Levodopa-sensitive, dynamic changes in effective connectivity during simultaneous movements in Parkinson's disease

doi:10.1016/j.neuroscience.2008.06.053

Neuroscience

Volume 158, Issue 2, 23 January 2009, Pages 693-704

https://doi.org/10.1016/j.neuroscience.2008.06.053 Get rights and content

Abstract

Changes in effective connectivity during the performance of a motor task appear important for the pathogenesis of motor symptoms in Parkinson's disease (PD). One type of task that is typically difficult for individuals with PD is simultaneous or bimanual movement, and here we investigate the changes in effective connectivity as a potential mechanism. Eight PD subjects off and on l-DOPA medication and 10 age-matched healthy control subjects performed both simultaneous and unimanual motor tasks in an fMRI scanner. Changes in effective connectivity between regions of interest (ROIs) during simultaneous and unimanual task performance were determined with structural equation modeling (SEM), and changes in the temporal dynamics of task performance were determined with multivariate autoregressive modeling (MAR). PD subjects demonstrated alterations in both effective connectivity and temporal dynamics compared with control subjects during the performance of a simultaneous task. l-DOPA treatment was able to partially normalize effective connectivity and temporal patterns of activity in PD, although some connections remained altered in PD even after medication. Our results suggest that difficulty performing simultaneous movements in PD is at least in part mediated by a disruption of effective communication between widespread cortical and subcortical areas, and l-DOPA assists in normalizing this disruption. These results suggest that even when the site of neurodegeneration is relatively localized, study of how disruption in a single region affects connectivity throughout the brain can lead to important advances in the understanding of the functional deficits caused by neurodegenerative disease.

Section snippets

Subjects

Ten volunteers with clinically diagnosed PD participated in the study (seven men, three women, mean age 64±8 years, all right-handed). Data from two PD subjects were subsequently removed from analysis due to problems with scanner and data reconstruction. All patients had mild to moderately severe PD (Hoehn and Yahr stage 1–3) (Hoehn and Yahr, 1967). Exclusion criteria included atypical Parkinsonism, presence of other neurological or psychiatric conditions, and use of antidepressants, hypnotics,

Behavioral data

ANOVA results demonstrate that there were no significant differences in the error rates between each subject group (F(2,37)=3.09, P>0.94), or between the bimanual and unimanual task (F(1,37)=0.09, P>0.23). Fig. 4 shows the squeeze-bulb force output for each subject against the target pathway. Individual forces were scaled to be comparable between subjects. The data demonstrate that all subjects performed the task accurately.

All subjects were given practice on the task before data collection to

Discussion

Our results confirm that changes in connectivity between brain regions, as opposed to activation of discrete loci, are important for the performance of simultaneous tasks. Even when using individually-drawn ROIs to avoid misregistration errors caused by the usual practice of warping individual subjects' brain images to a common template (Nieto-Castanon et al., 2003), and using a discriminant method robust to intersubject variability (McKeown et al., 2007), we found only four ROIs had

