A link between synaptic plasticity and reorganization of brain activity in Parkinson's disease

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.

The structural connectivity of the human angular gyrus as revealed by microdissection and diffusion tractography

“…This cortical-subcortical circuitry includes different deep nuclei and brainstem regions, segregated in direct and indirect pathways (between others, the pulvinar thalami, intralaminar nuclei, mesopontine tegmentum, basal forebrain, globus pallidus, subthalamic nucleus, substantia nigra, and caudate nucleus) (LaBerge 1995; Kinomura et al 1996). More recently, a functional imbalance (hypo-vs. hyper-activation) between the functional connectivity of certain cortical territories of the fronto-parietal network involved in oculomotor control (notably, the frontal and parietal eyes elds) and the striatal structures (putamen and caudate) was demonstrated as a pathological substrate in Parkinson Disease (Rebelo et al 2021).…”

Normalization effect of dopamine replacement therapy on brain functional connectome in Parkinson's disease

“…Increased FC within CTC possibly played a compensating role for long‐term dopaminergic denervation, which was characterized by enhanced bursting and oscillatory neural activity (Blesa et al, 2017 ; Sen et al, 2010 ). Such aberrant neural activity was triggered by synaptic changes to offset chronic dopaminergic depletion, including upregulation of dopamine synthesis and release, downregulation of dopamine transporter, and increased receptor expression (Blesa et al, 2017 ; Rebelo et al, 2021 ). This increased connectome was normalized under long‐term DRT but not after the levodopa challenge test, which demonstrated CTC restoration was based on long‐term and repeated dopaminergic medication.…”

Automatic classification of idiopathic Parkinson’s disease and atypical Parkinsonian syndromes combining [11C]raclopride PET uptake and MRI grey matter morphometry

“…The ROI-based quantitative analysis of [ 11 C]raclopride images was implemented in the PET images native space using an in-house made software used previously in other PET studies [30]. In this [ 11 C]raclopride PET study, the reversible tracer binding to D2/D3 receptor was quantified by the distribution volume ratio (DVR) model parameter [31].…”

“…No previous machine learning molecular imaging approaches have used kinetic parameters obtained from dynamic [ 11 C]raclopride PET data, although the dopaminergic system has been studied in this context using other tracers. Recently, Oliveira et al (2021) applied the quantitative analysis of [ 123 I]ioflupane SPECT data to differentiate healthy CTRL from DLB and PD [21]. Segovia et al used [ 18 F]DMFP PET to quantify postsynaptic D2/D3 striatal dopamine receptors and designed SVM classifiers to distinguish between PD, MSA and PSP patients [22].…”