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. 2023 Oct 25:17:1178473.
doi: 10.3389/fnins.2023.1178473. eCollection 2023.

In humans, striato-pallido-thalamic projections are largely segregated by their origin in either the striosome-like or matrix-like compartments

Adrian T Funk  1 , Asim A O Hassan  2 , Norbert Brüggemann  3 , Nutan Sharma  4 , Hans C Breiter  5   6 , Anne J Blood  5   7   8   9 , Jeff L Waugh  1   8   9
Affiliations

In humans, striato-pallido-thalamic projections are largely segregated by their origin in either the striosome-like or matrix-like compartments

Adrian T Funk et al. Front Neurosci. .

Abstract

Cortico-striato-thalamo-cortical (CSTC) loops are fundamental organizing units in mammalian brains. CSTCs process limbic, associative, and sensorimotor information in largely separated but interacting networks. CTSC loops pass through paired striatal compartments, striosome (aka patch) and matrix, segregated pools of medium spiny projection neurons with distinct embryologic origins, cortical/subcortical structural connectivity, susceptibility to injury, and roles in behaviors and diseases. Similarly, striatal dopamine modulates activity in striosome and matrix in opposite directions. Routing CSTCs through one compartment may be an anatomical basis for regulating discrete functions. We used differential structural connectivity, identified through probabilistic diffusion tractography, to distinguish the striatal compartments (striosome-like and matrix-like voxels) in living humans. We then mapped compartment-specific projections and quantified structural connectivity between each striatal compartment, the globus pallidus interna (GPi), and 20 thalamic nuclei in 221 healthy adults. We found that striosome-originating and matrix-originating streamlines were segregated within the GPi: striosome-like connectivity was significantly more rostral, ventral, and medial. Striato-pallido-thalamic streamline bundles that were seeded from striosome-like and matrix-like voxels transited spatially distinct portions of the white matter. Matrix-like streamlines were 5.7-fold more likely to reach the GPi, replicating animal tract-tracing studies. Striosome-like connectivity dominated in six thalamic nuclei (anteroventral, central lateral, laterodorsal, lateral posterior, mediodorsal-medial, and medial geniculate). Matrix-like connectivity dominated in seven thalamic nuclei (centromedian, parafascicular, pulvinar-anterior, pulvinar-lateral, ventral lateral-anterior, ventral lateral-posterior, ventral posterolateral). Though we mapped all thalamic nuclei independently, functionally-related nuclei were matched for compartment-level bias. We validated these results with prior thalamostriate tract tracing studies in non-human primates and other species; where reliable data was available, all agreed with our measures of structural connectivity. Matrix-like connectivity was lateralized (left > right hemisphere) in 18 thalamic nuclei, independent of handedness, diffusion protocol, sex, or whether the nucleus was striosome-dominated or matrix-dominated. Compartment-specific biases in striato-pallido-thalamic structural connectivity suggest that routing CSTC loops through striosome-like or matrix-like voxels is a fundamental mechanism for organizing and regulating brain networks. Our MRI-based assessments of striato-thalamic connectivity in humans match and extend the results of prior tract tracing studies in animals. Compartment-level characterization may improve localization of human neuropathologies and improve neurosurgical targeting in the GPi and thalamus.