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Freezing of gait (FOG) is a paroxysmal gait disorder that often occurs at advanced stages of Parkinson's disease (PD). FOG consists of abrupt walking interruption and severe difficulty in locomotion with an increased risk of falling. Pathophysiological mechanisms underpinning FOG in PD are still unclear. However, advanced MRI and nuclear medicine studies have gained relevant insights into the pathophysiology of FOG in PD. Neuroimaging studies have demonstrated structural and functional abnormalities in a number of cortical and subcortical brain regions in PD patients with FOG. In this paper, we systematically review existing neuroimaging literature on the structural and functional brain changes described in PD patients with FOG, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We evaluate previous studies using various MRI techniques to estimate grey matter loss and white matter degeneration. Moreover, we review functional brain changes by examining functional MRI and nuclear medicine imaging studies. The current review provides up-to-date knowledge in this field and summarizes the possible mechanisms responsible for FOG in PD.
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Other studies have found remapping of striatal connectivity in PD at rest, with reduced spatial segregation between different cortico-striatal loops (Hacker et al., 2012; Helmich et al., 2010), and even accurately predicting whether PD subjects would develop dyskinesia (Herz et al., 2016). Task-based alterations in striatal connectivity in PD have also been investigated (Palmer et al., 2009; Wu et al., 2011a, 2011b). For instance, during a self-initiated right hand tapping task, connectivity between the putamen and M1, PMC, SMA and cerebellum were found to be decreased in PD patients (Wu et al., 2011a, 2011b).
Parkinson's Disease (PD) is associated with decreased ability to perform habitual tasks, relying instead on goal-directed behaviour subserved by different cortical/subcortical circuits, including parts of the putamen. We explored the functional subunits in the putamen in PD using novel dynamic connectivity features derived from resting state fMRI recorded from thirty PD subjects and twenty-eight age-matched healthy controls (HC). Dynamic functional segmentation of the putamina was obtained by determining the correlation between each voxel in each putamen along a moving window and applying a joint temporal clustering algorithm to establish cluster membership of each voxel at each window. Contiguous voxels that had consistent cluster membership across all windows were then considered to be part of a homogeneous functional subunit. As PD subjects robustly had two homogenous clusters in the putamina, we also segmented the putamina in HC into two dynamic clusters for a fair comparison. We then estimated the dynamic connectivity using sliding windowed correlation between the mean signal from the identified homogenous subunits and 56 other predefined cortical and subcortical ROIs. Specifically, the mean dynamic connectivity strength and connectivity deviation were then compared to evaluate subregional differences.
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Clinical NeuroscienceLevodopa-sensitive, dynamic changes in effective connectivity during simultaneous movements in Parkinson's disease

Abstract

Section snippets

Subjects

Behavioral data

Discussion

Neuroimage

Neuroimage

Neuroimage

Neuroimage

Neuroimage

Neuroimage

Electroencephalogr Clin Neurol

The role of striatum in initiation and execution of learned action sequences in rats

J Neurosci

Simple and complex movements off and on treatment in patients with Parkinson's disease

J Neurol Neurosurg Psychiatry

Performance of simultaneous movements in patients with Parkinson's disease

Brain

Continuous functional magnetic resonance imaging reveals dynamic nonlinearities of dose-response curves for finger opposition

J Neurosci

Functional connectivity in the motor cortex of resting human brain using echo-planar MRI

Magn Reson Med

The psychophysics toolbox

Spat Vis

Bad oscillations in Parkinson's disease

J Neural Transm Suppl

Characterizing functional integration

Increased dependence on visual information for movement control in patients with Parkinson's disease

Can J Neurol Sci

Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands

Cereb Cortex

Mapping functionally related regions of brain with functional connectivity MR imaging

Am J Neuroradiol

The role of the striatum and hippocampus in planningA PET activation study in Parkinson's disease

Brain

Dissociating the roles of the rostral anterior cingulate and the lateral prefrontal cortices in performing two tasks simultaneously or successively

Cereb Cortex

Simultaneous movements of upper and lower limbs are coordinated by motor representations that are shared by both limbs: A PET study

Eur J Neurosci

Control of simultaneous movements distinguishes depressive motor retardation from Parkinson's disease and neuroleptic parkinsonism

Brain

Neural correlates of dual task interference can be dissociated from those of divided attention: An fMRI study

Cereb Cortex

Parkinsonism: Onset, progression and mortality

Neurology

Bimanual simultaneous motor performance and impaired ability to shift attention in Parkinson's disease

J Neurol Neurosurg Psychiatry

Self-initiated versus externally triggered movementsAn investigation using measurement of regional cerebral blood flow with PET and movement-related potentials in normal and Parkinson's disease subjects

Brain

Parkinson's disease: clinical features and diagnosis

J Neurol Neurosurg Psychiatry

Clinical Neuroscience
Levodopa-sensitive, dynamic changes in effective connectivity during simultaneous movements in Parkinson's disease