Abstract
Electrical stimulation of the right median nerve can aid coma arousal after traumatic brain injury (TBI). This study aimed to confirm the efficacy further and explore possible mechanisms of right median nerve electrical stimulation (RMNS). Five comatose patients after severe TBI from May to September 2020 in the Tianjin Medical University General Hospital received RMNS for 2 weeks besides standard management. After the 2-week treatment, the mean Glasgow Coma Scale (GCS) and neurophysiological examination were used. We then investigated the alterations in microRNA (miRNA) expression in cerebrospinal fluid (CSF) by high-throughput whole transcriptome sequencing, analyzed the data by Gene Ontology (GO) and pathway analysis, and constructed the miRNA–target gene network. Patient awareness and brain function showed a more rapid increase after treatment. We also found 38 differently expressed miRNAs, 34 of which were upregulated and 4 downregulated. GO analysis showed a relation of these differentially expressed miRNAs with neuronal growth, repair, and neural signal transmission. The most highly correlated pathways were primarily associated with the tumor necrosis factor (TNF) signaling pathway and dopaminergic synapse. The application of RMNS effectively promoted early awakening in comatose patients with severe TBI. Moreover, differentially expressed miRNAs might reduce neuronal apoptosis and increase dopamine levels by regulating target gene expression, thus participating in the specific biological process after arousal therapy. Our study provided novel targets for further research on the molecular mechanisms of RMNS arousal treatment and a new way to treat neurotraumatic diseases.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00221-022-06414-7/MediaObjects/221_2022_6414_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00221-022-06414-7/MediaObjects/221_2022_6414_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00221-022-06414-7/MediaObjects/221_2022_6414_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00221-022-06414-7/MediaObjects/221_2022_6414_Fig4_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00221-022-06414-7/MediaObjects/221_2022_6414_Fig5_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00221-022-06414-7/MediaObjects/221_2022_6414_Fig6_HTML.png)
Similar content being viewed by others
Availability of data and materials
The datasets used and/or analyzed are available from the corresponding author on reasonable request.
References
Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP (2008) The impact of microRNAs on protein output. Nature 455:64–71. https://doi.org/10.1038/nature07242
Bales JW, Kline AE, Wagner AK, Dixon CE (2010) Targeting dopamine in acute traumatic brain injury. Open Drug Discov J 2:119–128. https://doi.org/10.2174/1877381801002010119
Betel D, Koppal A, Agius P, Sander C, Leslie C (2010) Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome Biol 11:R90. https://doi.org/10.1186/gb-2010-11-8-r90
Bian S, Sun T (2011) Functions of noncoding RNAs in neural development and neurological diseases. Mol Neurobiol 44:359–373. https://doi.org/10.1007/s12035-011-8211-3
Bosio Y, Berto G, Camera P, Bianchi F, Ambrogio C, Claus P, Di Cunto F (2012) PPP4R2 regulates neuronal cell differentiation and survival, functionally cooperating with SMN. Eur J Cell Biol 91:662–674. https://doi.org/10.1016/j.ejcb.2012.03.002
Burgos K, Malenica I, Metpally R et al (2014) Profiles of extracellular miRNA in cerebrospinal fluid and serum from patients with Alzheimer’s and Parkinson’s diseases correlate with disease status and features of pathology. PLoS ONE 9:e94839. https://doi.org/10.1371/journal.pone.0094839
Cooper EB, Cooper JB (2003) Electrical treatment of coma via the median nerve. Acta Neurochir Suppl 87:7–10. https://doi.org/10.1007/978-3-7091-6081-7_2
Cooper JB, Jane JA, Alves WM, Cooper EB (1999) Right median nerve electrical stimulation to hasten awakening from coma. Brain Inj 13:261–267. https://doi.org/10.1080/026990599121638
Dai R, Ahmed SA (2011) MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases. Transl Res 157:163–179. https://doi.org/10.1016/j.trsl.2011.01.007
Essandoh K, Fan GC (2014) Role of extracellular and intracellular microRNAs in sepsis. Biochim Biophys Acta 1842:2155–2162. https://doi.org/10.1016/j.bbadis.2014.07.021
Frenette AJ, Kanji S, Rees L et al (2012) Efficacy and safety of dopamine agonists in traumatic brain injury: a systematic review of randomized controlled trials. J Neurotrauma 29:1–18. https://doi.org/10.1089/neu.2011.1812
Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105. https://doi.org/10.1101/gr.082701.108
Fujino K, Horie M, Kojima S et al (2021) A human endogenous bornavirus-like nucleoprotein encodes a mitochondrial protein associated with cell viability. J Virol 95:e0203020. https://doi.org/10.1128/jvi.02030-20
Gao FB (2008) Posttranscriptional control of neuronal development by microRNA networks. Trends Neurosci 31:20–26. https://doi.org/10.1016/j.tins.2007.10.004
Hall JW 3rd, Huang-fu M, Gennarelli TA (1982) Auditory function in acute severe head injury. Laryngoscope 92:883–890
Hamzei Taj S, Kho W, Riou A, Wiedermann D, Hoehn M (2016) MiRNA-124 induces neuroprotection and functional improvement after focal cerebral ischemia. Biomaterials 91:151–165. https://doi.org/10.1016/j.biomaterials.2016.03.025
Hetman M, Kanning K, Cavanaugh JE, Xia Z (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J Biol Chem 274:22569–22580. https://doi.org/10.1074/jbc.274.32.22569
Huang T, Solano J, He D, Loutfi M, Dietrich WD, Kuluz JW (2009) Traumatic injury activates MAP kinases in astrocytes: mechanisms of hypothermia and hyperthermia. J Neurotrauma 26:1535–1545. https://doi.org/10.1089/neu.2008.0743
Huntley RP, Sawford T, Mutowo-Meullenet P, Shypitsyna A, Bonilla C, Martin MJ, O’Donovan C (2015) The GOA database: gene ontology annotation updates for 2015. Nucleic Acids Res 43:D1057-1063. https://doi.org/10.1093/nar/gku1113
Jayakumar AR, Tong XY, Ruiz-Cordero R, Bregy A, Bethea JR, Bramlett HM, Norenberg MD (2014) Activation of NF-κB mediates astrocyte swelling and brain edema in traumatic brain injury. J Neurotrauma 31:1249–1257. https://doi.org/10.1089/neu.2013.3169
Jennett B, Teasdale G (1977) Aspects of coma after severe head injury. Lancet 1:878–881. https://doi.org/10.1016/s0140-6736(77)91201-6
Jin W, Wang H, Yan W et al (2008) Disruption of Nrf2 enhances upregulation of nuclear factor-kappaB activity, proinflammatory cytokines, and intercellular adhesion molecule-1 in the brain after traumatic brain injury. Mediators Inflamm 2008:725174. https://doi.org/10.1155/2008/725174
Judson JA, Cant BR, Shaw NA (1990) Early prediction of outcome from cerebral trauma by somatosensory evoked potentials. Crit Care Med 18:363–368. https://doi.org/10.1097/00003246-199004000-00003
Khoshnam SE, Winlow W, Farbood Y, Moghaddam HF, Farzaneh M (2017) Emerging roles of microRNAs in ischemic stroke: as possible therapeutic agents. J Stroke 19:166–187. https://doi.org/10.5853/jos.2016.01368
Kraus MF, Smith GS, Butters M, Donnell AJ, Dixon E, Yilong C, Marion D (2005) Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET). Brain Inj 19:471–479. https://doi.org/10.1080/02699050400025059
Lan YL, Li S, Lou JC, Ma XC, Zhang B (2019) The potential roles of dopamine in traumatic brain injury: a preclinical and clinical update. Am J Transl Res 11:2616–2631
Lei J, Wang L, Gao G, Cooper E, Jiang J (2015) Right median nerve electrical stimulation for acute traumatic coma patients. J Neurotrauma 32:1584–1589. https://doi.org/10.1089/neu.2014.3768
Lendraitienė E, Petruševičienė D, Savickas R, Žemaitienė I, Mingaila S (2016) The impact of physical therapy in patients with severe traumatic brain injury during acute and post-acute rehabilitation according to coma duration. J Phys Ther Sci 28:2048–2054. https://doi.org/10.1589/jpts.28.2048
Levin HS, Saydjari C, Eisenberg HM et al (1991) Vegetative state after closed-head injury. a traumatic coma data bank report. Arch Neurol 48:580–585. https://doi.org/10.1001/archneur.1991.00530180032013
Meza-Sosa KF, Valle-García D, Pedraza-Alva G, Pérez-Martínez L (2012) Role of microRNAs in central nervous system development and pathology. J Neurosci Res 90:1–12. https://doi.org/10.1002/jnr.22701
Napolitano E, Elovic EP, Qureshi AI (2005) Pharmacological stimulant treatment of neurocognitive and functional deficits after traumatic and non-traumatic brain injury. Med Sci Monit 11(6):Ra212-220
Nishikimi A, Meller N, Uekawa N, Isobe K, Schwartz MA, Maruyama M (2005) Zizimin2: a novel, DOCK180-related Cdc42 guanine nucleotide exchange factor expressed predominantly in lymphocytes. FEBS Lett 579:1039–1046. https://doi.org/10.1016/j.febslet.2005.01.006
Numakawa T, Suzuki S, Kumamaru E, Adachi N, Richards M, Kunugi H (2010) BDNF function and intracellular signaling in neurons. Histol Histopathol 25:237–258. https://doi.org/10.14670/hh-25.237
Parrado A (2020) Expression of DOCK9 and DOCK11 analyzed with commercial antibodies: focus on regulation of mutually exclusive first exon isoforms. Antibodies (basel). https://doi.org/10.3390/antib9030027
