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)^38,39 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 atlas¹⁰⁴ registered to MNI space¹⁰⁵, with anatomical labels from the hypothalamus⁹⁵ (https://zenodo.org/records/3942115), brainstem (https://doi.org/10.25790/bml0cm.96), ascending arousal network³⁸ (https://doi.org/10.5061/dryad.zw3r228d2), thalamus⁹³ (https://zenodo.org/records/13918589), striatum⁹⁴, 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).