Semin Neurol 2022; 42(03): 348-362
DOI: 10.1055/s-0042-1755562
Review Article

Noninvasive Brain Stimulation Therapies to Promote Recovery of Consciousness: Where We Are and Where We Should Go

1   Coma Science Group, GIGA Consciousness - GIGA Research, University of Liège, Liège, Belgium
2   Centre du Cerveau, University Hospital of Liège, Liège, Belgium
Martin Monti
3   Department of Psychology, University of California Los Angeles, Los Angeles, California
4   Department of Neurosurgery, UCLA Brain Injury Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
Aurore Thibaut
1   Coma Science Group, GIGA Consciousness - GIGA Research, University of Liège, Liège, Belgium
2   Centre du Cerveau, University Hospital of Liège, Liège, Belgium
› Author Affiliations


Therapeutic options for patients with disorders of consciousness (DoC) are still underexplored. Noninvasive brain stimulation (NIBS) techniques modulate neural activity of targeted brain areas and hold promise for the treatment of patients with DoC. In this review, we provide a summary of published research using NIBS as therapeutic intervention for DoC patients, with a focus on (but not limited to) randomized controlled trials (RCT). We aim to identify current challenges and knowledge gaps specific to NIBS research in DoC. Furthermore, we propose possible solutions and perspectives for this field. Thus far, the most studied technique remains transcranial electrical stimulation; however, its effect remains moderate. The identified key points that NIBS researchers should focus on in future studies are (1) the lack of large-scale RCTs; (2) the importance of identifying the endotypes of responders; and (3) the optimization of stimulation parameters to maximize the benefits of NIBS.

Publication History

Article published online:
13 September 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

  • References

  • 1 Giacino JT, Katz DI, Schiff ND. et al. Practice Guideline Update Recommendations Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Arch Phys Med Rehabil 2018; 99 (09) 1699-1709
  • 2 Giacino JT, Ashwal S, Childs N. et al. The minimally conscious state: definition and diagnostic criteria. Neurology 2002; 58 (03) 349-353
  • 3 Taylor CM, Aird VH, Tate RL, Lammi MH. Sequence of recovery during the course of emergence from the minimally conscious state. Arch Phys Med Rehabil 2007; 88 (04) 521-525
  • 4 Wannez S, Heine L, Thonnard M, Gosseries O, Laureys S. Coma Science Group Collaborators. The repetition of behavioral assessments in diagnosis of disorders of consciousness. Ann Neurol 2017; 81 (06) 883-889
  • 5 Giacino JT, Kalmar K, Whyte J. The JFK Coma Recovery Scale-Revised: measurement characteristics and diagnostic utility. Arch Phys Med Rehabil 2004; 85 (12) 2020-2029
  • 6 Kondziella D, Bender A, Diserens K. et al; EAN Panel on Coma, Disorders of Consciousness. European Academy of Neurology guideline on the diagnosis of coma and other disorders of consciousness. Eur J Neurol 2020; 27 (05) 741-756
  • 7 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 2014; 20 (26) 4167-4184
  • 8 Barra ME, Edlow BL, Brophy G. Pharmacologic therapies to promote recovery of consciousness. Semin Neurol 2022; accepted
  • 9 Thibaut A, Schiff N, Giacino J, Laureys S, Gosseries O. Therapeutic interventions in patients with prolonged disorders of consciousness. Lancet Neurol 2019; 18 (06) 600-614
  • 10 Schnakers C, Monti MM. Disorders of consciousness after severe brain injury: therapeutic options. Curr Opin Neurol 2017; 30 (06) 573-579
  • 11 Knotkova H, Rasche D. Textbook of Neuromodulation: Principles, Methods and Clinical Applications. New York: Springer Science; 2015
  • 12 Angelakis E, Liouta E, Andreadis N. et al. Transcranial direct current stimulation effects in disorders of consciousness. Arch Phys Med Rehabil 2014; 95 (02) 283-289
  • 13 Bai Y, Xia X, Wang Y. et al. Fronto-parietal coherence response to tDCS modulation in patients with disorders of consciousness. Int J Neurosci 2018; 128 (07) 587-594
  • 14 Bai Y, Xia X, Kang J, Yang Y, He J, Li X. TDCS modulates cortical excitability in patients with disorders of consciousness. Neuroimage Clin 2017; 15: 702-709