Peri CV, Shaffrey ME, Farace E et al (2001) Pilot study of electrical stimulation on median nerve in comatose severe brain injured patients: 3-month outcome. Brain Inj 15:903–910. https://doi.org/10.1080/02699050110065709
Redell JB, Liu Y, Dash PK (2009) Traumatic brain injury alters expression of hippocampal microRNAs: potential regulators of multiple pathophysiological processes. J Neurosci Res 87:1435–1448. https://doi.org/10.1002/jnr.21945
Reinhard DL, Whyte J, Sandel ME (1996) Improved arousal and initiation following tricyclic antidepressant use in severe brain injury. Arch Phys Med Rehabil 77:80–83. https://doi.org/10.1016/s0003-9993(96)90225-7
Sami MB, Faruqui R (2015) The effectiveness of dopamine agonists for treatment of neuropsychiatric symptoms post brain injury and stroke. Acta Neuropsychiatr 27:317–326. https://doi.org/10.1017/neu.2015.17
Sánchez-Barrena MJ, Vallis Y, Clatworthy MR, Doherty GJ, Veprintsev DB, Evans PR, McMahon HT (2012) Bin2 is a membrane sculpting N-BAR protein that influences leucocyte podosomes, motility and phagocytosis. PLoS ONE 7:e52401. https://doi.org/10.1371/journal.pone.0052401
Sawyer E, Mauro LS, Ohlinger MJ (2008) Amantadine enhancement of arousal and cognition after traumatic brain injury. Ann Pharmacother 42:247–252. https://doi.org/10.1345/aph.1K284
Stoicea N, Du A, Lakis DC, Tipton C, Arias-Morales CE, Bergese SD (2016) The MiRNA journey from theory to practice as a CNS biomarker. Front Genet 7:11. https://doi.org/10.3389/fgene.2016.00011
Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness. A Practical Scale Lancet 2:81–84. https://doi.org/10.1016/s0140-6736(74)91639-0
Tiwari A, Mukherjee B, Dixit M (2018) MicroRNA Key to Angiogenesis Regulation: MiRNA Biology and Therapy. Curr Cancer Drug Targets 18:266–277. https://doi.org/10.2174/1568009617666170630142725
Walgrave H, Balusu S, Snoeck S et al (2021) Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer’s disease. Cell Stem Cell 28:1805-1821.e1808. https://doi.org/10.1016/j.stem.2021.05.001
Wu X, Zhang C, Feng J, Mao Q, Gao G, Jiang J (2017) Right median nerve electrical stimulation for acute traumatic coma (the Asia Coma Electrical Stimulation trial): study protocol for a randomised controlled trial. Trials 18:311. https://doi.org/10.1186/s13063-017-2045-x
Yang J, Wu Z, Renier N et al (2015) Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Cell 160:161–176. https://doi.org/10.1016/j.cell.2014.11.053
Yau KW, van Beuningen SF, Cunha-Ferreira I et al (2014) Microtubule minus-end binding protein CAMSAP2 controls axon specification and dendrite development. Neuron 82:1058–1073. https://doi.org/10.1016/j.neuron.2014.04.019
Yelo E, Bernardo MV, Gimeno L, Alcaraz-García MJ, Majado MJ, Parrado A (2008) Dock10, a novel CZH protein selectively induced by interleukin-4 in human B lymphocytes. Mol Immunol 45:3411–3418. https://doi.org/10.1016/j.molimm.2008.04.003
Yokobori S, Hosein K, Burks S, Sharma I, Gajavelli S, Bullock R (2013) Biomarkers for the clinical differential diagnosis in traumatic brain injury–a systematic review. CNS Neurosci Ther 19:556–565. https://doi.org/10.1111/cns.12127
Young GB, McLachlan RS, Kreeft JH, Demelo JD (1997) An electroencephalographic classification for coma. Can J Neurol Sci 24:320–325. https://doi.org/10.1017/s0317167100032996
Young GB, Doig G, Ragazzoni A (2005) Anoxic-ischemic encephalopathy: clinical and electrophysiological associations with outcome. Neurocrit Care 2:159–164. https://doi.org/10.1385/ncc:2:2:159
Funding
This work was supported by the National Natural Science Foundation of China (81971173), the National Youth Natural Science Foundation of China (81501057), and the Tianjin Key Medical Discipline (Specialty) Construction Project.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no conflict of interests regarding the publication of this article.
Ethics approval
This study has been approved by the Ethics Committee of Tianjin Medical University General Hospital. All procedures performed in studies were in accordance with the ethical standards in China.
Consent for publication
All authors read and approved the final manuscript.
Additional information
Communicated by Sreedharan Sajikumar.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Jia, Y., He, Yf., Tian, Y. et al. MicroRNA alteration in cerebrospinal fluid from comatose patients with traumatic brain injury after right median nerve stimulation. Exp Brain Res 240, 2459–2470 (2022). https://doi.org/10.1007/s00221-022-06414-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-022-06414-7