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Cited by 82Long-Term Effects of COVID-19Transcranial Magnetic Stimulation StudiesTraumatic Brain Injury Research

Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19

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Ortelli, Paola, Ferrazzoli, Davide, Sebastianelli, Luca, Maestri, Roberto, Dezi, Sabrina, Spampinato, Danny, Saltuari, Leopold, Alibardi, Alessia +6 more·2022·European Journal of Neurology
DOI 10.1111/ene.15278PMC PMC9111319
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Abstract

Background and purpose: Fatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS‐CoV‐2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions. Methods: Sixty‐seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS‐CoV‐2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16‐item questionnaire. Fatigue, exertion, cognitive difficulties, mood and ‘well‐being’ were evaluated through self‐administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short‐interval intracortical inhibition, intracortical facilitation, long‐interval intracortical inhibition and short‐latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks. Results: Post COVID‐19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well‐being and reduced mental well‐being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long‐interval intracortical inhibition and short‐latency afferent inhibition were also impaired, indicating altered GABA B ‐ergic and cholinergic neurotransmission. Short‐interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention. Conclusions: Patients with fatigue and cognitive difficulties following mild COVID‐19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

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  • In a post-COVID-19 study, COVID-19 infection resulted in executive function and language deficits, as well as lower scores in frontal assessment battery, as in AD overall.

    “This was observed in a post-COVID-19 study, wherein COVID-19 infection resulted in executive function and language deficits, as well as lower scores in frontal assessment battery [86], as in AD overall [87].”

    From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [86]

    Table 3 and the Conclusions report lower executive-function and language scores, as well as lower frontal assessment battery scores, in post-COVID-19 patients than in healthy controls. The study examined patients with fatigue and cognitive difficulties after COVID-19; this comparison does not establish that infection caused the deficits. The AD comparison is attached to a different citation and is not judged here. (LLM, conf=0.87)

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Research works printed but not linked: 52

