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      Distinct neural signatures detected for ADHD subtypes after controlling for micro-movements in resting state functional connectivity MRI data

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          Abstract

          In recent years, there has been growing enthusiasm that functional magnetic resonance imaging (MRI) could achieve clinical utility for a broad range of neuropsychiatric disorders. However, several barriers remain. For example, the acquisition of large-scale datasets capable of clarifying the marked heterogeneity that exists in psychiatric illnesses will need to be realized. In addition, there continues to be a need for the development of image processing and analysis methods capable of separating signal from artifact. As a prototypical hyperkinetic disorder, and movement-related artifact being a significant confound in functional imaging studies, ADHD offers a unique challenge. As part of the ADHD-200 Global Competition and this special edition of Frontiers, the ADHD-200 Consortium demonstrates the utility of an aggregate dataset pooled across five institutions in addressing these challenges. The work aimed to (1) examine the impact of emerging techniques for controlling for “micro-movements,” and (2) provide novel insights into the neural correlates of ADHD subtypes. Using support vector machine (SVM)-based multivariate pattern analysis (MVPA) we show that functional connectivity patterns in individuals are capable of differentiating the two most prominent ADHD subtypes. The application of graph-theory revealed that the Combined (ADHD-C) and Inattentive (ADHD-I) subtypes demonstrated some overlapping (particularly sensorimotor systems), but unique patterns of atypical connectivity. For ADHD-C, atypical connectivity was prominent in midline default network components, as well as insular cortex; in contrast, the ADHD-I group exhibited atypical patterns within the dlPFC regions and cerebellum. Systematic motion-related artifact was noted, and highlighted the need for stringent motion correction. Findings reported were robust to the specific motion correction strategy employed. These data suggest that resting-state functional connectivity MRI (rs-fcMRI) data can be used to characterize individual patients with ADHD and to identify neural distinctions underlying the clinical heterogeneity of ADHD.

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          Most cited references45

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          Modularity and community structure in networks

          M. Newman (2006)
          Many networks of interest in the sciences, including a variety of social and biological networks, are found to divide naturally into communities or modules. The problem of detecting and characterizing this community structure has attracted considerable recent attention. One of the most sensitive detection methods is optimization of the quality function known as "modularity" over the possible divisions of a network, but direct application of this method using, for instance, simulated annealing is computationally costly. Here we show that the modularity can be reformulated in terms of the eigenvectors of a new characteristic matrix for the network, which we call the modularity matrix, and that this reformulation leads to a spectral algorithm for community detection that returns results of better quality than competing methods in noticeably shorter running times. We demonstrate the algorithm with applications to several network data sets.
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            A dual-networks architecture of top-down control.

            Complex systems ensure resilience through multiple controllers acting at rapid and slower timescales. The need for efficient information flow through complex systems encourages small-world network structures. On the basis of these principles, a group of regions associated with top-down control was examined. Functional magnetic resonance imaging showed that each region had a specific combination of control signals; resting-state functional connectivity grouped the regions into distinct 'fronto-parietal' and 'cingulo-opercular' components. The fronto-parietal component seems to initiate and adjust control; the cingulo-opercular component provides stable 'set-maintenance' over entire task epochs. Graph analysis showed dense local connections within components and weaker 'long-range' connections between components, suggesting a small-world architecture. The control systems of the brain seem to embody the principles of complex systems, encouraging resilient performance.
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              Intrinsic functional connectivity as a tool for human connectomics: theory, properties, and optimization.

