The Multi-Level Modelling Project

 

Significance

Implantable medical devices have been developed to treat neurological disorders such as deafness and Parkinson's disease. These devices have had remarkable success, in spite of the fact that they employ relatively unsophisticated neural interfaces. Building on this success, prototype retinal prosthetics to restore partial vision to the blind affected by retinal degeneration and cortical devices to remedy for lost cognitive and memory functions have been developed over the past several years by members of this research team and their associates.

The effectiveness of these devices has been outpacing initial expectations. In fact, the retinal prosthesis developed by the "artificial retina consortium," to be marketed in the near future by the company "Second Sight," underwent clinical trials by stimulating electrode arrays with 16 and 60 electrodes; subjects have shown the ability to perceive motion, crude shapes, and perform a variety of tasks. The cortical implant is currently being tested in rats and other animals, with the first test in humans predicted over the next five years; ultimately, we envision this device to be able to be a partial remedy to various cognitive and neural conditions, ranging from Alzheimer's disease to memory loss.

A common trait in these devices lies in the assumption that a greater number of electrodes will lead to "better" stimulation, whether more detailed in terms of spatial visual percepts (in the case of the artificial retina) or simply providing a richer array of stimulation points for a cortical implant. However, the complexity of the interface portends significant challenges, and a better understanding of the interaction between the applied field and the biomolecular/neuronal network, is necessary. Better neural predictive models in terms of resolution, accuracy of topology, and bioelectrical behavior modeling will help to reach this understanding.

 

The Team

Our research team is composed of engineers, biophysicists, surgeons, and computer scientists that are experts in all aspects necessary to fill the existing gaps in multi-scale modeling, simulation, and visualization.

Our research effort will capitalize on our accomplishments in the realm of retinal and cortical prostheses, and use these as testbeds for the methods that we will develop within the proposed activity. We expect that the results of this work will profoundly affect the way we design neurostimulating electrodes and provide a deep understanding of the optimal shape and size of electrodes, waveform characteristics and timing differences between stimulating currents in adjacent electrodes, and current levels to name a few.

 

Approach

Specific Aim 1: Develop Multi-Scale Models and Software Modeling Tools

Spatial Scales:

  • From Biomolecular Level to Synaptic Level
  • From Synapse Level to Neuron Level
  • From Individual Neurons Level to Network Level
  • From Network Level to Global Level


Temporal Scales:
An additional critical multi-scale dimension is time. The nervous system integrates mechanisms that occur rapidly, within microseconds, with other mechanisms taking place at a much slower time scale. Computational simulation of mechanisms spanning such broad scales inherently imposes constraints on the numerical and computational methods used to integrate these multi-scale events.

Specific Aim 2: Develop Predictive Case studies

We will develop experimental procedures for the validation of the predictive models for both the hippocampus and the retina in the presence of neural interface applicators and associated hardware (integrated models of cellular scale tissue, neural tissue, and neural interface). These integrated models will incorporate the neural interfacing devices, and possibly account for specific conditions, such as morphed retinal structure typical of subjects with retinal degeneration.

Specific Aim 3: Strategies for Multiscale Visual Analysis and Validation

  • Information Visualization Research and Development Aims
  • Scientific Visualization Research and Development Aims

 

Partnership Plan

The PI (Lazzi) at the University of Utah is an expert in computational bioelectromagnetics. Together with Prof. Cela, Prof. Lazzi will lead the technical development of the connection between network model and global model. Prof. Lazzi will serve as the Project Director: he will coordinate the efforts within the University of Utah and interact with the Investigators at the University of Southern California to converge toward a multiscale platform that will extend from biomolecular-level modeling to global bioelectromagnetic modeling. The investigators at the University of Utah SCI (Scientific Computing and Imaging) Institute will lead the development of three-dimensional visualization tools for the proposed multiscale modeling method. The University of Southern California will lead the development of multiscale tools from biomolecular to neuron and network model, and provide the necessary experimental validation for both testbeds – hippocampus and retina.

The expertise available to the entire team includes the following: computational modeling and bioelectromagnetics (Lazzi, Cela), computational and experimental neuroscience (Berger, Bouteiller, Song), ophthalmology (Humayun, Weiland), scientific and information visualization (Johnson, Meyer), image processing and model generation (Tasdizen).