A precise atlas of the human subcortex
Helen Friedrich, Ilkem Aysu SahiniD, Eduardo Joaquim Lopes AlhoiD, Nanditha RajamaniiD, Vanessa Milanese Holanda, Simón OxenfordiD, Malte BrammerlohiD, Maike Mustin, Patricia ZvarovaiD, Lara KrügeriD, Richard Demann, Lukas L. GoedeiD, Garance M. MeyeriD, Evgeniya P. KirilinaiD, Cordula MatthiesiD, Jens VolkmanniD, Julianna PijariD, Shiro HorisawaiD, Calvin HowardiD, Arun H. GarimellaiD, Ningfei LiiD, Michael FoxiD, Maximilian U. Friedrich, Anja Bochtler, Brian L. EdlowiD, , Andreas HorniD
Abstract
Clinical interventions and neuroimaging in the subcortex require anatomical definitions that exceed the resolution and anatomical detail of currently available deformable brain atlases. Here, we introduce a high-resolution human brain atlas comprising 95 manually segmented grey and white matter structures as well as 82 white matter tracts compiled from a multitude of resources including ex-vivo MRI, histology, fibre dissections, and neuroanatomy textbooks. The atlas is defined at an isotropic resolution of 100 m and can be precisely deformed to individual subject brain anatomy. By providing precise definitions of both grey and white matter structures within and around the basal ganglia, thalamus, subthalamus, midbrain and cerebellum, the atlas provides a foundational resource for stereotactic surgery and subcortical brain imaging research, as well as for development of next-generation neuromodulation strategies.
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In-depth summary
Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (14 Sept 2026)
FOCUS, a 100 µm atlas of 180 manually segmented subcortical grey and white matter regions and 77 hand-built tracts, registered to MNI 2009b space for warping to individual brains.
Standard neuroimaging atlases map only 7% of 455 listed subcortical structures (as cited), histology-derived atlases suffer 2D-to-3D reconstruction distortions, and MRI-derived ones are limited to roughly 0.5-1 mm resolution. FOCUS anchors manual delineations on one 100 µm ex vivo 7T MRI brain, cross-checks them against 48 further resources, and adds a hand-refined warp to MNI space plus hand-built tracts.
Key results
ShownFOCUS delineates 85 bilateral and 10 midline subcortical grey and white matter structures (180 segmentations) at 100 µm isotropic resolution. It concentrates on deep brain stimulation (DBS) target zones, especially the mesencephalic-diencephalic transition zone.
Drawn on the Edlow et al. 100 µm ex vivo 7T FLASH MRI of one postmortem brain. Boundaries were checked against 48 additional resources: histology with Gallyas, Nissl and H.E. stains, dark-field microscopy, fibre dissections and textbooks. Coverage includes basal ganglia laminae, thalamic nuclei, the Fields of Forel and the cerebellar nuclei (Fig. 1). · Abstract; Results; Manual segmentation of grey and white matter…; Figure legends
SuggestedA hand-refined nonlinear warp moves the 100 µm segmentations into MNI ICBM 2009b space at full resolution. It also yields an updated MNI version of the ex vivo template, which the authors report fits subcortical regions better than the original release.
Five-stage ANTs registration (rigid, affine, whole-brain SyN, then two subcortex-focused SyN stages), refined with 62 paired anchor segmentations (31 per hemisphere) over 37 iterations plus local WarpDrive edits. Accuracy was judged by expert visual inspection and by matching to histological sections (Fig. 3). The comparison of original and refined templates is in Supplementary Materials, not in this text. · Results; Registration to MNI space using advanced…; Figure legends
SuggestedManual 'tract architectonics' with the new CurveToBundle tool produced 77 tracts. They include thin or tortuous pathways (the pallidohypothalamic tract, under 2 mm across; the fasciculus retroflexus; the oculomotor nerve) that the authors say diffusion tractography handles poorly.
Streamlines were sampled along drawn curves (1000 for large cortico-cortical/cortico-subcortical tracts, 500 for major subcortical projections, 250 for smaller bundles), constrained by atlas structures. With segmentation guidance the ansa lenticularis matched fields H and H1, missed by an earlier 0.5 mm MNI reconstruction; an analogous comparison covers the fasciculus lenticularis (Fig. 5g-j). · Results; Manually curated Pathway Atlas; Figure legends
ShownIn a published subthalamic nucleus DBS fibre-filtering analysis, swapping the Netstim Atlas connectome for FOCUS tracts added subcortical tracts to the hyperdirect projections: indirect-pathway surrogates and substantia nigra, pedunculopontine and centromedian connections. Predictive performance did not change.