  • 15 Cavinato M, Genna C, Formaggio E. et al. Behavioural and electrophysiological effects of tDCS to prefrontal cortex in patients with disorders of consciousness. Clin Neurophysiol 2019; 130 (02) 231-238
  • 16 Estraneo A, Pascarella A, Moretta P. et al. Repeated transcranial direct current stimulation in prolonged disorders of consciousness: a double-blind cross-over study. J Neurol Sci 2017; 375: 464-470
  • 17 Huang W, Wannez S, Fregni F. et al. Repeated stimulation of the posterior parietal cortex in patients in minimally conscious state: a sham-controlled randomized clinical trial. Brain Stimul 2017; 10 (03) 718-720
  • 18 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 2017; 11 (November): 524
  • 19 Martens G, Lejeune N, O'Brien AT. et al. Randomized controlled trial of home-based 4-week tDCS in chronic minimally conscious state. Brain Stimul 2018; 11 (05) 982-990
  • 20 Naro A, Russo M, Leo A. et al. Cortical connectivity modulation induced by cerebellar oscillatory transcranial direct current stimulation in patients with chronic disorders of consciousness: a marker of covert cognition?. Clin Neurophysiol 2016; 127 (03) 1845-1854
  • 21 Thibaut A, Wannez S, Donneau AF. et al. Controlled clinical trial of repeated prefrontal tDCS in patients with chronic minimally conscious state. Brain Inj 2017; 31 (04) 466-474
  • 22 Zhang Y, Song W, Du J, Huo S, Shan G, Li R. Transcranial direct current stimulation in patients with prolonged disorders of consciousness: combined behavioral and event-related potential evidence. Front Neurol 2017; 8 (Nov): 620
  • 23 Cincotta M, Giovannelli F, Chiaramonti R. et al. No effects of 20 Hz-rTMS of the primary motor cortex in vegetative state: a randomised, sham-controlled study. Cortex 2015; 71: 368-376
  • 24 He F, Wu M, Meng F. et al. Effects of 20 Hz repetitive transcranial magnetic stimulation on disorders of consciousness: a resting-state electroencephalography study. Neural Plast 2018; 2018: 5036184
  • 25 Liu P, Gao J, Pan S. et al. Effects of high-frequency repetitive transcranial magnetic stimulation on cerebral hemodynamics in patients with disorders of consciousness: a sham-controlled study. Eur Neurol 2016; 76 (1-2): 1-7
  • 26 Liu X, Meng F, Gao J. et al. Behavioral and resting state functional connectivity effects of high frequency rTMS on disorders of consciousness: a sham-controlled study. Front Neurol 2018; 9 (Nov): 982
  • 27 Wilson JTL, Pettigrew LELL, Teasdale GM. Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J Neurotrauma 1998; 15 (08) 573-585
  • 28 Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry (Edgmont) 2007; 4 (07) 28-37
  • 29 Gelijns AC. Institute of Medicine (US) Committee on Technological Innovation in Medicine. Modern Methods of Clinical Investigation: Medical Innovation at the Crossroads. Washington, DC: National Academies Press; 1990
  • 30 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 2020; 31 (08) 905-914
  • 31 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 2019; 33 (13-14): 1679-1683
  • 32 Martens G, Kroupi E, Bodien Y. et al. Behavioral and electrophysiological effects of network-based frontoparietal tDCS in patients with severe brain injury: a randomized controlled trial. Neuroimage Clin 2020; 28: 102426
  • 33 Carrière M, Mortaheb S, Raimondo F. 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 2020; 10 (07) 1-17
  • 34 Xia X, Liu Y, Bai Y. et al. Long-lasting repetitive transcranial magnetic stimulation modulates electroencephalography oscillation in patients with disorders of consciousness. Neuroreport 2017; 28 (15) 1022-1029
  • 35 Rana KD, Vaina LM. Functional roles of 10 Hz alpha-band power modulating engagement and disengagement of cortical networks in a complex visual motion task. PLoS One 2014; 9 (10) e107715
  • 36 Romei V, Gross J, Thut G. On the role of prestimulus alpha rhythms over occipito-parietal areas in visual input regulation: correlation or causation?. J Neurosci 2010; 30 (25) 8692-8697
  • 37 Kropotov JD. Frontal midline theta rhythm. Quant EEG, event-related potentials. Neurother 2009; 77-95 DOI: 10.1016/b978-0-12-374512-5.00004-9.
