Loss of functional specificity in basal ganglia in Parkinson's disease: a rs-fMRI study
Anne-Charlotte PHILIPPE1, Pierre BERROIR1, Marie VIDAILHET2, and Stéphane LEHERICY1

1Brain and Spine Institute, CENIR, INSERM U1127/CNRS UMR7225, Sorbonne Universités, UPMC, CHU Pitié-Salpêtrière, Paris, France, 2Brain and Spine Institute, INSERM U1127/CNRS UMR7225, Sorbonne Universités, UPMC, CHU Pitié-Salpêtrière, Paris, France

Synopsis

Loss of neuronal specificity in the basal ganglia (BG) has been reported In Parkinson’s disease (PD)[1]. However, loss of specificity has not been characterized using non-invasive methods in PD. We proposed an innovative method to characterize the functional specificity of BG. We tested the hypothesis that loss of specificity may result in larger spatial extent of overlap between anatomo-functional territories in the BG. We performed population statistics to compare the extent of overlap between PD subjects and controls. As expected, the motor territories had larger extent of overlap in PD subject than in controls revealing a loss of specificity of the BG in PD.

Purpose

The basal ganglia (BG) are organized in specific anatomo-functional territories including sensorimotor, associative and limbic territories. BG neurons display highly specific movement-related activity modulations [1]. In PD, BG neurons lose their selective movement-related activity profiles and display activity modulations related to a larger range of behavioral events [1]. This loss of specificity may result in reduced specificity and larger overlap of BG anatomo-functional territories. Here, we tested the hypothesis that loss of specificity of the BG in PD would result in increased overlap between anatomo-functional territories. To this aim, we used diffusion tensor imaging and resting state functional MRI (rs-fMRI) to study anatomical and functional connectivity profiles in PD as compared to healthy volunteers.

Methods

The study included 56 patients with idiopatic PD and 29 healthy volunteers (HV) matched for age. Each PD patient had two MRI acquisitions, one without (PD-Off) and another with L-dopa (PD-On) medication. Magnetic resonance images were acquired using a 3.0T scanner (Siemens Trio) including: T1 weighted MRI and resting state BOLD fMRI (rs-fMRI) with T2*-weighted echo planar images (EPI's) (repetition time: 2.95ms; echo time: 25ms; 48 slices, field of view: 224*224mm², flip angle: 90°; voxel size: 2mm isotropic; acquisition time: 10mn). The method pipeline is illustrated in the flowchart in figure 1. Rs-fMRI were preprocessed using SPM8 [soft1] (slice timing, motion correction, spatial smoothing, low-pass filter at 0.1Hz). Then EPI's were coregistered into the T1 space of each subject. Cortical territories were extracted from T1 MRI using Freesurfer [soft2] based on the Desikan atlas [2] generating 114 ROI: 20 for sensorimotor (SM), 58 for associative (As) and 36 for limbic (Li) cortical areas (see Figure 2). We studied: pallidum, caudate and putamen, segmented with the histological deformable YeB atlas [3]. We computed the functional connectivity profile $$$\mathcal{C}_v$$$ of each voxel $$$v$$$ of BG. After averaging the BOLD signal over all voxels in each cortical region, the correlation $$$r$$$ between BG voxel v and each cortical territory (As,SM,Li) is computed resulting a vector $$$\mathcal{C}_v=[r(v,SM),r(v,As),r(v,Li)]$$$. We postulate that BG can be divided into these seven following territories : the specific ones SM, As, Li and the overlapping ones SM-As, SM-Li, As-Li, SM-As-Li. Thus, we performed a functional profile-based hierarchical clustering into seven clusters of the voxels of each BG. Then for each cluster$$$l$$$, we computed its functional profile $$$\mathcal{C}_l$$$ as the normalized mean of the functional profiles of voxels composing this cluster. Finally, to determine the functional territory of the cluster, we computed the binarized functional profiles $$$\mathring{\mathcal{C}}_l$$$ such as $$\mathring{\mathcal{C}}_{l}(k) = \begin{cases} 1 \: \: \: if \: \: \: {\mathcal{C}}_{l}(k)> t \: * \: \smash{\displaystyle\max_{1 \leq k \leq 3}} {\mathcal{C}}_{l}(k) \\ 0 \: \: \: otherwise \end{cases}$$. The computation of the proportion of each territory implies that the threshold $$$t$$$ has to be fixed resulting a direct consequence on comparative results. For this reason, we analyzed the evolution of the proportion of each territory as a function of $$$t$$$ sampling between 0% to 100%. Thus, for each subject, we computed $$$Ps(t)$$$ and $$$Po(t)$$$ respectively equal to the proportion of specific and overlapping territories in BG as a function of $$$t$$$. Then, we computed the intersection point $$$ti$$$ such as $$$Ps(ti) = Po(ti)$$$. Finally, we performed $$$ti$$$-based population statistics between the three groups using ANOVA. Then for p-values inferior to 0.05, post-hoc comparison using two sample t-test was used between each pair of groups.

