Dataset Information

Network Structure and Function in Parkinson's Disease.

ABSTRACT: Little is known of the structural and functional properties of abnormal brain networks associated with neurological disorders. We used a social network approach to characterize the properties of the Parkinson's disease (PD) metabolic topography in 4 independent patient samples and in an experimental non-human primate model. The PD network exhibited distinct features. Dense, mutually facilitating functional connections linked the putamen, globus pallidus, and thalamus to form a metabolically active core. The periphery was formed by weaker connections linking less active cortical regions. Notably, the network contained a separate module defined by interconnected, metabolically active nodes in the cerebellum, pons, frontal cortex, and limbic regions. Exaggeration of the small-world property was a consistent feature of disease networks in parkinsonian humans and in the non-human primate model; this abnormality was only partly corrected by dopaminergic treatment. The findings point to disease-related alterations in network structure and function as the basis for faulty information processing in this disorder.

SUBMITTER: Ko JH

PROVIDER: S-EPMC6215468 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Network Structure and Function in Parkinson's Disease.

Ko Ji Hyun JH Spetsieris Phoebe G PG Eidelberg David D

Cerebral cortex (New York, N.Y. : 1991) 20181201 12

Little is known of the structural and functional properties of abnormal brain networks associated with neurological disorders. We used a social network approach to characterize the properties of the Parkinson's disease (PD) metabolic topography in 4 independent patient samples and in an experimental non-human primate model. The PD network exhibited distinct features. Dense, mutually facilitating functional connections linked the putamen, globus pallidus, and thalamus to form a metabolically acti ...[more]

PMID: 29088324

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Project description:Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ?10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.

Dataset Information

Network Structure and Function in Parkinson's Disease.

Publications

Network Structure and Function in Parkinson's Disease.

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