Accelerating Translational Neurotechnology: Fourth Annual Aspen Brain Forum

Agenda

* Presentation titles and times are subject to change.

Abstracts — Day 2: Thursday, September 19, 2013

Session 1: Neuroprosthetics and Neuroengineering

Neuroprosthetic Technologies to Restore Motor Function After Severe Paralysis
Grégoire Courtine, PhD, Swiss Federal Institute of Technology (EPFL)

There are over 3 million persons living with a spinal cord injury worldwide. Damage to the spinal cord leads to a range of disabilities that seriously lower the patient's quality of life. Functional restoration after spinal cord injury has been interpreted as the need to promote long-distance regeneration of severed fibers to their original targets. A radically new and more immediately applicable approach may instead capitalize on the capacity of neuronal circuits within the spinal cord to generate effective postural and locomotor tasks. To exploit this potential, however, the spinal circuitry must be reactivated and remodeled in the context of the post-injury neurophysiological state of the spinal cord. Here, we will introduce neuroprosthetic technologies combining robotic and electrochemical systems that are capable of reactivating spinal locomotor networks after a spinal cord injury and of remodeling spared neuronal pathways in response to training. This new paradigm, termed multi-system neurorehabilitation, restored voluntary control over a range of leg movements in severely paralyzed rats. These findings may inspire new thinking for the design of strategies to return motor function after spinal cord injury and other neuromotor disorders in humans.

Neurotechnology to Predict, Prevent, and Control Seizures
Brian Litt, MD, University of Pennsylvania

One of the most successful areas of clinical of translation in epilepsy research is in anti-seizure devices and the engineering behind them. Two automated implantable devices, the "open loop" anterior thalamic nucleus stimulator and "closed loop" cortical / hippocampal responsive neurostimulation device, have completed pivotal human trials. Other start-up technologies have recently recorded continuous intracranial EEG in humans and dogs with epilepsy for over 1 year. Other devices for cranial nerve stimulation continue to evolve in human therapy. Rapid engineering advances to define epileptic networks using high resolution, high-bandwidth electrophysiology, new hardware, classification / control algorithms, and mining "big" neural data are rapidly improving our ability to treat seizures. New fields, such as optogenetics, in vivo imaging or large cellular ensembles, bioelectronics and nanotechnology insure a rich pipeline of technologies for nearer term translation. Together these developments promise a revolution of new diagnostic and therapeutic options for individuals with epilepsy and other brain-network disorders.

Developing Algorithms for Enhanced Brain-Machine Interfaces
Steven M. Chase, PhD, Carnegie Mellon University

Brain-machine interfaces map the activity of dozens to hundreds of neurons to the control of some device, such as a cursor on a computer screen or a robotic arm. By creating a direct link between brain and machine, they hold promise as a breakthrough technology for alleviating paralysis due to stroke, disease, or injury. To build these devices, it is necessary to design a decoding algorithm that estimates user intent from recorded neural activity. A common method for vetting the performance of these algorithms is to evaluate how well they predict actual arm movements from simultaneously recorded neural data. This is known as 'open-loop' performance. A subject actually using such an algorithm during prosthetic control, however, operates in closed-loop: they receive real-time feedback about their movements. In closed-loop control, subjects can use this feedback to adapt to the specifics of the decoding algorithm and increase performance. In this talk, I will demonstrate how open-loop performance assessment often fails to predict the ultimate closed-loop performance of a decoding algorithm. I will then discuss some design principles that can be used to increase closed-loop decoding performance, even though they might worsen the algorithm's open-loop performance.

Session 2: Neuroimaging

Imaging Biomarkers for Prediction and Progression of Neurodegenerative Disease
Susan M. De Santi, PhD, GE Healthcare

New Neuroimaging Tools for Understanding and Predicting Neurological Disease
Arthur Toga, PhD, University of California, Los Angeles

The complexity of neurodegenerative diseases often requires the collection of numerous data types from multiple modalities. These can be genetic, imaging, clinical, and biosample data. In combination, they can provide biomarkers critical to chart the progression of the disease and to measure the efficacy of therapeutic intervention. The difficulties lie in how can these diverse data from different subjects, collected across multiple laboratories on a wide range of instruments using non-identical protocols be aggregated and mined to discover meaningful patterns.
 
Mapping the human brain, and the brains of other species, has long been hampered by the fact that there is substantial variance in both the structure and function of this organ among individuals within a species. Previous brain atlases have relied on information from, at best, a few samples to draw conclusions. These limitations and the lack of quantification for the variance in brain structure and function have limited the pace and accuracy of research in the field of neuroscience. There are numerous probabilistic atlases that describe specific subpopulations, measure their variability, and characterize the structural differences between them. Utilizing data from structural, functional, diffusion MRI, along with GWAS studies, and clinical measures we have built atlases with defined coordinate systems creating a framework for mapping and relating diverse data across studies. This talk describes the development and application of theoretical framework and computational tools for the construction of probabilistic atlases of large numbers of individuals in a population. These approaches are useful in understanding multidimensional data and their relationships over time.
 
A specific and important example of mapping multimodal data is the study of Alzheimer's disease (AD). The dynamic changes that occur in brain structure and function throughout life make the study of degenerative disorders of the aged difficult. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a large national consortium established to collect longitudinally, distribute, and describe cohorts of age matched normals, MCIs (mild cognitive impairment), and Alzheimer's patients. AD results from the abnormal accumulation of misfolded amyloid and tau proteins in neurons and the extracellular space, ultimately leading to cell death and progressive cognitive decline. The consequences of this insult can be seen using a variety of imaging and other data analyzed from the ADNI database.
 
