A practical method to experimentally evaluate the Hausdorff dimension: An alternative phase-transition-based methodology

International audienceno abstrac

A non-linear deterministic model of action selection in the basal ganglia to simulate motor fluctuations in Parkinson's disease

Motor fluctuations and dyskinesias are severe complications of Parkinson's disease (PD), especially evident at its advanced stage, under long-term levodopa therapy. Despite their strong clinical prevalence, the neural origin of these motor symptoms is still a subject of intense debate. In this work, a non-linear deterministic neurocomputational model of the basal ganglia (BG), inspired by biology, is used to provide more insights into possible neural mechanisms at the basis of motor complications in PD. In particular, the model is used to simulate the finger tapping task. The model describes the main neural pathways involved in the BG to select actions [the direct or Go, the indirect or NoGo, the hyperdirect pathways via the action of the sub-thalamic nucleus (STN)]. A sensitivity analysis is performed on some crucial model parameters (the dopamine level, the strength of the STN mechanism, the strength of competition among different actions in the motor cortex) at different levels of synapses, reflecting major or minor motor training. Depending on model parameters, results show that the model can reproduce a variety of clinically relevant motor patterns, including normokinesia, bradykinesia, several attempts before movement, freezing, repetition, also irregular fluctuations. Motor symptoms are, especially, evident at low or high dopamine levels, with excessive strength of the STN and with weak competition among alternative actions. Moreover, these symptoms worsen if the synapses are subject to insufficient learning. The model may help improve the comprehension of motor complications in PD and, ultimately, may contribute to the treatment design

An integrative model of Parkinson\u2019s disease treatment including levodopa pharmacokinetics, dopamine kinetics, basal ganglia neurotransmission and motor action throughout disease progression

Levodopa is considered the gold standard treatment of Parkinson\u2019s disease. Although very effective in alleviating symptoms at their onset, its chronic use with the progressive neuronal denervation in the basal ganglia leads to a decrease in levodopa\u2019s effect duration and to the appearance of motor complications. This evolution challenges the establishment of optimal regimens to manage the symptoms as the disease progresses. Based on up-to-date pathophysiological and pharmacological knowledge, we developed an integrative model for Parkinson\u2019s disease to evaluate motor function in response to levodopa treatment as the disease progresses. We combined a pharmacokinetic model of levodopa to a model of dopamine\u2019s kinetics and a neurocomputational model of basal ganglia. The parameter values were either measured directly or estimated from human and animal data. The concentrations and behaviors predicted by our model were compared to available information and data. Using this model, we were able to predict levodopa plasma concentration, its related dopamine concentration in the brain and the response performance of a motor task for different stages of disease

Nonlinear pharmacodynamics of levodopa through Parkinson's disease progression

The effect of levodopa in alleviating the symptoms of Parkinson's disease is altered in a highly nonlinear manner as the disease progresses. This can be attributed to different compensation mechanisms taking place in the basal ganglia where the dopaminergic neurons are progressively lost. This alteration in the effect of levodopa complicates the optimization of a drug regimen. The present work aims at investigating the nonlinear dynamics of Parkinson's disease and its therapy through mechanistic mathematical modeling. Using a holistic approach, a pharmacokinetic model of levodopa was combined to a dopamine dynamics and a neurocomputational model of basal ganglia. The influence of neuronal death on these different mechanisms was also integrated. Using this model, we were able to investigate the nonlinear relationships between the levodopa plasma concentration, the dopamine brain concentration, and a response to a motor task. Variations in dopamine concentrations in the brain for different levodopa doses were also studied. Finally, we investigated the narrowing of a levodopa therapeutic index with the progression of the disease as a result of these nonlinearities. In conclusion, various consequences of nonlinear dynamics in Parkinson's disease treatment were studied by developing an integrative model. This model paves the way toward individualization of a dosing regimen. Using sensor based information, the parameters of the model could be fitted to individual data to propose optimal individual regimens

Morphological analysis of H I features. II. wavelet-based multifractal formalism.

International audienc

Pharmacometrics-based decision tools facilitate mHealth implementation.

The healthcare system is experiencing a paradigm shift in delivering its services, evolving from a reactive 'one size-fits-all' structure to a patient-centric model focusing on individualized medicine. This change is driven by scientific progress, including quantitative evaluation and optimization of treatment strategies through pharmacometric approaches, harnessing the power of the digital revolution. Areas covered: This review describes four main steps to apply pharmacometrics-based decision support tools, consisting of validated scientific components, available technical options, consideration of regulatory aspects, and achievement of efficient commercialization. Examples of pharmacometrics-based decision tools that support monitoring of patients and individualization of treatment strategies in neonates, children and adults are presented. Expert commentary: We envision that user-friendly decision support tools will facilitate implementation of mobile health approaches (mHealth) realizing benefits to paediatric and adult patients and their caregivers