggests that although a fundamental, core functional architecture is preserved across individuals, variable connections outside of that core encompass the inter-individual differences in personality that motivate diverse responses.

  
  

2010

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  Margulies DS, Bottger J, Long X, Lv Y, Kelly C, Schafer A, Goldhahn D, Abbushi A, Milham MP, Lohmann G, Villringer A (2010)
  Resting developments: a review of fMRI post-processing methodologies for spontaneous brain activity
  MAGMA 23(5-6): 289–307
  
  

  Analytic tools for addressing spontaneous brain activity, as acquired with fMRI during the "resting-state," have grown dramatically over the past decade. Along with each new technique, novel hypotheses about the functional organization of the brain are also available to researchers. We review six prominent categories of resting-state fMRI data analysis: seed-based functional connectivity, independent component analysis, clustering, pattern classification, graph theory, and two "local" methods. In surveying these methods, we address their underlying assumptions, methodologies, and novel applications.

  
  
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  Zuo X-N, Kelly C, Di Martino A, Mennes M, Margulies DS, Bangaru S, Grzadzinski R, Evans AC, Zang Y-F, Castellanos FX, Milham MP (2010)
  Growing together and growing apart: regional and sex differences in the lifespan developmental trajectories of functional homotopy
  J Neurosci 30(45): 15034–15043
  
  

  Functional homotopy, the high degree of synchrony in spontaneous activity between geometrically corresponding interhemispheric (i.e., homotopic) regions, is a fundamental characteristic of the intrinsic functional architecture of the brain. However, despite its prominence, the lifespan development of the homotopic resting-state functional connectivity (RSFC) of the human brain is rarely directly examined in functional magnetic resonance imaging studies. Here, we systematically investigated age-related changes in homotopic RSFC in 214 healthy individuals ranging in age from 7 to 85 years. We observed marked age-related changes in homotopic RSFC with regionally specific developmental trajectories of varying levels of complexity. Sensorimotor regions tended to show increasing homotopic RSFC, whereas higher-order processing regions showed decreasing connectivity (i.e., increasing segregation) with age. More complex maturational curves were also detected, with regions such as the insula and lingual gyrus exhibiting quadratic trajectories and the superior frontal gyrus and putamen exhibiting cubic trajectories. Sex-related differences in the developmental trajectory of functional homotopy were detected within dorsolateral prefrontal cortex (Brodmann areas 9 and 46) and amygdala. Evidence of robust developmental effects in homotopic RSFC across the lifespan should serve to motivate studies of the physiological mechanisms underlying functional homotopy in neurodegenerative and psychiatric disorders.

  
  
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  Kelly C, Uddin LQ, Shehzad Z, Margulies DS, Castellanos FX, Milham MP, Petrides M (2010)
  Broca’s region: linking human brain functional connectivity data and non-human primate tracing anatomy studies
  Eur J Neurosci 32(3): 383–398
  
  

  Brodmann areas 6, 44 and 45 in the ventrolateral frontal cortex of the left hemisphere of the human brain constitute the anterior language production zone. The anatomical connectivity of these areas with parietal and temporal cortical regions was recently examined in an autoradiographic tract-tracing study in the macaque monkey. Studies suggest strong correspondence between human resting state functional connectivity (RSFC) based on functional magnetic resonance imaging data and experimentally demonstrated anatomical connections in non-human primates. Accordingly, we hypothesized that areas 6, 44 and 45 of the human brain would exhibit patterns of RSFC consistent with patterns of anatomical connectivity observed in the macaque. In a primary analysis, we examined the RSFC associated with regions-of-interest placed in ventrolateral frontal areas 6, 44 and 45, on the basis of local sulcal and gyral anatomy. We validated the results of the primary hypothesis-driven analysis with a data-driven partitioning of ventrolateral frontal cortex into regions exhibiting distinct RSFC patterns, using a spectral clustering algorithm. The RSFC of ventrolateral frontal areas 6, 44 and 45 was consistent with patterns of anatomical connectivity shown in the macaque. We observed a striking dissociation between RSFC for the ventral part of area 6 that is involved in orofacial motor control and RSFC associated with Broca’s region (areas 44 and 45). These findings indicate rich and differential RSFC patterns for the ventrolateral frontal areas controlling language production, consistent with known anatomical connectivity in the macaque brain, and suggest conservation of connectivity during the evolution of the primate brain.

