Exploring the cortical and subcortical functional magnetic resonance imaging changes associated with freezing in Parkinson's disease

1 Parkinson's Disease Research Clinic, Brain and Mind Research Institute, The University of Sydney, NSW 2050, Australia.
Brain (Impact Factor: 9.2). 03/2013; 136(4). DOI: 10.1093/brain/awt049
Source: PubMed


Freezing of gait is a devastating symptom of advanced Parkinson's disease yet the neural correlates of this phenomenon remain poorly understood. In this study, severity of freezing of gait was assessed in 18 patients with Parkinson's disease on a series of timed 'up and go' tasks, in which all patients suffered from episodes of clinical freezing of gait. The same patients also underwent functional magnetic resonance imaging with a virtual reality gait paradigm, performance on which has recently been shown to correlate with actual episodes of freezing of gait. Statistical parametric maps were created that compared the blood oxygen level-dependent response associated with paroxysmal motor arrests (freezing) to periods of normal motor output. The results of a random effects analysis revealed that these events were associated with a decreased blood oxygen level-dependent response in sensorimotor regions and an increased response within frontoparietal cortical regions. These signal changes were inversely correlated with the severity of clinical freezing of gait. Motor arrests were also associated with decreased blood oxygen level-dependent signal bilaterally in the head of caudate nucleus, the thalamus and the globus pallidus internus. Utilizing a mixed event-related/block design, we found that the decreased blood oxygen level-dependent response in the globus pallidus and the subthalamic nucleus persisted even after controlling for the effects of cognitive load, a finding which supports the notion that paroxysmal increases in basal ganglia outflow are associated with the freezing phenomenon. This method also revealed a decrease in the blood oxygen level-dependent response within the mesencephalic locomotor region during motor arrests, the magnitude of which was positively correlated with the severity of clinical freezing of gait. These results provide novel insights into the pathophysiology underlying freezing of gait and lend support to models of freezing of gait that implicate dysfunction across coordinated neural networks.


