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Structural connectivity networks of putamen subregions in health and in early Parkinson’s Disease
Tonima Sumya Ali1,2, Jinglei Lv1,2, Arkiev D'Souza1,2,3, Claire O'Callaghan2,4, Marshall Dalton2,5, Mustafa Steve Kassem6, and Fernando Calamante1,2,7
1School of Biomedical Engineering, The University of Sydney, Sydney, Australia, 2Brain and Mind Centre, The University of Sydney, Sydney, Australia, 3National Imaging Facility, Sydney, Australia, 4School of Medical Science, The University of Sydney, Sydney, Australia, 5School of Psychology, The University of Sydney, Sydney, Australia, 6Neuroscience Research Australia, Sydney, Australia, 7Sydney Imaging, The University of Sydney, Sydney, Australia

Synopsis

Keywords: Parkinson's Disease, Parkinson's Disease, Brain connectivity, Diffusion MRI

Motivation: Putamen, a subcortical grey matter (SGM) structure and its associated brain connectivity networks are often implicated in the early stages of Parkinson’s Disease (PD).

Goal(s): With more detailed structural connectivity analysis using SGM parcellation, we characterise the structural connectivity of putamen subregions in healthy brains, and their alterations in early PD.

Approach: Using data from Parkinson’s Progressive Markers Initiative, structural connectivity analysis, and by incorporating SGM parcellation, we have revealed the connectivity networks specific to four putamen subregions.

Results: Heterogeneous connectivity alteration was identified in PD subjects, demonstrating weakening of intra-SGM connectivity within hemisphere and strengthening of it across hemispheres.

Impact: We identified structural connectivity networks specific to four putamen subregions in healthy brain and in early Parkinson’s Disease. Our method allows focused connectivity analysis while our findings provide new insight into the intra- and inter-hemispheric connectivity alterations with disease progression.

Introduction

Putamen is a subcortical grey matter (SGM) structure that plays key roles across learning, cognition and motor control1. The putamen and its associated brain connectivity are often implicated in the early stages of neurodegenerative disorders, such as in Parkinson’s disease (PD)2. Using MRI, putamen atrophy and increased functional connectivity of putamen have been identified as possible biomarkers for PD3,4. Parcellation of SGM has now enabled segregation of putamen subregions with distinct microarchitectural properties5. In this pilot study, we aim to improve the characterisation of putamen subregion’s structural connectivity in healthy brains, and then assess how connectivity is implicated in mild and moderate PD, as defined by the MDS-Unified Parkinson’s Disease Rating Scale Part-III (MDS-UPDRS-III)6.

Methods

T1w and dMRI data were downloaded from the Parkinson’s Progressive Markers Initiative (PPMI)7 for 20 control and 20 PD subjects. Disease severity for PD cases was evaluated by motor examination using the MDS-UPDRS part III, where higher scores indicate greater motor impairment6. Following standard preprocessing steps8 for each subject, 20M streamlines were generated, 10M by dynamic seeding and 10M seeded from the SGM region. For SGM parcellation atlas, all subjects were registered to 50-subject template space5 by multi-modal registration9. SGM parcellation5 was warped to subject space, the Desikan-Killiany (DK)10 and extended DK (DK-ex) atlases were computed for each subject using Freesurfer11. DK-ex atlas appends SGM parcellation (which includes putamen sub-regions per hemisphere)5 at the end of standard DK atlas10,11. Structural connectivity12 was computed using both atlases. Streamline weights were averaged for the healthy group. For the PD subjects, streamline weights for connections between each putamen subregion to each brain parcel, were correlated individually against the MDS-UPDRS part III scores.

Results

For the healthy group, different connectivity patterns were observed for the putamen subregions as shown in Figure 1: anterior body of putamen (ABPu, a), external putamen (EPu, b), fundus of putamen (FPu, c), and posterior body of putamen (PBPu, d). Intricate connectivity networks were observed when all the subregions were combined (e). For the PD subjects, MDS-UPDRS part III scores ranged from 4 to 41, which corresponds to mild to moderate PD6. Figure 2 shows illustrative examples of streamline weight alterations in three PD subjects with varying MDS-UPDRS part III scores for parcels corresponding to DK atlas and full putamen. This highlights the heterogeneous nature of PD connectivity alterations. For the same subjects, when using SGM parcellation and DK-ex atlas, more detailed information was obtained on structural connectivity to, and within, SGM subregions (Figure 3). The 20% strongest correlations between putamen connectivity and MDS-UPDRS-III score are shown for DK atlas in Figure 4. Between the left and right putamen, relatively high (inverse) correlation was observed for caudate on the same hemisphere, but not for other SGM structures, including contralateral caudate or thalamus. Remarkable correlations were observed when the same analysis was repeated for DK-ex atlas with putamen subregions (Figure 5).

