As the cerebellum has reciprocal communications with the frontal cortex, this retrospective cohort study examined the effects of dual-site repetitive transcranial magnetic stimulation (ds-rTMS: dorsolateral prefrontal cortex [DLPFC] + cerebellum) in disorders of consciousness (DoC).
Setting:
Single-center study in the Department of Rehabilitation of Jinhua Hospital of TCM Affiliated to Zhejiang University of Traditional Chinese Medicine.
Participants:
Twenty-nine patients with DoC.
Intervention:
Systematic review of clinical records comparing ds-TMS (DLPFC + cerebellum) with conventional single-site DLPFC-rTMS.
Main Measures:
Coma Recovery Scale-Revised (CRS-R) scores, mismatch negativity (MMN) latency, P300 latency, Judson grade, and Hall grade.
Results:
ds-TMS was associated with larger gains in consciousness (CRS-R scores) compared with DLPFC-rTMS in a retrospective cohort. Both interventions had comparable improvement in cognitive and somatosensory outcomes (MMN, P300, and Judson/Hall grades). Higher CRS-R scores correlated with shorter MMN latency and better Hall grades.
Conclusions:
ds-TMS treatment may represent an effective therapeutic approach for DoC, with potential effects on consciousness recovery.
Impact Statement
This study developed an effective dual-site transcranial magnetic stimulation treatment for patients with disorders of consciousness by targeting the dorsolateral prefrontal cortex and the cerebellum.
AdamaszekM, D’AgataF, FerrucciR, et al.Consensus paper: Cerebellum and emotion. Cerebellum, 2017; 16(2):552–576.
2.
AgrestiA. 2003. Categorical data analysis. John Wiley & Sons: New York.
3.
AttalN, Poindessous-JazatF, De ChauvignyE, et al.Repetitive transcranial magnetic stimulation for neuropathic pain: A randomized multicentre sham-controlled trial. Brain, 2021; 144(11):3328–3339.
4.
BaumannO, BorraRJ, BowerJM, et al.Consensus paper: The role of the cerebellum in perceptual processes. Cerebellum, 2015; 14(2):197–220.
5.
BlumbergerDM, Vila-RodriguezF, ThorpeKE, et al.Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): A randomised non-inferiority trial. Lancet, 2018; 391(10131):1683–1692.
6.
CasaliAG, CasarottoS, RosanovaM, et al.General indices to characterize the electrical response of the cerebral cortex to TMS. Neuroimage, 2010; 49(2):1459–1468.
7.
CheX, CashR, ChungSW, et al.The dorsomedial prefrontal cortex as a flexible hub mediating behavioral as well as local and distributed neural effects of social support context on pain: A Theta Burst Stimulation and TMS-EEG study. Neuroimage, 2019; 201:116053.
8.
ChenJM, ChenQF, WangZY, et al.Influence of high-frequency repetitive transcranial magnetic stimulation on neurobehavioral and electrophysiology in patients with disorders of consciousness. Neural Plast, 2022; 2022:7195699.
9.
ChenL, ThomasEH, KaewpijitP, et al.Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial. Brain Stimul, 2021; 14(5):1095–1105.
10.
ChungSW, HillAT, RogaschNC, et al.Use of theta-burst stimulation in changing excitability of motor cortex: A systematic review and meta-analysis. Neurosci Biobehav Rev, 2016; 63:43–64.
11.
ColeE, PhillipsA, BentzleyB, et al.A Double-Blind, Randomized, Sham-Controlled Trial of Accelerated Intermittent Theta-Burst (aiTBS) for Treatment-Resistant Depression. Biol Psychiatry, 2021; 89(9):S90.
12.
ColeEJ, StimpsonKH, BentzleyBS, et al.Stanford accelerated intelligent neuromodulation therapy for treatment-resistant depression. Am J Psychiatry, 2020; 177(8):716–726.
13.
CuiH, DingH, HuL, et al.A novel dual-site OFC-dlPFC accelerated repetitive transcranial magnetic stimulation for depression: A pilot randomized controlled study. Psychol Med, 2024; 54(14):1–14.
14.
DehaeneS, ChangeuxJP, NaccacheL, et al.Conscious, preconscious, and subliminal processing: A testable taxonomy. Trends Cogn Sci, 2006; 10(5):204–211.
15.
EapenB, GeorgekuttyJ, SubbaraoB, et al.Disorders of consciousness. Phys Med Rehabil Clin N Am, 2017; 28(2):245–258.
16.
EggermontJJ. Development of auditory evoked potentials. Acta Otolaryngol, 1992; 112(2):197–200.
17.
FanJ, ZhongY, WangH, et al.Repetitive transcranial magnetic stimulation improves consciousness in some patients with disorders of consciousness. Clin Rehabil, 2022; 36(7):916–925.
18.
