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Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study

Nature Medicine volume 29, pages 3162–3174 (2023)Cite this article

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Abstract

Converging evidence indicates that impairments in executive function and information-processing speed limit quality of life and social reentry after moderate-to-severe traumatic brain injury (msTBI). These deficits reflect dysfunction of frontostriatal networks for which the central lateral (CL) nucleus of the thalamus is a critical node. The primary objective of this feasibility study was to test the safety and efficacy of deep brain stimulation within the CL and the associated medial dorsal tegmental (CL/DTTm) tract.

Six participants with msTBI, who were between 3 and 18 years post-injury, underwent surgery with electrode placement guided by imaging and subject-specific biophysical modeling to predict activation of the CL/DTTm tract. The primary efficacy measure was improvement in executive control indexed by processing speed on part B of the trail-making test.

All six participants were safely implanted. Five participants completed the study and one was withdrawn for protocol non-compliance. Processing speed on part B of the trail-making test improved 15% to 52% from baseline, exceeding the 10% benchmark for improvement in all five cases.

CL/DTTm deep brain stimulation can be safely applied and may improve executive control in patients with msTBI who are in the chronic phase of recovery.

ClinicalTrials.gov identifier: NCT02881151.

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Fig. 1: CONSORT diagram.
Fig. 2: Behavioral results.
Fig. 3: Activation of CL/DTTm fibers in a representative participant and group summary.
Fig. 4: Placement and visualization of DBS contacts in common template space.
Fig. 5: Cortical evoked responses for each individual from the left and the right hemisphere.

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Data availability

A minimum dataset extracted from the REDCAP database has been made available on Dryadat https://doi.org/10.5061/dryad.41ns1rnmb

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Acknowledgements

Surgical implants (including leads and implantable neurostimulators) were provided by Medtronic. This work was supported by the National Institutes of Health BRAIN Initiative NINDS grant UH3 NS095554 (to N.D.S., J.T.G., C R.B., E.Y.C., J.L.B., K.P.O., A.P.J., M.B., L.D., A.F., L.M.G., J.M., M.R., S.A.S., J.S., A.W., S.A.K.-H, J.J.F., A.G.M., B.K.R. and J.M.H.). J.C. and L.M.G. were partially supported by the following grant: Clinical and Translational Science Center at Weill Cornell Medical College (1-UL1-TR002384-01). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the following personnel who supported this study: S. Taylor (Harvard/Spaulding); J. Lee (Weill Cornell); T. Prieto, H. Fortune, P. Rezaii, O. Rutledge, A. Bet, H.-B. Yeh, G. Qin, H. Fortune, T. Hornbeck, E. Lim (Stanford); S. Stanslaski, C. Zarns, N. Hopps, P. Stypulkowski (Medtronic); I. Korytov (Utah/Florida); D. Heyer (PatientWing); Biologics Consulting Group. We are grateful to S. Hwang for providing the artwork for Supplementary Fig. 1; L. Alkhoury for assistance with Extended Data Fig. 2; G. Iverson and C. Gaudet for discussion of practice effects in neuropsychological testing; and J. Whyte for comments on the manuscript.

Author information

Authors and Affiliations

  1. Feil Family Brain Mind Institute, Weill Cornell Medicine, New York, NY, USA

    Nicholas D. Schiff, Jonathan L. Baker, Laurel DeGeorge & Jonathan D. Victor

  2. Department of Neurology, Weill Cornell Medicine, New York, NY, USA

    Nicholas D. Schiff & Jonathan D. Victor

  3. Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Boston, MA, USA

    Joseph T. Giacino, Michael Bergin & Abigail Waters

  4. Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA, USA

    Joseph T. Giacino

  5. Scientific Computing and Imaging Institute Department of Bioengineering, University of Utah, Salt Lake City, UT, USA

    Christopher R. Butson, Kyle P. O’Sullivan & Andrew P. Janson

  6. Norman Fixel Institute for Neurological Diseases Departments of Neurology and Neurosurgery, University of Florida, Gainesville, FL, USA

    Christopher R. Butson

  7. Department of Neurosurgery, Stanford University, Stanford, CA, USA

    Eun Young Choi, Helen M. Bronte-Stewart, Adam Fogarty, Mark Krel, Stephanie A. Kolakowsky-Hayner & Jaimie M. Henderson