  • 38 Marcuse LV, Fields MC, Yoo J. The Normal Adult EEG. Rowan's Prim EEG. 2016: 39-66 DOI: 10.1016/b978-0-323-35387-8.00002-0
  • 39 Sarasso S, Rosanova M, Casali AG. et al. Quantifying cortical EEG responses to TMS in (un)consciousness. Clin EEG Neurosci 2014; 45 (01) 40-49
  • 40 Bodart O, Gosseries O, Wannez S. et al. Measures of metabolism and complexity in the brain of patients with disorders of consciousness. Neuroimage Clin 2017; 14: 354-362
  • 41 Casarotto S, Comanducci A, Rosanova M. et al. Stratification of unresponsive patients by an independently validated index of brain complexity. Ann Neurol 2016; 80 (05) 718-729
  • 42 Dell'osso B, Camuri G, Castellano F. et al. Meta-review of meta-analytic studies with repetitive transcranial magnetic stimulation (rTMS) for the treatment of major depression. Clin Pract Epidemiol Ment Health 2011; 7 (01) 167-177
  • 43 Fitzgerald PB, Daskalakis ZJ. A review of repetitive transcranial magnetic stimulation use in the treatment of schizophrenia. Can J Psychiatry 2008; 53 (09) 567-576
  • 44 Durmaz O, Ateş MA, Şenol MG. Repetitive transcranial magnetic stimulation (rTMS)-induced trigeminal autonomic cephalalgia. Noro Psikiyatri Arsivi 2015; 52 (03) 309-311
  • 45 He RH, Wang HJ, Zhou Z, Fan JZ, Zhang SQ, Zhong YH. The influence of high-frequency repetitive transcranial magnetic stimulation on endogenous estrogen in patients with disorders of consciousness. Brain Stimul 2021; 14 (03) 461-466
  • 46 Zhang XH, Han P, Zeng YY, Wang YL, Lv HL. The clinical effect of repetitive transcranial magnetic stimulation on the disturbance of consciousness in patients in a vegetative state. Front Neurosci 2021; 15 (April): 647517
  • 47 Naro A, Leo A, Bramanti P, Calabrò RS. Moving toward conscious pain processing detection in chronic disorders of consciousness: anterior cingulate cortex neuromodulation. J Pain 2015; 16 (10) 1022-1031
  • 48 Xie Y, Zhang T. Repetitive transcranial magnetic stimulation improves consciousness disturbance in stroke patients: a quantitative electroencephalography spectral power analysis. Neural Regen Res 2012; 7 (31) 2465-2472
  • 49 Xia X, Bai Y, Zhou Y. et al. Effects of 10 Hz repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in disorders of consciousness. Front Neurol 2017; 8 (May): 182
  • 50 Naro A, Russo M, Leo A, Bramanti P, Quartarone A, Calabrò RS. A single session of repetitive transcranial magnetic stimulation over the dorsolateral prefrontal cortex in patients with unresponsive wakefulness syndrome: preliminary results. Neurorehabil Neural Repair 2015; 29 (07) 603-613
  • 51 Johnson RL, Wilson CG. A review of vagus nerve stimulation as a therapeutic intervention. J Inflamm Res 2018; 11: 203-213
  • 52 Nemeroff CB, Mayberg HS, Krahl SE. et al. VNS therapy in treatment-resistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology 2006; 31 (07) 1345-1355
  • 53 Ellrich J. Transcutaneous auricular vagus nerve stimulation. J Clin Neurophysiol 2019; 36 (06) 437-442
  • 54 Rong PJ, Fang JL, Wang LP. et al. Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial. BMC Complement Altern Med 2012; 12 (01) 255
  • 55 Busch V, Zeman F, Heckel A, Menne F, Ellrich J, Eichhammer P. The effect of transcutaneous vagus nerve stimulation on pain perception–an experimental study. Brain Stimul 2013; 6 (02) 202-209
  • 56 Schulz-Stübner S, Kehl F. Treatment of persistent hiccups with transcutaneous phrenic and vagal nerve stimulation. Intensive Care Med 2011; 37 (06) 1048-1049
  • 57 Silberstein SD, Calhoun AH, Lipton RB. et al. Chronic migraine headache prevention with noninvasive vagus nerve stimulation: The EVENT study. Neurology 2016; 87 (05) 529-538
  • 58 Hakon J, Moghiseh M, Poulsen I, Øland CML, Hansen CP, Sabers A. Transcutaneous vagus nerve stimulation in patients with severe traumatic brain injury: a feasibility trial. Neuromodulation 2020; 23 (06) 859-864
  • 59 Noé E, Ferri J, Colomer C. et al. Feasibility, safety and efficacy of transauricular vagus nerve stimulation in a cohort of patients with disorders of consciousness. Brain Stimul 2020; 13 (02) 427-429
