Anxiety and depression severity in neuropsychiatric SLE are associated with perfusion and functional connectivity changes of the frontolimbic neural circuit: a resting-state f(unctional) MRI study.
autoimmune diseases; lupus erythematosus; magnetic resonance imaging; systemic; Anxiety; Anxiety Disorders; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Perfusion; Depression; Lupus Erythematosus, Systemic; Rheumatology; Immunology; General Medicine
Abstract :
[en] [en] OBJECTIVE: To examine the hypothesis that perfusion and functional connectivity disturbances in brain areas implicated in emotional processing are linked to emotion-related symptoms in neuropsychiatric SLE (NPSLE).
METHODS: Resting-state fMRI (rs-fMRI) was performed and anxiety and/or depression symptoms were assessed in 32 patients with NPSLE and 18 healthy controls (HC). Whole-brain time-shift analysis (TSA) maps, voxel-wise global connectivity (assessed through intrinsic connectivity contrast (ICC)) and within-network connectivity were estimated and submitted to one-sample t-tests. Subgroup differences (high vs low anxiety and high vs low depression symptoms) were assessed using independent-samples t-tests. In the total group, associations between anxiety (controlling for depression) or depression symptoms (controlling for anxiety) and regional TSA or ICC metrics were also assessed.
RESULTS: Elevated anxiety symptoms in patients with NPSLE were distinctly associated with relatively faster haemodynamic response (haemodynamic lead) in the right amygdala, relatively lower intrinsic connectivity of orbital dlPFC, and relatively lower bidirectional connectivity between dlPFC and vmPFC combined with relatively higher bidirectional connectivity between ACC and amygdala. Elevated depression symptoms in patients with NPSLE were distinctly associated with haemodynamic lead in vmPFC regions in both hemispheres (lateral and medial orbitofrontal cortex) combined with relatively lower intrinsic connectivity in the right medial orbitofrontal cortex. These measures failed to account for self-rated, milder depression symptoms in the HC group.
CONCLUSION: By using rs-fMRI, altered perfusion dynamics and functional connectivity was found in limbic and prefrontal brain regions in patients with NPSLE with severe anxiety and depression symptoms. Although these changes could not be directly attributed to NPSLE pathology, results offer new insights on the pathophysiological substrate of psychoemotional symptomatology in patients with lupus, which may assist its clinical diagnosis and treatment.
Disciplines :
Neurosciences & behavior
Author, co-author :
Antypa, Despina; Department of Psychiatry, University of Crete School of Medicine, Heraklion, Greece
Simos, Nikolaos-Ioannis ; Université de Liège - ULiège > GIGA > GIGA CRC In vivo Imaging - Sleep and chronobiology
Kavroulakis, Eleftherios; Department of Radiology, University of Crete, School of Medicine, Heraklion, Greece
Bertsias, George; Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece ; Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Heraklion, Crete, Greece
Fanouriakis, Antonis ; Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece ; "Attikon" University Hospital, Athens, Greece
Sidiropoulos, Prodromos; Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece
Boumpas, Dimitrios; Rheumatology, Clinical Immunology and Allergy, University Hospital of Heraklion, Heraklion, Greece ; "Attikon" University Hospital, Athens, Greece ; Laboratory of Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece ; Joint Academic Rheumatology Program, and 4th Department of Medicine, Medical School, National and Kapodestrian University of Athens, Athens, Greece
Papadaki, Efrosini ; Computational Bio-Medicine Laboratory, Institute of Computer Science, Foundation for Research and Technology - Hellas, Heraklion, Crete, Greece fpapada@otenet.gr ; Department of Radiology, University of Crete, School of Medicine, Heraklion, Greece
Language :
English
Title :
Anxiety and depression severity in neuropsychiatric SLE are associated with perfusion and functional connectivity changes of the frontolimbic neural circuit: a resting-state f(unctional) MRI study.
HFRI - Hellenic Foundation for Research and Innovation ERC - European Research Council
Funding text :
Funding The study received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation programme (grant agreement no 742390) to DB. Additional financial support was provided by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “second Call for H.F.R.I. Research Projects to support Post-Doctoral Researchers” (Project Number: 1220) to EK. AF’s contribution to this work has been supported in part by a grant from the Hellenic Society of Rheumatology.