  8. Radiology and Radiological Sciences, Vanderbilt University, Nashville, TN, USA

    Andrew P. Janson

  9. Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA

    Jason Chua & Linda M. Gerber

  10. Department of Rehabilitation Medicine, University of Washington, Seattle, WA, USA

    Sureyya Dikmen

  11. Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Linda M. Gerber & Joseph J. Fins

  12. Department of Psychiatry, Stanford University, Stanford, CA, USA

    Jose Maldonado

  13. Department of Computer Science, Stanford University, Stanford, CA, USA

    Matthew Radovan

  14. Department of Radiology, Weill Cornell Medicine, New York, NY, USA

    Sudhin A. Shah

  15. Department of Electrical Engineering, Stanford University, Stanford, CA, USA

    Jason Su

  16. Department of Neurological Surgery, University of Washington, Seattle, WA, USA

    Nancy Temkin

  17. Department of Neuroimaging, University of Bordeaux, Nouvelle-Aquitaine, France

    Thomas Tourdias

  18. Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    Andre G. Machado

  19. Department of Radiology, Stanford University, Stanford, CA, USA

    Brian K. Rutt

  20. Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA

    Brian K. Rutt & Jaimie M. Henderson

  21. Bio-X Program, Stanford University, Stanford, CA, USA

    Brian K. Rutt & Jaimie M. Henderson

Authors
  1. Nicholas D. Schiff
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Contributions

N.D.S., J.M.H., J.T.G., C.R.B. and A.G.M. designed the study. J.M. acted as an independent consultation-liaison psychiatrist responsible for determination of decision-making capacity for each participant before study enrollment. J.T.G., N.D.S. and L.M.G. developed study design for outcome assessment. J.T.G., A.W., L.M.G. and J.C. analyzed behavioral data. S.D. and N.T. contributed supplementary data from University of Washington study and support in the use, analysis and interpretation of these data (Dikmen et al.). N.D.S. and J.D.V. designed and performed analysis of supplementary Dikmen et al.5 dataset. T.T., J.S., M.R. and B.K.R. developed the CL segmentation method. E.Y.C. and B.K.R. acquired neuroimaging data. E.Y.C., T.T., J.S., M.R., B.K.R., A.P.J., K.P.O. and C.R.B. designed and performed analysis of neuroimaging data. C.R.B., A.P.J. and K.P.O. designed and performed analysis of bioelectrical field modeling. E.Y.C., J.L.B. and S.A.S. developed the overall study design for neurophysiological data acquisition. E.Y.C. and J.L.B. designed cortical evoked potential experiments. E.Y.C., J.L.B. and M.K. analyzed cortical evoked potential data. L.D. coordinated the study components, US FDA regulatory compliance and patient recruitment liaison with PatientWing. J.J.F. developed ethical framework and guidance; PI of companion BRAIN Initiative study (1RF1MH12378-01) tracking participant and family perspectives which informed subject selection and enrollment. N.D.S. acted as the administrative PI of UH3 grant. J.M.H. acted as physician sponsor of the US FDA Investigational Device Exemption and performed all surgical implants. H.M.B.S. provided neurophysiology acquisition and interpretation during surgical implants. N.D.S., J.M.H., J.T.G., C.R.B. and B.K.R. drafted the manuscript. All authors provided substantive feedback for revision of the manuscript.

Corresponding authors

Correspondence to Nicholas D. Schiff or Jaimie M. Henderson.

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Competing interests

The following authors are listed inventors on a patent application WO2023/043786 (jointly filed by Weill Cornell Medicine, University of Utah and Stanford University) describing detailed methods of integrating magnetic resonance imaging, biophysical modeling and electrophysiological methods for localization and placement of DBS electrodes in the CL/DTTm of the human thalamus as described in the manuscript: N.D.S., J.L.B., C.R.B., A.P.J., K.P.O., J.M.H., E.Y.C., B.K.R., J.S. and M.R. N.D.S., C.R.B. and J.L.B. are listed inventors on a related patent application WO2021/195062 (jointly filed by Weill Cornell Medicine, University of Utah). N.D.S. and J.L.B. are listed as inventors on US Patent 9,9592,383 assigned to Weill Cornell Medicine describing different apparatus but related methods. The remaining authors declare no competing interests.

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Nature Medicine thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Jerome Staal, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Mesocircuit theory for recovery of anterior forebrain function with CL/DTTm DBS in msTBI.

