Abstract
The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's disease (PD) where functional up-regulation of postsynaptic D2 receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the oculomotor system as a model to study reorganization of dopaminergic networks. This model is ideal because this system reorganizes due to frontal-to-parietal shifts in blood oxygen level-dependent (BOLD) activity. We tested the prediction that functional activation plasticity is associated with postsynaptic dopaminergic modifications by combining positron emission tomography/functional magnetic resonance imaging to investigate striatal postsynaptic reorganization of dopamine D2 receptors (using 11C-raclopride) and neural activation in PD. We used covariance (connectivity) statistics at molecular and functional levels to probe striato-cortical reorganization in PD in on/off medication states to show that functional and molecular forms of reorganization are related. D2 binding across regions defined by prosaccades showed increased molecular connectivity between both caudate/putamen and hyperactive parietal eye fields in PD in contrast with frontal eye fields in controls, in line with the shift model. Concerning antisaccades, parietal-striatal connectivity dominated in again in PD, unlike frontal regions. Concerning molecular-BOLD covariance, a striking sign reversal was observed: PD patients showed negative frontal-putamen functional-molecular associations, consistent with the reorganization shift, in contrast with the positive correlations observed in controls. Follow-up analysis in off-medication PD patients confirmed the negative BOLD-molecular correlation. These results provide a link among BOLD responses, striato-cortical synaptic reorganization, and neural plasticity in PD.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder, triggered by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and is characterized by hypokinesia, tremor, rigidity, and postural instability [1]
First, we investigated the association between the density of receptors in the basal ganglia (BG) with the density of receptors in areas involved in saccades (FEF and parietal eye fields (PEFs)) and, second, the link between distribution volume ratio (DVR) in the BG with the blood oxygen level–dependent (BOLD) signal of regions involved in saccade execution (FEF and PEF), while performing performed to the stimulus (PSs) or AS tasks
Here we used combined positron emission tomography (PET)/functional magnetic resonance imaging (fMRI) to test the hypothesis that reorganization of dopaminergic networks is related with functional reorganization of brain activity patterns
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder, triggered by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and is characterized by hypokinesia, tremor, rigidity, and postural instability [1]. Reflexive saccades triggered in the direction of a stimulus (prosaccades) (PSs) are mainly hypometric, while voluntary saccades triggered in the opposite direction of a stimulus (antisaccades) (ASs) are often delayed and prone to directional errors [3, 5,6,7] These findings may be explained by an excessive inhibition of superior colliculus (SC) neurons by the BG and/or decreased preocular motor drive from the frontal cortex through the BG to the SC [8]. PD patients show hypoactivity in FEF, SEF, caudate nucleus, and concomitant relative hyperactivity in parietal areas, during saccade paradigms [7, 11] This leads to the hypothesis that the imbalance between FEF and PEF activation is related with reorganization of striatal connectivity, which we investigated here at molecular and functional levels using covariance statistics.
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