A human brain network linked to restoration of consciousness after deep brain stimulation

Abstract

Disorders of consciousness are characterized by severe impairments in arousal and awareness. Deep brain stimulation is a potential treatment, but outcomes vary-possibly due to differences in patient characteristics, electrode placement, or the specific brain network engaged. We describe 40 patients with disorders of consciousness undergoing deep brain stimulation targeting the thalamic centromedian-parafascicular complex. Improvements in consciousness are associated with better-preserved gray matter, particularly in the striatum. Electric field modeling reveals that stimulation is most effective when it extends below the centromedian nucleus, engaging the inferior parafascicular nucleus and the adjacent ventral tegmental tract-a pathway that connects the brainstem and hypothalamus and runs along the midbrain-thalamus border. External validation analyzed show that effective stimulation engages a brain network overlapping with disrupted patterns of brain activity observed in two independent cohorts with impaired consciousness: one with arousal-impairing stroke lesions and the other with awareness-impairing seizures. Together, these findings advance the field by informing patient selection, refining stimulation targets, and identifying a brain network linked to recovery that may have broader therapeutic relevance across consciousness-impairing conditions.

Fig. 1. Clinical outcomes and DBS electrode localizations in improved and non-improved patient groups.

A Raincloud plots showing DoC severity before and 12 months after DBS, measured using the Coma Recovery Scale-Revised (CRS-R), where higher scores indicate better function. Patients were categorized as improved (n = 11; pink) or non-improved (n = 29; blue). Box plots show the median (thick line), interquartile range (IQR; 25th–75th percentile), and whiskers extending to 1.5× IQR. Individual patient scores are shown as jittered dots connected by lines; adjacent density plots show score distributions. Longitudinal scores at additional timepoints (1, 3, 6, and 12 months post-DBS) are shown in Supplementary Fig. 2. B Three-dimensional reconstructions of DBS electrodes. All leads were implanted unilaterally. Electrode positions are shown relative to the centromedian (CM) and parafascicular (Pf) nuclei, defined by the atlas of Krauth et al. based on the histological work of Morel. Supplementary Fig. 3 shows additional views of entry trajectories via the frontal lobe. Reconstructions were performed for patients with successful nonlinear image registrations to MNI space (n = 10 improved, n = 18 non-improved). C Coronal slices showing the centre of each patient’s volume of tissue activated (i.e., the modelled electric field around stimulated contacts) overlaid on the BigBrain atlas registered to MNI space. Circles indicate locations from improved (pink; n = 10) and non-improved (blue; n = 18) patients. Y-coordinates reflect coronal slice position (mm) in MNI 152 ICBM 2009b nonlinear asymmetric template space. Individual patient coordinates are listed in Supplementary Data 1. Source data are provided as a Source Data file. Abbreviations: A, Anterior, CL, Central lateral nucleus, CM, Centromedian nucleus, CRS-R, Coma Recovery Scale—Revised, I, Inferior, L, Left, Lat., Lateral, LD, Lateral dorsal nucleus, Md, Mediodorsal nucleus, Pf, Parafascicular nucleus, R, Right, RN, Red nucleus, S, Superior, sPf, Subparafascicular nucleus, STh, Subthalamic nucleus.

Fig. 2. Comparison of MRI brain region volumes between improved and non-improved groups.

Whole-brain tissue volumes (left panel: gray matter [GM], white matter [WM], and cerebrospinal fluid [CSF]) and regional subcortical gray matter volumes (right panel) are shown for the improved (pink) and non-improved (blue) groups. The dashed horizontal line indicates the average value in age-matched controls from the Nathan Kline Institute-Rockland Sample. Volumes are expressed as z-scores relative to the control mean. Analyses included patients with available T1-weighted MRI (n = 8 improved; n = 18 non-improved). Box plots show the median (thick line), interquartile range (IQR; 25th–75th percentile), and whiskers extending to 1.5× IQR. Individual patient values are overlaid as jittered dots. Statistical comparisons between groups were performed using two-sided, non-parametric, permutation-based t-tests (10,000 permutations). Four regions showed significantly greater volume in the improved group compared to the non-improved group (*p < 0.05, uncorrected): GM: t(24) = 2.14, p = 0.04, Hedges’ g = 0.9, 95% CI = [0.14, 1.8]; Putamen: t(24) = 2.7, p = 0.01, Hedges’ g = 1.1, 95% CI = [0.6, 1.8]; Caudate: t(24) = 2.3, p = 0.03, Hedges’ g = 0.9, 95% CI = [0.4, 1.5]; Cerebellum: t(24) = 2.6, p = 0.01, Hedges’ g = 1.1, 95% CI = [0.5, 1.8]. Source data are provided as a Source Data file. CSF Cerebrospinal fluid, GM Gray matter, WM White matter, Ventral DC Ventral diencephalon.

Fig. 3. Anatomical localization and cross-validation of the optimal stimulation site.