Schematic diagram illustrating mesocircuit model for alteration of function following coma and moderate to severe brain injury and restoration of function with CL/DTTm DBS27,60. Left figure element: Healthy normative function of corticothalamic system. Projections of central lateral thalamic neurons to anterior forebrain mesocircuit and posterior medial complex27,60. CL co-activates frontal-parietal corticocortical connections and modulates their feed-forward and feedback connectivity via layer-specific effects within cortical columns20,60. CL specifically targets supragranular and infragranular cortical layers avoiding projections into the input layers23; these anatomical specializations support a proposed selective role in modulation of long-range corticocortical functional connectivity61. CL projections to the striatum strongly activate this structure via projections to medium spiny neurons, MSNs and act via AMPA receptors, whereas Cm-Pf afferents act via NMDA receptors22. Middle figure element: msTBI produces widespread deafferentation of the corticothalamic system leading to loss of CL modulation of cortex and striatum27,60. Two major consequences of this downregulation of CL output in combination with overall reduction of cerebral background activity are: 1) marked reduction in corticothalamic and corticostriatal outflow, 2) shut down of the medium spiny neuron output from striatum to globus pallidum interna (GPi) producing increased thalamic inhibition and further reduction of thalamocortical and thalamostriatal outflow. Collectively, these changes are proposed to exert a disproportionate impact on the anterior forebrain27,60. Right figure element: CL/DTTm DBS is proposed to reverse the mesocircuit level effects of reduced corticothalamic, corticostriatal, and striato-pallidal output by direct overdrive pacing of CL output via the DTTm. This model for the effects of direct electrical stimulation of CL/DTTm in msTBI is supported by animal studies that demonstrate broad activation of the frontal cortex and striatum with CL electrical stimulation19,24,25. These and related studies further show that CL electrical stimulation modulates executive attention and arousal in intact24,25,62 and brain-injured rodents63, intact nonhuman primates19,29,61,64,65, and a human subject in the minimally conscious state28. Cortical evoked responses overlapping those observed here have been obtained in a human subject with CL DBS supporting the further generalizability of the findings28.

Extended Data Fig. 2 TMT-B completion time measurements across trial phases (all participants).

TMT-B completion time raw scores obtained from each participant across each phase of the study. Four time points are shown for all participants except for P2 who was withdrawn before initiating the titration phase. The two intermediate time points between presurgical baseline (first timepoint, Day 0 all participants) and treatment end measurements reflect many sources of inter-participant variation in times of measurements after surgery, surgical procedures (see Supplemental Methods, Surgical targeting and implantation) and hours of exposure to stimulation prior to “Treatment Start” TMT-B completion time measurement (see Supplemental Methods Titration Phase and Study design considerations). Exposure to stimulation is indicated by shaded gray regions and includes a brief exposure to stimulation at the time of surgery (green marker on gray bar). The range of separation for the 4 time points across participants varied: Baseline to Post-Surgery (range 55-91 days), Post-Surgery to Treatment Start (7-33 days) and Treatment Start to Treatment End (89-107 days). Abrupt changes with initial exposure to continuous DBS were evident in P3, P5, and P6.

Extended Data Fig. 3 Placement of DBS electrodes within the CL/DTTm target for P1.

A. Active contact locations and fiber bundles for left hemisphere of P1 rendered within P1 space, CL nucleus (red), MD (green), VPL (purple) Cm (cyan). B. Histograms of fiber activation for left sided CL. MD, VPL, and Cm. C. DBS activation of fibers (red), inactive fibers rendered in blue. D. Active contact locations and fiber bundles for right hemisphere of P1 rendered within P1 space, CL nucleus (red), MD (green), VPL (purple) Cm (cyan). E. Histograms of fiber activation for right-sided CL. MD, VPL, and Cm. F. DBS activation of fibers (red), inactive fibers rendered in blue.

Extended Data Fig. 4 Placement of DBS electrodes within the CL/DTTm target for P4.

A. Active contact locations and fiber bundles for left hemisphere of P3 rendered within P3 space, CL nucleus (red), MD (green), VPL (purple) Cm (cyan). B. Histograms of fiber activation for left sided CL. MD, VPL, and Cm. C. DBS activation of fibers (red), inactive fibers rendered in blue. D. Active contact locations and fiber bundles for right hemisphere of P3 rendered within P3 space, CL nucleus (red), MD (green), VPL (purple) CM (cyan). E. Histograms of fiber activation for right-sided CL. MD, VPL, and Cm. F. DBS activation of fibers (red), inactive fibers rendered in blue.

Extended Data Fig. 5 Alteration of DTI model of CL/DTTm in P4 by local hemorrhage within right thalamus.

