Characterization of responders to transcranial direct current stimulation in disorders of consciousness: A retrospective study of 8 clinical trials - 2025
Edlow, B.L., Sanz, L.R., Polizzotto, L., Pouratian, N., Rolston, J.D., Snider, S.B., et al. Therapies to restore consciousness in patients with severe brain injuries: a gap analysis and future directions. Neurocritical Care 35:S1 (Jul. 2021), 68–85, 10.1007/s12028-021-01227-y.
Laureys, S., Celesia, G.G., Cohadon, F., Lavrijsen, J., León-Carrión, J., Sannita, W.G., et al. Unresponsive wakefulness syndrome: a new name for the vegetative state or apallic syndrome. BMC Med 8 (2010), 2–5, 10.1186/1741-7015-8-68.
Giacino, J.T., Ashwal, S., Childs, N., Cranford, R., Jennett, B., Katz, D.I., et al. The minimally conscious state. Neurology 58:3 (Feb. 2002), 349–353, 10.1212/WNL.58.3.349.
Nakase-Richardson, R., Yablon, S.A., Sherer, M., Nick, T.G., Evans, C.C., Emergence from minimally conscious state: insights from evaluation of posttraumatic confusion. Neurology 73:14 (Oct. 2009), 1120–1126, 10.1212/WNL.0b013e3181bacf34.
Estraneo, A., Moretta, P., Loreto, V., Lanzillo, B., Santoro, L., Trojano, L., Late recovery after traumatic, anoxic, or hemorrhagic long-lasting vegetative state. Neurology 75:3 (2010), 239–245.
Estraneo, A., Magliacano, A., Fiorenza, S., Formisano, R., Grippo, A., Angelakis, E., et al. Risk factors for 2-year mortality in patients with prolonged disorders of consciousness: an international multicentre study. Eur J Neurol 29:2 (Feb. 2022), 390–399, 10.1111/ene.15143.
Gosseries, O., Charland-Verville, V., Thonnard, M., Bodart, O., Laureys, S., Demertzi, A., Amantadine, apomorphine and zolpidem in the treatment of disorders of consciousness. Curr Pharm Des 20:26 (Sep. 2014), 4167–4184, 10.2174/13816128113196660654.
Giacino, J.T., Whyte, J., Bagiella, E., Kalmar, K., Childs, N., Khademi, A., et al. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med 366:5 (Mar. 2013), 819–826, 10.1056/NEJMoa1102609.
Nitsche, M.A., Cohen, L.G., Wassermann, E.M., Priori, A., Lang, N., Antal, A., et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimul 1:3 (2008), 206–223.
Thibaut, A., Bruno, M.A., Ledoux, D., Demertzi, A., Laureys, S., TDCS in patients with disorders of consciousness: sham-controlled randomized double-blind study. Neurology, 82(13), 2014, 10.1212/WNL.0000000000000260.
Bai, Y., Xia, X., Kang, J., Yang, Y., He, J., Li, X., TDCS modulates cortical excitability in patients with disorders of consciousness. Neuroimage Clin 15 (2017), 702–709, 10.1016/j.nicl.2017.01.025.
Martens, G., Fregni, F., Carrière, M., Barra, A., Laureys, S., Thibaut, A., Single tDCS session of motor cortex in patients with disorders of consciousness: a pilot study. Brain Inj 33:13–14 (2019), 1679–1683, 10.1080/02699052.2019.1667537.
Carrière, M., Mortaheb, S., Raimondo, F., Annen, J., Barra, A., Binda Fossati, M.C., et al. Neurophysiological correlates of a single session of prefrontal tdcs in patients with prolonged disorders of consciousness: a pilot double-blind randomized controlled study. Brain Sci 10:7 (2020), 1–17, 10.3390/brainsci10070469.
Cavinato, M., Genna, C., Formaggio, E., Gregorio, C., Storti, S.F., Manganotti, P., et al. Behavioural and electrophysiological effects of tDCS to prefrontal cortex in patients with disorders of consciousness. Clin Neurophysiol 130:2 (2019), 231–238, 10.1016/j.clinph.2018.10.018.
Mancuso, M., Abbruzzese, L., Canova, S., Landi, G., Rossi, S., Santarnecchi, E., Transcranial random noise stimulation does not improve behavioral and neurophysiological measures in patients with subacute Vegetative-Unresponsive Wakefulness State (VS-UWS). Front Hum Neurosci 11:November (2017), 1–10, 10.3389/fnhum.2017.00524.
