title: Functional reorganization of the locomotor network in Parkinson patients with freezing of gait.
abstract: Freezing of gait (FoG) is a transient inability to initiate or maintain stepping that often accompanies advanced Parkinson's disease (PD) and significantly impairs mobility. The current study uses a multimodal neuroimaging approach to assess differences in the functional and structural locomotor neural network in PD patients with and without FoG and relates these findings to measures of FoG severity. Twenty-six PD patients and fifteen age-matched controls underwent resting-state functional magnetic resonance imaging and diffusion tensor imaging along with self-reported and clinical assessments of FoG. After stringent movement correction, fifteen PD patients and fourteen control participants were available for analysis. We assessed functional connectivity strength between the supplementary motor area (SMA) and the following locomotor hubs: 1) subthalamic nucleus (STN), 2) mesencephalic and 3) cerebellar locomotor region (MLR and CLR, respectively) within each hemisphere. Additionally, we quantified structural connectivity strength between locomotor hubs and assessed relationships with metrics of FoG. FoG+ patients showed greater functional connectivity between the SMA and bilateral MLR and between the SMA and left CLR compared to both FoG- and controls. Importantly, greater functional connectivity between the SMA and MLR was positively correlated with i) clinical, ii) self-reported and iii) objective ratings of freezing severity in FoG+, potentially reflecting a maladaptive neural compensation. The current findings demonstrate a re-organization of functional communication within the locomotor network in FoG+ patients whereby the higher-order motor cortex (SMA) responsible for gait initiation communicates with the MLR and CLR to a greater extent than in FoG- patients and controls. The observed pattern of altered connectivity in FoG+ may indicate a failed attempt by the CNS to compensate for the loss of connectivity between the STN and SMA and may reflect a loss of lower-order, automatic control of gait by the basal ganglia.
authors.affiliation: Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Brett W
authors.initials: BW
authors.lastname: Fling
authors.affiliation: Department of Psychology and Communication Studies, University of Idaho Moscow, Idaho, United States of America.
authors.forename: Rajal G
authors.initials: RG
authors.lastname: Cohen
authors.affiliation: Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Martina
authors.initials: M
authors.lastname: Mancini
authors.affiliation: Department of Behavioral Neuroscience, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Carpenter
authors.affiliation: Department of Behavioral Neuroscience, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America; Department of Psychiatry, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: Damien A
authors.initials: DA
authors.lastname: Fair
authors.affiliation: Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America.
authors.forename: John G
authors.initials: JG
authors.lastname: Nutt
authors.affiliation: Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, Oregon, United States of America; Portland VA Medical Center, Portland, Oregon, United States of America.
authors.forename: Fay B
authors.initials: FB
authors.lastname: Horak
mesh_terms: D000368:Aged; D001931:Brain Mapping; D016022:Case-Control Studies; D056324:Diffusion Tensor Imaging; D005260:Female; D005500:Follow-Up Studies; D005615:Freezing; D020233:Gait Disorders, Neurologic / Q000209:etiology* / Q000473:pathology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008124:Locomotion / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology*; D010300:Parkinson Disease / Q000150:complications*; D011379:Prognosis