Psychoneurological disorders in the stage of post-COVID syndrome

Аim. Generalization and systematization of ideas about the pathophysiological mechanisms of asthenic syndrome development against the background of COVID-19.

Materials and methods. The work analyzed scientific articles and monographs devoted to the etiopathogenesis of post-COVID asthenic syndrome (PCAS). The search was carried out by the keywords «COVID-19», «post-COVID syndrome», «psychoneurological disorders», «asthenic syndrome» using the PubMed, Medline, eLibrary.ru databases.

Results and discussion. The ideas about the clinical structure of PCAS are systematized, the mechanisms of penetration of the SARS-CoV-2 virus into the nervous system are presented, modern views on the molecular mechanisms of the development of neurological symptoms in COVID-19 convalescents are highlighted. The key pathogenetic links of PCAS are described, including immune deviations associated with cytokine imbalance, oxidative and nitrosative stress reactions with subsequent activation of anaerobic metabolic pathways in brain and muscle tissues; neurometabolic changes accompanied by dysfunction of the serotonergic, dopaminergic, noradrenergic and GABAergic systems.

Conclusion. Analysis of world literature data, as well as our own clinical experience, allows us to conclude that psychoneurological disorders associated with COVID-19 infection are multifaceted and complex and are accompanied by highly variable symptoms. At the same time, the existing fragmentary knowledge regarding the pathomechanisms of psychoneurological disorders against the background of COVID-19 dictates an urgent need to continue further research in this area.

1. Carod-Artal F. J. Post-COVID-19 syndrome: epidemiology, diagnostic criteria and pathogenic mechanisms involved. Síndrome post-COVID-19: epidemiología, criterios diagnósticos y mecanismos patogénicos implicados. Rev. Neurol. 2021; 72 (11): 384–396. DOI: 10.33588/rn.7211.2021230

2. Simpson R., Robinson L. Rehabilitation After Critical Illness in People With COVID-19 Infection. Am. J. Phys. Med. Rehabil. 2020; 99 (6): 470–474. DOI: 10.1097/PHM.0000000000001443

3. Li L. Q., Huang T., Wang Y. Q. et al. COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis. J. Med. Virol. 2020; 92 (6): 577–583. DOI: 10.1002/jmv.25757

4. Chou S. H., Beghi E., Helbok R. et al. Global Incidence of Neurological Manifestations Among Patients Hospitalized With COVID-19-A Report for the GCS-NeuroCOVID Consortium and the ENERGY Consortium. JAMA Netw Open. 2021; 4 (5): e2112131. DOI: 10.1001/jamanetworkopen.2021.12131

5. Ceban F., Ling S., Lui L. M.W. et al. Fatigue and cognitive impairment in Post-COVID-19 Syndrome: A systematic review and meta-analysis. Brain Behav Immun. 2022; 101: 93–135. DOI: 10.1016/j.bbi.2021.12.020

6. Vanichkachorn G., Newcomb R., Cowl C. T. et al. Post-COVID-19 Syndrome (Long Haul Syndrome): Description of a Multidisciplinary Clinic at Mayo Clinic and Characteristics of the Initial Patient Cohort. Mayo Clin. Proc. 2021; 96 (7): 1782–1791. DOI: 10.1016/j.mayocp.2021.04.024

7. Simani L., Ramezani M., Darazam I. A. et al. Prevalence and correlates of chronic fatigue syndrome and post-traumatic stress disorder after the outbreak of the COVID-19. J. Neurovirol. 2021; 27 (1): 154–159. DOI: 10.1007/s13365-021-00949-1

8. Halpin S. J., McIvor C., Whyatt G. et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: A cross-sectional evaluation. J. Med. Virol. 2021; 93 (2): 1013–1022. DOI: 10.1002/jmv.26368

9. Huang C., Huang L., Wang Y. et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021; 397 (10270): 220–232. DOI: 10.1016/S0140–6736(20)32656-8

10. Li Y. C., Bai W. Z., Hashikawa T. The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients. J. Med. Virol. 2020; 92 (6): 552–555. DOI: 10.1002/jmv.25728

11. Yong S. J. Persistent Brainstem Dysfunction in Long-COVID: A Hypothesis. ACS Chem Neurosci. 2021; 12 (4): 573–580. DOI: 10.1021/acschemneuro.0c00793

12. Erickson M. A., Rhea E. M., Knopp R. C., Banks W. A. Interactions of SARS-CoV-2 with the Blood-Brain Barrier. Int J. Mol. Sci. 2021; 22 (5): 2681. DOI: 10.3390/ijms22052681

13. Jha N. K., Ojha S., Jha S. K. et al. Evidence of Coronavirus (CoV) Pathogenesis and Emerging Pathogen SARS-CoV-2 in the Nervous System: A Review on Neurological Impairments and Manifestations. J. Mol. Neurosci. 2021; 71 (11): 2192–2209. DOI: 10.1007/s12031-020-01767-6