  
  
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  Sajonz B, Kahnt T, Margulies DS, Park SQ, Wittmann A, Stoy M, Strohle A, Heinz A, Northoff G, Bermpohl F (2010)
  Delineating self-referential processing from episodic memory retrieval: common and dissociable networks
  Neuroimage 50(4): 1606–1617
  
  

  Self-referential processing involves a complex set of cognitive functions, posing challenges to delineating its independent neural correlates. While self-referential processing has been considered functionally intertwined with episodic memory, the present study explores their overlap and dissociability. Standard tasks for self-referential processing and episodic memory were combined into a single fMRI experiment. Contrasting the effects of self-relatedness and retrieval success allowed for the two processes to be delineated. Stimuli judged as self-referential specifically activated the posterior cingulate/anterior precuneus, the medial prefrontal cortex, and an inferior division of the inferior parietal lobule. In contrast, episodic memory retrieval specifically involved the posterior precuneus, the right anterior prefrontal cortex, and a superior division of the inferior parietal lobule (extending into superior parietal lobule). Overlapping activations were found in intermediate zones in the precuneus and the inferior parietal lobule, but not in the prefrontal cortex. While our data show common networks for both processes in the medial and lateral parietal cortex, three functional differentiations were also observed: (1) an anterior-posterior differentiation within the medial parietal cortex; (2) a medial-anterolateral differentiation within the prefrontal cortex; and, (3) an inferior-superior differentiation within the lateral parietal cortex for self-referential processing versus episodic memory retrieval.

  
  
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  Lohmann G, Margulies DS, Horstmann A, Pleger B, Lepsien J, Goldhahn D, Schloegl H, Stumvoll M, Villringer A, Turner R (2010)
  Eigenvector centrality mapping for analyzing connectivity patterns in fMRI data of the human brain
  PLoS One 5(4): e10232
  
  

  Functional magnetic resonance data acquired in a task-absent condition ("resting state") require new data analysis techniques that do not depend on an activation model. In this work, we introduce an alternative assumption- and parameter-free method based on a particular form of node centrality called eigenvector centrality. Eigenvector centrality attributes a value to each voxel in the brain such that a voxel receives a large value if it is strongly correlated with many other nodes that are themselves central within the network. Google’s PageRank algorithm is a variant of eigenvector centrality. Thus far, other centrality measures - in particular "betweenness centrality" - have been applied to fMRI data using a pre-selected set of nodes consisting of several hundred elements. Eigenvector centrality is computationally much more efficient than betweenness centrality and does not require thresholding of similarity values so that it can be applied to thousands of voxels in a region of interest covering the entire cerebrum which would have been infeasible using betweenness centrality. Eigenvector centrality can be used on a variety of different similarity metrics. Here, we present applications based on linear correlations and on spectral coherences between fMRI times series. This latter approach allows us to draw conclusions of connectivity patterns in different spectral bands. We apply this method to fMRI data in task-absent conditions where subjects were in states of hunger or satiety. We show that eigenvector centrality is modulated by the state that the subjects were in. Our analyses demonstrate that eigenvector centrality is a computationally efficient tool for capturing intrinsic neural architecture on a voxel-wise level.

