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      Distinct thalamocortical network dynamics are associated with the pathophysiology of chronic low back pain

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          Abstract

          Thalamocortical dysrhythmia is a key pathology of chronic neuropathic pain, but few studies have investigated thalamocortical networks in chronic low back pain (cLBP) given its non-specific etiology and complexity. Using fMRI, we propose an analytical pipeline to identify abnormal thalamocortical network dynamics in cLBP patients and validate the findings in two independent cohorts. We first identify two reoccurring dynamic connectivity states and their associations with chronic and temporary pain. Further analyses show that cLBP patients have abnormal connectivity between the ventral lateral/posterolateral nucleus (VL/VPL) and postcentral gyrus (PoCG) and between the dorsal/ventral medial nucleus and insula in the less frequent connectivity state, and temporary pain exacerbation alters connectivity between the VL/VPL and PoCG and the default mode network in the more frequent connectivity state. These results extend current findings on thalamocortical dysfunction and dysrhythmia in chronic pain and demonstrate that cLBP pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

          Abstract

          Thalamocortical dysrhythmia is a key pathology of chronic pain. Here, the authors propose an analytical pipeline to study dynamic fMRI brain networks and demonstrate that chronic low back pain pathophysiology and clinical pain intensity are associated with distinct thalamocortical network dynamics.

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          Most cited references43

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          Chronic back pain is associated with decreased prefrontal and thalamic gray matter density.

          The role of the brain in chronic pain conditions remains speculative. We compared brain morphology of 26 chronic back pain (CBP) patients to matched control subjects, using magnetic resonance imaging brain scan data and automated analysis techniques. CBP patients were divided into neuropathic, exhibiting pain because of sciatic nerve damage, and non-neuropathic groups. Pain-related characteristics were correlated to morphometric measures. Neocortical gray matter volume was compared after skull normalization. Patients with CBP showed 5-11% less neocortical gray matter volume than control subjects. The magnitude of this decrease is equivalent to the gray matter volume lost in 10-20 years of normal aging. The decreased volume was related to pain duration, indicating a 1.3 cm3 loss of gray matter for every year of chronic pain. Regional gray matter density in 17 CBP patients was compared with matched controls using voxel-based morphometry and nonparametric statistics. Gray matter density was reduced in bilateral dorsolateral prefrontal cortex and right thalamus and was strongly related to pain characteristics in a pattern distinct for neuropathic and non-neuropathic CBP. Our results imply that CBP is accompanied by brain atrophy and suggest that the pathophysiology of chronic pain includes thalamocortical processes.
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            The Human Thalamus Is an Integrative Hub for Functional Brain Networks

            The thalamus is globally connected with distributed cortical regions, yet the functional significance of this extensive thalamocortical connectivity remains largely unknown. By performing graph-theoretic analyses on thalamocortical functional connectivity data collected from human participants, we found that most thalamic subdivisions display network properties that are capable of integrating multimodal information across diverse cortical functional networks. From a meta-analysis of a large dataset of functional brain-imaging experiments, we further found that the thalamus is involved in multiple cognitive functions. Finally, we found that focal thalamic lesions in humans have widespread distal effects, disrupting the modular organization of cortical functional networks. This converging evidence suggests that the human thalamus is a critical hub region that could integrate diverse information being processed throughout the cerebral cortex as well as maintain the modular structure of cortical functional networks. SIGNIFICANCE STATEMENT The thalamus is traditionally viewed as a passive relay station of information from sensory organs or subcortical structures to the cortex. However, the thalamus has extensive connections with the entire cerebral cortex, which can also serve to integrate information processing between cortical regions. In this study, we demonstrate that multiple thalamic subdivisions display network properties that are capable of integrating information across multiple functional brain networks. Moreover, the thalamus is engaged by tasks requiring multiple cognitive functions. These findings support the idea that the thalamus is involved in integrating information across cortical networks.
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              Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography.

              Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency theta rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent theta activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic gamma-band activation, which we refer to as the "edge effect." This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level.
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                Author and article information

                Contributors
                kongj@nmr.mgh.harvard.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                7 August 2020
                7 August 2020
                2020
                : 11
                : 3948
                Affiliations
                [1 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Psychiatry, Massachusetts General Hospital, , Harvard Medical School, ; Charlestown, MA USA
                [2 ]Department of Radiology, Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA USA
                [3 ]Tri-Institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, GA USA
                [4 ]Department of Medical Imaging, First Affiliated Hospital of Xi’An Jiao Tong University College of Medicine, Xi’an, Shaan’Xi China
                [5 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Center for Functional MRI, , University of California San Diego, ; La Jolla, CA USA
                [6 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, , Harvard Medical School, ; Boston, MA USA
                [7 ]GRID grid.38142.3c, ISNI 000000041936754X, Beth Israel Deaconess Medical Center, , Harvard Medical School, ; Boston, MA USA
                Author information
                http://orcid.org/0000-0002-3495-9549
                http://orcid.org/0000-0002-9434-4044
                http://orcid.org/0000-0002-2053-9180
                http://orcid.org/0000-0002-2253-1940
                http://orcid.org/0000-0002-2744-6067
                Article
                17788
                10.1038/s41467-020-17788-z
                7414843
                32769984
                fea2e2a5-6dbd-48bc-9406-4bf03d1e5f2b
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 30 July 2019
                : 21 July 2020
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                © The Author(s) 2020

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                chronic pain
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                chronic pain

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