Huang, W., Wannez, S., Fregni, F., Hu, X., Jing, S., Martens, G., et al. Repeated stimulation of the posterior parietal cortex in patients in minimally conscious state: a sham-controlled randomized clinical trial. Brain Stimul 10:3 (2017), 718–720, 10.1016/j.brs.2017.02.001.
Martens, G., Kroupi, E., Bodien, Y., Frasso, G., Annen, J., Cassol, H., et al. Behavioral and electrophysiological effects of network-based frontoparietal tDCS in patients with severe brain injury: a randomized controlled trial. Neuroimage Clin, 28, Jan. 2020, 102426, 10.1016/j.nicl.2020.102426.
Thibaut, A., Piarulli, A., Martens, G., Chatelle, C., Laureys, S., Effect of multichannel transcranial direct current stimulation to reduce hypertonia in individuals with prolonged disorders of consciousness: a randomized controlled pilot study. Ann Phys Rehabil Med 62:6 (2019), 418–425, 10.1016/j.rehab.2019.05.009.
Thibaut, A., Wannez, S., Donneau, A.F., Chatelle, C., Gosseries, O., Bruno, M.A., et al. Controlled clinical trial of repeated prefrontal tDCS in patients with chronic minimally conscious state. Brain Inj, 31(4), 2017, 10.1080/02699052.2016.1274776.
Barra, A., Monti, M., Thibaut, A., Noninvasive brain stimulation therapies to promote recovery of consciousness: where we are and where we should go. Seminars in neurology, 2022, Thieme Medical Publishers, Inc. 333 Seventh Avenue, 18th Floor, New York, NY, 348–362.
Giacino, J.T., Kalmar, K., Whyte, J., The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil 85:12 (2004), 2020–2029.
Seel, R.T., Sherer, M., Whyte, J., Katz, D.I., Giacino, J.T., Rosenbaum, A.M., et al. Assessment scales for disorders of consciousness: evidence-based recommendations for clinical practice and research. Arch Phys Med Rehabil 91:12 (Dec. 2010), 1795–1813, 10.1016/j.apmr.2010.07.218.
Annen, J., Filippini, M.M., Bonin, E., Cassol, H., Aubinet, C., Carrière, M., et al. Diagnostic accuracy of the CRS-R index in patients with disorders of consciousness. Brain Inj 0:0 (2019), 1–4, 10.1080/02699052.2019.1644376.
Liu, Z., Zhang, X., Yu, B., Wang, J., Lu, X., Effectiveness on level of consciousness of non-invasive neuromodulation therapy in patients with disorders of consciousness: a systematic review and meta-analysis. Front Hum Neurosci, 17, 2023, 1129254.
Barra, A., Rosenfelder, M., Mortaheb, S., Carrière, M., Martens, G., Bodien, Y.G., et al. Transcranial pulsed-current stimulation versus transcranial direct current stimulation in patients with disorders of consciousness: a pilot, sham-controlled cross-over double-blind study. Brain Sci, 12(4), 2022, 429.
Giacino, J.T., Katz, D.I., Schiff, N.D., Whyte, J., Ashman, E.J., Ashwal, S., et al. Practice guideline update recommendations summary: disorders of consciousness. Neurology 91:10 (Sep. 2018), 450–460, 10.1212/WNL.0000000000005926.
Kondziella, D., Bender, A., Diserens, K., van Erp, W., Estraneo, A., Formisano, R., et al. European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness. Eur J Neurol 27:5 (May 2020), 741–756, 10.1111/ene.14151.
Papadimitriou, C., Weaver, J.A., Guernon, A., Walsh, E., Mallinson, T., Pape, T.L.B., “Fluctuation is the norm”: rehabilitation practitioner perspectives on ambiguity and uncertainty in their work with persons in disordered states of consciousness after traumatic brain injury. PLoS One, 17(4), 2022, e0267194.
Zou, G., A modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol 159:7 (2004), 702–706.
Kent, D.M., Rothwell, P.M., Ioannidis, J.P.A., Altman, D.G., Hayward, R.A., Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal. Trials, 11(1), 2010, 85, 10.1186/1745-6215-11-85.
Friedman, J., Hastie, T., Tibshirani, R., Regularization paths for generalized linear models via coordinate descent. J Stat Software, 33(1), 2010, 1.
Tibshirani, R., Regression shrinkage and selection via the lasso. J Roy Stat Soc B 58:1 (Jan. 1996), 267–288, 10.1111/j.2517-6161.1996.tb02080.x.
