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      Hyperactivity/restlessness is associated with increased functional connectivity in adults with ADHD: a dimensional analysis of resting state fMRI

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          Abstract

          Background

          Adult attention-deficit/hyperactivity disorder (ADHD) is a serious and frequent psychiatric disorder of multifactorial pathogenesis. Several lines of evidence support the idea that ADHD is, in its core, a disorder of dysfunctional brain connectivity within and between several neurofunctional networks. The primary aim of this study was to investigate associations between the functional connectivity within resting state brain networks and the individual severity of core ADHD symptoms (inattention, hyperactivity, and impulsivity).

          Methods

          Resting state functional magnetic resonance imaging (rs-fMRI) data of 38 methylphenidate-naïve adults with childhood-onset ADHD (20 women, mean age 40.5 years) were analyzed using independent component analysis (FSL’s MELODIC) and FSL’s dual regression technique. For motion correction, standard volume-realignment followed by independent component analysis-based automatic removal of motion artifacts (FSL’s ICA-AROMA) were employed. To identify well-established brain networks, the independent components found in the ADHD group were correlated with brain networks previously found in healthy participants (Smith et al. PNAS 2009;106:13040–5). To investigate associations between functional connectivity and individual symptom severity, sex, and age, linear regressions were performed.

          Results

          Decomposition of resting state brain activity of adults with ADHD resulted in similar resting state networks as previously described for healthy adults. No significant differences in functional connectivity were seen between women and men. Advanced age was associated with decreased functional connectivity in parts of the bilateral cingulate and paracingulate cortex within the executive control network. More severe hyperactivity was associated with increased functional connectivity in the left putamen, right caudate nucleus, right central operculum and a portion of the right postcentral gyrus within the auditory/sensorimotor network.

          Conclusions

          The present study supports and extends our knowledge on the involvement of the striatum in the pathophysiology of ADHD, in particular, in the pathogenesis of hyperactivity. Our results emphasize the usefulness of dimensional analyses in the study of ADHD, a highly heterogeneous disorder.

          Trial registration

          ISRCTN12722296 (10.1186/ISRCTN12722296).

          Electronic supplementary material

          The online version of this article (10.1186/s12888-019-2031-9) contains supplementary material, which is available to authorized users.

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          Most cited references30

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          Evaluation of ICA-AROMA and alternative strategies for motion artifact removal in resting state fMRI.

          We proposed ICA-AROMA as a strategy for the removal of motion-related artifacts from fMRI data (Pruim et al., 2015). ICA-AROMA automatically identifies and subsequently removes data-driven derived components that represent motion-related artifacts. Here we present an extensive evaluation of ICA-AROMA by comparing our strategy to a range of alternative strategies for motion-related artifact removal: (i) no secondary motion correction, (ii) extensive nuisance regression utilizing 6 or (iii) 24 realignment parameters, (iv) spike regression (Satterthwaite et al., 2013a), (v) motion scrubbing (Power et al., 2012), (vi) aCompCor (Behzadi et al., 2007; Muschelli et al., 2014), (vii) SOCK (Bhaganagarapu et al., 2013), and (viii) ICA-FIX (Griffanti et al., 2014; Salimi-Khorshidi et al., 2014), without re-training the classifier. Using three different functional connectivity analysis approaches and four different multi-subject resting-state fMRI datasets, we assessed all strategies regarding their potential to remove motion artifacts, ability to preserve signal of interest, and induced loss in temporal degrees of freedom (tDoF). Results demonstrated that ICA-AROMA, spike regression, scrubbing, and ICA-FIX similarly minimized the impact of motion on functional connectivity metrics. However, both ICA-AROMA and ICA-FIX resulted in significantly improved resting-state network reproducibility and decreased loss in tDoF compared to spike regression and scrubbing. In comparison to ICA-FIX, ICA-AROMA yielded improved preservation of signal of interest across all datasets. These results demonstrate that ICA-AROMA is an effective strategy for removing motion-related artifacts from rfMRI data. Our robust and generalizable strategy avoids the need for censoring fMRI data and reduces motion-induced signal variations in fMRI data, while preserving signal of interest and increasing the reproducibility of functional connectivity metrics. In addition, ICA-AROMA preserves the temporal non-artifactual time-series characteristics and limits the loss in tDoF, thereby increasing statistical power at both the subject- and the between-subject analysis level.
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            Reorganization of brain networks in aging: a review of functional connectivity studies

