Elsevier

NeuroImage

Volume 41, Issue 2, June 2008, Pages 212-222
NeuroImage

Increased cortico-cortical functional connectivity in early-stage Parkinson's disease: An MEG study

https://doi.org/10.1016/j.neuroimage.2008.02.027Get rights and content

Abstract

We set out to determine whether changes in resting-state cortico-cortical functional connectivity are a feature of early-stage Parkinson's disease (PD), explore how functional coupling might evolve over the course of the disease and establish its relationship with clinical deficits.

Whole-head magnetoencephalography was performed in an eyes-closed resting-state condition in 70 PD patients with varying disease duration (including 18 recently diagnosed, drug-naive patients) in an “OFF” medication state and 21 controls. Neuropsychological testing was performed in all subjects. Data analysis involved calculation of three synchronization likelihood (SL, a general measure of linear and non-linear temporal correlations between time series) measures which reflect functional connectivity within (local) and between (intrahemispheric and interhemispheric) ten major cortical regions in five frequency bands.

Recently diagnosed, drug-naive patients showed an overall increase in alpha1 SL relative to controls. Cross-sectional analysis in all patients revealed that disease duration was positively associated with alpha2 and beta SL measures, while severity of parkinsonism was positively associated with theta and beta SL measures. Moderately advanced patients had increases in theta, alpha1, alpha2 and beta SL, particularly with regard to local SL. In recently diagnosed patients, cognitive perseveration was associated with increased interhemispheric alpha1 SL.

Increased resting-state cortico-cortical functional connectivity in the 8–10 Hz alpha range is a feature of PD from the earliest clinical stages onward. With disease progression, neighboring frequency bands become increasingly involved. These findings suggest that changes in functional coupling over the course of PD may be linked to the topographical progression of pathology over the brain.

Introduction

Synchronization of neuronal activity between distributed brain regions plays a key role in the integration of their activity (Varela et al., 2001). This phenomenon can be studied by measuring statistical interdependencies between physiological signals derived from different brain regions over a certain time interval (Pereda et al., 2005), a concept aptly named functional connectivity (Lee et al., 2003). As functional integration is essential to normal brain function, clinical deficits in brain disorders may well be associated with changes in the synchronization of oscillatory brain signals (Schnitzler and Gross, 2005, Uhlhaas and Singer, 2006), which might even be observed during a no-task, resting-state condition (Uhlhaas and Singer 2006). The resting state is a far more stable and active condition than previously assumed (Gusnard and Raichle 2001) and is characterized by activation within a series of functional–anatomic networks implicated in motor, sensory and cognitive functions (Damoiseaux et al., 2006). Each of these resting-state networks appears to have a specific electrophysiological signature that combines the involvement of different brain rhythms (Mantini et al., 2007). Utilizing neurophysiological indices of functional connectivity, changes in cortico-cortical coupling during a resting state have now been demonstrated in diverse brain disorders: mild cognitive impairment (Stam et al., 2003, Pijnenburg et al., 2004, Koenig et al., 2005, Babiloni et al., 2006), Alzheimer’s disease (Leuchter et al., 1992, Besthorn et al., 1994, Locatelli et al., 1998, Berendse et al., 2000, Stam et al., 2002, Pijnenburg et al., 2004, Koenig et al., 2005, Stam et al., 2006b, Stam et al., 2007), multiple sclerosis (Cover et al., 2006), brain tumor patients (Bartolomei et al., 2006a, Bartolomei et al., 2006b) and schizophrenia (Micheloyannis et al., 2006). In mild cognitive impairment and Alzheimer’s disease, changes were correlated with cognitive deficits (Stam et al., 2003, Babiloni et al., 2006, Stam et al., 2006b).

In a recent electroencephalography (EEG) study in advanced Parkinson’s disease patients, resting-state cortico-cortical coupling in the ~ 10–35 Hz range was positively correlated with “OFF” treatment severity of parkinsonism (Silberstein et al., 2005). Both dopaminergic therapy and deep brain stimulation led to a reduction in coupling in parallel with motor improvement. From these data, it would appear that at least in the advanced stages of Parkinson’s disease increased functional connectivity may play a role in the pathophysiology of parkinsonism. So far, it is unclear whether a similar phenomenon might occur in early-stage Parkinson’s disease and whether it plays a role in Parkinson’s disease-related cognitive dysfunction. Moreover, increased functional connectivity in Parkinson’s disease has never been demonstrated relative to controls (Hammond et al., 2007).

The present study was undertaken to determine whether changes in resting-state functional connectivity occur in the earliest clinical stages of Parkinson’s disease and to explore how functional coupling might evolve over the disease course. In addition, we investigated its relationship with clinical measures of motor and cognitive function. To this end, synchronization likelihood (SL, a general measure of linear and non-linear temporal correlations between time series) was calculated from whole-head magnetoencephalography (MEG) recordings obtained during an eyes-closed resting-state condition in a group of 70 Parkinson’s disease patients with varying disease duration (including 18 recently diagnosed, drug-naive patients) as well as in 21 healthy controls that were age-matched to the recently diagnosed patients.

Section snippets

Subjects

A total of 70 patients with idiopathic Parkinson’s disease (disease duration 0–13 years) and 21 healthy controls were recruited and selected for analysis as described in a previous MEG study in the same subjects (Stoffers et al., 2007). Out of these 70 patients, two subgroups were constructed, i.e. a group of recently diagnosed, untreated patients (diagnosed in the last six months prior to participation in this study, disease duration of less than two years, never treated with anti-Parkinson

Subject characteristics and confounders

There were no significant differences in the distribution of sex or education level between groups, nor were there differences in age, pre-morbid IQ (NART) or global cognitive function (CAMCOG). Since age and sex could be modifiers of functional connectivity, they were nonetheless added as covariants in all initial analyses of SL. Since age and pre-morbid IQ are well-known modifiers of cognitive performance, they were initially added as covariants in all analyses of cognitive performance, as

Discussion

This is the first study to demonstrate widespread increases in alpha1 band functional connectivity in early-stage Parkinson’s disease. With increasing disease duration and severity of parkinsonism, there appear to be rising levels of functional coupling in the theta, alpha2 and beta frequency bands. This results in significantly increased theta, alpha2 and beta band functional connectivity in moderately advanced Parkinson’s disease patients, in addition to the widespread increases in the alpha1

Acknowledgments

The financial support of the Dutch Parkinson Foundation (Parkinson Patiënten Vereniging) and the Dutch Foundation for Brain Research (Nederlandse Hersenstichting, grant no. 11F03(2)05) are gratefully acknowledged. We would like to thank G. de Vos and J.P.A. Verbunt, MS, for technical assistance; M.M. Ponsen, MD, and A. Winogrodzka, MD, for clinical (UPDRS) testing; and E.M. van Deventer for librarian assistance.

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