14. Al-Ramadan A., Rabab'h O., Shah J., Gharaibeh A. Acute and Post-Acute Neurological Complications of COVID-19. Neurol Int. 2021; 13 (1): 102–119. Published 2021 Mar 9. DOI: 10.3390/neurolint13010010

15. Ramani A., Müller L., Ostermann P. N. et al. SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J. 2020; 39 (20): e106230. DOI: 10.15252/embj.2020106230

16. Lu Y., Li X., Geng D. et al. Cerebral Micro-Structural Changes in COVID-19 Patients – An MRI-based 3-month Follow-up Study. EClinicalMedicine. 2020; 25: 100484. DOI: 10.1016/j.eclinm.2020.100484

17. Aghagoli G., Gallo Marin B., Katchur N. J. et al. Neurological Involvement in COVID-19 and Potential Mechanisms: A Review. Neurocrit Care. 2021; 34 (3): 1062–1071. DOI: 10.1007/s12028-020-01049-4

18. Chan J. F., Chan K. H., Choi G. K. et al. Differential cell line susceptibility to the emerging novel human betacoronavirus 2c EMC/2012: implications for disease pathogenesis and clinical manifestation. J. Infect. Dis. 2013; 207 (11): 1743–1752. DOI: 10.1093/infdis/jit123

19. Desforges M., Miletti T. C., Gagnon M., Talbot P. J. Activation of human monocytes after infection by human coronavirus 229E. Virus Res. 2007; 130 (1–2): 228–240. DOI: 10.1016/j.virusres.2007.06.016

20. Li J., Gao J., Xu Y. P. et al. Zhonghua Yi Xue Za Zhi. 2007; 87 (12): 833–837.

21. Li Y. C., Bai W. Z., Hirano N. et al. Neurotropic virus tracing suggests a membranous-coating-mediated mechanism for transsynaptic communication. J. Comp. Neurol. 2013; 521 (1): 203–212. DOI: 10.1002/cne.23171

22. Ali Awan H., Najmuddin Diwan M., Aamir A. et al. SARS-CoV-2 and the Brain: What Do We Know about the Causality of 'Cognitive COVID? J. Clin. Med. 2021; 10 (15): 3441. DOI: 10.3390/jcm10153441

23. Huber J. D., Witt K. A., Hom S. et al. Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression. Am. J. Physiol. Heart. Circ. Physiol. 2001; 280: 1241–1248.

24. Beishon L., Panerai R. B. The Neurovascular Unit in Dementia: An Opinion on Current Research and Future Directions. Front Aging Neurosci. 2021; 13: 721937. DOI: 10.3389/fnagi.2021.721937

25. Besteher B., Rocktäschel T., Garza A. P. et al. Cortical thickness alterations and systemic inflammation define long-COVID patients with cognitive impairment. Brain Behav Immun. 2024; 116: 175–184. DOI: 10.1016/j.bbi.2023.11.028

26. Lahiri D., Ardila A. COVID-19 Pandemic: A Neurological Perspective. Cureus. 2020; 12 (4): e7889. DOI: 10.7759/cureus.7889

27. Berentschot J. C., Drexhage H. A., Aynekulu Mersha D. G. et al. Severe fatigue as symptom of long COVID is characterized by increased expression of inflammatory genes in monocytes, increased serum pro-inflammatory cytokines, and increased CD 8+ T-lymphocytes: A putative dysregulation of the immune-brain axis, the coagulation process, and auto-inflammation to explain the diversity of long COVID symptoms. medRxiv; 2022. DOI: 10.1101/2022.09.15.22279970

28. Khairova R. A., Machado-Vieira R., Du J., Manji H. K. A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. Int J. Neuropsychopharmacol. 2009; 12 (4): 561–578. DOI: 10.1017/S1461145709009924

29. Kluger M. J. Fever: role of pyrogens and cryogens. Physiol Rev. 1991; 71 (1): 93–127. DOI: 10.1152/physrev.1991.71.1.93

30. Dunn A. J. Systemic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism parallelling the increased plasma corticosterone. Life Sci. 1988; 43 (5): 429–435. DOI: 10.1016/0024–3205(88)90522-x

31. Levin S. G., Godukhin O. V. Modulating Effect of Cytokines on Mechanisms of Synaptic Plasticity in the Brain. Biochemistry (Mosc). 2017; 82 (3): 264–274. DOI: 10.1134/S000629791703004X

32. Pearson V. L., Rothwell N. J., Toulmond S. Excitotoxic brain damage in the rat induces interleukin-1beta protein in microglia and astrocytes: correlation with the progression of cell death. Glia. 1999; 25 (4): 311–323.