  
  
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  Biswal BB, Mennes M, Zuo X-N, Gohel S, Kelly C, Smith SM, Beckmann CF, Adelstein JS, Buckner RL, Colcombe S, Dogonowski A-M, Ernst M, Fair D, Hampson M, Hoptman MJ, Hyde JS, Kiviniemi VJ, Kotter R, Li S-J, Lin C-P, Lowe MJ, Mackay C, Madden DJ, Madsen KH, Margulies DS, Mayberg HS, McMahon K, Monk CS, Mostofsky SH, Nagel BJ, Pekar JJ, Peltier SJ, Petersen SE, Riedl V, Rombouts SARB, Rypma B, Schlaggar BL, Schmidt S, Seidler RD, Siegle GJ, Sorg C, Teng G-J, Veijola J, Villringer A, Walter M, Wang L, Weng X-C, Whitfield-Gabrieli S, Williamson P, Windischberger C, Zang Y-F, Zhang H-Y, Castellanos FX, Milham MP (2010)
  Toward discovery science of human brain function
  Proc Natl Acad Sci U S A 107(10): 4734–4739
  
  

  Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (<0.1 Hz) fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual’s "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual’s functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/.

  
  

2009

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  Margulies DS, Vincent JL, Kelly C, Lohmann G, Uddin LQ, Biswal BB, Villringer A, Castellanos FX, Milham MP, Petrides M (2009)
  Precuneus shares intrinsic functional architecture in humans and monkeys
  Proc Natl Acad Sci U S A 106(47): 20069–20074
  
  

  Evidence from macaque monkey tracing studies suggests connectivity-based subdivisions within the precuneus, offering predictions for similar subdivisions in the human. Here we present functional connectivity analyses of this region using resting-state functional MRI data collected from both humans and macaque monkeys. Three distinct patterns of functional connectivity were demonstrated within the precuneus of both species, with each subdivision suggesting a discrete functional role: (i) the anterior precuneus, functionally connected with the superior parietal cortex, paracentral lobule, and motor cortex, suggesting a sensorimotor region; (ii) the central precuneus, functionally connected to the dorsolateral prefrontal, dorsomedial prefrontal, and multimodal lateral inferior parietal cortex, suggesting a cognitive/associative region; and (iii) the posterior precuneus, displaying functional connectivity with adjacent visual cortical regions. These functional connectivity patterns were differentiated from the more ventral networks associated with the posterior cingulate, which connected with limbic structures such as the medial temporal cortex, dorsal and ventromedial prefrontal regions, posterior lateral inferior parietal regions, and the lateral temporal cortex. Our findings are consistent with predictions from anatomical tracer studies in the monkey, and provide support that resting-state functional connectivity (RSFC) may in part reflect underlying anatomy. These subdivisions within the precuneus suggest that neuroimaging studies will benefit from treating this region as anatomically (and thus functionally) heterogeneous. Furthermore, the consistency between functional connectivity networks in monkeys and humans provides support for RSFC as a viable tool for addressing cross-species comparisons of functional neuroanatomy.

  
  
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  Shehzad Z, Kelly AMC, Reiss PT, Gee DG, Gotimer K, Uddin LQ, Lee SH, Margulies DS, Roy AK, Biswal BB, Petkova E, Castellanos FX, Milham MP (2009)
  The resting brain: unconstrained yet reliable
  Cereb Cortex 19(10): 2209–2229
  
  

  Recent years have witnessed an upsurge in the usage of resting-state functional magnetic resonance imaging (fMRI) to examine functional connectivity (fcMRI), both in normal and pathological populations. Despite this increasing popularity, concerns about the psychologically unconstrained nature of the "resting-state" remain. Across studies, the patterns of functional connectivity detected are remarkably consistent. However, the test-retest reliability for measures of resting state fcMRI measures has not been determined. Here, we quantify the test-retest reliability, using resting scans from 26 participants at 3 different time points. Specifically, we assessed intersession (>5 months apart), intrasession (<1 h apart), and multiscan (across all 3 scans) reliability and consistency for both region-of-interest and voxel-wise analyses. For both approaches, we observed modest to high reliability across connections, dependent upon 3 predictive factors: 1) correlation significance (significantly nonzero > nonsignificant), 2) correlation valence (positive > negative), and 3) network membership (default mode > task positive network). Short- and long-term measures of the consistency of global connectivity patterns were highly robust. Finally, hierarchical clustering solutions were highly reproducible, both across participants and sessions. Our findings provide a solid foundation for continued examination of resting state fcMRI in typical and atypical populations.