Albizu, A., Indahlastari, A., Suen, P., Huang, Z., Waner, J.L., Stolte, S.E., et al. Machine learning-optimized non-invasive brain stimulation and treatment response classification for major depression. Bioelectron Med, 10(1), 2024, 25, 10.1186/s42234-024-00157-2.
Thibaut, A., Bruno, M.-A., Ledoux, D., Demertzi, A., Laureys, S., tDCS in patients with disorders of consciousness Sham-controlled randomized double-blind study. Neurology 82:13 (2014), 1112–1118, 10.1212/WNL.0000000000000260.
Estraneo, A., Pascarella, A., Moretta, P., Masotta, O., Fiorenza, S., Chirico, G., et al. Repeated transcranial direct current stimulation in prolonged disorders of consciousness: a double-blind cross-over study. J Neurol Sci 375 (2017), 464–470, 10.1016/j.jns.2017.02.036.
Feng, Y., Zhang, J., Zhou, Y., Bai, Z., Yin, Y., Noninvasive brain stimulation for patients with a disorder of consciousness: a systematic review and meta-analysis. Rev Neurosci 31:8 (Nov. 2020), 905–914, 10.1515/revneuro-2020-0033.
Estraneo, A., Moretta, P., Loreto, V., Santoro, L., Trojano, L., Clinical and neuropsychological long-term outcomes after late recovery of responsiveness: a case series. Arch Phys Med Rehabil 95:4 (Apr. 2014), 711–716, 10.1016/j.apmr.2013.11.004.
Estraneo, A., De Bellis, F., Masotta, O., Loreto, V., Fiorenza, S., Lo Sapio, M., et al. Demographical and clinical indices for long-term evolution of patients in vegetative or in minimally conscious state. Brain Inj 33:13–14 (2019), 1633–1639.
Thibaut, A., Fregni, F., Estraneo, A., Fiorenza, S., Noe, E., Llorens, R., et al. Sham-controlled randomized multicentre trial of transcranial direct current stimulation for prolonged disorders of consciousness. Eur J Neurol 30:10 (Oct. 2023), 3016–3031, 10.1111/ene.15974.
Thibaut, A., Di Perri, C., Chatelle, C., Bruno, M.A., Bahri, M.A., Wannez, S., et al. Clinical response to tDCS depends on residual brain metabolism and grey matter integrity in patients with minimally conscious state. Brain Stimul 8:6 (2015), 1116–1123, 10.1016/j.brs.2015.07.024.
Thibaut, A., Chennu, S., Chatelle, C., Martens, G., Annen, J., Cassol, H., et al. Theta network centrality correlates with tDCS response in disorders of consciousness. Brain Stimul 11:6 (2018), 1407–1409, 10.1016/j.brs.2018.09.002.
Tarantino, V., Fontana, M.L., Buttà, A., Ficile, S., Oliveri, M., Mandalà, G., et al. Increase in EEG alpha-to-theta ratio after transcranial direct current stimulation (tDCS) in patients with disorders of consciousness: a pilot study. NeuroRehabilitation, 2024, 10538135241296372.
Chennu, S., Annen, J., Wannez, S., Thibaut, A., Chatelle, C., Cassol, H., et al. Brain networks predict metabolism, diagnosis and prognosis at the bedside in disorders of consciousness. Brain 140:8 (Aug. 2017), 2120–2132, 10.1093/brain/awx163.
Sitt, J.D., King, J.R., El Karoui, I., Rohaut, B., Faugeras, F., Gramfort, A., et al. Large scale screening of neural signatures of consciousness in patients in a vegetative or minimally conscious state. Brain 137:8 (Aug. 2014), 2258–2270, 10.1093/brain/awu141.
Gangemi, A., De Luca, R., Fabio, R.A., Bonanno, M., Cardile, D., Mignacca, M.R., et al. Cognitive effects of transcranial direct current stimulation plus robotic verticalization in minimally conscious state. Biomedicines, 12(10), Oct. 2024, 10.3390/biomedicines12102244.
Wang, Y., Liu, W., Wang, Y., Ouyang, G., Guo, Y., Long-term HD-tDCS modulates dynamic changes of brain activity on patients with disorders of consciousness: a resting-state EEG study. Comput Biol Med, 170, 2024, 108084.
Edlow, B.L., Claassen, J., Schiff, N.D., Greer, D.M., Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies. Nat Rev Neurol 17:3 (Mar. 2020), 135–156, 10.1038/s41582-020-00428-x.
