Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases1,2. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS)3,4, a condition that is characterized by intermittent evidence of awareness of self or the environment5. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.
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Funding for this study came from the NINDS, Charles A. Dana Foundation, Cleveland Clinic Foundation Brain Neuromodulation Center, Ohio Department of Development BRTT and Third Frontier Program, Jane and Lee Seidman Neuromodulation Research Fund, Cleveland Clinic Innovations, IntElect Medical and the NIDDR. We thank L. Turkstra, E. Montgomery, A. Sharan, D. Vegh and K. Purpura for contributions in planning stages of this work; E. Bagiella for statistical consultation; and C. Allen, D. Pfaff, J. Whyte, M. Gizzi and R. Grewal for expert editorial review.
Author Contributions N.D.S., J.T.G. and A.R.R. contributed equally to the design, implementation and scholarly preparation of this work. N.D.S. and J.T.G. wrote the manuscript. N.D.S., J.T.G. and A.R.R. acted as principal investigators at their performance sites and participated in all phases of the study including evaluation of data and preparation of all parts of the manuscript. A.R.R. and N.D.S. acted as co-principal investigators for the Investigational Device Exemption (Food and Drug Administration, IDE) covering the use of the brain stimulation methods. N.D.S. acted as principal investigator for the initiation of the project and the development grant that formed the basis of the studies. J.T.G. developed, organized and supervised the collection and primary analysis of behavioural data along with K.K. and an independent statistical consultant (E. Bagiella, Columbia University). J.D.V. assisted with the development of the study design, developed the logistic regression models and supervised this data analysis, and assisted in the preparation of manuscript. K.B. analysed the evoked potential response data and prepared the manuscript presentation of the results; K.B. and N.D.S. collected the evoked potential data. M.G., B.F., B.E. and J.O. collected behavioural data and assisted in the development of secondary outcome measures. C.M. served as the patient’s primary care physician and supervised and administered the deep brain electrical stimulation of the patient. Owing to role sequestration, she had no role in data collection or analysis. A.R.R. organized, supervised and carried out the neurosurgical planning, procedures and follow-up, supervised the programming of the neurostimulation and assisted in preparation of the manuscript. J.J.F. developed formal consent procedures and conceptual frameworks with the study primary investigators to address ethical considerations arising in all aspects of the study and preparation of the manuscript. E.J.K., A.M. and K.B. participated in the pre-surgical evaluation, operative and post-operative patient evaluations and neurophysiological evaluations. S.F. provided expert assistance in the design and evaluation of the stimulation protocols. F.P. acted as principal investigator for the planning study for the first year and as a senior advisor throughout the development of the work.
N.D.S. is an inventor at Cornell University of some of the technology used here. N.D.S., A.M. and A.R.R. are paid consultants and advisors to IntElect Medical Inc., to which the technology has been licensed by Cornell University and in which Cleveland Clinic Foundation and Cornell University have an equity interest. IntElect Medical Inc. provided partial support for the clinical studies reported.
This file contains Supplementary Notes, Supplementary Tables S1-S2, Supplementary Figures 1-7 with Legends, Supplementary Methods; Supplementary Discussion and additional references. The Supplementary Figures illustrate behavioral data from post-operative testing, titration and cross-over phases not included in main text. The Supplementary Notes include narrative clinical history and description of all behavioral metrics and detailed description of logistic regression modeling. The Supplementary Methods include supplementary neurosurgical and titration testing methods. DBS evoked potential studies are also discussed. (PDF 768 kb)
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Schiff, N., Giacino, J., Kalmar, K. et al. Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 448, 600–603 (2007). https://doi.org/10.1038/nature06041
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