Available from: James M Shine, Nov 23, 2015
    • "in - stem and basal ganglia , we defined a number of regions of interest ( ROIs ) : the primary motor cortex , dorsal pre - motor area , dorsolateral prefrontal cortex , medial pre - frontal cortex , posterior parietal cortex , subthalamic nucleus , thalamus , putamen , globus pallidus , caudate nucleus , ventral striatum and MLR , as described by Shine et al . ( 2013a ) . The coordinates of each ROI were registered on each PET scan ( normalized in MNI space ) ."
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    ABSTRACT: Freezing of gait (FoG) is a debilitating gait disorder in Parkinson's disease (PD). In advanced PD patients with FoG, the supraspinal locomotor network may be dysregulated (relative to similar patients without FoG) during gait. Here, we sought to characterize the metabolism of locomotor networks involved in FoG. Twenty-two PD patients (11 with off-drug FoG and 11 without) each underwent two [(18)F]-fluorodeoxyglucose PET brain scans in the off-drug state: one at rest and another during radiotracer uptake while performing a standardized gait trajectory that incorporated the usual triggers for FoG. For the 11 freezers, FoG was present for 39% (±23%) of the time during the gait trajectory. The FoG-associated abnormalities were characterized by (i) hypometabolism in frontal regions (the associative premotor, temporopolar and orbitofrontal areas, i.e. Brodmann areas 6 and 8), (ii) hypermetabolism in the paracentral lobule (Brodmann area 5), and (iii) deregulation of the basal ganglia output (the globus pallidus and the mesencephalic locomotor region). FoG during a real gait task was associated with impaired frontoparietal cortical activation, as characterized by abnormally low metabolic activity of the premotor area (involved in the indirect locomotor pathway) and abnormally high metabolic activity of the parietal area (reflecting the harmful effect of external cueing). Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 09/2015; 307. DOI:10.1016/j.neuroscience.2015.08.063 · 3.36 Impact Factor
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    • "Deep brain stimulation of the globus pallidus has been shown to have variable effects on gait and balance problems in Parkinson's disease (Krack et al., 1998; Pö tter-Nerger and Volkmann, 2013), and can even provoke gait freezing in patients with cervical dystonia (Berman et al., 2009). Moreover, recent functional MRI studies have demonstrated that freezing of gait is associated with decreased blood oxygen level-dependent signal in the globus pallidus during a virtual reality gait task (Shine et al., 2013; Peterson et al., 2014). We speculate that loss of PDE10A in the globus pallidus Figure 2 Statistical parametric maps of 11 C-IMA107 BP ND (MNI co-ordinates x = 17.99, y = 3.59, z = 7.42). "
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    ABSTRACT: The mechanisms underlying neurodegeneration and loss of dopaminergic signalling in Parkinson's disease are still only partially understood. Phosphodiesterase 10A (PDE10A) is a basal ganglia expressed dual substrate enzyme, which regulates cAMP and cGMP signalling cascades, thus having a key role in the regulation of dopaminergic signalling in striatal pathways, and in promoting neuronal survival. This study aimed to assess in vivo the availability of PDE10A in patients with Parkinson's disease using positron emission tomography molecular imaging with (11)C-IMA107, a highly selective PDE10A radioligand. We studied 24 patients with levodopa-treated, moderate to advanced Parkinson's disease. Their positron emission tomography imaging data were compared to those from a group of 12 healthy controls. Parametric images of (11)C-IMA107 binding potential relative to non-displaceable binding (BPND) were generated from the dynamic (11)C-IMA107 scans using the simplified reference tissue model with the cerebellum as the reference tissue. Corresponding region of interest analysis showed lower mean (11)C-IMA107 BPND in the caudate (P < 0.001), putamen (P < 0.001) and globus pallidus (P = 0.025) in patients with Parkinson's disease compared to healthy controls, which was confirmed with voxel-based analysis. Longer Parkinson's duration correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.65; P = 0.005), putamen (r = -0.51; P = 0.025), and globus pallidus (r = -0.47; P = 0.030). Higher Unified Parkinson's Disease Rating Scale part-III motor scores correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.54; P = 0.011), putamen (r = -0.48; P = 0.022), and globus pallidus (r = -0.70; P < 0.001). Higher Unified Dyskinesia Rating Scale scores in those Parkinson's disease with levodopa-induced dyskinesias (n = 12), correlated with lower (11)C-IMA107 BPND in the caudate (r = -0.73; P = 0.031) and putamen (r = -0.74; P = 0.031). Our findings demonstrate striatal and pallidal loss of PDE10A expression, which is associated with Parkinson's duration and severity of motor symptoms and complications. PDE10A is an enzyme that could be targeted with novel pharmacotherapy, and this may help improve dopaminergic signalling and striatal output, and therefore alleviate symptoms and complications of Parkinson's disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Brain 07/2015; DOI:10.1093/brain/awv219 · 9.20 Impact Factor
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    • " ( Aron and Poldrack , 2006 ; Frank et al . , 2007 ; Isoda and Hikosaka , 2008 ) . Indeed , the STN is differentially activated in Parkinsons ' s disease patients with freezing of gait ( Vercruysse et al . , 2014 ) as well as in patients with Parkinson ' s disease navigating a virtual environment with cognitive loading that induced motor arrests ( Shine et al . , 2013 ) . Such complex situations likely arise during natural locomotion , raising the possibility that the PPN and STN can interact during natural locomotor behaviour to adapt automatic gait programs to internal and external needs . There is strong evidence that the PPN and STN interact . In Parkinson ' s disease , high frequency STN stimula"
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    ABSTRACT: The brainstem pedunculopontine nucleus has a likely, although unclear, role in gait control, and is a potential deep brain stimulation target for treating resistant gait disorders. These disorders are a major therapeutic challenge for the ageing population, especially in Parkinson's disease where gait and balance disorders can become resistant to both dopaminergic medication and subthalamic nucleus stimulation. Here, we present electrophysiological evidence that the pedunculopontine and subthalamic nuclei are involved in distinct aspects of gait using a locomotor imagery task in 14 patients with Parkinson's disease undergoing surgery for the implantation of pedunculopontine or subthalamic nuclei deep brain stimulation electrodes. We performed electrophysiological recordings in two phases, once during surgery, and again several days after surgery in a subset of patients. The majority of pedunculopontine nucleus neurons (57%) recorded intrasurgically exhibited changes in activity related to different task components, with 29% modulated during visual stimulation, 41% modulated during voluntary hand movement, and 49% modulated during imaginary gait. Pedunculopontine nucleus local field potentials recorded post-surgically were modulated in the beta and gamma bands during visual and motor events, and we observed alpha and beta band synchronization that was sustained for the duration of imaginary gait and spatially localized within the pedunculopontine nucleus. In contrast, significantly fewer subthalamic nucleus neurons (27%) recorded intrasurgically were modulated during the locomotor imagery, with most increasing or decreasing activity phasically during the hand movement that initiated or terminated imaginary gait. Our data support the hypothesis that the pedunculopontine nucleus influences gait control in manners extending beyond simply driving pattern generation. In contrast, the subthalamic nucleus seems to control movement execution that is not likely to be gait-specific. These data highlight the crucial role of these two nuclei in motor control and shed light on the complex functions of the lateral mesencephalus in humans. http://www.ncbi.nlm.nih.gov/pubmed/25765327
    Brain 05/2015; 138(5):1284-1296. DOI:10.1093/brain/awv047 · 9.20 Impact Factor
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