  1. Alwan NA. The road to addressing long COVID. Science. 2021;373(6554):491-493.
  2. Ladds E, Rushforth A, Wieringa S, et al. Persistent symptoms after COVID-19: qualitative study of 114 'long COVID' patients and draft quality principles for services. BMC Health Serv Res. 2020;20(1):1144.
  3. Graham EL, Clark JR, Orban ZS, et al. Persistent neurologic symp- toms and cognitive dysfunction in non-hospitalized COVID-19 'long haulers'. Ann Clin Transl Neurol. 2021;8(5):1073-1085.
  4. Liotta EM, Batra A, Clark JR, et al. Frequent neurologic manifes- tations and encephalopathy-associated morbidity in COVID-19 pa- tients. Ann Clin Transl Neurol. 2020;7(11):2221-2230.
  5. Ortelli P, Ferrazzoli D, Sebastianelli L, et al. Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challeng- ing symptom. J Neurol Sci. 2021;420:117271.
  6. Versace V, Sebastianelli L, Ferrazzoli D, et al. Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19. Clin Neurophysiol. 2021;132(5):1138-1143.
  7. Hosp JA, Dressing A, Blazhenets G, et al. Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19. Brain. 2021;144(4):1263-1276.
  8. Guedj E, Campion JY, Dudouet P, et al. (18)F-FDG brain PET hy- pometabolism in patients with long COVID. Eur J Nucl Med Mol Imaging. 2021;48:1-11.
  9. Sollini M, Morbelli S, Ciccarelli M, et al. Long COVID hallmarks on [18F]FDG-PET/CT: a case-control study. Eur J Nucl Med Mol Imaging. 2021;48:1-11.
  10. Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in mul- tiple sclerosis. Arch Neurol. 1988;45(4):435-437.
  11. Mordillo-Mateos L, Soto-Leon V, Torres-Pareja M, et al. Fatigue in multiple sclerosis: general and perceived fatigue does not depend on corticospinal tract dysfunction. Front Neurol. 2019;10:339.
  12. Borg E, Borg G. A comparison of AME and CR100 for scaling per- ceived exertion. Acta Psychol (Amst). 2002;109(2):157-175.
  13. Helms J, Kremer S, Merdji H, et al. Neurologic features in severe SARS-CoV-2 infection. N Engl J Med. 2020;382(23):2268-2270.
  14. Becker JH, Lin JJ, Doernberg M, et al. Assessment of cognitive function in patients after COVID-19 infection. JAMA Netw Open. 2021;4(10):e2130645.
  15. Rothwell JC, Thompson PD, Day BL, Boyd S, Marsden CD. Stimulation of the human motor cortex through the scalp. Exp Physiol. 1991;76(2):159-200.
  16. Nardone R, Versace V, Sebastianelli L, et al. Cortical involvement in myopathies: insights from transcranial magnetic stimulation. Clin Neurophysiol. 2017;128(10):1971-1977.
  17. Badawy RA, Loetscher T, Macdonell RA, Brodtmann A. Cortical ex- citability and neurology: insights into the pathophysiology. Funct Neurol. 2012;27(3):131-145.
  18. Hiew FL, Rajabally YA. Sural sparing in Guillain-Barré ® syndrome subtypes: a reappraisal with historical and recent definitions. Clin Neurophysiol. 2016;127(2):1683-1688.
  19. Tanaka M, Watanabe Y. Supraspinal regulation of physical fatigue. Neurosci Biobehav Rev. 2012;36(1):727-734.
  20. Picard N, Strick PL. Motor areas of the medial wall: a review of their location and functional activation. Cereb Cortex. 1996;6(3):342-353.
  21. Boecker H, Jankowski J, Ditter P, Scheef L. A role of the basal ganglia and midbrain nuclei for initiation of motor sequences. NeuroImage. 2008;39(3):1356-1369.
  22. Alexander GE, DeLong MR, Strick PL. Parallel organization of func- tionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357-381.
  23. Chen R, Lozano AM, Ashby P. Mechanism of the silent period fol- lowing transcranial magnetic stimulation. Evidence from epidural recordings. Exp Brain Res. 1999;128(4):539-542.
  24. Inghilleri M, Berardelli A, Cruccu G, Manfredi M. Silent period evoked by transcranial stimulation of the human cortex and cervi- comedullary junction. J Physiol. 1993;466:521-534.
  25. Orth M, Rothwell JC. The cortical silent period: intrinsic variability and relation to the waveform of the transcranial magnetic stimula- tion pulse. Clin Neurophysiol. 2004;115(5):1076-1082.
  26. Chaves AR, Kelly LP, Moore CS, Stefanelli M, Ploughman M. Prolonged cortical silent period is related to poor fitness and fa- tigue, but not tumor necrosis factor, in multiple sclerosis. Clin Neurophysiol. 2019;130(4):474-483.
  27. Knorr S, Rice CL, Garland SJ. Perspective on neuromuscular factors in poststroke fatigue. Disabil Rehabil. 2012;34(26):2291-2299.
  28. Morris AJ, Christie AD. The effect of mental fatigue on neuro- muscular function is similar in young and older women. Brain Sci. 2020;10(4):191.
  29. Ziemann U, Reis J, Schwenkreis P, et al. TMS and drugs revisited 2014. Clin Neurophysiol. 2015;126(10):1847-1868.
  30. Oliviero A, Corbo G, Tonali PA, et al. Functional involvement of cen- tral nervous system in acute exacerbation of chronic obstructive pulmonary disease. A preliminary transcranial magnetic stimulation study. J Neurol. 2002;249(9):1232-1236.
  31. Liepert J, Mingers D, Heesen C, Bäumer T, Weiller C. Motor cortex excitability and fatigue in multiple sclerosis: a transcranial magnetic stimulation study. Mult Scler. 2005;11(3):316-321.
  32. McDonald C, Newton J, Lai HM, Baker SN, Jones DE. Central ner- vous system dysfunction in primary biliary cirrhosis and its relation- ship to symptoms. J Hepatol. 2010;53(6):1095-1100.
  33. Vucic S, Cheah BC, Kiernan MC. Maladaptation of cortical circuits underlies fatigue and weakness in ALS. Amyotroph Lateral Scler. 2011;12(6):414-420.
  34. Sumner P, Edden RA, Bompas A, Evans CJ, Singh KD. More GABA, less distraction: a neurochemical predictor of motor decision speed. Nat Neurosci. 2010;13(7):825-827.
  35. Porges EC, Woods AJ, Edden RA, et al. Frontal gamma-aminobutyric acid concentrations are associated with cognitive performance in older adults. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2(1):38-44.
  36. Benussi A, Grassi M, Palluzzi F, et al. Classification accuracy of tran- scranial magnetic stimulation for the diagnosis of neurodegenera- tive dementias. Ann Neurol. 2020;87(3):394-404.
  37. Benussi A, Di Lorenzo F, Dell'Era V, et al. Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia. Neurology. 2017;89(7):665-672.
  38. Benussi A, Grassi M, Palluzzi F, et al. Classification accuracy of TMS for the diagnosis of mild cognitive impairment. Brain Stimul. 2021;14(2):241-249.
  39. Assogna M, Casula EP, Borghi I, et al. Effects of palmitoyleth- anolamide combined with luteoline on frontal lobe functions, high frequency oscillations, and GABAergic transmission in patients with frontotemporal dementia. J Alzheimers Dis. 2020;76(4):1297-1308.
  40. Chen R. Interactions between inhibitory and excitatory circuits in the human motor cortex. Exp Brain Res. 2004;154(1):1-10.
  41. McDonnell MN, Orekhov Y, Ziemann U. The role of GABA B recep- tors in intracortical inhibition in the human motor cortex. Exp Brain Res. 2006;173(1):86-93.
  42. Di Lazzaro V, Oliviero A, Profice P, et al. Muscarinic recep- tor blockade has differential effects on the excitability of in- tracortical circuits in the human motor cortex. Exp Brain Res. 2000;135(4):455-461.
  43. Kar S, Slowikowski SP, Westaway D, Mount HT. Interactions be- tween beta-amyloid and central cholinergic neurons: implications for Alzheimer's disease. J Psychiatry Neurosci. 2004;29(6):427-441.
  44. Shao Z, Janse E, Visser K, Meyer AS. What do verbal fluency tasks measure? Predictors of verbal fluency performance in older adults. Front Psychol. 2014;5:772.
  45. Guo Z, Chen R, Liu X, et al. The impairing effects of mental fatigue on response inhibition: an ERP study. PLoS One. 2018;13(6):e0198206.
  46. Mackie MA, Van Dam NT, Fan J. Cognitive control and attentional functions. Brain Cogn. 2013;82(3):301-312.
  47. Östberg A, Ledig C, Katila A, et al. Volume change in frontal cholin- ergic structures after traumatic brain injury and cognitive outcome. Front Neurol. 2020;11:832.
  48. Kandemirli SG, Dogan L, Sarikaya ZT, et al. Brain MRI findings in pa- tients in the intensive care unit with COVID-19 infection. Radiology. 2020;297(1):E232-E235.
  49. Kremer S, Lersy F, Anheim M, et al. Neurologic and neuroimaging findings in patients with COVID-19: a retrospective multicenter study. Neurology. 2020;95(13):e1868-e1882.
  50. Antony AR, Haneef Z. Systematic review of EEG findings in 617 pa- tients diagnosed with COVID-19. Seizure. 2020;83:234-241.
  51. Karimi-Galougahi M, Yousefi-Koma A, Bakhshayeshkaram M, Raad N, Haseli S. (18)FDG PET/CT scan reveals hypoactive orbitofrontal cortex in anosmia of COVID-19. Acad Radiol. 2020;27(7):1042-1043.
  52. Meinhardt J, Radke J, Dittmayer C, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci. 2021;24(2):168-175.