            Healthy aging (HA) is associated with certain declines in cognitive functions, even in individuals that are free of any process of degenerative illness. Functional magnetic resonance imaging (fMRI) has been widely used in order to link this age-related cognitive decline with patterns of altered brain function. A consistent finding in the fMRI literature is that healthy old adults present higher activity levels in some brain regions during the performance of cognitive tasks. This finding is usually interpreted as a compensatory mechanism. More recent approaches have focused on the study of functional connectivity, mainly derived from resting state fMRI, and have concluded that the higher levels of activity coexist with disrupted connectivity. In this review, we aim to provide a state-of-the-art description of the usefulness and the interpretations of functional brain connectivity in the context of HA. We first give a background that includes some basic aspects and methodological issues regarding functional connectivity. We summarize the main findings and the cognitive models that have been derived from task-activity studies, and we then review the findings provided by resting-state functional connectivity in HA. Finally, we suggest some future directions in this field of research. A common finding of the studies included is that older subjects present reduced functional connectivity compared to young adults. This reduced connectivity affects the main brain networks and explains age-related cognitive alterations. Remarkably, the default mode network appears as a highly compromised system in HA. Overall, the scenario given by both activity and connectivity studies also suggests that the trajectory of changes during task may differ from those observed during resting-state. We propose that the use of complex modeling approaches studying effective connectivity may help to understand context-dependent functional reorganizations in the aging process.
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              Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication.

              Structural neuroimaging studies in attention-deficit hyperactivity disorder (ADHD) have been relatively inconsistent and have mainly been conducted with pediatric samples. Furthermore, there is evidence that stimulant medication may have an effect on brain structure. The authors conducted a meta-analysis of voxel-based morphometry studies in children and adults with ADHD and examined the potential effects of age and stimulant medication on regional gray matter volumes. The PubMed, ScienceDirect, Web of Knowledge, and Scopus databases were searched for articles published between 2001 and 2011. Manual searches were also conducted, and authors of studies were contacted for additional data. Coordinates were extracted from clusters of significant gray matter difference between ADHD patients and healthy comparison subjects. Metaregression methods were used to explore potential age and stimulant medication effects. Fourteen data sets comprising 378 patients with ADHD and 344 healthy subjects met inclusion criteria. The ADHD group had global reductions in gray matter volumes, which were robustly localized in the right lentiform nucleus and extended to the caudate nucleus. Both increasing age and percentage of patients taking stimulant medication were found to be independently associated with more normal values in this region. Patients also had slightly greater gray matter volumes in the left posterior cingulate cortex. These findings confirm that the most prominent and replicable structural abnormalities in ADHD are in the basal ganglia. They furthermore suggest that ADHD patients may progressively catch up with their developmental delay with advancing age and that use of stimulant medication may be associated with normalization of structural abnormalities in ADHD, although longitudinal studies are needed to confirm both observations.
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                Author and article information

                Contributors
                peter.soros@gmail.com
                eliza.hoxhaj@uniklinik-freiburg.de
                patricia.borel@t-online.de
                mail@praxis-sadohara.com
                bernd.feige@uniklinik-freiburg.de
                swantje.matthies@uniklinik-freiburg.de
                helge.mueller@ukbonn.de
                katharina.bachmann@uni-oldenburg.de
                marcel.schulze@ukbonn.de
                alexandra.philipsen@ukbonn.de
                Journal
                BMC Psychiatry
                BMC Psychiatry
                BMC Psychiatry
                BioMed Central (London )
                1471-244X
                25 January 2019
                25 January 2019
                2019
                : 19
                : 43
                Affiliations
                [1 ]ISNI 0000 0001 1009 3608, GRID grid.5560.6, Psychiatry and Psychotherapy, School of Medicine and Health Sciences, , University of Oldenburg, ; Oldenburg, Germany
                [2 ]ISNI 0000 0001 1009 3608, GRID grid.5560.6, Research Center Neurosensory Science, , University of Oldenburg, ; Oldenburg, Germany
                [3 ]GRID grid.5963.9, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, , University of Freiburg, ; Freiburg, Germany
                [4 ]ISNI 0000 0001 2240 3300, GRID grid.10388.32, Department of Psychiatry and Psychotherapy, , University of Bonn, ; Bonn, Germany
                Author information
                http://orcid.org/0000-0002-8848-5158
                Article
                2031
                10.1186/s12888-019-2031-9
                6347794
                30683074
                aa916dc3-30ba-45e8-bff9-ff59157c395e
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 April 2018
                : 16 January 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: 01GV0606
                Award Recipient :
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                Clinical Psychology & Psychiatry
                adhd,adult,resting state fmri,functional connectivity,inattention,hyperactivity,impulsivity,age

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