Introduction

Parkinson’s disease (PD) patients was categorized into posture instability gait difficulty (PIGD) and tremor-dominant (TD) subtypes according to the predominant motor symptoms for past decades[1]. The disparate neural basis in different subtypes may allow for more personalized treatment. However, the pathophysiological mechanisms of different PD subtypes are not yet well understood. The thalamus is involved in the pathophysiology of both classical striatal-thalamo-cortical (STC)[2] and cerebellothalamic (CTC) circuit[3, 4] in PD. The direction of connectivity differences involving STC and CTC circuit is lacking in PD, which is important for understanding the pathophysiological differences between PD motor subtypes. Therefore, we hypothesize that the subregion of thalamus may be the core pathophysiological region in different PD subtypes, and may mediate different effective connectivity pattern in STC and CTC circuits between PD phenotypes.

Methods

79 PD patients (43TD and 36 PIGD) and 31 normal controls (NC) were recruited and scanned using the arterial spin labeling, T1 structural imaging and resting-state functional magnetic resource imaging. We firstly compared the grey matter volume and perfusion characteristics within the thalamus between PD phenotypes by using one-way analysis of variance (P< 0.05, false discovery rate (FDR) corrected), and then located the result subregion within thalamus. Secondly, we performed a 3x2 full ANOVA (full factorial design) with factors Group (TD, PIGD, NC) and Hemisphere (most affected, least affected) to compare the effective connectivity between subregion of thalamus nucleus and the STC and CTC pathways based on Granger causality analysis (GCA, P< 0.05, FDR corrected). Finally, correlation between these variables and motor deterioration were analyzed in PD subtypes.

Results

There were no statistically significant differences in gender, age, educational levels or MMSE scores among the three groups (table1). The post hoc analysis exhibited that TD subtype showed significant increased perfusion, but not grey volume, in ventral intermediate nucleus(Vim), where the perfusion value was positively correlated with clinical tremor scores (Fig.1, A-C). Even though the difference of perfusion value between PIGD group and NC didn’t have statistical significance, there was a trend of increased CBF value from NC to TD groups. GCA exposed that TD patients have enhanced effective connectivity from bilateral Vim to contralateral paracentral, bilateral M1 and cerebellum compared with NC. PIGD subtype revealed increased effective connectivity from bilateral Vim to bilateral pre-motor cortex and putamen. Directly comparing TD and PIGD, the connectivity from bilateral Vim to bilateral cerebellum significantly increased in TD. What’s more, there were positive correlations between tremor scores and effective connectivity from Vim to cerebellum. Patients with higher connectivity (from right Vim to right precentral and right putamen) showed higher clinical PIGD scores (Fig. 2).

Discussion

This study established that the Vim nucleus perfusion was significantly increased in the TD group, and these perfusion values showed relationship with tremor scores, but this phenomenon was not found in PIGD group. The result highlighted the Vim is the characteristic tremor-related nucleus, which is largely consistent with a recent report[5]. Our findings indicated that the enhanced connectivity from the Vim to the M1 and cerebellum is associated with parkinsonian tremor. This confirmed the Vim-M1-cerebellum circuit is the characteristic pattern optimally described our heterogeneous TD population. The cerebellum is a vital marker in this circuit. It plays a critical role in parkinsonian tremor amplitude and modulation[6]. The putamen is the major input structure of the basal ganglia and receive afferents from thalamus [7]. Single photon emission computed tomography studies found that patients with worse rigidity had more pronounced dopaminergic loss in the posterior putamen[8]. In present study, the Vim nucleus had increased connectivity to putamen in the PIGD patients. What’s more, this connectivity was correlated with the severity of PIGD scores. These findings provide further evidence of a role for the putamen in phenotypic subtype manifestations. We suspected the enhanced connectivity from Vim to the putamen may be a feedback mechanism of dopaminergic loss.

Conclusion

This multilevel analysis showed that the core pathophysiology in TD subtype may lie in the Vim, and a differential effective connectivity pattern existed in TD and PIGD-related networks that related to behavioral heterogeneity in PD.

Acknowledgements

No acknowledgement found.

References

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