A K-fold cross-validation (k = 10) demonstrating that DBS E-field locations are significantly associated with clinical outcomes in left-out patients (p = 0.047; two-sided, non-parametric, permutation-based t-test, 10,000 permutations). Box plots show the median (thick line), interquartile range (IQR; 25th–75th percentile), and whiskers extending to 1.5× IQR. Individual patient values are overlaid as jittered dots. B Three-dimensional visualization of the stimulation sweet spot, defined as the center of gravity of the largest suprathreshold cluster (p < 0.05, uncorrected) identified via two-sided, voxel-wise, two-sample t-tests comparing E-field magnitudes between improved and non-improved groups. The sweet spot is displayed relative to the centromedian (CM), parafascicular (Pf), and subparafascicular (sPf) nuclei, as defined by the atlas of Krauth et al. based on the histological work of Morel. Analyses included patients with successful nonlinear image registration to MNI space (n = 10 improved, n = 18 non-improved). C Orthogonal slices showing the unthresholded t-score map. Positive values indicate voxels where E-field magnitude was higher in the improved group; negative values indicate higher E-field magnitude in the non-improved group. Slice coordinates (X, Y, Z) reflect mm positions in MNI152 ICBM 2009b nonlinear asymmetric template space. The unthresholded map is available in NIfTI format at: https://osf.io/bjah5. The map is displayed on the BigBrain atlas registered to MNI space. D Thresholded map (p < 0.05, uncorrected; two-sided, voxel-wise two-sample t-tests) highlighting the peak location associated with clinical improvement. Source data are provided as a Source Data file. A Anterior, CL Central lateral nucleus, I Inferior, L Left, Lat. Lateral, Md Mediodorsal nucleus, Med. Medial, P Posterior, PC Posterior commissure, Pulv Pulvinar nucleus, R Right, RN Red nucleus, S Superior.

Fig. 4. Anatomical localization and cross-validation of optimal structural connectivity.

Box plots (top left) show results of k-fold (k = 10) cross-validation, demonstrating that structural connectivity is associated with clinical outcome in left-out patients (p = 0.03; two-sided, non-parametric, permutation-based t-test with 10,000 permutations). Box plots display the median (thick line), interquartile range (IQR; 25th–75th percentile), and whiskers extending to 1.5x IQR. Individual patient values are overlaid as jittered dots. Analyses included patients with successful nonlinear image registration to MNI space (n = 10 improved, n = 18 non-improved). Sagittal (left) and coronal (right) panels show white matter fiber tracts more strongly connected to the stimulation sites of improved versus non-improved patients (p < 0.05, uncorrected; two-sided, streamline-wise two-sample t-tests), including portions of the ventral tegmental tract (VTT)^, that course along the midbrain-thalamus border to link the brainstem and hypothalamus. The previously identified stimulation sweet spot (Fig. 3) is indicated in the zoomed-in thalamic view. Results are displayed on the BigBrain atlas registered to MNI space, with anatomical labels from the hypothalamus (https://zenodo.org/records/3942115), brainstem (10.25790/bml0cm.96), ascending arousal network (10.5061/dryad.zw3r228d2), thalamus (https://zenodo.org/records/13918589), striatum, and cerebellum (https://www.diedrichsenlab.org/imaging/propatlas.htm). White matter fiber tract results are available as an NIfTI file at: https://osf.io/bjah5. Source data are provided as a Source Data file. A Anterior, AHA Anterior hypothalamic area, AN Arcuate nucleus, DR Dorsal raphe nucleus, iMRt Inferior medullary reticular formation, Lat. Lateral, LC Locus coeruleus, Med. Medial, MPB Medial parabrachial nucleus, mRt Mesencephalic reticular formation, PA Paraventricular nucleus, PE Periventricular nucleus, Pf Parafascicular nucleus, PH Posterior hypothalamus, RN Red nucleus, S Superior, SCh Suprachiasmatic nucleus, sMRt Superior medullary reticular formation, sPf Subparafascicular nucleus, SubC Subcoeruleus, Ve Vestibular nuclei complex, VSM Viscero-sensory-motor nuclei complex, VTA PBP Ventral tegmental area (parabrachial pigmented nucleus complex).

Fig. 5. Optimal functional connectivity and alignment with brain networks disrupted in other consciousness-impairing conditions.

A The DBS improvement network was derived by comparing the functional connectivity of stimulation sites between improved and non-improved groups using normative resting-state fMRI data^,. The resulting map shows unthresholded t-scores, where positive values indicate regions with stronger connectivity in the improved group, and negative values indicate stronger connectivity in the non-improved group. Cortical surfaces are displayed on the fs_LR_32k template (https://balsa.wustl.edu/QXj2), and subcortical anatomy is shown using the BigBrain histological atlas registered to MNI space. The unthresholded map is available in GIfTI format at: https://osf.io/bjah5. Analyses included patients with successful nonlinear image registration to MNI space (n = 10 improved, n = 18 non-improved). B We assessed whether the DBS improvement network was associated with arousal outcomes in an independent cohort of 45 patients with arousal-impairing stroke lesions^,. Axial slices show lesion frequency. For each lesion, a whole-brain connectivity map was computed, and its spatial similarity to the DBS improvement network was correlated with behavioral arousal ratings (6-point ordinal scale; lower scores = greater impairment). The scatter plot shows a significant association (two-sided Spearman correlation), with a linear fit and 95% confidence interval overlaid. C We further compared the DBS improvement network to brain regions showing BOLD signal changes during generalized spike-wave discharges in 15 patients with absence epilepsy scanned using simultaneous EEG-fMRI^–. An example EEG trace recorded inside the MRI scanner is shown using a longitudinal bipolar montage, with channels grouped by region: R1 = right lateral (Fp2-F8, F8-T4, T4-T6, T6-O2); L1 = left lateral (Fp1-F7, F7-T3, T3-T5, T5-O1); R2 = right parasagittal (Fp2-F4, F4-C4, C4-P4, P4-O2); L2 = left parasagittal (Fp1-F3, F3-C3, C3-P3, P3-O1); M = midline (Cz-Pz); E = electrocardiogram. EEG-fMRI results are displayed as z-score maps, where positive values indicate BOLD increases during discharges, and negative values indicate decreases. The histogram shows results from spin-permutation testing (10,000 spins), revealing a significant negative correlation (two-sided Spearman correlation) between the EEG-fMRI map and the DBS improvement network. Source data are provided as a Source Data file. Conn. connectivity, EEG electroencephalogram, ECG electrocardiogram, Func. functional, L left, Lat. lateral, Med. medial, Perm. permutations, R right.