Skip to main content

Advertisement

SpringerLink
Log in

Is the Human Touch Always Therapeutic? Patient Stimulation and Spreading Depolarization after Acute Neurological Injuries

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

A Publisher Correction to this article was published on 19 May 2022

This article has been updated

Abstract

Touch and other types of patient stimulation are necessary in critical care and generally presumed to be beneficial. Recent pre-clinical studies as well as randomized trials assessing early mobilization have challenged the safety of such routine practices in patients with acute neurological injury such as stroke. We sought to determine whether patient stimulation could result in spreading depolarization (SD), a dramatic pathophysiological event that likely contributes to metabolic stress and ischemic expansion in such patients. Patients undergoing surgical intervention for severe acute neurological injuries (stroke, aneurysm rupture, or trauma) were prospectively consented and enrolled in an observational study monitoring SD with implanted subdural electrodes. Subjects also underwent simultaneous video recordings (from continuous EEG monitoring) to assess for physical touch and other forms of patient stimulation (such as suctioning and positioning). The association of patient stimulation with subsequent SD was assessed. Increased frequency of patient stimulation was associated with increased risk of SD (OR = 4.39 [95%CI = 1.71–11.24]). The overall risk of SD was also increased in the 60 min following patient stimulation compared to times with no stimulation (OR = 1.19 [95%CI = 1.13–1.26]), though not all subjects demonstrated this effect individually. Positioning of the subject was the subtype of stimulation with the strongest overall effect on SD (OR = 4.92 [95%CI = 3.74–6.47]). We conclude that in patients with some acute neurological injuries, touch and other patient stimulation can induce SD (PS-SD), potentially increasing the risk of metabolic and ischemic stress. PS-SD may represent an underlying mechanism for observed increased risk of early mobilization in such patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Availability of data and materials

Data available upon reasonable request, subject to institutional and IRB oversight policies

Change history

References

  1. Watt JA, Goodarzi Z, Veroniki AA, Nincic V, Khan PA, Ghassemi M, Lai Y, Treister V, Thompson Y, Schneider R, Tricco AC, Straus SE. Comparative efficacy of interventions for reducing symptoms of depression in people with dementia: systematic review and network meta-analysis. BMJ. 2021;372: n532. https://doi.org/10.1136/bmj.n532.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jabre P, Belpomme V, Azoulay E, Jacob L, Bertrand L, Lapostolle F, Tazarourte K, Bouilleau G, Pinaud V, Broche C, Normand D, Baubet T, Ricard-Hibon A, Istria J, Beltramini A, Alheritiere A, Assez N, Nace L, Vivien B, Turi L, Launay S, Desmaizieres M, Borron SW, Vicaut E, Adnet F. Family presence during cardiopulmonary resuscitation. N Engl J Med. 2013;368(11):1008–18. https://doi.org/10.1056/NEJMoa1203366.

    Article  CAS  PubMed  Google Scholar 

  3. Zhang L, Hu W, Cai Z, Liu J, Wu J, Deng Y, Yu K, Chen X, Zhu L, Ma J, Qin Y. Early mobilization of critically ill patients in the intensive care unit: A systematic review and meta-analysis. PLoS ONE. 2019;14(10): e0223185. https://doi.org/10.1371/journal.pone.0223185.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. von Bornstadt D, Houben T, Seidel JL, Zheng Y, Dilekoz E, Qin T, Sandow N, Kura S, Eikermann-Haerter K, Endres M, Boas DA, Moskowitz MA, Lo EH, Dreier JP, Woitzik J, Sakadzic S, Ayata C. Supply-Demand Mismatch Transients in Susceptible Peri-infarct Hot Zones Explain the Origins of Spreading Injury Depolarizations. Neuron. 2015;85(5):1117–31. https://doi.org/10.1016/j.neuron.2015.02.007.