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Authors
Ortelli, P., Ferrazzoli, D., Sebastianelli, L., Maestri, R., Dezi, S., Spampinato, D., Saltuari, L., Alibardi, A., Engl, M., Kofler, M., Quartarone, A., Koch, G., Oliviero, A., & Versace, V.
Affiliations
  • Azienda Sanitaria dell'Alto Adige (IT)
  • Istituti Clinici Scientifici Maugeri (IT)
  • Fondazione Santa Lucia (IT)
  • Department of Neurology Hochzirl Hospital Zirl Austria
  • University of Messina (IT)
  • University of Ferrara (IT)
  • Servicio de Salud de Castilla La Mancha (ES)
Corresponding author
Ortelli, Paola
ORCID
Venue
European Journal of Neurology
Publisher
Wiley
Published
2022-02-24
Volume
29
Issue
6
Pages
1652-1662
ISSN
  • 1351-5101 (ISSN-L)
  • 1468-1331
DOI
10.1111/ene.15278
PMC
PMC9111319
OpenAlex
W4210893304
Cited by
82
References
6
Citations by year
2026: 8 · 2025: 14 · 2024: 20 · 2023: 26 · 2022: 14
FWCI
9.71
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • European Journal of Neurology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Neurology › Long-Term Effects of COVID-19
  • Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
Keywords
long COVID, fatigue, cognitive impairment, motor cortex excitability, primary motor cortex, executive function, sustained attention, short-interval intracortical inhibition, long-interval intracortical inhibition, short-latency afferent inhibition, cortical silent period, motor evoked potentials, resting motor threshold, GABAergic neurotransmission, cholinergic neurotransmission, neuropsychological assessment
MeSH terms
COVID-19, SARS-CoV-2, Cognition, Fatigue, Humans, Motor Cortex, Neural Inhibition, Evoked Potentials, Motor, Transcranial Magnetic Stimulation

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