Results

We studied the specificity of all territories as well as the specificity of SM territories ($$$Ps(t)$$$ equal to the proportion of SM territory and $$$Po(t)$$$ to the proportion of overlapping territories where SM is involved), as well as As and Li territories. Results presented in Figure 3 show that the intersection point was significantly lower in HV than in PD-Off in the SM territories (P= 0.0357). Considering the intersection values, we fixed for each BG the threshold of 95% and compared the proportion of territories between groups. Results are presented in Figure 4. In the right pallidum, the proportion of the SM-As-Li territory was significatively lower in the PD-Off than PD-On subjects whereas the spatial proportion of the SM-As territory was greater in the PD-Off than both PD-On and HV. The spatial proportion of the SM territory in HV was greater than in both the PD-On and PD-Off groups in the left putamen.

Discussion

Increased proportion of the SM-As-Li overlap may indicate reduced specificity of neuronal representations in the BG. SM (specific or overlapping) territories were involved in all between-group differences. This result was in accordance with the known predominance of PD-pathological changes in SM regions of the BG [4].

Conclusion

We proposed an innovative method allowing to characterize the functional specificity of territories without hypothesis on the functional correlation threshold. Results are in agreement with the loss of specificity of functional territories in PD and showed predominant involvement of the SM territory. This method can be applied to all modalities which give access to cortico-BG connectivity. Thus the same technique - applied on diffusion MRI in order to get structural territories - would allow investigating the link between structure and function in the BG.

Acknowledgements

The research leading to these results has received fund-ing from the program "Investissements d’avenir" ANR-10-IAIHU-06 and the "Agence Nationale de la Recherche"(ANRMNP 2009, Nucleipark), DHOS-Inserm (2010, Nucleipark), France Parkinson (2008), Ecole Neuroscience de Paris.

References

[1] Bronfeld, M., & Bar-Gad, I. (2011). Loss of specificity in Basal Ganglia related movement disorders. Frontiers in systems neuroscience, 5.

[2] Desikan, R. S., Ségonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker, D., ... & Killiany, R. J. (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage, 31(3), 968-980.

[3] Yelnik, J., Bardinet, E., Dormont, D., Malandain, G., Ourselin, S., Tandé, D., ... & Agid, Y. (2007). A three-dimensional, histological and deformable atlas of the human basal ganglia. I. Atlas construction based on immunohistochemical and MRI data. Neuroimage, 34(2), 618-638.

[4] Kish, S. J., Shannak, K., & Hornykiewicz, O. (1988). Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. New England Journal of Medicine, 318(14), 876-880.

[soft1] www.fil.ion.ucl.ac.uk/spm/software/spm8/

[soft2] freesurfer.net/

Figures

Figure 1: Computational processing flowchart for the characterization of functional specificity of BG.

Figure 2: Segmentation of cortical territories using Freesurfer: sensorimotor (SM) in red, limbic (Li) in blue and associative (As) in green. Each territory comprised respectively 20, 36 and 58 subregions.

Figure 3: Characterization of the functional specificity of territories. Graphical representation of the mean of $$$Ps(t)$$$ (continuous lines) and $$$Po(t)$$$ (dashed lines) between HV (in green), PD-On (in red) and PD-Off (in blue) in the four configurations described section Methods.

Figure 4: Results of the analysis of the right pallidum and the left putamen. Territories presenting significant differences are framed in red.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
3788