    Article  CAS  Google Scholar 

  5. Langhorne P, Collier JM, Bate PJ, Thuy MNT, Bernhardt J (2018) Very early versus delayed mobilisation after stroke. Cochrane Database of Systematic Reviews (10). doi:ARTN CD006187. https://doi.org/10.1002/14651858.CD006187.pub

  6. Frostig RD, Lay CC, Davis MF. A rat’s whiskers point the way toward a novel stimulus-dependent, protective stroke therapy. Neuroscientist. 2013;19(3):313–28. https://doi.org/10.1177/1073858412462607.

    Article  PubMed  Google Scholar 

  7. von Bornstadt D, Gertz K, Lagumersindez Denis N, Seners P, Baron JC, Endres M. Sensory stimulation in acute stroke therapy. J Cereb Blood Flow Metab. 2018;38(10):1682–9. https://doi.org/10.1177/0271678X18791073.

    Article  Google Scholar 

  8. Leao AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7(6):359–90.

    Article  Google Scholar 

  9. Hartings JA, Shuttleworth CW, Kirov SA, Ayata C, Hinzman JM, Foreman B, Andrew RD, Boutelle MG, Brennan KC, Carlson AP, Dahlem MA, Drenckhahn C, Dohmen C, Fabricius M, Farkas E, Feuerstein D, Graf R, Helbok R, Lauritzen M, Major S, Oliveira-Ferreira AI, Richter F, Rosenthal ES, Sakowitz OW, Sanchez-Porras R, Santos E, Scholl M, Strong AJ, Urbach A, Westover MB, Winkler MK, Witte OW, Woitzik J, Dreier JP. The continuum of spreading depolarizations in acute cortical lesion development: Examining Leao’s legacy. J Cereb Blood Flow Metab. 2017;37(5):1571–94. https://doi.org/10.1177/0271678X16654495.

    Article  PubMed  Google Scholar 

  10. Dreier JP, Lemale CL, Kola V, Friedman A, Schoknecht K. Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke. Neuropharmacology. 2018;134(Pt B):189–207. https://doi.org/10.1016/j.neuropharm.2017.09.027.

    Article  CAS  PubMed  Google Scholar 

  11. Mestre H, Du T, Sweeney AM, Liu G, Samson AJ, Peng W, Mortensen KN, Staeger FF, Bork PAR, Bashford L, Toro ER, Tithof J, Kelley DH, Thomas JH, Hjorth PG, Martens EA, Mehta RI, Solis O, Blinder P, Kleinfeld D, Hirase H, Mori Y, Nedergaard M (2020) Cerebrospinal fluid influx drives acute ischemic tissue swelling. Science 367 (6483). https://doi.org/10.1126/science.aax7171

  12. group ATC. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial. Lancet. 2015;386(9988):46–55. https://doi.org/10.1016/S0140-6736(15)60690-0.

    Article  Google Scholar 

  13. Bernhardt J, Borschmann K, Collier JM, Thrift AG, Langhorne P, Middleton S, Lindley RI, Dewey HM, Bath P, Said CM, Churilov L, Ellery F, Bladin C, Reid CM, Frayne JH, Srikanth V, Read SJ, Donnan GA, Group ATC (2020) Fatal and non-fatal events within 14 days after early, intensive mobilization post stroke. Neurology. https://doi.org/10.1212/WNL.0000000000011106

  14. Kwakkel G. Very early mobilisation within 24 hours of stroke results in a less favourable outcome at 3 months [commentary 2]. J Physiother. 2015;61(4):220. https://doi.org/10.1016/j.jphys.2015.07.012.

    Article  PubMed  Google Scholar 

  15. Luft AR, Kesselring J. Critique of A Very Early Rehabilitation Trial (AVERT). Stroke. 2016;47(1):291–2. https://doi.org/10.1161/Strokeaha.115.010483.

    Article  PubMed  Google Scholar 

  16. Barer D, Watkins C. Could upright posture be harmful in the early stages of stroke? Lancet. 2015;386(10005):1734. https://doi.org/10.1016/S0140-6736(15)00691-1.

    Article  PubMed  Google Scholar 

  17. Cui Y, Kataoka Y, Li QH, Yokoyama C, Yamagata A, Mochizuki-Oda N, Watanabe J, Yamada H, Watanabe Y. Targeted tissue oxidation in the cerebral cortex induces local prolonged depolarization and cortical spreading depression in the rat brain. Biochem Biophys Res Commun. 2003;300(3):631–6. https://doi.org/10.1016/S0006-291X(02)02906-6.