  
  
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  Roy AK, Shehzad Z, Margulies DS, Kelly AMC, Uddin LQ, Gotimer K, Biswal BB, Castellanos FX, Milham MP (2009)
  Functional connectivity of the human amygdala using resting state fMRI
  Neuroimage 45(2): 614–626
  
  

  The amygdala is composed of structurally and functionally distinct nuclei that contribute to the processing of emotion through interactions with other subcortical and cortical structures. While these circuits have been studied extensively in animals, human neuroimaging investigations of amygdala-based networks have typically considered the amygdala as a single structure, which likely masks contributions of individual amygdala subdivisions. The present study uses resting state functional magnetic resonance imaging (fMRI) to test whether distinct functional connectivity patterns, like those observed in animal studies, can be detected across three amygdala subdivisions: laterobasal, centromedial, and superficial. In a sample of 65 healthy adults, voxelwise regression analyses demonstrated positively-predicted ventral and negatively-predicted dorsal networks associated with the total amygdala, consistent with previous animal and human studies. Investigation of individual amygdala subdivisions revealed distinct differences in connectivity patterns within the amygdala and throughout the brain. Spontaneous activity in the laterobasal subdivision predicted activity in temporal and frontal regions, while activity in the centromedial nuclei predicted activity primarily in striatum. Activity in the superficial subdivision positively predicted activity throughout the limbic lobe. These findings suggest that resting state fMRI can be used to investigate human amygdala networks at a greater level of detail than previously appreciated, allowing for the further advancement of translational models.

  
  
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  Kelly AMC, Di Martino A, Uddin LQ, Shehzad Z, Gee DG, Reiss PT, Margulies DS, Castellanos FX, Milham MP (2009)
  Development of anterior cingulate functional connectivity from late childhood to early adulthood
  Cereb Cortex 19(3): 640–657
  
  

  Human cerebral development is remarkably protracted. Although microstructural processes of neuronal maturation remain accessible only to morphometric post-mortem studies, neuroimaging tools permit the examination of macrostructural aspects of brain development. The analysis of resting-state functional connectivity (FC) offers novel possibilities for the investigation of cerebral development. Using seed-based FC methods, we examined the development of 5 functionally distinct cingulate-based intrinsic connectivity networks (ICNs) in children (n = 14, 10.6 +/- 1.5 years), adolescents (n = 12, 15.4 +/- 1.2) and young adults (n=14, 22.4 +/- 1.2). Children demonstrated a more diffuse pattern of correlation with voxels proximal to the seed region of interest (ROI) ("local FC"), whereas adults exhibited more focal patterns of FC, as well as a greater number of significantly correlated voxels at long distances from the seed ROI. Adolescents exhibited intermediate patterns of FC. Consistent with evidence for different maturational time courses, ICNs associated with social and emotional functions exhibited the greatest developmental effects. Our findings demonstrate the utility of FC for the study of developing functional organization. Moreover, given that ICNs are thought to have an anatomical basis in neuronal connectivity, measures of FC may provide a quantitative index of brain maturation in healthy subjects and those with neurodevelopmental disorders.

