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Converging evidence of impaired brain function in systemic lupus erythematosus: changes in perfusion dynamics and intrinsic functional connectivity

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Abstract

Purpose

Τhe study examined changes in hemodynamics and functional connectivity in patients with systemic lupus erythematosus (SLE) with or without neuropsychiatric manifestations.

Methods

Participants were 44 patients with neuropsychiatric SLE (NPSLE), 20 SLE patients without such manifestations (non-NPSLE), and 35 healthy controls. Resting-state functional MRI (rs-fMRI) was used to obtain whole-brain maps of (a) perfusion dynamics derived through time shift analysis (TSA), (b) regional functional connectivity (intrinsic connectivity contrast (ICC) coefficients), and (c) hemodynamic-connectivity coupling. Group differences were assessed through independent samples t-tests, and correlations of rs-fMRI indices with clinical variables and neuropsychological test scores were, also, computed.

Results

Compared to HC, NPSLE patients demonstrated intrinsic hypoconnectivity of anterior Default Mode Network (DMN) and hyperconnectivity of posterior DMN components. These changes were paralleled by elevated hemodynamic lag. In NPSLE, cognitive performance was positively related to higher intrinsic connectivity in these regions, and to higher connectivity-hemodynamic coupling in posterior DMN components. Uncoupling between hemodynamics and connectivity in the posterior DMN was associated with worse task performance. Non-NPSLE patients displayed hyperconnectivity in posterior DMN and sensorimotor regions paralleled by relatively increased hemodynamic lag.

Conclusion

Adaptation of regional brain function to hemodynamic changes in NPSLE may involve locally decreased or locally increased intrinsic connectivity (which can be beneficial for cognitive function). This process may also involve elevated coupling of hemodynamics with functional connectivity (beneficial for cognitive performance) or uncoupling, which may be detrimental for the cognitive skills of NPSLE patients.

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Data availability

The computed metrics derived from resting state fMRI recordings will be available upon request.

References

  1. Bertsias GK, Boumpas DT (2010) Pathogenesis, diagnosis and management of neuropsychiatric SLE manifestations. Nat Rev Rheumatol 6:358–367

    Article  Google Scholar 

  2. Ainiala H, Loukkola J, Peltola J, Abady M, Shoenfeld Y, Zandman-Goddard G (2001) The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology. 57:496–500

    Article  CAS  Google Scholar 

  3. Cohen D, Rijnink EC, Nabuurs RJA et al (2017) Brain histopathology in patients with systemic lupus erythematosus: identification of lesions associated with clinical neuropsychiatric lupus syndromes and the role of complement. Rheumatology 56:77–86

    Article  CAS  Google Scholar 

  4. Emmer BJ, van Osch MJ, Wu O et al (2010) Perfusion MRI in neuropsychiatric systemic lupus erythemathosus. J Magn Reson Imaging 32:283–288

    Article  Google Scholar 

  5. Zimny A, Szmyrka-Kaczmarek M, Szewczyk P et al (2014) In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy, perfusion weighted and diffusion-tensor imaging. Lupus 23:10–19

    Article  CAS  Google Scholar 

  6. Papadaki E, Fanouriakis A, Kavroulakis E et al (2018) Neuropsychiatric lupus or not? Cerebral hypoperfusion by perfusion-weighted MRI in normal-appearing white matter in primary neuropsychiatric lupus erythematosus. Ann Rheum Dis 77:441–448

    Article  CAS  Google Scholar 

  7. Wang PI, Cagnoli PC, McCune WJ et al (2012) Perfusion-weighted MR imaging in cerebral lupus erythematosus. Acad Radiol 19:965–970

    Article  Google Scholar 

  8. Gasparovic CM, Roldan CA, Sibbitt WL et al (2010) Elevated cerebral blood flow and volume in systemic lupus measured by dynamic susceptibility contrast magnetic resonance imaging. J Rheumatol 37:1834–1843

    Article  Google Scholar 

  9. Jia J, Xie J, Li H et al (2019) Cerebral blood flow abnormalities in neuropsychiatric systemic lupus erythematosus. Lupus. 28(9):1128–1133. https://doi.org/10.1177/0961203319861677

    Article  CAS  PubMed  Google Scholar 

  10. Zhuo Z, Su L, Duan Y et al (2020) Different patterns of cerebral perfusion in SLE patients with and without neuropsychiatric manifestations. Hum Brain Mapp 41(3):755–766. https://doi.org/10.1002/hbm.24837

    Article  PubMed  Google Scholar 

  11. Cao ZY, Wang N, Jia JT et al (2021) Abnormal topological organization in systemic lupus erythematosus: a resting-state functional magnetic resonance imaging analysis. Brain Imag Behav 15:14–24. https://doi.org/10.1007/s11682-019-00228-y

    Article  Google Scholar 

  12. Preziosa P, Rocca MA, Ramirez GA et al (2020) Structural and functional brain connectomes in patients with systemic lupus erythematosus. Eur J Neurol 27(1):113–1e2. https://doi.org/10.1111/ene.14041