    Article  CAS  PubMed  Google Scholar 

  18. Aiba I, Carlson AP, Sheline CT, Shuttleworth CW. Synaptic release and extracellular actions of Zn2+ limit propagation of spreading depression and related events in vitro and in vivo. J Neurophysiol. 2012;107(3):1032–41. https://doi.org/10.1152/jn.00453.2011.

    Article  CAS  PubMed  Google Scholar 

  19. Gao Q, Tao Z, Zhang M, Chen H. Differential contribution of bilateral supplementary motor area to the effective connectivity networks induced by task conditions using dynamic causal modeling. Brain Connect. 2014;4(4):256–64. https://doi.org/10.1089/brain.2013.0194.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yushkevich PA, Piven J, Hazlett HC, Smith RG, Ho S, Gee JC, Gerig G. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;31(3):1116–28. https://doi.org/10.1016/j.neuroimage.2006.01.015.

    Article  PubMed  Google Scholar 

  21. Hill AB. The Environment and Disease: Association or Causation? Proc R Soc Med. 1965;58:295–300.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health. 2005;95(Suppl 1):S144-150. https://doi.org/10.2105/AJPH.2004.059204.

    Article  PubMed  Google Scholar 

  23. Hadjikhani N, Sanchez Del Rio M, Wu O, Schwartz D, Bakker D, Fischl B, Kwong KK, Cutrer FM, Rosen BR, Tootell RB, Sorensen AG, Moskowitz MA. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci U S A. 2001;98(8):4687–92. https://doi.org/10.1073/pnas.071582498[pii].

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Olesen J, Larsen B, Lauritzen M. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol. 1981;9(4):344–52. https://doi.org/10.1002/ana.410090406.

    Article  CAS  PubMed  Google Scholar 

  25. Dietz RM, Weiss JH, Shuttleworth CW. Contributions of Ca2+ and Zn2+ to spreading depression-like events and neuronal injury. J Neurochem. 2009;109(Suppl 1):145–52. https://doi.org/10.1111/j.1471-4159.2009.05853.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kleinfeld D, Mitra PP, Helmchen F, Denk W. Fluctuations and stimulus-induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. Proc Natl Acad Sci U S A. 1998;95(26):15741–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hartings JA, Strong AJ, Fabricius M, Manning A, Bhatia R, Dreier JP, Mazzeo AT, Tortella FC, Bullock MR. Spreading depolarizations and late secondary insults after traumatic brain injury. J Neurotrauma. 2009;26(11):1857–66. https://doi.org/10.1089/neu.2009-0961.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lapilover EG, Lippmann K, Salar S, Maslarova A, Dreier JP, Heinemann U, Friedman A. Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges. Neurobiol Dis. 2012;48(3):495–506. https://doi.org/10.1016/j.nbd.2012.06.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Petzold GC, Haack S, Vonbohlen Und Halbach O, Priller J, Lehmann TN, Heinemann U, Dirnagl U, Dreier JP. Nitric oxide modulates spreading depolarization threshold in the human and rodent cortex. Stroke. 2008;39(4):1292–9. https://doi.org/10.1161/STROKEAHA.107.500710.

    Article  CAS  PubMed  Google Scholar 

  30. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2011;31(1):17–35. https://doi.org/10.1038/jcbfm.2010.191.

    Article  PubMed  Google Scholar 

  31. Oka F, Hoffmann U, Lee JH, Shin HK, Chung DY, Yuzawa I, Chen SP, Atalay YB, Nozari A, Hopson KP, Qin T, Ayata C. Requisite ischemia for spreading depolarization occurrence after subarachnoid hemorrhage in rodents. J Cereb Blood Flow Metab. 2017;37(5):1829–40. https://doi.org/10.1177/0271678X16659303.

