Resting-state brain connectivity in patients with Parkinson's disease and freezing of gait

doi:10.1016/j.parkreldis.2012.03.018

Parkinsonism & Related Disorders

Volume 18, Issue 6, July 2012, Pages 781-787

https://doi.org/10.1016/j.parkreldis.2012.03.018 Get rights and content

Abstract

Background

Freezing of gait is a common cause of disability and falls in patients with Parkinson's disease. We studied brain functional connectivity, by means of resting-state functional magnetic resonance imaging, in patients with Parkinson's disease and freezing of gait.

Methods

Resting-state functional magnetic resonance imaging at 3 T was collected in 29 patients with Parkinson's disease, of whom 16 presented with freezing of gait as determined by a validated freezing of gait questionnaire, and 15 matched healthy controls. Single-subject and group-level independent component analysis was used to identify the main resting-state networks differing between Parkinson's disease patients with and without freezing of gait. Statistical analysis was performed using BrainVoyager QX.

Results

Between-group differences in resting-state networks revealed that patients with freezing of gait exhibit significantly reduced functional connectivity within both “executive-attention” (in the right middle frontal gyrus and in the angular gyrus) and visual networks (in the right occipito-temporal gyrus) [p < 0.05 corrected for multiple comparisons]. Freezing of gait clinical severity was significantly correlated with decreased connectivity within the two networks. Consistent with their “executive-attention” network impairment, patients with freezing of gait scored lower on tests of frontal lobe functions (phonemic verbal fluency: p = 0.005; frontal assessment battery: p < 0.001; ten point clock test: p = 0.04).

Conclusions

Our findings suggest that a resting-state functional connectivity disruption of “executive-attention” and visual neural networks may be associated with the development of freezing of gait in patients with Parkinson's disease.

Introduction

Freezing of gait (FOG) is a troublesome gait disorder frequently associated with Parkinson's disease (PD) and characterized by the episodic feeling of feet “glued” to the floor that prevents locomotion generally occurring during gait initiation and/or turning [1]. It has been suggested that FOG may be an independent cardinal sign of PD not correlated with bradykinesia and significantly associated with balance and cognitive impairment [2]. Recent evidences [3], [4] have shown that FOG correlates with cognitive frontal lobe dysfunction and in a 2-year follow-up study, FOG was associated with a faster progression of executive dysfunction in PD patients [5]. To date only a few imaging studies have investigated neural correlates of FOG in PD patients, and these have suggested involvement of both frontal and posterior sensory association cortices [6]. To directly address the potential contributions of different neural networks to FOG in PD we studied a group of patients with and without FOG using resting-state functional MRI (RS-fMRI). This non-invasive MRI method, in the absence of experimental tasks, takes full advantage of the neural origin of spontaneous blood-oxygen-level-dependent (BOLD) signal fluctuations to represent the amount of intrinsic activity synchronization across the entire brain [7]. In fact, signal processing tools like independent component analysis (ICA) [8], when applied to whole-brain RS-fMRI, allow extracting from each individual patient's data set a series of activation images describing the BOLD signal temporal correlations within and between functionally connected brain regions, forming highly reproducible neural networks called resting-state networks (RSN) [9]. We hypothesized that PD patients with FOG would exhibit a decreased functional resting connectivity within cognitive RSN as compared to patients without FOG.

Section snippets

Patients population

We investigated 29 patients (8 women and 21 men) with a diagnosis of PD according to the clinical diagnostic criteria of the United Kingdom Parkinson's disease Society Brain Bank [10]. Inclusion criteria were: (1) age of 45 years or older; (2) a Hoehn & Yahr (H&Y) stage equal or less than 2.5 while in an “on state”; (3) disease duration less than 10 years; and (4) antiparkinsonian treatment at a stable and optimized daily dosage during the 4 weeks prior to study entry. Exclusion criteria were:

Clinical and motor evaluation

Among the 29 subjects, 16 were classified as FOG+ and 13 FOG−. The two groups did not differ in age, male/female ratio, disease duration, H&Y score, UPDRS I, III, IV scores and antiparkinsonian treatment. The UPDRS II score differed significantly between two groups, due to the fact that the scale contains two gait-related items (item 14: freezing; item 15: walking) which score significantly higher in presence of FOG.The two groups did not differ on tremor UPDRS sub score. The total Postural

Discussion

This is the first study exploring the resting-state brain functional connectivity in PD patients with and without FOG. Our findings revealed relatively reduced functional brain connectivity within regions of the “executive-attention” network (RFPN), and the visual network in FOG+ patients. Such differences were not statistically significant between FOG− patients and healthy controls. Moreover, consistent with these alterations and with previous reports [3], [4], presence of FOG was associated

Acknowledgments

The authors thank Ahmad Hariri for the critical review of the manuscript and Antonella Paccone for technical assistance.

