Objective: To investigate the resting state connectivity in cortico-striatal-thalamo-cortical networks pre-conversion and pre- to post-conversion to Freezing of Gait in Parkinson’s disease.

Background: Freezing of gait (FOG) is a debilitating gait disorder, common in persons with Parkinson’s disease (PwPD). Prospective data is lacking on the neural mechanisms that reduce the threshold for FOG to emerge with time¹. Previous work showed that morphological alterations in the medial thalamus predicted conversion to FOG². Here, we investigated the functional connectivity changes in networks involving the thalamus, prior to and during conversion to FOG.

Method: Forty-six PwPD were included if they had not previously experienced FOG, and conversion was assessed annually. Resting state fMRI (rs-fMRI) was acquired at two time points, two years apart. Rs-fMRI volumes were preprocessed using fMRIPrep³ and further denoising and statistical analyses were performed using the CONN toolbox⁴. ROI-to-ROI coupling within the motor, limbic and associative cortico-striatal circuits⁵ was analysed between PwPD who developed FOG (converters – CONV) and those that did not (non-converters – NCONV) using multivariate pattern analysis. Three CONV and two NCONV were excluded due to high-motion censoring.

Results: Over the two years, 10 out of the 46 PwPD developed FOG. Compared to NCONV, CONV had similar disease duration (U = 130.5, p = 0.191), but higher MDS-UPDRS motor scores pre-conversion (U = 100.5, p = 0.033). Rs-fMRI analyses at this time point revealed CONV showed stronger coupling in the limbic network (thalamus mediodorsal nucleus – left: F(4,33) = 6.79, p_FDR = 0.016; right: F(4,33) = 6.12, p_FDR = 0.016), and associative network (right dorsolateral prefrontal cortex: F(4,33) = 5.89, p_FDR = 0.047; right caudate: F(4,33) = 5.38, p_FDR = 0.047). Over the two years, coupling reduced within the limbic network (mid cingulate cortex: F(4,33) = 5.50, p_FDR = 0.062) in CONV compared to NCONV, as well as within the associative network, although this did not survive multiple comparison correction.

Conclusion: Prior to conversion, converters showed stronger coupling within the limbic and associative networks, possibly to compensate for motor deficits. Conversion to FOG was accompanied by decoupling within these networks, suggesting that functional decompensation within these non-motor circuits predisposes PwPD to experience FOG.

References: 1: Weiss D, Schoellmann A, Fox MD, Bohnen NI, Factor SA, Nieuwboer A, Hallett M, Lewis SJG. Freezing of gait: understanding the complexity of an enigmatic phenomenon. Brain. 2020 Jan 1;143(1):14-30. doi: 10.1093/brain/awz314. PubMed PMID: 31647540; PubMed Central PMCID: PMC6938035. 2: N. D’Cruz, G. Vervoort, W. Vandenberghe, A. Nieuwboer. Alteration to Basal Ganglia Morphology in Freezing of Gait in Parkinson’s Disease [abstract]. Mov Disord. 2018; 33 (suppl 2). https://www.mdsabstracts.org/abstract/alteration-to-basal-ganglia-morphology-in-freezing-of-gait-in-parkinsons-disease/. Accessed February 28, 2020. 3: Esteban O, Markiewicz CJ, Blair RW, Moodie CA, Isik AI, Erramuzpe A, Kent JD, Goncalves M, DuPre E, Snyder M, Oya H, Ghosh SS, Wright J, Durnez J, Poldrack RA, Gorgolewski KJ. fMRIPrep: a robust preprocessing pipeline for functional MRI. Nat Methods. 2019 Jan;16(1):111-116. doi: 10.1038/s41592-018-0235-4. Epub 2018 Dec 10. PubMed PMID: 30532080; PubMed Central PMCID: PMC6319393. 4: Whitfield-Gabrieli, S., & Nieto-Castanon, A. (2012). Conn: A functional connectivity toolbox for correlated and anticorrelated brain networks. Brain connectivity, 2(3), 125-141 5: Galvan A, Devergnas A, Wichmann T. Alterations in neuronal activity in basal ganglia-thalamocortical circuits in the parkinsonian state. Front Neuroanat. 2015;9:5. Published 2015 Feb 5. doi:10.3389/fnana.2015.00005

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MDS Abstracts - https://www.mdsabstracts.org/abstract/non-motor-network-decoupling-accompanies-conversion-to-freezing-of-gait-in-parkinsons-disease/