              Resting state functional connectivity MRI (fcMRI) is widely used to investigate brain networks that exhibit correlated fluctuations. While fcMRI does not provide direct measurement of anatomic connectivity, accumulating evidence suggests it is sufficiently constrained by anatomy to allow the architecture of distinct brain systems to be characterized. fcMRI is particularly useful for characterizing large-scale systems that span distributed areas (e.g., polysynaptic cortical pathways, cerebro-cerebellar circuits, cortical-thalamic circuits) and has complementary strengths when contrasted with the other major tool available for human connectomics-high angular resolution diffusion imaging (HARDI). We review what is known about fcMRI and then explore fcMRI data reliability, effects of preprocessing, analysis procedures, and effects of different acquisition parameters across six studies (n = 98) to provide recommendations for optimization. Run length (2-12 min), run structure (1 12-min run or 2 6-min runs), temporal resolution (2.5 or 5.0 s), spatial resolution (2 or 3 mm), and the task (fixation, eyes closed rest, eyes open rest, continuous word-classification) were varied. Results revealed moderate to high test-retest reliability. Run structure, temporal resolution, and spatial resolution minimally influenced fcMRI results while fixation and eyes open rest yielded stronger correlations as contrasted to other task conditions. Commonly used preprocessing steps involving regression of nuisance signals minimized nonspecific (noise) correlations including those associated with respiration. The most surprising finding was that estimates of correlation strengths stabilized with acquisition times as brief as 5 min. The brevity and robustness of fcMRI positions it as a powerful tool for large-scale explorations of genetic influences on brain architecture. We conclude by discussing the strengths and limitations of fcMRI and how it can be combined with HARDI techniques to support the emerging field of human connectomics.
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                Author and article information

                Journal
                Front Syst Neurosci
                Front Syst Neurosci
                Front. Syst. Neurosci.
                Frontiers in Systems Neuroscience
                Frontiers Media S.A.
                1662-5137
                24 September 2012
                04 February 2013
                2012
                : 6
                : 80
                Affiliations
                [1] 1Department of Behavioral Neuroscience, Advanced Imaging Research Center, Oregon Health and Science University Portland, OR, USA
                [2] 2Department of Psychiatry, Advanced Imaging Research Center, Oregon Health and Science University Portland, OR, USA
                [3] 3Department of Computer Science and Engineering, Indian Institute of Technology Ropar Rupnagar, Punjab, India
                [4] 4Department of Neurology, Washington University St. Louis, MO, USA
                [5] 5Phyllis Green and Randolph Cowen Institute for Pediatric Neuroscience, NYU Langone Medical Center New York, NY, USA
                [6] 6Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Center Nijmegen, Netherlands
                [7] 7PediMIND Program, Bradley Hospital, Brown University School of Medicine East Providence RI, USA
                [8] 8University of Massachusetts Medical Center Worcester, MA, USA
                [9] 9Department of Psychiatry, University of Pittsburgh PA, USA
                [10] 10Departments of Psychiatry, Behavioral Sciences, and the MIND Institute, University of California Davis School of Medicine Sacramento, CA, USA
                [11] 11Institute of Mental Health, Peking University Beijing, China
                [12] 12Key Laboratory of Mental Health, Ministry of Health, Peking University Beijing, China
                [13] 13Kennedy Krieger Institute Baltimore, MD, USA
                [14] 14Johns Hopkins University Baltimore, MD, USA
                [15] 15Nathan Kline Institute Orangeburg, NY, USA
                [16] 16Center for the Developing Brain, Child Mind Institute New York, NY, USA
                Author notes

                Edited by: Ranulfo Romo, Universidad Nacional Autónoma de México, Mexico

                Reviewed by: Valentin Dragoi, University of Texas Medical School at Houston, USA; David C. Somers, Boston University, USA

                *Correspondence: Damien A. Fair, Department of Psychiatry, Oregon Health and Science University, 3181 SW Sam Jackson Park Road UHN88, Portland, OR 97239, USA. e-mail: faird@ 123456ohsu.edu
                Michael P. Milham, Child Mind Institute, Center for the Developing Brain, 445 Park Avenue, New York, NY 10022, USA. e-mail: michael.milham@ 123456childmind.org
                Article
                10.3389/fnsys.2012.00080
                3563110
                23382713
                2e90edd8-0c02-4847-ac2a-f999ed8cc031
                Copyright © 2013 Fair, Nigg, Iyer, Bathula, Mills, Dosenbach, Schlaggar, Mennes, Gutman, Bangaru, Buitelaar, Dickstein, Di Martino, Kennedy, Kelly, Luna, Schweitzer, Velanova, Wang, Mostofsky, Castellanos and Milham.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                : 09 July 2012
                : 30 December 2012
                Page count
                Figures: 20, Tables: 4, Equations: 9, References: 85, Pages: 31, Words: 17566
                Categories
                Neuroscience
                Original Research Article

                Neurosciences
                adhd,functional connectivity,support vector machines,rdoc,research domain criteria
                Neurosciences
                adhd, functional connectivity, support vector machines, rdoc, research domain criteria

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