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Compared with healthy controls, patients with PD showed increased ALFF in the bilateral motor area and decreased ALFF in the bilateral temporal cortex and cerebellum. The Hoehn-Yahr stages correlated with ALFF within the bilateral cerebellum (p = 0.021), and UPDRS-III improvement correlated with ALFF in the left (p < 0.001) and right (p = 0.005) motor areas. The regression model showed a significant correlation between the predicted and observed UPDRS-III changes (R = 0.65, p < 0.001). The ROC analysis revealed an area under the curve (AUC) of 0.94 which differentiated moderate and superior DBS responders.
The results revealed altered ALFF patterns in patients with PD and their correlations with clinical variables. Both binary and continuous ALFF can potentially serve as predictive biomarkers for DBS response.
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Therefore, we analyzed RSNs of 27 PD patients (8 females, 59.0 +- 8.7 years) using magnetoencephalography and compared them to RSNs of 24 age-matched healthy controls (8 females, 62.8 +- 5.1 years). We recorded 30 min of resting-state activity two days before and one day after implantation of the electrodes with and without dopaminergic medication. RSNs were determined by use of phase-amplitude coupling between a low frequency phase and a high gamma amplitude and examined for differences between conditions (i.e., pre vs post surgery).
We identified four RSNs across all conditions: sensory-motor, visual, fronto-occipital, and frontal. Each RSN was altered due to electrode implantation. Importantly, these changes were not restricted to spatially close areas to the electrode trajectory.
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We previously showed that both open-loop (beat of a metronome) and closed-loop (phase-dependent tactile feedback) cueing may be similarly effective in reducing Freezing of Gait (FoG), assessed with a quantitative FoG Index, while turning in place in the laboratory in a group of people with Parkinson’s disease (PD). Despite the similar changes on the FoG Index, it is not known whether both cueing responses require attentional control, which would explain FoG Index improvement. The mechanisms underlying cueing responses are poorly understood. Here, we tested the hypothesis that the salience network would predict responsiveness (i.e., FoG Index improvement) to open-loop and closed-loop cueing in people with and without FoG of PD, as salience network contributes to tasks requiring attention to external stimuli in healthy adults. Thirteen people with PD with high-quality imaging data were analyzed to characterize relationships between resting-state MRI functional connectivity and responses to cues. The interaction of the salience network and retrosplenial-temporal networks was the best predictor of responsiveness to open-loop cueing, presenting the largest effect size (d = 1.16). The interaction between the salience network and subcortical as well as cingulo-parietal and subcortical networks were the strongest predictors of responsiveness to closed-loop cueing, presenting the largest effect sizes (d = 1.06 and d = 0.84, respectively). Salience network activity was a common predictor of responsiveness to both cueing, which suggests that auditory and proprioceptive stimuli during turning may require some level of cognitive and insular activity, anchored within the salience network, which explain FoG Index improvements in people with PD.
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Citation Excerpt :
Due to conflicting findings in the literature [23,46,57], we were less able to predict the spectral pattern underlying motor dysfunction in freezers. Concerning brain functional connectivity in PD+FoG, in line with previous fMRI studies, we expected abnormal functional connectivity in frontal networks, brain regions responsible for frontal executive and attention abilities [5,38,62,71], but also in posterior rather than in anterior brain areas, especially in the right hemisphere in parieto-occipital networks that are regions responsible for visuospatial abilities [9,62]. It is, however, quite difficult to compare EEG results with those from fMRI studies.
The pathophysiology of freezing of gait in people with Parkinson's disease (PD) remains unclear, despite its association with motor, cognitive, limbic and sensory-perceptual impairments. Resting-state electroencephalography (EEG) may provide functional information for a better understanding of freezing of gait by studying spectral power and connectivity between brain regions in different frequency bands.
High-resolution EEG was recorded in 36 patients with PD (18 freezers, 18 non-freezers), and 18 healthy controls during a 5-min resting-state protocol with eyes open, followed by a basic spectral analysis in the sensor space and a more advanced analysis of functional connectivity at the source level.
Freezers showed a diffusely higher theta-band relative spectral power than controls. This increased power was correlated with a deficit in executive control. Concerning resting-state functional connectivity, connectivity strength within a left fronto-parietal network appeared to be higher in freezers than in controls in the theta band, and to be correlated with freezing severity and a history of falls.
We have shown that spectral power and connectivity analyses of resting-state EEG provide useful and complementary information to better understand freezing of gait in PD. The higher connectivity strength seen within the left ventral attention network in freezers is in keeping with an excessive guidance of behavior by external cues, due to executive dysfunction, and spectral analysis also found changes in freezers that was closely correlated with executive control deficits. This exaggerated influence of the external environment might result in behavioral consequences that contribute to freezing of gait episodes. These findings should be further investigated with a longitudinal study.

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¹: Equally contributed to the paper.

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Resting-state brain connectivity in patients with Parkinson's disease and freezing of gait

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Patients population

Clinical and motor evaluation

Discussion

Acknowledgments

Lancet Neurol

Parkinsonism Relat Disord

Neuroimage

Parkinsonism Relat Disord

J Neurol Sci

Neuropsychologia

Lancet Neurol

J Clin Neurosci

Freezing of gait. Clinical overview

Adv Neurol

Freezing of gait and executive functions in patients with Parkinson's disease

Mov Disord

The specific contributions of set-shifting to freezing of gait in Parkinson's disease

Mov Disord

A two-year follow-up study of executive dysfunctions in parkinsonian patients with freezing of gait at on-state

Mov Disord

Brain imaging in patients with freezing of gait

Mov Disord

Electrophysiological signatures of resting state networks in the human brain

Proc Natl Acad Sci U S A

Topographic independent component analysis

Neural Comput