A. Active contact locations and fiber bundles for left hemisphere of P4 rendered within P4 space, CL nucleus (red), MD (green), VPL (purple) Cm (cyan). B.Histograms of fiber activation for left sided CL. MD, VPL, and Cm. C.DBS activation of fibers (red), inactive fibers rendered in blue. D.Active contact locations and fiber bundles of P4 rendered within P4 space, CL nucleus (red), MD (green), VPL (purple) CM (cyan). E.Histograms of fiber activation for right-sided CL. MD, VPL, and Cm. F.DBS activation of fibers (red), inactive fibers rendered in blue.

Extended Data Fig. 6 Alteration of DTI model of CL/DTTm in P4 by local hemorrhage within right thalamus.

MRI image shows large susceptibility artifact in the right central thalamus secondary to duret hemorrhage. Right panels: Distortion of MRI signal in this region limits the formation of DTI modeled fibers as seen in the six views comparing the presurgical locations of electrode placements (green electrode models) and postsurgical actual locations (gray electrodes). As seen in each panel, postsurgical electrode placement is medial to planned location. As shown in Fig. 5, a relative symmetry of cortical response is nonetheless obtained suggesting that more medial fibers associated with this pattern activation did not appear in the DTI model due to the loss of local signal in the region of the hemorrhage.

Extended Data Fig. 7 Placement of DBS electrodes within the CL/DTTm target for P6.

A. Active contact locations and fiber bundles for left hemisphere of P6 rendered within P6 space, CL nucleus (red), MD (green), VPL (purple) Cm (cyan). DBS activation of fibers (red), inactive fibers rendered in blue. B. Histograms of fiber activation for left sided CL. MD, VPL, and Cm. C. DBS activation of fibers (red), inactive fibers rendered in blue. D. Active contact locations and fiber bundles for right hemisphere of P6 rendered within P6 space, CL nucleus (red), MD (green), VPL (purple) Cm (cyan). E. Histograms of fiber activation for right-sided CL. MD, VPL, and Cm. F. DBS activation of fibers (red), inactive fibers rendered in blue.

Extended Data Fig. 8 Structural MRI imaging overview all 5 subjects.

Figure shows representative horizontal MRI image from each participant along with demographic information and change in TMT-B performance from presurgical to treatment end timepoint.

Extended Data Table 1 Trial-Making-Test and Cognitive Self-Report Measure Results
Full size table
Extended Data Table 2 Localization of active contacts within synthetic atlas, means and variances
Full size table

Supplementary information

Supplementary Information

Supplementary Figs. 1–24, Tables 1–13, trial design information and post-hoc analyses.

Reporting Summary

Supplementary Video 1

Rocking images of preoperative left and right hemisphere electrode placements in common template space. Color code: P1 (yellow), P3 (orange), P4 (green), P5 (blue), P6 (magenta). Video illustrates clustering of left and right preoperative electrodes as projected into the common template (synthetic atlas) space (Methods). Left-hemisphere electrodes show a tighter clustering of the contacts for each contact position as compared to the right hemisphere electrode placements.

Supplementary Video 2

Rocking images of postoperative left and right hemisphere electrode placements in common template space. Color code: P1 (yellow), P3 (orange), P4 (green), P5 (blue), P6 (magenta). Video illustrates actual postoperative electrode placements after projection into the common template (synthetic atlas) space (Methods). Left-hemisphere electrodes show a tighter clustering of the postsurgical positioning as compared to the right hemisphere electrode placements. Right-sided electrodes demonstrate wider spatial variation at lower contact positions compared to contacts closer to the top of the thalamus/ventricle.

Supplementary Video 3

Rocking images of preoperative and postoperative left and right hemisphere electrode placements in common template space. Color code: P1 (yellow), P3 (orange), P4 (green), P5 (blue), P6 (magenta). Video illustrates locations of electrodes in common template (synthetic atlas) space, first the preoperative (planned) followed by the postoperative (actual) placements. Top and bottom active contacts are then identified and rendered as small spheres. Top and bottom active contact centroids are calculated and rendered as larger red spheres whose diameters reflect the spatial spread (s.d.) across the five participants.

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Schiff, N.D., Giacino, J.T., Butson, C.R. et al. Thalamic deep brain stimulation in traumatic brain injury: a phase 1, randomized feasibility study. Nat Med 29, 3162–3174 (2023). https://doi.org/10.1038/s41591-023-02638-4

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