    Article  CAS  PubMed  Google Scholar 

  13. Bonacchi R, Rocca MA, Ramirez GA et al (2020) Resting state network functional connectivity abnormalities in systemic lupus erythematosus: correlations with neuropsychiatric impairment. Mol Psychiatry. https://doi.org/10.1038/s41380-020-00907-z

  14. Simos NJ, Dimitriadis SI, Kavroulakis E et al (2020) Quantitative identification of functional connectivity disturbances in neuropsychiatric lupus based on resting-state fMRI: a robust machine learning approach. Brain Sci 10(11):777. https://doi.org/10.3390/brainsci10110777

    Article  PubMed Central  Google Scholar 

  15. Nystedt J, Mannfolk P, Jönsen A, Nilsson P, Strandberg TO, Sundgren PC (2019) Functional connectivity changes in core resting state networks are associated with cognitive performance in systemic lupus erythematosus. J Comp Neurol 527(11):1837–1856

    Article  CAS  Google Scholar 

  16. Yu H, Qiu X, Zhang YQ et al (2019) Abnormal amplitude of low frequency fluctuation and functional connectivity in non-neuropsychiatric systemic lupus erythematosus: a resting-state fMRI study. Neuroradiology. 61(3):331–340

    Article  Google Scholar 

  17. Liu S, Cheng Y, Xie Z et al (2018) A conscious resting state fMRI study in SLE patients without major neuropsychiatric manifestations. Front Psychiatry 9:677

    Article  Google Scholar 

  18. Niu C, Tan X, Liu X et al (2018) Cortical thickness reductions associate with abnormal resting-state functional connectivity in non-neuropsychiatric systemic lupus erythematosus. Brain Imaging Behav 12(3):674–684

    Article  Google Scholar 

  19. Nystedt J, Mannfolk P, Jönsen A et al (2018) Functional connectivity changes in systemic lupus erythematosus: a resting-state study. Brain Connect 8(4):220–234

    Article  Google Scholar 

  20. Zhang XD, Jiang XL, Cheng Z et al (2017) Decreased coupling between functional connectivity density and amplitude of low frequency fluctuation in non-neuropsychiatric systemic lupus erythematosus: a resting-stage functional MRI study. Mol Neurobiol 54(7):5225–5235

    Article  CAS  Google Scholar 

  21. Hou J, Lin Y, Zhang W et al (2013) Abnormalities of frontal-parietal resting-state functional connectivity are related to disease activity in patients with systemic lupus erythematosus. PLoS One 8(9):e74530. https://doi.org/10.1371/journal.pone.0074530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Khalil AA, Ostwaldt A-C, Nierhaus T et al (2017) Relationship between changes in the temporal dynamics of the blood-oxygen-level-dependent signal and hypoperfusion in acute ischemic stroke. Stroke 48:925–931

    Article  CAS  Google Scholar 

  23. Khalil AA, Villringer K, Filleböck V et al (2020) Non-invasive monitoring of longitudinal changes in cerebral hemodynamics in acute ischemic stroke using BOLD signal delay. J Cereb Blood Flow Metab 40:23–34

    Article  Google Scholar 

  24. Lv Y, Margulies DS, Cameron Craddock R et al (2013) Identifying the perfusion deficit in acute stroke with resting-state functional magnetic resonance imaging. Ann Neurol 73:136–140

    Article  Google Scholar 

  25. Tong Y, Lindsey KP, Hocke LM, Vitaliano G, Mintzopoulos D, Frederick BD (2017) Perfusion information extracted from resting state functional magnetic resonance imaging. J Cereb Blood Flow Metab 37:564–576

    Article  Google Scholar 

  26. Mitra A, Snyder AZ, Hacker CD, Raichle ME (2014) Lag structure in resting-state fMRI. J Neurophysiol 111:2374–2391

    Article  CAS  Google Scholar 

  27. Siegel JS, Snyder AZ, Ramsey L, Shulman GL, Corbetta M (2016) The effects of hemodynamic lag on functional connectivity and behavior after stroke. J Cereb Blood Flow Metab 36(12):2162–2176

    Article  Google Scholar 

  28. Amemiya S, Kunimatsu A, Saito N, Ohtomo K (2014) Cerebral hemodynamic impairment: assessment with resting-state functional MR imaging. Radiology. 270(2):548–555

    Article  Google Scholar 

  29. Yan S, Qi Z, An Y, Zhang M, Qian T, Lu J (2019) Detecting perfusion deficit in Alzheimer’s disease and mild cognitive impairment patients by resting-state fMRI. J Magn Reson Imaging 49(4):1099–1104

    Article  Google Scholar 

  30. Antypa D, Simos NJ, Kavroulakis E et al (2021) 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. Lupus Sci Med 8(1):e000473. https://doi.org/10.1136/lupus-2020-000473

    Article  PubMed  PubMed Central  Google Scholar 

  31. Hochberg MC (1997) Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 40(9):1725–1725

    Article  CAS  Google Scholar 

  32. Gladman DD, Ibañez D, Urowitz MB (2002) Systemic lupus erythematosus disease activity index 2000. J Rheumatol 29:288–291