Thibaut, A., Chatelle, C., Vanhaudenhuyse, A., Martens, G., Cassol, H., Martial, C., et al. Transcranial direct current stimulation unveils covert consciousness. Brain Stimul 11:3 (2018), 642–644, 10.1016/j.brs.2018.02.002.
Demertzi, A., Antonopoulos, G., Heine, L., Voss, H.U., Crone, J.S., de Los Angeles, C., et al. Intrinsic functional connectivity differentiates minimally conscious from unresponsive patients. Brain 138:9 (Sep. 2015), 2619–2631, 10.1093/brain/awv169.
Bolognini, N., Convento, S., Banco, E., Mattioli, F., Tesio, L., Vallar, G., Improving ideomotor limb apraxia by electrical stimulation of the left posterior parietal cortex. Brain 138:2 (2015), 428–439.
Bradnam, L.V., Stinear, C.M., Barber, P.A., Byblow, W.D., Contralesional hemisphere control of the proximal paretic upper limb following stroke. Cerebr Cortex 22:11 (2012), 2662–2671.
Hermann, B., Raimondo, F., Hirsch, L., Huang, Y., Denis-Valente, M., Pérez, P., et al. Combined behavioral and electrophysiological evidence for a direct cortical effect of prefrontal tDCS on disorders of consciousness. Sci Rep 10:1 (2020), 1–16, 10.1038/s41598-020-61180-2.
Mensen, A., Bodart, O., Thibaut, A., Wannez, S., Annen, J., Laureys, S., et al. Decreased evoked slow-activity after tDCS in disorders of consciousness. Front Syst Neurosci, 14, Sep. 2020, 62, 10.3389/fnsys.2020.00062.
Bodien, Y.G., Martens, G., Ostrow, J., Sheau, K., Giacino, J.T., Cognitive impairment, clinical symptoms and functional disability in patients emerging from the minimally conscious state. NeuroRehabilitation 46:1 (2020), 65–74.
Caplan, B., Ponsford, J., Jones, H., McKay, A., Comparing the Westmead posttraumatic amnesia scale, Galveston orientation and amnesia test, and confusion assessment protocol as measures of acute recovery following traumatic brain injury. J Head Trauma Rehabil 36:3 (2021), 156–163.
Estraneo, A., Trojano, L., Prognosis in disorders of consciousness. Schnakers, C., Laureys, S., (eds.) Coma and disorders of consciousness, 2018, Springer International Publishing, Cham, 17–36.
Estraneo, A., Loreto, V., Masotta, O., Pascarella, A., Trojano, L., Do medical complications impact long-term outcomes in prolonged disorders of consciousness?. Arch Phys Med Rehabil 99:12 (2018), 2523–2531.
Milosevic, M., Nakanishi, T., Sasaki, A., Yamaguchi, A., Nomura, T., Popovic, M.R., et al. Cortical re-organization after traumatic brain injury elicited using functional electrical stimulation therapy: a case report. Front Neurosci, 2021, 1046.
Chen, R., Cohen, L.G., Hallett, M., Nervous system reorganization following injury. Neuroscience 111:4 (2002), 761–773.
Ramanathan, P., Liu, R., Chen, M.H., Kennedy, M.R.T., Memory and executive functions subserving judgments of learning: cognitive reorganization after traumatic brain injury. Neuropsychol Rehabil 0:0 (2021), 1–24, 10.1080/09602011.2021.1929345.
Batschelett, M., Gibbs, S., Holder, C.M., Holcombe, B., Wheless, J.W., Narayana, S., Plasticity in the developing brain: neurophysiological basis for lesion-induced motor reorganization. Brain Commun 4:1 (2022), 1–15, 10.1093/braincomms/fcab300.
Moreau-Debord, I., Serrano, É., Quessy, S., Dancause, N., Rapid and bihemispheric reorganization of neuronal activity in premotor cortex after brain injury. J Neurosci 41:44 (2021), 9112–9128, 10.1523/JNEUROSCI.0196-21.2021.
Ghasemian-Shirvan, E., Farnad, L., Mosayebi-Samani, M., Verstraelen, S., Meesen, R.L., Kuo, M.F., et al. Age-related differences of motor cortex plasticity in adults: a transcranial direct current stimulation study. Brain Stimul 13:6 (2020), 1588–1599, 10.1016/j.brs.2020.09.004.
Barra, A., Bodien, Y.G., Tan, C.O., Martens, G., Malone, C., Giacino, J.T., Behavioral fluctuation in disorders of consciousness: a retrospective analysis. Arch Phys Med Rehabil, 2025.