  
  

2008

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  Stark DE, Margulies DS, Shehzad ZE, Reiss P, Kelly AMC, Uddin LQ, Gee DG, Roy AK, Banich MT, Castellanos FX, Milham MP (2008)
  Regional variation in interhemispheric coordination of intrinsic hemodynamic fluctuations
  J Neurosci 28(51): 13754–13764
  
  

  Electrophysiological studies have long demonstrated a high degree of correlated activity between the left and right hemispheres, however little is known about regional variation in this interhemispheric coordination. Whereas cognitive models and neuroanatomical evidence suggest differences in coordination across primary sensory-motor cortices versus higher-order association areas, these have not been characterized. Here, we used resting-state functional magnetic resonance imaging data acquired from 62 healthy volunteers to examine interregional correlation in spontaneous low-frequency hemodynamic fluctuations. Using a probabilistic atlas, we correlated probability-weighted time series from 112 regions comprising the entire cerebrum. We then examined regional variation in correlated activity between homotopic regions, contrasting primary sensory-motor cortices, unimodal association areas, and heteromodal association areas. Consistent with previous studies, robustly correlated spontaneous activity was noted between all homotopic regions, which was significantly higher than that between nonhomotopic (heterotopic and intrahemispheric) regions. We further demonstrated substantial regional variation in homotopic interhemispheric correlations that was highly consistent across subjects. Specifically, there was a gradient of interhemispheric correlation, with highest correlations across primary sensory-motor cortices (0.758, SD=0.152), significantly lower correlations across unimodal association areas (0.597, SD=0.230) and still lower correlations across heteromodal association areas (0.517, SD=0.226). These results demonstrate functional differences in interhemispheric coordination related to the brain’s hierarchical subdivisions. Synchrony across primary cortices may reflect networks engaged in bilateral sensory integration and motor coordination, whereas lower coordination across heteromodal association areas is consistent with functional lateralization of these regions. This novel method of examining interhemispheric coordination may yield insights regarding diverse disease processes as well as healthy development.

  
  
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  Di Martino A, Scheres A, Margulies DS, Kelly AMC, Uddin LQ, Shehzad Z, Biswal B, Walters JR, Castellanos FX, Milham MP (2008)
  Functional connectivity of human striatum: a resting state FMRI study
  Cereb Cortex 18(12): 2735–2747
  
  

  Classically regarded as motor structures, the basal ganglia subserve a wide range of functions, including motor, cognitive, motivational, and emotional processes. Consistent with this broad-reaching involvement in brain function, basal ganglia dysfunction has been implicated in numerous neurological and psychiatric disorders. Despite recent advances in human neuroimaging, models of basal ganglia circuitry continue to rely primarily upon inference from animal studies. Here, we provide a comprehensive functional connectivity analysis of basal ganglia circuitry in humans through a functional magnetic resonance imaging examination during rest. Voxelwise regression analyses substantiated the hypothesized motor, cognitive, and affective divisions among striatal subregions, and provided in vivo evidence of a functional organization consistent with parallel and integrative loop models described in animals. Our findings also revealed subtler distinctions within striatal subregions not previously appreciated by task-based imaging approaches. For instance, the inferior ventral striatum is functionally connected with medial portions of orbitofrontal cortex, whereas a more superior ventral striatal seed is associated with medial and lateral portions. The ability to map multiple distinct striatal circuits in a single study in humans, as opposed to relying on meta-analyses of multiple studies, is a principal strength of resting state functional magnetic resonance imaging. This approach holds promise for studying basal ganglia dysfunction in clinical disorders.

  
  
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  Uddin LQ, Mooshagian E, Zaidel E, Scheres A, Margulies DS, Kelly AMC, Shehzad Z, Adelstein JS, Castellanos FX, Biswal BB, Milham MP (2008)
  Residual functional connectivity in the split-brain revealed with resting-state functional MRI
  Neuroreport 19(7): 703–709
  
  

  Split-brain patients present a unique opportunity to address controversies regarding subcortical contributions to interhemispheric coordination. We characterized residual functional connectivity in a complete commissurotomy patient by examining patterns of low-frequency BOLD functional MRI signal. Using independent components analysis and region-of-interest-based functional connectivity analyses, we demonstrate bilateral resting state networks in a patient lacking all major cerebral commissures. Compared with a control group, the patient’s interhemispheric correlation scores fell within the normal range for two out of three regions examined. Thus, we provide evidence for bilateral resting state networks in a patient with complete commissurotomy. Such continued interhemispheric interaction suggests that, at least in part, cortical networks in the brain can be coordinated by subcortical mechanisms.