FengY, ZhangJ, ZhouY, et al.Noninvasive brain stimulation for patients with a disorder of consciousness: A systematic review and meta-analysis. Rev Neurosci, 2020; 31(8):905–914.
19.
FernandezL, BiabaniM, DoM, et al.Assessing cerebellar-cortical connectivity using concurrent TMS-EEG: A feasibility study. J Neurophysiol, 2021; 125(5):1768–1787.
20.
FinsJJ. Disorders of consciousness, past, present, and future. Camb Q Healthc Ethics, 2019; 28(4):603–615.
21.
FirstMB, ReedGM, HymanSE, et al.The development of the ICD-11 clinical descriptions and diagnostic guidelines for mental and behavioural disorders. World Psychiatry, 2015; 14(1):82–90.
22.
GaleaJM, JayaramG, AjagbeL, et al.Modulation of cerebellar excitability by polarity-specific noninvasive direct current stimulation. J Neurosci, 2009; 29(28):9115–9122.
23.
GassmannL, GordonPC, ZiemannU. Assessing effective connectivity of the cerebellum with cerebral cortex using TMS-EEG. Brain Stimul, 2022; 15(6):1354–1369.
24.
GiacinoJT, KalmarK, WhyteJ. The JFK Coma Recovery Scale-Revised: Measurement characteristics and diagnostic utility. Arch Phys Med Rehabil, 2004; 85(12):2020–2029.
25.
GiacinoJT, WhyteJ, BagiellaE, et al.Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med, 2012; 366(9):819–826.
26.
GuldenmundP, SodduA, BaqueroK, et al.Structural brain injury in patients with disorders of consciousness: A voxel-based morphometry study. Brain Inj, 2016; 30(3):343–352.
27.
HallettM. Transcranial magnetic stimulation: A primer. Neuron, 2007; 55(2):187–199.
28.
HeF, WuM, MengF, et al.Effects of 20 Hz repetitive transcranial magnetic stimulation on disorders of consciousness: A resting-state electroencephalography study. Neural Plast, 2018; 2018:5036184.
29.
HeR, FanJ, WangH, et al.Differentiating responders and non-responders to rTMS treatment for disorder of consciousness using EEG after-effects. Front Neurol, 2020; 11:583268.
30.
HuangYZ, EdwardsMJ, RounisE, et al.Theta burst stimulation of the human motor cortex. Neuron, 2005; 45(2):201–206.
31.
HuangZ, WangY, YanY, et al.Identifying neural circuitry abnormalities in neuropathic pain with transcranial magnetic stimulation and electroencephalogram co-registration. Neurotherapeutics, 2025; 22(2):e00496.
32.
JudsonJA, CantBR, ShawNA. Early prediction of outcome from cerebral trauma by somatosensory evoked potentials. Crit Care Med, 1990; 18(4):363–368.
33.
KondziellaD, BenderA, DiserensK, 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(5):741–756.
34.
LaureysS, CelesiaGG, CohadonF, et al.; European Task Force on Disorders of Consciousness. Unresponsive wakefulness syndrome: A new name for the vegetative state or apallic syndrome. BMC Med, 2010; 8:68.
35.
LemaireJJ, PontierB, ChaixR, et al.Neural correlates of consciousness and related disorders: From phenotypic descriptors of behavioral and relative consciousness to cortico-subcortical circuitry. Neurochirurgie, 2022; 68(2):212–222.
36.
LiuJ, ShuY, WuG, et al.A neuroimaging study of brain activity alterations in treatment-resistant depression after a dual target accelerated transcranial magnetic stimulation. Front Psychiatry, 2024a;14:1321660.
37.
LiuY, SunJ, WuC, et al.Characterizing the opioidergic mechanisms of repetitive transcranial magnetic stimulation-induced analgesia: A randomized controlled trial. Pain, 2024b;165(9):2035–2043.
38.
LuoX, CheX, LiH. Concurrent TMS-EEG and EEG reveal neuroplastic and oscillatory changes associated with self-compassion and negative emotions. Int J Clin Health Psychol, 2023; 23(1):100343.
39.
LvY, WangM, YangJ, et al.Cerebellar repetitive transcranial magnetic stimulation versus propranolol for essential tremor. Brain Behav, 2023; 13(3):e2926.
40.
MantoM, BowerJM, ConfortoAB, et al.Consensus paper: Roles of the cerebellum in motor control—the diversity of ideas on cerebellar involvement in movement. Cerebellum, 2012; 11(2):457–487.
41.
MariënP, AckermannH, AdamaszekM, et al.Consensus paper: Language and the cerebellum: An ongoing enigma. Cerebellum, 2014; 13(3):386–410.
42.
NäätänenR, KujalaT, EsceraC, et al.The mismatch negativity (MMN)—a unique window to disturbed central auditory processing in ageing and different clinical conditions. Clin Neurophysiol, 2012; 123(3):424–458.
43.