  • 60 Yu YT, Yang Y, Wang LB. et al. Transcutaneous auricular vagus nerve stimulation in disorders of consciousness monitored by fMRI: the first case report. Brain Stimul 2017; 10 (02) 328-330
  • 61 Cain JA, Visagan S, Johnson MA. et al. Real time and delayed effects of subcortical low intensity focused ultrasound. Sci Rep 2021; 11 (01) 6100
  • 62 ter Haar G. Therapeutic applications of ultrasound. Prog Biophys Mol Biol 2007; 93 (1-3): 111-129
  • 63 Pasquinelli C, Hanson LG, Siebner HR, Lee HJ, Thielscher A. Safety of transcranial focused ultrasound stimulation: a systematic review of the state of knowledge from both human and animal studies. Brain Stimul 2019; 12 (06) 1367-1380
  • 64 Fomenko A, Neudorfer C, Dallapiazza RF, Kalia SK, Lozano AM. Low-intensity ultrasound neuromodulation: an overview of mechanisms and emerging human applications. Brain Stimul 2018; 11 (06) 1209-1217
  • 65 Yagita Y, Etani H, Handa N. et al. Effect of transcranial Doppler intensity on successful recording in Japanese patients. Ultrasound Med Biol 1996; 22 (06) 701-705
  • 66 Tyler WJ, Tufail Y, Finsterwald M, Tauchmann ML, Olson EJ, Majestic C. Remote excitation of neuronal circuits using low-intensity, low-frequency ultrasound. PLoS One 2008; 3 (10) e3511
  • 67 Yoo SS, Kim H, Min BK, Franck E, Park S. Seung-Schik Yooa. Transcranial focused ultrasound to the thalamus alters anesthesia time in rats. Neuroreport 2011; 22 (15) 783-787
  • 68 Monti MM, Schnakers C, Korb AS, Bystritsky A, Vespa PM. Non-invasive ultrasonic thalamic stimulation in disorders of consciousness after severe brain injury: a first-in-man report. Brain Stimul 2016; 9 (06) 940-941
  • 69 Schiff ND. Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends Neurosci 2010; 33 (01) 1-9
  • 70 Cain JA, Spivak NM, Coetzee JP. et al. Ultrasonic thalamic stimulation in chronic disorders of consciousness. Brain Stimul 2021; 14 (02) 301-303
  • 71 Werner C, Byhahn M, Hesse S. Non-invasive brain stimulation to promote alertness and awareness in chronic patients with disorders of consciousness: low-level, near-infrared laser stimulation vs. focused shock wave therapy. Restor Neurol Neurosci 2016; 34 (04) 561-569
  • 72 Hesse S, Schattat N, Werner C. Transkortikale nah-infrarot-lasertherapie des wachkomapatienten nach schwerem schädelhirntrauma zur förderung der wachheit und des bewusstseins: Fallberichte. Neurol und Rehabil 2014; 20 (01) 39-43
  • 73 Lohse-Busch H, Reime U, Falland R. Transkranielle fokussierte extrakorporale Stoßwellen (TESW) verbessern die Vigilanz von Patienten im Wachkoma - Eine Fallstudie. Phys Medizin Rehabil Kurortmedizin 2013; 23 (03) 171-179
  • 74 Edlow BL, Sanz LRD, Polizzotto L. et al; Curing Coma Campaign and Its Contributing Members. Therapies to restore consciousness in patients with severe brain injuries: a gap analysis and future directions. Neurocrit Care 2021; 35 (Suppl. 01) 68-85
  • 75 Thibaut A, Di Perri C, Chatelle C. et al. Clinical response to tDCS depends on residual brain metabolism and grey matter integrity in patients with minimally conscious state. Brain Stimul 2015; 8 (06) 1116-1123
  • 76 Thibaut A, Chennu S, Chatelle C. et al. Theta network centrality correlates with tDCS response in disorders of consciousness. Brain Stimul 2018; 11 (06) 1407-1409
  • 77 Mensen A, Bodart O, Thibaut A. et al. Decreased evoked slow-activity after tDCS in disorders of consciousness. Front Syst Neurosci 2020; 14: 62
  • 78 Edlow BL, Barra ME, Zhou DW. et al. Personalized connectome mapping to guide targeted therapy and promote recovery of consciousness in the intensive care unit. Neurocrit Care 2020; 33 (02) 364-375
  • 79 Nguyen DT, Berisha DE, Konofagou EE, Dmochowski JP. Neuronal responses to focused ultrasound are gated by pre-stimulation brain rhythms. Brain Stimul 2022; 15 (01) 233-243
  • 80 Lutkenhoff ES, Nigri A, Rossi Sebastiano D. et al. EEG power spectra and subcortical pathology in chronic disorders of consciousness. Psychol Med 2022; 52 (08) 1491-1500