  
  
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  Uddin LQ, Kelly AMC, Biswal BB, Margulies DS, Shehzad Z, Shaw D, Ghaffari M, Rotrosen J, Adler LA, Castellanos FX, Milham MP (2008)
  Network homogeneity reveals decreased integrity of default-mode network in ADHD
  J Neurosci Methods 169(1): 249–254
  
  

  Examination of spontaneous intrinsic brain activity is drawing increasing interest, thus methods for such analyses are rapidly evolving. Here we describe a novel measure, "network homogeneity", that allows for assessment of cohesiveness within a specified functional network, and apply it to resting-state fMRI data from adult ADHD and control participants. We examined the default mode network, a medial-wall based network characterized by high baseline activity that decreases during attention-demanding cognitive tasks. We found reduced network homogeneity within the default mode network in ADHD subjects compared to age-matched controls, particularly between the precuneus and other default mode network regions. This confirms previously published results using seed-based functional connectivity measures, and provides further evidence that altered precuneus connectivity is involved in the neuropathology of ADHD. Network homogeneity provides a potential alternative method for assessing functional connectivity of specific large-scale networks in clinical populations.

  
  
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  Castellanos FX, Margulies DS, Kelly C, Uddin LQ, Ghaffari M, Kirsch A, Shaw D, Shehzad Z, Di Martino A, Biswal B, Sonuga-Barke EJS, Rotrosen J, Adler LA, Milham MP (2008)
  Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder
  Biol Psychiatry 63(3): 332–337
  
  

  BACKGROUND: Pathophysiologic models of attention-deficit/hyperactivity disorder (ADHD) have focused on frontal-striatal circuitry with alternative hypotheses relatively unexplored. On the basis of evidence that negative interactions between frontal foci involved in cognitive control and the non-goal-directed "default-mode" network prevent attentional lapses, we hypothesized abnormalities in functional connectivity of these circuits in ADHD. METHODS: Resting-state blood oxygen level-dependent functional magnetic resonance imaging (fMRI) scans were obtained at 3.0-Tesla in 20 adults with ADHD and 20 age- and sex-matched healthy volunteers. RESULTS: Examination of healthy control subjects verified presence of an antiphasic or negative relationship between activity in dorsal anterior cingulate cortex (centered at x = 8, y = 7, z = 38) and in default-mode network components. Group analyses revealed ADHD-related compromises in this relationship, with decreases in the functional connectivity between the anterior cingulate and precuneus/posterior cingulate cortex regions (p < .0004, corrected). Secondary analyses revealed an extensive pattern of ADHD-related decreases in connectivity between precuneus and other default-mode network components, including ventromedial prefrontal cortex (p < 3 x 10(-11), corrected) and portions of posterior cingulate (p < .02, corrected). CONCLUSIONS: Together with prior unbiased anatomic evidence of posterior volumetric abnormalities, our findings suggest that the long-range connections linking dorsal anterior cingulate to posterior cingulate and precuneus should be considered as a candidate locus of dysfunction in ADHD.

