The NoTremor Objectives
As intimated above, PD is a multifaceted condition with both motor and non-motor symptoms. NoTremor will focus on motor behavior and symptoms. This approach will ensure tractability, as motor behavior and symptoms have the advantage that they can be more readily objectified and quantified. Accordingly, NoTremor will produce PD patient models that fully integrate sub-cortical and neuromuscular models. The result will be a virtual patient model, which will produce motion primitives and lead to solution strategies that are influenced by its own capabilities and disabilities. A typical example is the case of pathological gait patterns: a virtual user will walk according to its own capabilities, limiting as far as possible, the effects of impairments like bradykinesia, rigidity, poor balance and freezing. Model validation will be performed based on the correspondence between virtual and real patient behavior and the model will be used for the understanding of future patient behavior and diagnosis of internal pathological state.
Research will focus on improving the understanding of low-level functions of the basal ganglia, striatum, the substantia nigra and the interaction of these systems with motor cortex and the brainstem control of the musculoskeletal system. The ultimate aim is to minimize future therapy costs, while also significantly enhancing treatment effectiveness. The patient specific model will be also used as an open virtual patient model repository to boost research on the treatment of PD. The project will be coupled with existing clinical methodologies for PD characterization and will also propose customized visual analytics tools for the exploration of “hidden” correlations between raw clinical information and associated biomarkers of PD progression and corresponding impact on quality of life. Such correlations may be highly non-linear and hard to identify statistically also due to the vast amount and heterogeneity of the underlying information. Outputs will be targeted towards the development of advanced computational models for the understanding of the evolution, evaluation and monitoring of PD that can generalize to other neurodegenerative disorders characterized by sub-cortical damage.
The specific objectives of NoTremor are:
- Objective 1: Provision of novel patient-specific parametric computational models
Research and development on virtual patient models, i.e. patient-specific, parametric, computational models of: (i) The subcortical motor system, including the basal ganglia, substantia nigra and brainstem motor centers at the level of microcircuits with realistic neural models. (ii) Sufficient cortical motor systems to represent the tasks of interest and exercise the subcortical circuitry appropriately; these will be modelled at a comparatively high level of description thereby enabling computational tractability (iii) The neuromuscular system to allow (i) and (ii) to express behavior in sufficient depth to achieve our overall aim, i.e. the analysis and monitoring of the progression of patient’s Parkinsonian pathology. Towards this goal, a multi-scale approach will be adopted by integrating existing frameworks available in the consortium members for patients that are not heavily affected by PD, as described in detail in Section 1.1.3, and modelling in more detail for specific sub-cortical areas.
- Objective 2: Coupled cognitive-motor simulation engine
Development of a simulation engine that will replicate motor behavior based on specific physiological input parameters. The simulation engine will not only run the parametric computational models of the sub-cortical structures including the basal ganglia, striatum, etc., but it will also provide integrated patient-specific modelling whilst taking into account basal ganglia-brainstem pathways. In this way, biomechanical simulation of the patients will be driven by their low level neurological state through the computational modelling of the neural pathology. As a direct consequence, through the simulated evaluation of medical treatment effects, pharmaceutical companies will be empowered with highly efficient means for rapid evaluation of new therapies using virtual patient models. The development of the simulation engine will be iterative in close coordination with the test campaigns with the beneficiaries (Objective 5)
- Objective 3: Inverse simulation for clinical state assessment and progress monitoring
The NoTremor simulation engine will allow for inverse modelling, that is the estimation of the internal parameters of an individual patient’s neuropathology, based on detailed observations of their motor behavior. This will allow us to observe and monitor the progression of future disease states, i.e. to correlate clinical scales and objective metrics, and to monitor the progression of these indicators in a cohort of patients during project lifetime, based on their high level motor behavior. Additionally, the project will determine the pharmacological basis of some of the parameters of the NoTremor models and further test performance of the model through application of our line tracking and saccadometry tests off and on levodopa.
- Objective 4: Analytics and new metrics for simulated evaluation and monitoring of medical treatment
The NoTremor visual analytics module will serve as the front end of the NoTremor simulation-based clinical decision support tool and will allow for the direct and intuitive visualization of all simulation parameters and results. It will also support differential visual analysis of a specific parameter of a simulation session with respect to the same average parameter of a cohort of real or virtual PD patients. Moreover, of significant investigative value is the support for visual correlation analysis that aims to provide to the expert visual tools to identify correlations among seemingly slightly related or unrelated quantities. The latter is expected to be very helpful in the analysis of the simulation results and in the formulation of novel metrics and biomarkers that implicitly link the macroscopic behavioral profile of the patient to the microscopic clinical state.
- Objective 5: Test campaigns with beneficiaries
Evaluation and quantification of the patient specific computational models will be made in two test campaigns with patients, both in terms of their motor abilities and neurological characteristics. For both test campaigns NoTremor will utilize and extend a well-studied cohort of patients with Parkinson’s disease enrolled in the Monument Discovery project already funded by Parkinson’s UK. The aim of NoTremor test campaigns will be twofold. In the first half of the project they will be performed so as to quantify and fine-tune the developed computational models and simulation framework. In the second half of the project, they will serve both model optimization and validation purposes:
- Correlation of objective and clinical scales and monitoring of cohort evolution with the aim of correlating clinical scales with the NoTremor suite of newly developed test, metrics and internal states estimates.
- Determine the pharmacological basis of some of the parameters of the NoTremor models and further test performance of these models through application of new line tracking and saccadometry tests off and on levodopa.