33. Galic M. A., Riazi K., Pittman Q. J. Cytokines and brain excitability. Front Neuroendocrinol. 2012; 33 (1): 116–125. DOI: 10.1016/j.yfrne.2011.12.002

34. Khomich O. A., Kochetkov S. N., Bartosch B., Ivanov A. V. Redox Biology of Respiratory Viral Infections. Viruses. 2018; 10 (8): 392. DOI: 10.3390/v10080392

35. Lin C. W., Lin K. H., Hsieh T. H. et al. Severe acute respiratory syndrome coronavirus 3C-like protease-induced apoptosis. FEMS Immunol Med Microbiol. 2006; 46 (3): 375–380. DOI: 10.1111/j.1574–695X.2006.00045.x

36. Padhan K., Minakshi R., Towheed M. A.B, Jameel S. Severe acute respiratory syndrome coronavirus 3a protein activates the mitochondrial death pathway through p38 MAP kinase activation. J. Gen. Virol. 2008; 89 (Pt 8): 1960–1969. DOI: 10.1099/vir.0.83665–0

37. Voronina T. A. Antioxidants/antihypoxants – the missing puzzle of effective pathogenetic therapy of patients with COVID-19. Infectious diseases. 2020; 2: 97–102.

38. Zhang G. X., Lu X. M., Kimura S., Nishiyama A. Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation. Cardiovasc Res. 2007; 76 (2): 204–212. DOI: 10.1016/j.cardiores.2007.07.014

39. Maes M., Kubera M., Uytterhoeven M. et al. Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med. Sci. Monit. 2011; 17 (4): SC 11–SC 15. DOI: 10.12659/msm.881699

40. Petrova L. V., Kostenko E. V., Eneyeva M. A. Asthenia in the structure of post-covid syndrome: pathogenesis, clinical features, diagnostics and medical rehabilitation. Doctor.Ru. 2021; 20 (9): 36–42. (In Russ.).

41. Zhang G. X., Lu X. M., Kimura S., Nishiyama A. Role of mitochondria in angiotensin II-induced reactive oxygen species and mitogen-activated protein kinase activation. Cardiovasc Res. 2007; 76 (2): 204–212. DOI: 10.1016/j.cardiores.2007.07.014

42. Mueller C., Lin J. C., Sheriff S. et al. Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging Behav. 2020; 14 (2): 562–572. DOI: 10.1007/s11682-018-0029-4

43. Hatziagelaki E., Adamaki M., Tsilioni I. et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus? J. Pharmacol. Exp. Ther. 2018; 367 (1): 155–167. DOI: 10.1124/jpet.118.250845

44. Feuerstein C. Donnees neurophysiologiques de la fatigue. Role du systeme reticulaire activateur. 1992; 1: 11–19.

45. Nataf S. An alteration of the dopamine synthetic pathway is possibly involved in the pathophysiology of COVID-19. J. Med. Virol. 2020; 92 (10): 1743–1744. DOI: 10.1002/jmv.25826

46. Klempin F., Mosienko V., Matthes S. et al. Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response. Cell. Mol. Life Sci. 2018; 75 (19): 3625–3634. DOI: 10.1007/s00018–018–2815-y

47. Khaindrava V., Salin P., Melon C. et al. High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease. Neurobiol. Dis. 2011; 42 (3): 284–291. DOI: 10.1016/j.nbd.2011.01.018

48. Villar-Cheda B., Dominguez-Meijide A., Valenzuela R. et al. Aging-related dysregulation of dopamine and angiotensin receptor interaction. Neurobiol Aging. 2014; 35 (7): 1726–1738. DOI: 10.1016/j.neurobiolaging.2014.01.017

49. Rodriguez-Perez A.I., Garrido-Gil P., Pedrosa M. A. et al. Angiotensin type 2 receptors: Role in aging and neuroinflammation in the substantia nigra. Brain Behav Immun. 2020; 87: 256–271. DOI: 10.1016/j.bbi.2019.12.011

50. Antonini A., Leta V., Teo J., Chaudhuri K. R. Outcome of Parkinson's Disease Patients Affected by COVID-19. Mov Disord. 2020; 35 (6): 905–908. DOI: 10.1002/mds.28104

51. Castiglione M., Calafiore M., Costa L. et al. Group I metabotropic glutamate receptors control proliferation, survival and differentiation of cultured neural progenitor cells isolated from the subventricular zone of adult mice. Neuropharmacology. 2008; 55 (4): 560–567. DOI: 10.1016/j.neuropharm.2008.05.021

52. Ramani A., Müller L., Ostermann P. N. et al. SARS-CoV-2 targets neurons of 3D human brain organoids. EMBO J. 2020; 39 (20): e106230. DOI: 10.15252/embj.2020106230

53. Galic M. A., Riazi K., Pittman Q. J. Cytokines and brain excitability. Front Neuroendocrinol. 2012; 33 (1): 116–125. DOI: 10.1016/j.yfrne.2011.12.002