  
  

2007

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  Michanie C, Kunst G, Margulies DS, Yakhkind A (2007)
  Symptom prevalence of ADHD and ODD in a pediatric population in Argentina
  J Atten Disord 11(3): 363–367
  
  

  OBJECTIVE: To assess the prevalence of DSM III-R symptoms of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) in an outpatient pediatric population; to compare oppositional behavior and grade retention rates; and to establish local means and standard deviations (SD) for the ADHD rating scale. METHOD: 300 children (149m, 151f; 6 to12 yrs) were evaluated for ADHD and ODD symptoms with the DuPaul and an author-designed rating scale, respectively. Scores 1.5 SD above the mean were considered positive for each disorder. RESULTS: A total of 27 subjects (13m, 14f), 9%, had positive scores consistent with ADHD. These children had an oppositional behavior rate of 33.3% and a grade retention rate of 30.7%. Those who did not have positive scores for ADHD had a rate of 5.5% and 7.3%, respectively. The mean scores for the boys on the ADHD rating scale was 17.1 (SD = 8.6); the girls had a mean of 14.7 (SD = 7.3). CONCLUSION: The prevalence rates in our study are similar to those found in other countries.

  
  
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  Kelly AMC, Margulies DS, Castellanos FX (2007)
  Recent advances in structural and functional brain imaging studies of attention-deficit/hyperactivity disorder
  Curr Psychiatry Rep 9(5): 401–407
  
  

  The field of neuroimaging of attention-deficit/hyperactivity disorder (ADHD) is now 30 years old. This brief selective review highlights the increasing sophistication of recent structural and functional neuroimaging studies of ADHD. In volumetric studies, investigators are examining extra-frontal, as well as frontal-striatal circuits and beginning to differentiate the potential effects of medication exposure. Functional MRI studies are focusing on familial/genetic influences and enrolling medication naive, as well as medicated children with ADHD. A promising trend is the application of resting state approaches to mapping functional connectivity, which provides unexpectedly detailed information about interregional relationships while bypassing potentially confounding issues related to task performance. These developments allow us to conclude that neuroimaging studies of ADHD will increasingly inform our understanding of the neuronal substrates of ADHD.

  
  
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  Margulies DS, Kelly AMC, Uddin LQ, Biswal BB, Castellanos FX, Milham MP (2007)
  Mapping the functional connectivity of anterior cingulate cortex
  Neuroimage 37(2): 579–588
  
  

  Anterior cingulate cortex (ACC) is a nexus of information processing and regulation in the brain. Reflecting this central role, ACC is structurally and functionally heterogeneous, a fact long appreciated in studies of non-human primates. Human neuroimaging studies also recognize this functional heterogeneity, with meta-analyses and task-based studies demonstrating the existence of motor, cognitive and affective subdivisions. In contrast to task-based approaches, examinations of resting-state functional connectivity enable the characterization of task-independent patterns of correlated activity. In a novel approach to understanding ACC functional segregation, we systematically mapped ACC functional connectivity during rest. We examined patterns of functional connectivity for 16 seed ROIs systematically placed throughout caudal, rostral, and subgenual ACC in each hemisphere. First, our data support the commonly observed rostral/caudal distinction, but also suggest the existence of a dorsal/ventral functional distinction. For each of these distinctions, more fine-grained patterns of differentiation were observed than commonly appreciated in human imaging studies. Second, we demonstrate the presence of negatively predicted relationships between distinct ACC functional networks. In particular, we highlight negative relationships between rostral ACC-based affective networks (including the "default mode network") and dorsal-caudal ACC-based frontoparietal attention networks. Finally, interhemispheric activations were more strongly correlated between homologous regions than in non-homologous regions. We discuss the implications of our work for understanding ACC function and potential applications to clinical populations.

  
  

2006

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  Lamprecht R, Margulies DS, Farb CR, Hou M, Johnson LR, LeDoux JE (2006)
  Myosin light chain kinase regulates synaptic plasticity and fear learning in the lateral amygdala
  Neuroscience 139(3): 821–829
  
  