    Article  PubMed  Google Scholar 

  32. Hartings JA, Bullock MR, Okonkwo DO, Murray LS, Murray GD, Fabricius M, Maas AI, Woitzik J, Sakowitz O, Mathern B, Roozenbeek B, Lingsma H, Dreier JP, Puccio AM, Shutter LA, Pahl C, Strong AJ. Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study. Lancet Neurol. 2011;10(12):1058–64. https://doi.org/10.1016/S1474-4422(11)70243-5.

    Article  PubMed  Google Scholar 

  33. Dohmen C, Sakowitz OW, Fabricius M, Bosche B, Reithmeier T, Ernestus RI, Brinker G, Dreier JP, Woitzik J, Strong AJ, Graf R. Spreading depolarizations occur in human ischemic stroke with high incidence. Ann Neurol. 2008;63(6):720–8. https://doi.org/10.1002/ana.21390.

    Article  PubMed  Google Scholar 

  34. Baird TA, Parsons MW, Phan T, Butcher KS, Desmond PM, Tress BM, Colman PG, Chambers BR, Davis SM. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcome. Stroke. 2003;34(9):2208–14. https://doi.org/10.1161/01.STR.0000085087.41330.FF.

    Article  CAS  PubMed  Google Scholar 

  35. Aarabi B, Hesdorffer DC, Ahn ES, Aresco C, Scalea TM, Eisenberg HM. Outcome following decompressive craniectomy for malignant swelling due to severe head injury. J Neurosurg. 2006;104(4):469–79. https://doi.org/10.3171/jns.2006.104.4.469.

    Article  PubMed  Google Scholar 

  36. Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010;41(10):2391–5. https://doi.org/10.1161/STROKEAHA.110.589275.

    Article  PubMed  Google Scholar 

  37. Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med. 2011;17(4):439–47. https://doi.org/10.1038/nm.2333.

    Article  CAS  PubMed  Google Scholar 

  38. Bogdanov VB, Middleton NA, Theriot JJ, Parker PD, Abdullah OM, Ju YS, Hartings JA, Brennan KC. Susceptibility of Primary Sensory Cortex to Spreading Depolarizations. J Neurosci. 2016;36(17):4733–43. https://doi.org/10.1523/JNEUROSCI.3694-15.2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Reinhart KM, Shuttleworth CW. Ketamine reduces deleterious consequences of spreading depolarizations. Exp Neurol. 2018;305:121–8. https://doi.org/10.1016/j.expneurol.2018.04.007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Carlson AP, Abbas M, Alunday RL, Qeadan F, Shuttleworth CW (2018) Spreading depolarization in acute brain injury inhibited by ketamine: a prospective, randomized, multiple crossover trial. J Neurosurg:1–7. https://doi.org/10.3171/2017.12.JNS171665

  41. Carlson AP, Alchbli A, Hanggi D, Macdonald RL, Shuttleworth CW. Effect of Locally Delivered Nimodipine Microparticles on Spreading Depolarization in Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care. 2020. https://doi.org/10.1007/s12028-020-00935-1.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Dreier JP, Fabricius M, Ayata C, Sakowitz OW, William Shuttleworth C, Dohmen C, Graf R, Vajkoczy P, Helbok R, Suzuki M, Schiefecker AJ, Major S, Winkler MK, Kang EJ, Milakara D, Oliveira-Ferreira AI, Reiffurth C, Revankar GS, Sugimoto K, Dengler NF, Hecht N, Foreman B, Feyen B, Kondziella D, Friberg CK, Piilgaard H, Rosenthal ES, Westover MB, Maslarova A, Santos E, Hertle D, Sanchez-Porras R, Jewell SL, Balanca B, Platz J, Hinzman JM, Luckl J, Schoknecht K, Scholl M, Drenckhahn C, Feuerstein D, Eriksen N, Horst V, Bretz JS, Jahnke P, Scheel M, Bohner G, Rostrup E, Pakkenberg B, Heinemann U, Claassen J, Carlson AP, Kowoll CM, Lublinsky S, Chassidim Y, Shelef I, Friedman A, Brinker G, Reiner M, Kirov SA, Andrew RD, Farkas E, Guresir E, Vatter H, Chung LS, Brennan KC, Lieutaud T, Marinesco S, Maas AI, Sahuquillo J, Dahlem MA, Richter F, Herreras O, Boutelle MG, Okonkwo DO, Bullock MR, Witte OW, Martus P, van den Maagdenberg AM, Ferrari MD, Dijkhuizen RM, Shutter LA, Andaluz N, Schulte AP, MacVicar B, Watanabe T, Woitzik J, Lauritzen M, Strong AJ, Hartings JA. Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group. J Cereb Blood Flow Metab. 2017;37(5):1595–625. https://doi.org/10.1177/0271678X16654496.