Bertsias GK, Boumpas DT, Pathogenesis BDT. Pathogenesis, diagnosis and management of neuropsychiatric SLE manifestations. Nat Rev Rheumatol 2010;6:358-67. doi:10.1038/nrrheum.2010.62 http://www.ncbi.nlm.nih.gov/pubmed/20458332
Moustafa AT, Moazzami M, Engel L, et al. Prevalence and metric of depression and anxiety in systemic lupus erythematosus: a systematic review and meta-analysis. Semin Arthritis Rheum 2020;50:84-94. doi:10.1016/j.semarthrit.2019.06.017 http://www.ncbi.nlm.nih.gov/pubmed/31303437
Zhang L, Fu T, Yin R, et al. Prevalence of depression and anxiety in systemic lupus erythematosus: a systematic review and meta-analysis. BMC Psychiatry 2017;17:70. doi:10.1186/s12888-017-1234-1 http://www.ncbi.nlm.nih.gov/pubmed/28196529
Ainiala H, Loukkola J, Peltola J, et al. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology 2001;57:496-500. doi:10.1212/WNL.57.3.496 http://www.ncbi.nlm.nih.gov/pubmed/11502919
Hanly JG, Su L, Urowitz MB, et al. Mood disorders in systemic lupus erythematosus: results from an international inception cohort study. Arthritis Rheumatol 2015;67:1837-47. doi:10.1002/art.39111 http://www.ncbi.nlm.nih.gov/pubmed/25778456
Shehata GA, Elserogy YM, Ahmad HEK, et al. Multimodal neurophysiological and psychometric evaluation among patients with systemic lupus erythematosus. Int J Gen Med 2011;4:325-32. doi:10.2147/IJGM.S16492 http://www.ncbi.nlm.nih.gov/pubmed/21674025
Tisseverasinghe A, Peschken C, Hitchon C. Anxiety and mood disorders in systemic lupus erythematosus: current insights and future directions. Curr Rheumatol Rep 2018;20:85. doi:10.1007/s11926-018-0797-2 http://www.ncbi.nlm.nih.gov/pubmed/30417270
Bortoluzzi A, Scirè CA, Bombardieri S, et al. Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatology 2015;54:891-8. doi:10.1093/rheumatology/keu384 http://www.ncbi.nlm.nih.gov/pubmed/25339643
Cohen D, Rijnink EC, Nabuurs RJA, et al. Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. Rheumatology 2017;56:77-86. doi:10.1093/rheumatology/kew341 http://www.ncbi.nlm.nih.gov/pubmed/28028157
FilleyCM, KozoraE, BrownMS. White matter microstructure and cognition in non-neuropsychiatric systemic lupus erythematosus. Cognitive and Behavioral Neurology, 2009. Available: https://journals.lww.com/cogbehavneurol/Fulltext/2009/03000/White_Matter_Microstructure_and_Cognition_in.4.aspx
Papadaki E, Fanouriakis A, Kavroulakis E, et al. Neuropsychiatric lupus or not? Cerebral hypoperfusion by perfusion-weighted MRI in normal-appearing white matter in primary neuropsychiatric lupus erythematosus. Ann Rheum Dis 2018;77:441-8. doi:10.1136/annrheumdis-2017-212285 http://www.ncbi.nlm.nih.gov/pubmed/29259047
Fitzgibbon BM, Fairhall SL, Kirk IJ, et al. Functional MRI in NPSLE patients reveals increased parietal and frontal brain activation during a working memory task compared with controls. Rheumatology 2008;47:50-3. doi:10.1093/rheumatology/kem287 http://www.ncbi.nlm.nih.gov/pubmed/18037687
Nystedt J, Mannfolk P, Jönsen A, et al. Functional connectivity changes in systemic lupus erythematosus: a resting-state study. Brain Connect 2018;8:220-34. doi:10.1089/brain.2017.0557 http://www.ncbi.nlm.nih.gov/pubmed/29498293
Khalil AA, Ostwaldt A-C, Nierhaus T, et al. Relationship between changes in the temporal dynamics of the blood-oxygen-level-dependent signal and hypoperfusion in acute ischemic stroke. Stroke 2017;48:925-31. doi:10.1161/STROKEAHA.116.015566 http://www.ncbi.nlm.nih.gov/pubmed/28275197