NäätänenR, KujalaT, WinklerI. Auditory processing that leads to conscious perception: A unique window to central auditory processing opened by the mismatch negativity and related responses. Psychophysiology, 2011; 48(1):4–22.
44.
NaroA, RussoM, LeoA, et al.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(7):603–613.
45.
QiuY-T, ChenY, TanH-X, et al.Efficacy and safety of repetitive transcranial magnetic stimulation in cerebellar ataxia: A systematic review and meta-analysis. Cerebellum, 2024; 23(1):243–254.
46.
RogaschNC, ThomsonRH, FarzanF, et al.Removing artefacts from TMS-EEG recordings using independent component analysis: Importance for assessing prefrontal and motor cortex network properties. Neuroimage, 2014; 101:425–439.
47.
RohautB, RaimondoF, GalanaudD, et al.Probing consciousness in a sensory-disconnected paralyzed patient. Brain Inj, 2017; 31(10):1398–1403.
48.
SchnakersC, PerrinF, SchabusM, et al.Voluntary brain processing in disorders of consciousness. Neurology, 2008; 71(20):1614–1620.
49.
SchnakersC. Update on diagnosis in disorders of consciousness. Expert Rev Neurother, 2020; 20(10):997–1004.
50.
ShenL, HuangY, LiaoY, et al.Effect of high-frequency repetitive transcranial magnetic stimulation over M1 for consciousness recovery after traumatic brain injury. Brain Behav, 2023; 13(5):e2971.
51.
StoodleyCJ, SchmahmannJD. Evidence for topographic organization in the cerebellum of motor control versus cognitive and affective processing. Cortex, 2010; 46(7):831–844.
52.
TanX, ZhouZ, GaoJ, et al.White matter connectometry in patients with disorders of consciousness revealed by 7-Tesla magnetic resonance imaging. Brain Imaging Behav, 2022; 16(5):1983–1991.
53.
The Multi-Society Task Force on PVS. Medical aspects of the persistent vegetative state. N Engl J Med, 1994; 330(21):1499–1508.
54.
ThibautA, SchiffN, GiacinoJ, et al.Therapeutic interventions in patients with prolonged disorders of consciousness. Lancet Neurol, 2019; 18(6):600–614.
55.
Van MalderenS, HehlM, VerstraelenS, et al.Dual-site TMS as a tool to probe effective interactions within the motor network: A review. Rev Neurosci, 2023; 34(2):129–221.
56.
WangH, HuY, DengJ, et al.A Randomised Sham-controlled Study Evaluating rTMS Analgesic Efficacy for Postherpetic Neuralgia. Front Neurosci, 2023; 17:1158737.
57.
WangY, TanB, ShiS, et al.Dopamine D2 receptor antagonist modulates rTMS-induced pain experiences and corticospinal excitability dependent on stimulation targets. Int J Clin Health Psychol, 2024; 24(1):100413.
58.
XiaX, BaiY, ZhouY, et al.Effects of 10 Hz repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in disorders of consciousness. Front Neurol, 2017; 8:182.
59.
XiaX, WangY, LiC, et al.Transcranial magnetic stimulation-evoked connectivity reveals modulation effects of repetitive transcranial magnetic stimulation on patients with disorders of consciousness. Neuroreport, 2019; 30(18):1307–1315.
60.
XiongQ, LeK, TangY, et al.Effect of single and combined median nerve stimulation and repetitive transcranial magnetic stimulation in patients with prolonged disorders of consciousness: A prospective, randomized, single-blinded, controlled trial. Front Aging Neurosci, 2023; 15:1112768.
61.
XuB, LinC, WangY, et al.Using dual-target rTMS, single-target rTMS, or sham rTMS on post-stroke cognitive impairment. J Integr Neurosci, 2024; 23(8):161.
62.
XuC, YuanZ, ChenZ, et al.Perturbational complexity index in assessing responsiveness to rTMS treatment in patients with disorders of consciousness: A cross-over randomized controlled trial study. J Neuroeng Rehabil, 2024; 21(1):167.
63.
YeY, WangJ, CheX. Concurrent TMS-EEG to Reveal the Neuroplastic Changes in the Prefrontal and Insular Cortices in the Analgesic Effects of DLPFC-rTMS. Cereb Cortex, 2022; 32(20):4436–4446.
64.
ZhanW, WangL, GaoF, et al.Exploring cerebellar transcranial magnetic stimulation in post-stroke limb dysfunction rehabilitation: a narrative review. Front Neurosci, 2025; 19:1405637.
65.
ZhaoH, JiangC, ZhaoM, et al.Comparisons of accelerated continuous and intermittent theta burst stimulation for treatment-resistant depression and suicidal Ideation. Biol Psychiatry, 2024; 96(1):26–33.
66.
ZiemannU, RothwellJC, RiddingMC. Interaction between intracortical inhibition and facilitation in human motor cortex. J Physiol, 1996; 496(Pt 3):873–881.
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