    PubMed  Google Scholar 

  33. Gladman DD, Goldsmith CH, Urowitz MB et al (2000) The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index for systemic lupus erythematosus international comparison. J Rheumatol 27:373–376

    CAS  PubMed  Google Scholar 

  34. (1999) The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 42:599–608

  35. Whitefield-Gabrieli S, Nieto-Castanon A (2012 Jun) Conn: a functional connectivity toolbox for correlated and anticorrelated brain networks. Brain Connectivity 2(3):125–141

    Article  Google Scholar 

  36. Layden E. Intrinsic_connectivity_contrast [Internet]. MATLAB Central File Exchange. 2020 [cited 2020 Apr 2]. Available from: https://ch.mathworks.com/matlabcentral/fileexchange/68248-intrinsic_connectivity_contrast

  37. Slotnick SD (2017) Cluster success: fMRI inferences for spatial extent have acceptable false-positive rates. Cogn Neurosci 8:150–155

    Article  Google Scholar 

  38. Slotnick SD, Moo LR, Segal JB, Hart J Jr (2003) Distinct prefrontal cortex activity associated with item memory and source memory for visual shapes. Brain Res Cogn Brain Res 17:75–82

    Article  Google Scholar 

  39. Wiseman SJ, Bastin ME, Jardine CL et al (2016) Cerebral small vessel disease burden is increased in systemic lupus erythematosus. Stroke 47:2722–2728

    Article  CAS  Google Scholar 

  40. Barraclough M, McKie S, Parker B et al (2019) Altered cognitive function in systemic lupus erythematosus and associations with inflammation and functional and structural brain changes. Ann Rheum Dis 78(7):934–940

    Article  Google Scholar 

  41. Mikdashi JA (2016) Altered functional neuronal activity in neuropsychiatric lupus: a systematic review of the fMRI investigations. Semin Arthritis Rheum 45(4):455–462

    Article  Google Scholar 

Download references

Funding

Financial support for this work was provided by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “2nd Call for H.F.R.I. Research Projects to support Post-Doctoral Researchers” (Project Number: 1220).

Author information

Authors and Affiliations

  1. Department of Radiology, School of Medicine, University of Crete, University Hospital of Heraklion, 71003, Heraklion, Crete, Greece

    Efrosini Papadaki, Eleftherios Kavroulakis & Thomas Maris

  2. Computational Bio-Medicine Laboratory, Institute of Computer Science, Foundation for Research and Technology – Hellas, Heraklion, Greece

    Efrosini Papadaki, Nicholas J. Simos & Thomas Maris

  3. Department of Electrical and Computer Engineering, Technical University of Crete, Chania, Crete, Greece

    Nicholas J. Simos

  4. Department of Rheumatology, Clinical Immunology and Allergy, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Crete, Greece

    George Bertsias, Antonis Fanouriakis, Prodromos Sidiropoulos & Dimitrios T Boumpas

  5. Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology-Hellas, Voutes, Heraklion, Greece

    George Bertsias

  6. Department of Psychiatry, School of Medicine, University of Crete, University Hospital of Heraklion, Heraklion, Crete, Greece

    Despina Antypa

  7. 4th Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodestrian University of Athens, Athens, Greece

    Antonis Fanouriakis & Dimitrios T Boumpas

  8. Laboratory of Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece

    Dimitrios T Boumpas

  9. Joint Academic Rheumatology Program, and 4th Department of Medicine, Medical School, National and Kapodestrian University of Athens, Athens, Greece

    Dimitrios T Boumpas

Authors
  1. Efrosini Papadaki
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  2. Nicholas J. Simos
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  3. Eleftherios Kavroulakis
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  4. George Bertsias
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  6. Antonis Fanouriakis
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  7. Thomas Maris
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  8. Prodromos Sidiropoulos
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  9. Dimitrios T Boumpas
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Contributions

Conceptualization: Efrosini Papadaki; Nicholas Simos

Methodology: Efrosini Papadaki; Nicholas Simos; Eleftherios Kavroulakis

Formal analysis and investigation: Nicholas Simos; Eleftherios Kavroulakis

Writing — original draft preparation: Efrosini Papadaki; Despina Antypa; Nicholas Simos

Writing — review and editing: Efrosini Papadaki; George Bertsias; Thomas Maris; Dimitrios Boumpas

Funding acquisition: Eleftherios Kavroulakis

Resources: George Bertsias; Antonis Fanouriakis; Prodromos Sidiropoulos

Supervision: Efrosini Papadaki; Dimitrios Boumpas

Corresponding author

Correspondence to Efrosini Papadaki.

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Competing interests

The authors have no competing interests to declare that are relevant to the content of this article.

Ethical approval

The hospital review board approved this study and the procedure was thoroughly explained to all patients and volunteers who signed informed consent.

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Papadaki, E., Simos, N.J., Kavroulakis, E. et al. Converging evidence of impaired brain function in systemic lupus erythematosus: changes in perfusion dynamics and intrinsic functional connectivity. Neuroradiology 64, 1593–1604 (2022). https://doi.org/10.1007/s00234-022-02924-x

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  • DOI: https://doi.org/10.1007/s00234-022-02924-x

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