Keywords: classification targets tractography; cortico-striato-thalamo-cortical circuit; globus pallidus interna; patch; probabilistic diffusion tractography; striatum; striosome and matrix compartments; thalamus.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Streamline bundles originating in striosome-like or matrix-like voxels reach and traverse the GPi by different paths. Tracts seeded by matrix-like or striosome-like striatal voxels follow distinct paths through the globus pallidus interna (GPi). The averaged streamlines (A–G, range: 0.63–0.96) for all subjects are visualized in red-yellow (striosome-like seeds) and blue-light blue (matrix-like seeds) overlaid by the GPi mask (green). The GPi mask is shown at 50% opacity to visualize overlap with streamline bundles. In the x-plane (panels A–E), views of the right GPi (from x = 23–19) demonstrate segregation of the two streamline bundles at all lateral-to-medial (left to right) points. The bundles remain segregated in the y- (F), and z-planes (G) as well. The locations of peak amplitude for averaged matrix-like and striosome-like streamlines had significantly different locations in each plane (x plane, p < 1.1×10−35; y plane, p < 1.3×10−53; z plane, p < 3.8×10−42). The core of streamline bundles that originated in matrix-like and striosome-like voxels (the uppermost 25% of each bundle, by amplitude) do not overlap in any GPi voxel. Voxelwise significance testing with randomise (H,I) demonstrated this segregation of streamlines seeded by striosome-like and matrix-like voxels as well (significance threshold, p < 0.025, corrected for multiple comparisons; visualized range: 0.025–0.00001). Bundles seeded by striosome-like voxels (red-yellow) and matrix-like voxels (blue-light blue) occupy distinct zones of the GPi (H) and the subcortical white matter (I). In H, green voxels illustrate the few pallidal voxels where bundles were not significantly different. In (I), green voxels illustrate the whole of the GPi, as significance testing in this panel included only white matter voxels. Optimal visualization in the z-plane (G) was offset by 1 mm in the left and right hemispheres (vertical dashed line). Images follow radiologic convention. Coordinates follow MNI convention. Ca, caudate; Pu, putamen; Th, thalamus.
Figure 2
Figure 2
Mean probability of striato-pallido-thalamic connectivity for striosome-originating and matrix-originating streamlines. Compartment-specific biases in structural connectivity parallel the anatomic organization of the thalamus. In axial (A) and coronal (B,C) views, probability maps that favored striosome-like voxels (red-yellow) or matrix-like voxels (blue-light blue) were overlaid on the MNI_152_1mm template brain. Larger biases can be seen in yellow voxels (striosome-like) and light blue voxels (matrix-like). The coronal planes of section in B and C are indicated by dashed lines in A. Maps are the averaged probabilities from all subjects, with left and right hemispheres run independently. These views demonstrate probability values between 0.55–0.85, voxels with substantial compartment-specific bias in structural connectivity. Voxels with indeterminate bias (those with connection probabilities of 0.45–0.55) do not appear in either probability map (white voxels). The anterior and medial nuclear groups have strong bias towards striosome-like striatal voxels, while the lateral nuclear group is mostly biased towards matrix-like voxels. Voxels with indeterminate bias closely approximate the internal medullary lamina. The pulvinar nucleus, the caudal-most portion of the thalamus, has a divided pattern of connectivity, with some pulvinar zones biased towards matrix-like voxels and other zones biased towards striosome-like voxels (panel C). Note that in this mode of tractography (classification targets) each thalamic voxel was mapped individually – the similarity of these probability maps to prior histology-based divisions of thalamic nuclei underscores the fact that probabilistic tractography follows the intrinsic anatomic and functional anatomy of the thalamus. Images follow radiologic convention. Coordinates follow MNI convention. Ca, caudate; Pu, putamen.
Figure 3
Figure 3
Connectivity to matrix-like voxels is stronger in the left hemisphere for most thalamic nuclei. Biased connectivity from the matrix-like compartment is larger in the left hemisphere. While this bias was significant in only six of 20 nuclei, bias was larger in the left for 18 of the 20 nuclei assessed. Note that the darker horizontal line (0.5) indicates the point of equal connectivity between thalamic seed voxels and matrix- or striosome-like target voxels. Higher values on the y axis indicate greater matrix-like connectivity (blue arrow), with lower values indicating greater striosome-like connectivity (red arrow). For any given nucleus, the values for matrix-like and striosome-like connectivity sum to one. Therefore, we present only the matrix-like connectivity for left and right hemispheres. Error bars indicate the standard error of the mean. Three nuclei whose data originated from the HCP cohort alone are indicated by arrowheads. Significance threshold: **, p < 2.5×10−6; *, p < 2.5×10−3.
Figure 4
Figure 4
Connectivity with most thalamic nuclei is biased toward either striosome-like or matrix-like voxels. Disynaptic projections from striatum to thalamus (via the globus pallidus interna) are biased: streamlines that originate in striosome-like or matrix-like voxels largely reach different thalamic nuclei. Seven nuclei were dominated by projections from matrix-like voxels (blue bars), six nuclei were dominated by striosome-like projections (red bars), and three nuclei had no compartment bias (purple bars). Note that the darker horizontal line (0.5) indicates the point of neutral connectivity. Higher values on the y axis indicate greater matrix-like connectivity (blue arrow), with lower values indicating greater striosome-like connectivity (red arrow). For any given nucleus, the values for matrix-like and striosome-like connectivity sum to one. Therefore, we present only the matrix-like connectivity for each thalamic nucleus. Error bars indicate the standard error of the mean. Two nuclei whose data originated from the HCP cohort alone are indicated by arrowheads. Significance thresholds: *, p < 3.1×10−3; **, p < 3.1×10−9; ***, p < 3.1×10−15.
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