Parkinson's disease: 129-patient discovery cohort (three centres) and 89-patient independent test cohort (two centres); outcome was improvement in motor UPDRS-III. Netstim Atlas v2.2: Spearman ρ = 0.33 circular (p = 0.0004), 0.29 ten-fold cross-validation (p = 0.001), 0.30 test (p = 0.006). FOCUS: ρ = 0.36 (p = 0.0002), 0.30 (p = 0.0008), 0.30 test (p = 0.003). · Results; DBS Fiber Filtering; Figure legends
SuggestedIn three dystonia patients after radiofrequency pallidothalamic tractotomy, atlas overlap separated the two responders (largest share in Forel field H1) from the non-responder (mostly zona incerta, no H1 overlap), even though the lesion centroids lay only 2.75-3.23 mm apart.
Improvement on the Burke-Fahn-Marsden movement subscale (BFMDRS-M) was 89.8%, 66.7% and 0%. Share of lesion volume in H1: 32.8% and 38.7% in the responders. The non-responder's lesion was 61.1% zona incerta and 20.9% field H2. The region shared by both responders was 197 voxels, 55.8% of it within H1, and is crossed by the ansa and fasciculus lenticularis. · Results; Lesion study; Figure legends
Methods, data and reproducibility
One rater segmented structures by hand in 3D Slicer on the 100 µm ex vivo FLASH MRI of one postmortem brain, resolving ambiguous boundaries with histology, fibre dissections, reference atlases and textbooks. An ANTs warp to MNI 2009b space was refined with 62 anchor structures over 37 iterations and local WarpDrive edits, and 77 tracts were drawn with the CurveToBundle tool.
- 100 µm ex vivo 7T MRI (synthesized FLASH plus flip-angle volumes FA15-FA30) of a postmortem brain, Edlow et al. · human · n = a single post-mortem brain (58-year-old woman)
- MNI ICBM 2009b NLIN Asym template (T1, T2, PD), used as the registration target · human
- Additional anatomical resources: histological stacks and stains, gross dissections, structural and diffusion MRI libraries, textbooks · n = 48
- Klingler fibre dissections made for this project
- Openly available high-resolution 600-micron DTI data, used for tract cross-referencing
- Dystonia patients after unilateral radiofrequency pallidothalamic tractotomy, Tokyo Women's Medical University · human · n = 3 patients
- Parkinson's disease STN-DBS discovery cohort (Berlin, Würzburg, Amsterdam) · human · n = 129 patients
- Parkinson's disease STN-DBS independent test cohort (Beijing, Würzburg) · human · n = 89 patients
- Methods & tools
- 3D Slicer 5.6.2, WarpDrive (3D Slicer module), CurveToBundle (3D Slicer module), ANTs, Lead-DBS v3.1, OSS-DBS v2, MRIcroGL, MATLAB R2022b, Netstim Atlas v2.2, ICBM 2009b NLIN Asym (MNI) template, Klingler fibre dissection, Gallyas silver, Nissl and H.E. staining
- Code
- https://www.focusatlas.org/https://github.com/netstimhttps://github.com/netstim/SlicerNetstimhttps://github.com/netstim/leaddbs
- Data & accessions
- https://www.focusatlas.org/
- Software & environment
- 3D Slicer 5.6.2; Lead-DBS v3.1 in MATLAB R2022b; OSS-DBS v2; ANTs with the 'Effective: Low Variance, Default' preset; Netstim Atlas v2.2; atlas distributed in NIfTI format.
- Reproducibility gaps
- Atlas, protocol and original code are deposited at focusatlas.org but released only on the day of peer-reviewed publication; supplementary tables and the Key Resources Table are not in this text; access to patient lesion and DBS cohort imaging is not stated.
Limitations (6)
- Built from one postmortem brain (a 58-year-old woman), so it may miss differences between individuals, such as age and sex effects, as well as postmortem tissue changes. · stated by the authors
- Cortex is absent except cortico-subcortical projections and seed regions. Manual warp refinement concentrated on the prioritized subcortical zones; elsewhere the template fit reflects the automated whole-brain normalization without the same degree of dedicated refinement. · stated by the authors
- The clinical analyses are illustrative proof of concept rather than formal clinical validation; the lesion analysis uses only three selected cases. · stated by the authors
- Structural anatomy only: functional (motor, associative, limbic) subdivisions of the thalamus and basal ganglia are not included. · stated by the authors
- Atlas and registration accuracy rest on expert visual checks. The main text reports no quantitative registration error or overlap metrics, and gives no interrater results for the subset segmented by three extra raters. · noted in this summary
- All segmentations and warp refinements were made by a single rater, so boundary choices rest largely on one person's judgement despite team review. · noted in this summary
Who should read:Read this if you plan or analyse DBS or lesion surgery, or study subcortical imaging, and need sub-millimetre definitions of thalamic, subthalamic, midbrain and basal ganglia nuclei and tracts in MNI space.
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