  • 81 Goldman-Rakic PS. Architecture of the prefrontal cortex and the central executive. Ann N Y Acad Sci 1995; 769 (01) 71-83
  • 82 Li J, Curley WH, Guerin B. et al. Mapping the subcortical connectivity of the human default mode network. Neuroimage 2021; 245 (July): 118758
  • 83 Fridman EA, Beattie BJ, Broft A, Laureys S, Schiff ND. Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain. Proc Natl Acad Sci U S A 2014; 111 (17) 6473-6478
  • 84 Mencarelli L, Biagi MC, Salvador R. et al. Network mapping of connectivity alterations in disorder of consciousness: towards targeted neuromodulation. J Clin Med 2020; 9 (03) 1-29
  • 85 Martens G, Ibáñez-Soria D, Barra A. et al. A novel closed-loop EEG-tDCS approach to promote responsiveness of patients in minimally conscious state: a study protocol. Behav Brain Res 2021; 409 (21) 113311
  • 86 Thibaut A, Panda R, Annen J. et al. Preservation of brain activity in unresponsive patients identifies MCS star. Ann Neurol 2021; 90 (01) 89-100
  • 87 Thibaut A, Chatelle C, Vanhaudenhuyse A. et al. Transcranial direct current stimulation unveils covert consciousness. Brain Stimul 2018; 11 (03) 642-644
  • 88 Brunoni AR, Ferrucci R, Bortolomasi M. et al. Interactions between transcranial direct current stimulation (tDCS) and pharmacological interventions in the major depressive episode: findings from a naturalistic study. Eur Psychiatry 2013; 28 (06) 356-361
  • 89 Ilić NV, Dubljanin-Raspopović E, Nedeljković U. et al. Effects of anodal tDCS and occupational therapy on fine motor skill deficits in patients with chronic stroke. Restor Neurol Neurosci 2016; 34 (06) 935-945
  • 90 Nair DG, Renga V, Lindenberg R, Zhu L, Schlaug G. Optimizing recovery potential through simultaneous occupational therapy and non-invasive brain-stimulation using tDCS. Restor Neurol Neurosci 2011; 29 (06) 411-420
  • 91 Tsagaris KZ, Labar DR, Edwards DJ. A framework for combining rTMS with behavioral therapy. Front Syst Neurosci 2016; 10 (Nov): 82
  • 92 Vedeniapin A, Cheng L, George MS. Feasibility of simultaneous cognitive behavioral therapy and left prefrontal rTMS for treatment resistant depression. Brain Stimul 2010; 3 (04) 207-210
  • 93 Miniussi C, Bonato C, Bignotti S. et al. Repetitive transcranial magnetic stimulation (rTMS) at high and low frequency: an efficacious therapy for major drug-resistant depression?. Clin Neurophysiol 2005; 116 (05) 1062-1071
  • 94 Cantello R, Rossi S, Varrasi C. et al. Slow repetitive TMS for drug-resistant epilepsy: clinical and EEG findings of a placebo-controlled trial. Epilepsia 2007; 48 (02) 366-374
  • 95 Brunoni AR, Sampaio-Junior B, Moffa AH. et al. The Escitalopram versus Electric Current Therapy for Treating Depression Clinical Study (ELECT-TDCS): rationale and study design of a non-inferiority, triple-arm, placebo-controlled clinical trial.. Sao Paulo Med J 2015; 133 (03) 252-263
  • 96 Schnakers C. The Use of LIFUP in Chronic Disorders of Consciousness. Accessed July 10, 2022 at:
  • 97 Monti MM. Thalamic Low Intensity Focused Ultrasound in Brain Injury (LIFUP). Accessed July 10, 2022 at:
  • 98 Oh B-M. Low-intensity focused ultrasound on individuals with disorder of consciousness of traumatic brain injury. Accessed July 10, 2022 at:
  • 99 Kuo MF, Nitsche MA. Effects of transcranial electrical stimulation on cognition. Clin EEG Neurosci 2012; 43 (03) 192-199
  • 100 Kobayashi M, Pascual-Leone A. Basic principles of magnetic stimulation. Lancet 2003; 2: 145-156
  • 101 di Biase L, Falato E, Di Lazzaro V. Transcranial focused ultrasound (tFUS) and transcranial unfocused ultrasound (tUS) neuromodulation: from theoretical principles to stimulation practices. Front Neurol 2019; 10 (Jun): 549
  • 102 Wu M, Yu Y, Luo L. et al. Efficiency of repetitive transcranial direct current stimulation of the dorsolateral prefrontal cortex in disorders of consciousness: a randomized sham-controlled study. Neural plasticity 2019