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

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 Five participants completed the study and one was withdrawn for protocol non-compliance.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 .

Extended Figure 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 DBS^,. Left figure element: Healthy normative function of corticothalamic system. Projections of central lateral thalamic neurons to anterior forebrain mesocircuit and posterior medial complex^,. CL co-activates frontal-parietal cortico-cortical connections and modulates their feed-forward and feedback connectivity via layer-specific effects within cortical columns^,–. CL specifically targets supragranular and infragranular cortical layers avoiding projections into the input layers; these anatomical specializations support a proposed selective role in modulation of long-range corticocortical functional connectivity. 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 receptors. Middle figure element: msTBI produces widespread deafferentation of the corticothalamic system leading to loss of CL modulation of cortex and striatum^,. Two major consequences of this down-regulation 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 forebrain^,. 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 stimulation^,,. These and related studies further show that CL electrical stimulation modulates executive attention and arousal in intact^,, and brain-injured rodents, intact non-human primates^,,,–, and a human subject in the minimally conscious state. Cortical evoked responses overlapping those observed here have been obtained in a human subject with CL DBS supporting the further generalizability of the findings.

Extended Figure 2.. Placement of DBS electrodes within the CL/DTTm target for subject participant 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 Figure 3.. Placement of DBS electrodes within the CL/DTTm target for P3.

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 Figure 4.. Placement of DBS electrodes within the CL/DTTm target for P4.

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 for right hemisphere 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 Figure 5.. 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 pre-surgical locations of electrode placements (green electrode models) and post-surgical actual locations (grey electrodes). As seen in each panel, post-surgical electrode placement is medial to planned location. As shown in Figure 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 Figure 6.. 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 Figure 7.. 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 pre-surgical to treatment end timepoint.

Extended Figure 8:. 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 timepoints are shown for all participants except for P2 who was withdrawn before initiating the titration phase. The two intermediate time points between pre-surgical 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 MethodsTitration Phase and Study design considerations). Exposure to stimulation is indicated by shaded grey regions and includes a brief exposure to stimulation at the time of surgery (green marker on grey 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.

Figure 1.

CONSORT Diagram

Figure 2.. Behavioral results.

A. TMT-B raw scores for each subject. Red line indicates 10% improvement level, the pre-selected benchmark. B. Test-retest scattergram. Scattergram of data from two groups of msTBI subjects (blue dots) followed as part of the Dikmen et al. study with available TMT-B measurements at time points: 1) (n=146) 6 months post-injury and again 1 year post-injury, and 2) (n= 118) who were followed 1 year post-injury and again between 3 and to 5 years post-injury (provided by Dr. Dikmen) together with the five msTBI participants studied here (red dots). The CL/DTTm subjects cluster on the lower edge of the “natural recovery” group distributions. Statistical tests demonstrate that it is unlikely that the CL/DTTm DBS participant values have been drawn from either of the “natural recovery” distributions: A) p<0.02 Kolmogorov-Smirnov test, one-sided [p=0.011], B) p<0.005 Kolmogorov-Smirnov, one-sided [0.004070]. C. Percent change of non-primary measures from pre-surgical baseline to treatment end. All non-primary measures obtained across all 5 participants completing the study are shown. Improvement on measure is indicated by positive change in percentage, worsening is indicated by a negative change in percentage (see Supplemental Material). For Ruff 2&7 measures complete pre-surgical data were only available for 4 subjects (see Supplementary Table 1).

Figure 3.. Activation of CL/DTTm fibers in a representative subject and group summary.