Khalil AA, Villringer K, Filleböck V, et al. Non-invasive monitoring of longitudinal changes in cerebral hemodynamics in acute ischemic stroke using BOLD signal delay. J Cereb Blood Flow Metab 2020;40:23-34. doi:10.1177/0271678X18803951 http://www.ncbi.nlm.nih.gov/pubmed/30334657
Lv Y, Margulies DS, Cameron Craddock R, et al. Identifying the perfusion deficit in acute stroke with resting-state functional magnetic resonance imaging. Ann Neurol 2013;73:136-40. doi:10.1002/ana.23763 http://www.ncbi.nlm.nih.gov/pubmed/23378326
Tong Y, Lindsey KP, Hocke LM, et al. Perfusion information extracted from resting state functional magnetic resonance imaging. J Cereb Blood Flow Metab 2017;37:564-76. doi:10.1177/0271678X16631755 http://www.ncbi.nlm.nih.gov/pubmed/26873885
Mitra A, Snyder AZ, Hacker CD, et al. Lag structure in resting-state fMRI. J Neurophysiol 2014;111:2374-91. doi:10.1152/jn.00804.2013 http://www.ncbi.nlm.nih.gov/pubmed/24598530
Emmer BJ, van Osch MJ, Wu O, et al. Perfusion MRI in neuro-psychiatric systemic lupus erthemathosus. J Magn Reson Imaging 2010;32:283-8. doi:10.1002/jmri.22251 http://www.ncbi.nlm.nih.gov/pubmed/20677252
Wang PI, Cagnoli PC, McCune WJ, et al. Perfusion-weighted MR imaging in cerebral lupus erythematosus. Acad Radiol 2012;19:965-70. doi:10.1016/j.acra.2012.03.023 http://www.ncbi.nlm.nih.gov/pubmed/22608862
Zimny A, Szmyrka-Kaczmarek M, Szewczyk P, et al. In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy, perfusion-weighted and diffusion-tensor imaging. Lupus 2014;23:10-19. doi:10.1177/0961203313511556 http://www.ncbi.nlm.nih.gov/pubmed/24192079
Borrelli M, Tamarozzi R, Colamussi P, et al. Evaluation with MR, perfusion MR and cerebral flowSPECT in NPSLE patients. Radiol Med 2003;105:482-9 http://www.ncbi.nlm.nih.gov/pubmed/12949459
Zhuo Z, Su L, Duan Y, et al. Different patterns of cerebral perfusion in SLE patients with and without neuropsychiatric manifestations. Hum Brain Mapp 2020;41:755-66. doi:10.1002/hbm.24837 http://www.ncbi.nlm.nih.gov/pubmed/31650651
Gasparovic CM, Roldan CA, Sibbitt WL, et al. Elevated cerebral blood flow and volume in systemic lupus measured by dynamic susceptibility contrast magnetic resonance imaging. J Rheumatol 2010;37:1834-43. doi:10.3899/jrheum.091276 http://www.ncbi.nlm.nih.gov/pubmed/20551095
Papadaki E, Kavroulakis E, Bertsias G, et al. Regional cerebral perfusion correlates with anxiety in neuropsychiatric SLE: evidence for a mechanism distinct from depression. Lupus 2019;28:1678-89. doi:10.1177/0961203319887793 http://www.ncbi.nlm.nih.gov/pubmed/31718491
Goodkind M, Eickhoff SB, Oathes DJ, et al. Identification of a common neurobiological substrate for mental illness. JAMA Psychiatry 2015;72:305. doi:10.1001/jamapsychiatry.2014.2206 http://www.ncbi.nlm.nih.gov/pubmed/25651064
Sha Z, Wager TD, Mechelli A, et al. Common dysfunction of large-scale neurocognitive networks across psychiatric disorders. Biol Psychiatry 2019;85:379-88. doi:10.1016/j.biopsych.2018.11.011
Tay SH, Cheung PPM, Mak A. Active disease is independently associated with more severe anxiety rather than depressive symptoms in patients with systemic lupus erythematosus. Lupus 2015;24:1392-9. doi:10.1177/0961203315591026 http://www.ncbi.nlm.nih.gov/pubmed/26085594
Bai R, Liu S, Zhao Y, et al. Depressive and anxiety disorders in systemic lupus erythematosus patients without major neuropsychiatric manifestations. J Immunol Res 2016;2016:1-7. doi:10.1155/2016/2829018 http://www.ncbi.nlm.nih.gov/pubmed/27747246
Tye KM, Prakash R, Kim S-Y, et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature 2011;471:358-62. doi:10.1038/nature09820 http://www.ncbi.nlm.nih.gov/pubmed/21389985