Discussion and Conclusions

FPu is a well-documented specialised sub-region in humans13 while EPu has previously been reported in rodent brains14 and has very recently been identified in human using ultra-high resolution MRI at 7T15. However, no putamen subregions have yet been added to extant MRI-based parcellations. Our SGM parcellation and the more detailed connectivity analysis have revealed the structural networks specific to putamen subregions. Fpu and ABPu demonstrated focused connectivity towards the frontal and motor regions while PBPu and Epu showed diffuse connectivity. These findings suggest differential roles of putamen subregions in cortical communication and function, confirming the need for focused connectivity analysis for putamen subregions while assessing PD. Note, our analysis approach can also be extended to explore connectivity in other SGM structures like thalamus.
Heterogeneous alterations were identified in structural connectivity of PD subjects, with both decreased and increased connectivity for different brain parcels. This observation agrees with PD studies where reduced structural connectivity were reported for motor16 and sensorimotor17 regions, while enhanced functional connectivity were recorded for putamen and supplementary motor region18. Relatively strong positive/negative correlations were observed among MDS-UPDRS part III scores and connectivity to cortical regions in a non-bilateral manner, consistent with the asymmetric motor symptoms typically seen in early PD19. Interestingly, negative correlation was found among putamen subregion-SGM structures on the same side of brain while positive correlations were found for contralateral parts (Figure 5) suggesting weakening of intra-SGM connectivity within hemisphere and strengthening of it across hemispheres with gradual increase of MDS-UPDRS part III scores, and thereby, the motor impairment in PD. Higher number of subjects should be assessed in future, with more quantitative measures, to further explore and validate these findings.

Acknowledgements

Data used in the preparation of this article were obtained from the Parkinson’s Progression Markers Initiative (PPMI) database (www.ppmi-info.org/access-dataspecimens/download-data), RRID:SCR 006431. For up-to-date information on the study, visit www.ppmi-info.org.

References

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Figures

Structural connectivity for putamen subregions (shown as inset): ABPu (a), EPu (b), FPu (c), PBPu (d), and all region combined (e) averaged across 20 healthy subjects using DK-ex atlas. Distinctive connectivity patterns are observed for each putamen subregion. Fpu and ABPu demonstrated focused connectivity towards the frontal and motor regions while PBPu and Epu showed diffuse connectivity with a wider coverage. Node sizes, thickness and colour of the connecting lines indicate the strength of connectivity.

Structural connectivity for full putamen in average healthy (a) and in three individual PD subjects with MDS-UPDRS part III score of 4 (b), 21 (c), and 39 (c), corresponding to mild to moderate level in PD severity. Connectivity was computed using DK atlas consisting whole SGM structures (e). Heterogeneous and variable alterations were observed throughout the brain, selected examples of increased and decreased connectivity shown by blue and cyan arrows, respectively. Node sizes, thickness and colour of the connecting lines indicate the strength of connectivity.

Structural connectivity for putamen subregions in average healthy (a) and in three individual PD subjects with MDS-UPDRS part III score of 4 (b), 21 (c), and 39 (c). Connectivity was computed using DK-ex atlas that subdivides SGM structures into nuclei and subregions (e). Heterogeneous and variable alterations, with more specific and detailed information, were observed throughout the brain, examples of increased and decreased connectivity shown by blue and cyan arrows, respectively. Node sizes, thickness and colour of the connecting lines indicate the strength of connectivity.

Strongest 20% positive/negative correlations between connectivity of whole putamen and DK atlas against MDS-UPDRS part III scores for 20 PD subjects. Top row shows the correlation for left putamen and bottom row for the right. Asymmetric correlations were observed for cortex, negative correlation was observer between putamen and caudate in the same hemisphere (black arrow), and not for other SGM structures. Positive correlations were found between right putamen and left caudate (purple arrow), and for contralateral SGM structures including thalamus and pallidum (green arrows).

Strongest 20% positive/negative correlations between putamen subregions and DK-ex atlas against MDS-UPDRS part III scores for 20 PD subjects. Asymmetric correlations were observed for cortex for all putamen subregions. Sub-region specific inter correlations were observed for SGM structures. For example, ABPu, Epu, and PBPu showed negative correlations for thalamic nuclei and subregions in the same hemisphere and positive correlations for matching contralateral structures. Putamen subregions and two of the caudate nuclei ( same hemisphere) showed negative correlations.

Proc. Intl. Soc. Mag. Reson. Med. 32 (2024)
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DOI: https://doi.org/10.58530/2024/2354