Taking on Parkinson’s
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Dopaminergic modulation and dosage effects on brain state dynamics and working memory component processes in Parkinson’s disease
Parkinson’s disease (PD) is primarily diagnosed through its characteristic motor deficits, yet it also encompasses progressive cognitive impairments that profoundly affect quality of life. While dopaminergic medications are routinely prescribed to manage motor symptoms in PD, their influence extends to cognitive functions as well. Here we investigate how dopaminergic medication influences aberrant brain circuit dynamics associated with encoding, maintenance and retrieval working memory (WM) task-phases processes. PD participants, both on and off dopaminergic medication, and healthy controls, performed a Sternberg WM task during fMRI scanning. We employ a Bayesian state-space computational model to delineate brain state dynamics related to different task phases. Importantly, a within-subject design allows us to examine individual differences in the effects of dopaminergic medication on brain circuit dynamics and task performance. We find that dopaminergic medication alters connectivity within prefrontal-basal ganglia-thalamic circuits, with changes correlating with enhanced task performance. Dopaminergic medication also restores engagement of task-phase-specific brain states, enhancing task performance. Critically, we identify an “inverted-U-shaped” relationship between medication dosage, brain state dynamics, and task performance. Our study provides valuable insights into the dynamic neural mechanisms underlying individual differences in dopamine treatment response in PD, paving the way for more personalized therapeutic strategies.
Preclinical and clinical study on type 3 metabotropic glutamate receptors in Parkinson’s disease
Metabotropic glutamate (mGlu) receptors are candidate drug targets for therapeutic intervention in Parkinson’s disease (PD). Here we focused on mGlu3, a receptor subtype involved in synaptic regulation and neuroinflammation. mGlu3−/− mice showed an enhanced nigro-striatal damage and microglial activation in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Expression of genes encoding anti-inflammatory proteins and neuroprotective factors was reduced in the striatum of MPTP-treated mGlu3−/− mice. We also examined polymorphic variants of GRM3 (the mGlu3 receptor encoding gene) in 723 PD patients and 826 healthy controls. Two GRM3 haplotypes were associated with PD, and gene variants correlated with motor and non-motor signs. Interestingly, PD patients carrying each of the two haplotypes showed an impaired cortical plasticity in the paired associated stimulation paradigm of magnetic transcranial stimulation. These findings suggest that mGlu3 receptors are neuroprotective in mouse models of parkinsonism and shape mechanisms of cortical plasticity in PD.
The effect of avatar identity on spontaneous perspective-taking in patients with schizophrenia
Controversy exists regarding whether the spontaneity of altercentric intrusion is impaired in patients with schizophrenia during implicit visual perspective-taking tasks. This study explored the characteristics of spontaneous visual perspective-taking in patients with schizophrenia and the effect of an avatar identity on their perspective-taking. We recruited 65 patients with schizophrenia and 65 healthy participants to complete 4 visual perspective-taking experiments for uncued other-avatar and self-avatar tasks and cued other-avatar and self-avatar tasks. In uncued other-avatar experiments, healthy controls showed a significant reduction in accuracy and an increase in response latency when the number of visible discs differed from that seen by the other-avatar (inconsistent condition), indicating altercentric intrusion. However, patients with schizophrenia did not exhibit this effect. In uncued self-avatar experiments, when the avatar was defined as the participant themselves, patients with schizophrenia did not show spontaneous perspective-taking. However, in cued other-avatar experiments, they showed altercentric intrusion in response latency, and in cued self-avatar experiments, they showed altercentric intrusion in accuracy and response latency. These results suggest that patients with schizophrenia have the tendency to spontaneously adopt the perspective of others, which is predicated on their awareness of the existence of perspectives. In addition, the avatar’s identity as a stranger hinders the spontaneous perspective-taking processes in patients with schizophrenia.
Transcutaneous auricular vagus nerve stimulation improves cortical functional topological properties and intracortical facilitation in patients with Parkinson’s disease
Our study aimed to investigate the neural mechanisms of taVNS in the motor symptoms of PD, focusing on the topological properties of cortical functional networks and cortical excitability. Thirty-two PD patients underwent functional near‐infrared spectroscopy and transcranial magnetic stimulation evaluation prior to and after two-week taVNS, which were controlled by 20 healthy controls (HCs). PD patients exhibited decreased nodal efficiency (Ne) in the right M1 and increased Ne in the left pre‐motor and supplementary motor area compared with HCs. The decreased Ne in the right M1 was negatively associated with UPDRS-III scores. Interestingly, taVNS treatment improved PD motor symptoms by increasing Ne in the right M1 and enhancing intracortical facilitation (ICF, ISI 10, and 15 ms). The increased Ne and ICF (ISI 15 ms) were negatively correlated with the decreased UPDRS-III scores. taVNS could improve nodal information processing efficiency in the M1 and enhance cortical facilitation to improve PD motor disorders.
Prodromal Parkinson’s disease and subsequent risk of Parkinson’s disease and mortality
Association of prodromal Parkinson’s disease (PD) with risk of PD and risk of mortality in individuals with PD warrant investigation through large-scale prospective study. We included 501,475 participants without PD at baseline. Eight prodromal features were measured. Incident PD cases were identified via hospital admission, death register, and self-report. Cox regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariable-adjusted HRs3+vs.0 prodromal PD features and 95%CIs were 3.12 (2.58–3.78) for men and 2.71 (2.11–3.47) for women. Prodromal PD predicted only PD onset occurred during the first 6 years of follow-up (HR3+vs.0 prodromal features = 10.5; 95% CI: 8.60–12.9), but not after 6 years (HR = 1.00; 95%CI: 0.76-1.32). The presence of prodromal PD conferred a higher risk of mortality among participants with PD. Having prodromal PD were associated with higher probability of developing PD in short-term and higher risk of mortality among individuals with PD.
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