He C, Gong L, Yin Y, et al. Amygdala connectivity mediates the association between anxiety and depression in patients with major depressive disorder. Brain Imaging Behav 2019;13:1146-59. doi:10.1007/s11682-018-9923-z http://www.ncbi.nlm.nih.gov/pubmed/30054873
Cheng W, Rolls ET, Qiu J, et al. Functional connectivity of the human amygdala in health and in depression. Soc Cogn Affect Neurosci 2018;13:557-68. doi:10.1093/scan/nsy032 http://www.ncbi.nlm.nih.gov/pubmed/29767786
Vatansever D, Manktelow AE, Sahakian BJ, et al. Cognitive flexibility: a default network and basal ganglia connectivity perspective. Brain Connect 2016;6:201-7. doi:10.1089/brain.2015.0388 http://www.ncbi.nlm.nih.gov/pubmed/26652748
Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:1725. doi:10.1002/art.1780400928 http://www.ncbi.nlm.nih.gov/pubmed/9324032
Gladman DD, Goldsmith CH, Urowitz MB, et al. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index for systemic lupus erythematosus international comparison. J Rheumatol 2000;27:373-6 http://www.ncbi.nlm.nih.gov/pubmed/10685799
Van Dijk KRA, Sabuncu MR, Buckner RL. The influence of head motion on intrinsic functional connectivity MRI. Neuroimage 2012;59:431-8. doi:10.1016/j.neuroimage.2011.07.044 http://www.ncbi.nlm.nih.gov/pubmed/21810475
Michopoulos I, Douzenis A, Kalkavoura C, et al. Hospital Anxiety and Depression Scale (HADS): validation in a Greek general hospital sample. Ann Gen Psychiatry 2008;7:4. doi:10.1186/1744-859X-7-4 http://www.ncbi.nlm.nih.gov/pubmed/18325093
Etkin A, Wager TD. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatry 2007;164:1476-88. doi:10.1176/appi.ajp.2007.07030504 http://www.ncbi.nlm.nih.gov/pubmed/17898336
Grupe DW, Nitschke JB. Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat Rev Neurosci 2013;14:488-501. doi:10.1038/nrn3524 http://www.ncbi.nlm.nih.gov/pubmed/23783199
Tovote P, Fadok JP, Lüthi A. Neuronal circuits for fear and anxiety. Nat Rev Neurosci 2015;16:317-31. doi:10.1038/nrn3945 http://www.ncbi.nlm.nih.gov/pubmed/25991441
Milad MR, Rauch SL. The role of the orbitofrontal cortex in anxiety disorders. Ann N Y Acad Sci 2007;1121:546-61. doi:10.1196/annals.1401.006 http://www.ncbi.nlm.nih.gov/pubmed/17698998
Laird KT, Siddarth P, Krause-Sorio B, et al. Anxiety symptoms are associated with smaller insular and orbitofrontal cortex volumes in late-life depression. J Affect Disord 2019;256:282-7. doi:10.1016/j.jad.2019.05.066 http://www.ncbi.nlm.nih.gov/pubmed/31200165
Curtis CE, D'Esposito M. Persistent activity in the prefrontal cortex during working memory. Trends Cogn Sci 2003;7:415-23. doi:10.1016/S1364-6613(03)00197-9 http://www.ncbi.nlm.nih.gov/pubmed/12963473
Dixon ML, Thiruchselvam R, Todd R, et al. Emotion and the prefrontal cortex: an integrative review. Psychol Bull 2017;143:1033-81. doi:10.1037/bul0000096 http://www.ncbi.nlm.nih.gov/pubmed/28616997
Ochsner KN, Gross JJ. The cognitive control of emotion. Trends Cogn Sci 2005;9:242-9. doi:10.1016/j.tics.2005.03.010 http://www.ncbi.nlm.nih.gov/pubmed/15866151
Schneider B, Koenigs M. Human lesion studies of ventromedial prefrontal cortex. Neuropsychologia 2017;107:84-93. doi:10.1016/j.neuropsychologia.2017.09.035 http://www.ncbi.nlm.nih.gov/pubmed/28966138
Stevens FL, Hurley RA, Taber KH. Anterior cingulate cortex: unique role in cognition and emotion. J Neuropsychiatry Clin Neurosci 2011;23:121-5. doi:10.1176/jnp.23.2.jnp121 http://www.ncbi.nlm.nih.gov/pubmed/21677237
Robinson OJ, Charney DR, Overstreet C, et al. The adaptive threat bias in anxiety: amygdala-dorsomedial prefrontal cortex coupling and aversive amplification. Neuroimage 2012;60:523-9. doi:10.1016/j.neuroimage.2011.11.096 http://www.ncbi.nlm.nih.gov/pubmed/22178453