A. Coronal WMn slices from left hemisphere of participant P5, zoomed to include only left thalamus and lateral ventricle. Four slices are shown: each intersects the middle of one of the four DBS electrode contacts. The two active contacts L3 and L4 (used as cathodes during stimulation) are indicated by red labels and arrows. The intersection of each slice with the outer boundary of four “key” thalamic nuclei are indicated by the color contours: CL (red), MD (green), VPL (purple), Cm (cyan). B. Histograms of fiber activation from left hemisphere of participant P5, for each of the four DBS contacts driven at five different voltages from 1V to 5V, for CL, MD, VPL, and Cm fibers. C. Modeled activation of P5’s left hemisphere CL/DTTm fibers (active fibers rendered in red, inactive fibers rendered in blue). D. Coronal WMn slices from right hemisphere of participant P5, zoomed to include only right thalamus and lateral ventricle. Four slices are shown: each intersects the middle of one of the four DBS electrode contacts. The two active electrode contacts R3 and R4 (used as cathodes during stimulation) are indicated by red labels and arrows. The intersection of each slice with the outer boundary of four “key” thalamic nuclei are indicated by the color contours: CL (red), MD (green), VPL (purple), Cm (cyan). E. Histograms of modeled fiber activation from right hemisphere of participant P5, for each of the four DBS electrode contacts driven at five different voltages from 1V to 5V, for CL, MD, VPL, and Cm fibers. F. Modeled activation of P5’s right hemisphere CL/DTTm fibers (active fibers rendered in red, inactive fibers rendered in black). G. Percent of fiber activation of target and avoidance fibers, all five participants. Color scheme is the same as in panels A, B, D, E: CL (red), MD (green), VPL (purple), Cm (cyan).

Figure 4.. Placement and visualization of DBS contacts in common template space.

A. CL and Cm. 3D rendering of CL (light brown) and Cm (cyan) nuclei within the thalamus (transparent grey). Post-op electrodes. Rendering of the four DBS electrodes for each of the five participants, color-coded by participant as follows: P1 (yellow), P3 (salmon), P4 (green), P5 (blue), P6 (magenta). These electrode renderings indicate the final post-operative locations, as determined by 30-day post-operative CT scanning, and like all other panels in this figure, these locations have been warped into common template space. B. Active contacts identified. Small spherical renderings are shown within two of the DBS electrodes on each of left and right sides, to indicate that these are the two (top and bottom) active contacts used during stimulation of this participant. Note that the top active contact on the right side for P4 (green) was shorted as a result of this contact being fully outside the thalamus and in the CSF of the lateral ventricle. For this reason this contact could not be used during stimulation and is therefore not shown in this panel, nor was it used for the computation of centroids. C. Active contact centroid spheres. Centroids of top and bottom contacts computed across the five participants, and rendered as red spheres, with location of the sphere showing the 3D location of the centroid and the diameter of the sphere set equal to the standard deviation (spatial spread) across the five participants, providing a graphical indication of the tightness-of-clustering of top and bottom active contacts in common space, in relation to CL and outer surface of thalamus.

Figure 5.. Cortical evoked responses for each individual subject from left and right hemisphere.

Top panels (A-D). DBS-evoked potentials obtained for the therapeutic contacts selected during the titration phase for treatment DBS for each subject (see also Supplementary Figures 2–11). Stimulation was applied for the first 100ms Robust evoked potentials localized to the ipsilateral frontal cortex, with a peak amplitude between medial and lateral regions of frontal cortex is noted in each panel. This is consistent with animal anatomical literature showing CL’s strong connectivity to the dorsomedial frontal cortex^,. Evoked potentials in the left hemisphere demonstrate greater inter-subject consistency than those in the right hemisphere. As shown below (and see Figure 4, Extended Table 2), right sided bottom active contacts demonstrate greater variance in location potentially influencing this greater right-sided variability. Bottom panels (E, F). Coronal slices through the common template WMn volume, zoomed to show thalamus and mid-line CSF only. Thin boundaries indicate the Intersection of each slice with the THOMAS segmentations for CL (light brown) and whole thalamus (white). Small circles show the active contacts, color-coded for each participant similarly to those shown in Figure 4, rendered as dim if out-of-plane or bright if in-plane. Bright red larger circles indicate the intersection between the centroid spheres and the slice plane, with top active contacts and centroids shown in panel E and bottom active contacts and centroids shown in panel F.