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      Local and Global Resting State Activity in the Noradrenergic and Dopaminergic Pathway Modulated by Reboxetine and Amisulpride in Healthy Subjects

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          Abstract

          Background:

          Various psychiatric populations are currently investigated with resting state fMRI, with the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-related neural alterations, but with the common psychopharmacological medication limiting interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers to further the understanding of the respective effects independent from disease-related alterations.

          Methods:

          Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19 healthy male subjects by resting state fMRI after the intake of reboxetine (4mg/d), amisulpride (200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state functional connectivity (rs-FC).

          Results:

          fALFF revealed alterations of local rs-activity within regions of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e. the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of regions within the dopaminergic pathway, with the altered signal in the putamen correlating with amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the dopaminergic pathway comprising the substantia nigra and putamen.

          Conclusion:

          Our data provide evidence of how psychopharmacological agents alter local and global rs-activity within the respective neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric populations.

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          Most cited references45

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          Effects of model-based physiological noise correction on default mode network anti-correlations and correlations.

          Previous studies have reported that the spontaneous, resting-state time course of the default-mode network is negatively correlated with that of the "task-positive network", a collection of regions commonly recruited in demanding cognitive tasks. However, all studies of negative correlations between the default-mode and task-positive networks have employed some form of normalization or regression of the whole-brain average signal ("global signal"); these processing steps alter the time series of voxels in an uninterpretable manner as well as introduce spurious negative correlations. Thus, the extent of negative correlations with the default mode network without global signal removal has not been well characterized, and it is has recently been hypothesized that the apparent negative correlations in many of the task-positive regions could be artifactually induced by global signal pre-processing. The present study aimed to examine negative and positive correlations with the default-mode network when model-based corrections for respiratory and cardiac noise are applied in lieu of global signal removal. Physiological noise correction consisted of (1) removal of time-locked cardiac and respiratory artifacts using RETROICOR (Glover, G.H., Li, T.Q., Ress, D., 2000. Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magn. Reson. Med. 44, 162-167), and (2) removal of low-frequency respiratory and heart rate variations by convolving these waveforms with pre-determined transfer functions (Birn et al., 2008; Chang et al., 2009) and projecting the resulting two signals out of the data. It is demonstrated that negative correlations between the default-mode network and regions of the task-positive network are present in the majority of individual subjects both with and without physiological noise correction. Physiological noise correction increased the spatial extent and magnitude of negative correlations, yielding negative correlations within task-positive regions at the group-level (p<0.05, uncorrected; no regions at the group level were significant at FDR=0.05). Furthermore, physiological noise correction caused region-specific decreases in positive correlations within the default-mode network, reducing apparent false positives. It was observed that the low-frequency respiratory volume and cardiac rate regressors used within the physiological noise correction algorithm displayed significant (but not total) shared variance with the global signal, and constitute a model-based alternative to correcting for non-neural global noise.
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            In vivo mapping of the human locus coeruleus.

            The locus coeruleus (LC) is a brainstem structure that has widespread cortical and sub-cortical projections to modulate states of attention. Our understanding of the LC's role in both normal attention and clinical populations affected by disrupted attention would be advanced by having in vivo functional and structural markers of the human LC. Evidence for LC activation can be difficult to interpret because of uncertainty about whether brainstem activity can be accurately localized to the LC. High resolution T1-turbo spin echo (T1-TSE) magnetic resonance imaging (MRI) (in-plane resolution of 0.4 mm x 0.4 mm) was used in this study to characterize the location and distribution probability of the LC across 44 adults ranging in age from 19 to 79 years. Utilizing a study-specific brainstem template, the individual brainstems were aligned into standard space, while preserving variations in LC signal intensity. Elevated T1-TSE signal was observed in the rostral pons that was strongly correlated with the position and concentration of LC cells previously reported in a study of post-mortem brains (r=0.90). The elevated T1-TSE signal was used to produce a probabilistic map of the LC in standard Montreal Neurological Institute (MNI) coordinate space. This map can be used to test hypotheses about the LC in human structural and functional imaging studies. Such efforts will contribute to our understanding of attention systems in normal and clinical populations.
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              Clinical applications of the functional connectome.

              Central to the development of clinical applications of functional connectomics for neurology and psychiatry is the discovery and validation of biomarkers. Resting state fMRI (R-fMRI) is emerging as a mainstream approach for imaging-based biomarker identification, detecting variations in the functional connectome that can be attributed to clinical variables (e.g., diagnostic status). Despite growing enthusiasm, many challenges remain. Here, we assess evidence of the readiness of R-fMRI based functional connectomics to lead to clinically meaningful biomarker identification through the lens of the criteria used to evaluate clinical tests (i.e., validity, reliability, sensitivity, specificity, and applicability). We focus on current R-fMRI-based prediction efforts, and survey R-fMRI used for neurosurgical planning. We identify gaps and needs for R-fMRI-based biomarker identification, highlighting the potential of emerging conceptual, analytical and cultural innovations (e.g., the Research Domain Criteria Project (RDoC), open science initiatives, and Big Data) to address them. Additionally, we note the need to expand future efforts beyond identification of biomarkers for disease status alone to include clinical variables related to risk, expected treatment response and prognosis. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Int J Neuropsychopharmacol
                Int. J. Neuropsychopharmacol
                ijnp
                ijnp
                International Journal of Neuropsychopharmacology
                Oxford University Press (US )
                1461-1457
                1469-5111
                February 2016
                25 July 2015
                : 19
                : 2
                : pyv080
                Affiliations
                Department of Psychiatry and Psychotherapy, Otto-von-Guericke University , Magdeburg, Germany (Drs Metzger and Walter); Department of Psychiatry, University of Ulm , Germany (Drs Wiegers, Abler, and Graf); Leibniz Institute for Neurobiology , Magdeburg, Germany (Drs Metzger and Walter); Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University , Magdeburg, Germany (Dr Metzger); German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany (Dr Metzger).
                Author notes
                Correspondence: Coraline D Metzger, MD, PhD, Department of Psychiatry and Psychotherapy and Institute for Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany ( coraline.metzger@ 123456med.ovgu.de ).
                Article
                10.1093/ijnp/pyv080
                4772816
                26209860
                fa4661e3-0768-4d12-91d5-3c4551fd76a3
                © The Author 2015. Published by Oxford University Press on behalf of CINP.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 March 2015
                : 10 July 2015
                Page count
                Pages: 9
                Categories
                Research Article

                Pharmacology & Pharmaceutical medicine
                amisulpride,dopamine,noradrenaline,pharmacological resting state fmri,reboxetine

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