Robinson OJ, Krimsky M, Lieberman L, et al. The dorsal medial prefrontal (anterior cingulate) cortex–amygdala aversive amplification circuit in unmedicated generalised and social anxiety disorders: an observational study. Lancet Psychiatry 2014;1:294-302. doi:10.1016/S2215-0366(14)70305-0
Vytal KE, Overstreet C, Charney DR, et al. Sustained anxiety increases amygdala-dorsomedial prefrontal coupling: a mechanism for maintaining an anxious state in healthy adults. J Psychiatry Neurosci 2014;39:321-9. doi:10.1503/jpn.130145 http://www.ncbi.nlm.nih.gov/pubmed/24886788
Jalbrzikowski M, Larsen B, Hallquist MN, et al. Development of white matter microstructure and intrinsic functional connectivity between the amygdala and ventromedial prefrontal cortex: associations with anxiety and depression. Biol Psychiatry 2017;82:511-21. doi:10.1016/j.biopsych.2017.01.008 http://www.ncbi.nlm.nih.gov/pubmed/28274468
Kujawa A, Wu M, Klumpp H, et al. Altered development of amygdala-anterior cingulate cortex connectivity in anxious youth and young adults. Biol Psychiatry Cogn Neurosci Neuroimaging 2016;1:345-52. doi:10.1016/j.bpsc.2016.01.006 http://www.ncbi.nlm.nih.gov/pubmed/27525316
Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008;213:93-118. doi:10.1007/s00429-008-0189-x http://www.ncbi.nlm.nih.gov/pubmed/18704495
Fitzgerald PB, Oxley TJ, Laird AR, et al. An analysis of functional neuroimaging studies of dorsolateral prefrontal cortical activity in depression. Psychiatry Res 2006;148:33-45. doi:10.1016/j.pscychresns.2006.04.006 http://www.ncbi.nlm.nih.gov/pubmed/17029760
Apazoglou K, Küng A-L, Cordera P, et al. Rumination related activity in brain networks mediating attentional switching in euthymic bipolar patients. Int J Bipolar Disord 2019;7:3. doi:10.1186/s40345-018-0137-5 http://www.ncbi.nlm.nih.gov/pubmed/30637531
Kaiser RH, Andrews-Hanna JR, Wager TD, et al. Large-scale network dysfunction in major depressive disorder: a meta-analysis of resting-state functional connectivity. JAMA Psychiatry 2015;72:603. doi:10.1001/jamapsychiatry.2015.0071 http://www.ncbi.nlm.nih.gov/pubmed/25785575
Mulders PC, van Eijndhoven PF, Schene AH, et al. Resting-state functional connectivity in major depressive disorder: a review. Neurosci Biobehav Rev 2015;56:330-44. doi:10.1016/j.neubiorev.2015.07.014 http://www.ncbi.nlm.nih.gov/pubmed/26234819
Amemiya S, Kunimatsu A, Saito N, et al. Cerebral hemodynamic impairment: assessment with resting-state functional MR imaging. Radiology 2014;270:548-55. doi:10.1148/radiol.13130982 http://www.ncbi.nlm.nih.gov/pubmed/24072777
Siegel JS, Snyder AZ, Ramsey L, et al. The effects of hemodynamic lag on functional connectivity and behavior after stroke. J Cereb Blood Flow Metab 2016;36:2162-76. doi:10.1177/0271678X15614846 http://www.ncbi.nlm.nih.gov/pubmed/26661223
Yan S, Qi Z, An Y, et al. Detecting perfusion deficit in Alzheimer's disease and mild cognitive impairment patients by resting-state fMRI. J Magn Reson Imaging 2019;49:1099-104. doi:10.1002/jmri.26283 http://www.ncbi.nlm.nih.gov/pubmed/30318645
Jeltsch-David H, Muller S. Neuropsychiatric systemic lupus erythematosus: pathogenesis and biomarkers. Nat Rev Neurol 2014;10:579-96. doi:10.1038/nrneurol.2014.148 http://www.ncbi.nlm.nih.gov/pubmed/25201240
Zhang J, Wei W, Wang CM. Effects of psychological interventions for patients with systemic lupus erythematosus: a systematic review and meta-analysis. Lupus 2012;21:1077-87. doi:10.1177/0961203312447667 http://www.ncbi.nlm.nih.gov/pubmed/22570339