    Article  PubMed  Google Scholar 

  43. Hartings JA, Li C, Hinzman JM, Shuttleworth CW, Ernst GL, Dreier JP, Wilson JA, Andaluz N, Foreman B, Carlson AP. Direct current electrocorticography for clinical neuromonitoring of spreading depolarizations. J Cereb Blood Flow Metab. 2017;37(5):1857–70. https://doi.org/10.1177/0271678X16653135.

    Article  PubMed  Google Scholar 

  44. Fritch CD, Qeadan F, Shuttleworth CW, Carlson AP. Spreading depolarization occurs in repeating, recognizable, patient-specific patterns after human brain injury. Brain Inj. 2021;35(3):299–303. https://doi.org/10.1080/02699052.2020.1861480.

    Article  PubMed  Google Scholar 

  45. Helbok R, Hartings JA, Schiefecker A, Balanca B, Jewel S, Foreman B, Ercole A, Balu R, Ayata C, Ngwenya L, Rosenthal E, Boutelle MG, Farkas E, Dreier JP, Fabricius M, Shuttleworth CW, Carlson A. What Should a Clinician Do When Spreading Depolarizations are Observed in a Patient? Neurocrit Care. 2019. https://doi.org/10.1007/s12028-019-00777-6.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Adarsh Vangala, Breannan Howell, Saul Fernandez, Emma Brandt, and Zainab Cheema for video scoring. Li Luo and Mark Krasberg for developmental statistical analysis Yiliang Zhu, Richard A Campbell for advisory support. Medical Illustration by Yvonne Wylie Walston.

Funding

National Institutes of Health grant P20 GM109089 (APC, CWS); National Institutes of Health grant NS 102978, 104742 (KCB).

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Neurosciences, and Neurology, University of New Mexico, NM, Albuquerque, USA

    Andrew P. Carlson

  2. Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA

    Herbert T. Davis

  3. Department of Psychiatry, University of New Mexico, Albuquerque, NM, USA

    Thomas Jones

  4. Department of Neurology, University of Utah, Salt Lake City, UT, USA

    K. C. Brennan

  5. Department of Neurology, University of New Mexico, Albuquerque, NM, USA

    Michel Torbey

  6. University of New Mexico School of Medicine, Albuquerque, NM, USA

    Rosstin Ahmadian

  7. Department of Public Health Sciences, Loyola University Chicago, Chicago, IL, USA

    Fares Qeadan

  8. Department of Neuroscience, University of New Mexico, Albuquerque, NM, USA

    C. William Shuttleworth

Authors
  1. Andrew P. Carlson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Herbert T. Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K. C. Brennan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michel Torbey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rosstin Ahmadian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fares Qeadan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. William Shuttleworth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

APC and CWS contributed to Conceptualization.

APC, TJ, HTD, FQ, and MT contributed to Methodology

APC contributed to Investigation

APC, TJ, and HTD contributed to Visualization

APC, CWS, and MT contributed to Funding acquisition

APC contributed to writing—original draft

KCB, HTD, and CWS contributed to writing—review & editing:

Corresponding author

Correspondence to Andrew P. Carlson.

Ethics declarations

Competing interests

Authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Carlson, A.P., Davis, H.T., Jones, T. et al. Is the Human Touch Always Therapeutic? Patient Stimulation and Spreading Depolarization after Acute Neurological Injuries. Transl. Stroke Res. 14, 160–173 (2023). https://doi.org/10.1007/s12975-022-01014-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-022-01014-7

Keywords

Search

Navigation