  Learning and memory depend on signaling molecules that affect synaptic efficacy. The cytoskeleton has been implicated in regulating synaptic transmission but its role in learning and memory is poorly understood. Fear learning depends on plasticity in the lateral nucleus of the amygdala. We therefore examined whether the cytoskeletal-regulatory protein, myosin light chain kinase, might contribute to fear learning in the rat lateral amygdala. Microinjection of ML-7, a specific inhibitor of myosin light chain kinase, into the lateral nucleus of the amygdala before fear conditioning, but not immediately afterward, enhanced both short-term memory and long-term memory, suggesting that myosin light chain kinase is involved specifically in memory acquisition rather than in posttraining consolidation of memory. Myosin light chain kinase inhibitor had no effect on memory retrieval. Furthermore, ML-7 had no effect on behavior when the training stimuli were presented in a non-associative manner. Anatomical studies showed that myosin light chain kinase is present in cells throughout lateral nucleus of the amygdala and is localized to dendritic shafts and spines that are postsynaptic to the projections from the auditory thalamus to lateral nucleus of the amygdala, a pathway specifically implicated in fear learning. Inhibition of myosin light chain kinase enhanced long-term potentiation, a physiological model of learning, in the auditory thalamic pathway to the lateral nucleus of the amygdala. When ML-7 was applied without associative tetanic stimulation it had no effect on synaptic responses in lateral nucleus of the amygdala. Thus, myosin light chain kinase activity in lateral nucleus of the amygdala appears to normally suppress synaptic plasticity in the circuits underlying fear learning, suggesting that myosin light chain kinase may help prevent the acquisition of irrelevant fears. Impairment of this mechanism could contribute to pathological fear learning.

  
  

Conference Proceedings

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  Margulies DS, Falkiewicz M, Huntenburg JM (2016)
  A cortical surface-based geodesic distance package for Python
  GigaScience 5(suppl_1): s13742–016-0147–0-q
  
  

  
  
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  Bottger J, Schafer A, Lohmann G, Villringer A, Margulies DS (2014)
  Three-dimensional mean-shift edge bundling for the visualization of functional connectivity in the brain
  IEEE Trans Vis Comput Graph 20(3): 471–480
  
  

  Functional connectivity, a flourishing new area of research in human neuroscience, carries a substantial challenge for visualization: while the end points of connectivity are known, the precise path between them is not. Although a large body of work already exists on the visualization of anatomical connectivity, the functional counterpart lacks similar development. To optimize the clarity of whole-brain and complex connectivity patterns in three-dimensional brain space, we develop mean-shift edge bundling, which reveals the multitude of connections as derived from correlations in the brain activity of cortical regions.

  
  
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  Gorgolewski KJ, Bazin P, Engen H, Margulies DS (2013)
  Fifty Shades of Gray, Matter: Using Bayesian Priors to Improve the Power of Whole-Brain Voxel- and Connexelwise Inferences
  2013 International Workshop on Pattern Recognition in Neuroimaging : 194–197
  
  

  To increase the power of neuroimaging analyses, it is common practice to reduce the whole-brain search space to subset of hypothesis-driven regions-of-interest (ROIs). Rather than strictly constrain analyses, we propose to incorporate prior knowledge using probabilistic ROIs (pROIs) using a hierarchical Bayesian framework. Each voxel prior probability of being "of-interest" or "of-non-interest" is used to perform a weighted fit of a mixture model. We demonstrate the utility of this approach through simulations with various pROIs, and the applicability using a prior based on the NeuroSynth database search term "emotion" for thresholding the fMRI results of an emotion processing task. The modular structure of pROI correction facilitates the inclusion of other innovations in Bayesian mixture modeling, and offers a foundation for balancing between exploratory analyses without neglecting prior knowledge.

  
  

Book chapters

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  Burns R, Haueis P, Margulies DS (2019)
  From regions to networks: Neuroimaging approaches to mapping brain organization
  In: Casting Light on the Dark Side of Brain Imaging, Academic Press: 135–138
  
  

  
  
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  Margulies DS (2011)
  The Salmon of Doubt
  In: Critical Neuroscience, Wiley-Blackwell: 273–285
  
  

  Summary This chapter contains sections titled: PART I: Voodoos and Don’ts PART II: Critical Tactics in Action Acknowledgements References