Essential elements in performing this type of population based research are the informatics infrastructure to assemble, describe, disseminate, and mine data collections along with computational resources necessary for large scale processing of big data such as whole genome sequence data and imaging data. This talk also describes the methods we have employed to address these challenges.

Session 3: Neuromodulation, Optogenetics, and Deep Brain Stimulation

Optogenetics and Other Tools for Analyzing and Controlling Neural Circuits
Edward Boyden, PhD, Massachusetts Institute of Technology

The brain is a complex, densely wired circuit made out of heterogeneous cells, which vary in their shapes, molecular composition, and patterns of connectivity. In order to help discover how neural circuits implement brain functions, and how these computations go awry in brain disorders, we invent technologies to enable the scalable, systematic observation, and control of biological structures and processes in the living brain. We have developed genetically-encoded reagents that, when expressed in specific neuron types in the nervous system, enable their electrical activities to be precisely driven or silenced in response to millisecond timescale pulses of light. I will give an overview of these "optogenetic" tools, adapted from natural photosensory and photosynthetic proteins, and discuss new tools we are developing, including molecules with novel color sensitivities and other unique capabilities. We have developed microfabricated hardware to enable complex and distributed neural circuits to be controlled and observed in a fully 3-D fashion, as well as robots that can automatically record neurons intracellularly and integratively in live brain. These tools are in widespread use to enable systematic analysis of neural circuit functions, are also opening up new frontiers on the understanding and treatment of brain disorders, and may serve as components of new platforms for diagnosing and treating brain disease.

DBS and Parkinson's Disease
Jerrold Vitek, MD, PhD, University of Minnesota

Recent Developments in Clinical Trials Using DBS for Depression
Donald Malone, Jr., MD, Cleveland Clinic

Deep Brain Stimulation (DBS) is being explored as a treatment for several neuropsychiatric conditions including obsessive-compulsive disorder (OCD), treatment refractory depression (TRD), and Tourette's syndrome. Open-label studies demonstrated benefit in OCD which led to FDA approval under a humanitarian device exemption (HDE). DBS for TRD is being investigated in several different target sites. These include subcallosal cingulate (SCC), ventral capsule/ventral striatum (VC/VS), nucleus accumbens (NAc), and medial forebrain bundle (MFB). To date, these investigations had been limited to open-label or crossover designs. The Reclaim Trial was a blinded, randomized, sham-controlled study of DBS to the VC/VS in highly refractory depression. Unblinded analysis of the first 30 patients demonstrated no difference in MADRS scores between sham and active treatment at 4 months. Modest improvements were noted over time during the open-label stimulation phase. 26 of 30 subjects remained in active stimulation at 24 months with a mean MADRS improvement of 40.2%. Adverse events included psychiatric effects, implant site infections, and lead revisions. One subject committed suicide after stimulation was discontinued in preparation for explantation due to non-response. Potential explanations for lack of efficacy may include true lack of effectiveness, sham response, restriction of stimulation options to protect the blind, and a need for different outcome measures in this very ill population. These issues need to be evaluated carefully to inform future study design.

Session 4: Stem Cells and Therapies

New Stem Cell Technologies Considered for Applications to Brain Diseases
Ole Isacson, MD, PhD, McLean Hospital/Harvard Medical School, Harvard Stem Cell Institute, and Massachusetts General Hospital

Regenerative medicine is evolving as an interdisciplinary field for novel treatments and discovery platforms. The nervous system provides a particularly broad scope for cell and tissue plasticity. This presentation will outline the basis for structural responses to brain degeneration in neurodegenerative disease and examine how human stem cells and induced pluripotent cells can be used as models for both (1) plastic and degenerative events in vitro, and (2) cell therapy in the patient. To discern the biology and any convergence of risk factors that lead to dysfunction in specific neural cell populations, we have created induced pluripotent stem cells (iPS) from fibroblasts of patients with several key genetic forms of Parkinson's disease (gPDiPS) or no disease. We have discovered cell type specific vulnerabilities in the CNS using diverse populations of neural cells, or purified populations of neurons. Our data from diverse populations of gPDiPS-derived neural clearly demonstrate that cell organelle-associated disease phenotypes (mitochondria -, lysosomes-) can be determined using in vitro and in vivo assays. The paramount objective is translation of the cellular data and assays into prototype discovery diagnostic and therapeutic tools. Stem cells in medicine therefore provide a tremendous opportunity to transform future technologies for addressing neurological conditions and aging.

Next-Gen Models for Drug Discovery — Combining Stem Cell-Based Technologies, NGS and High-Throughput Biology
Arnaud Lacoste, PhD, Novartis Institutes for BioMedical Research

Stem cell-based approaches have the potential to revolutionize drug discovery, however their integration into today's Pharma culture is challenging because stem-cell-related concepts are radically different from those of traditional R&D.
 
We will describe how we are developing stem cell-based drug discovery projects for neurobiology indications. We will discuss the scientific challenges that must be solved for high-throughput production of stem cell-based models and how we use stem-cell-based neuronal models for pathway dissection and drug discovery campaigns.

Clinical Cell Transplantation for Parkinson's Disease: Surgical Techniques and Methodology
Ivar M. Mendez, MD, PhD, University of Saskachewan and Royal University Hospital

The clinical use of cell transplantation for Parkinson's disease has been built on a strong foundation of basic research in animal models that spans more than 3 decades. Although, the clinical efficacy of fetal cell transplantation reported in clinical trials has been variable, the importance of cell transplantation as a strategy for brain repair for Parkinson's disease cannot be dismissed. As research on stem cells continues to advance, the lessons learned from clinical fetal cell transplantation are crucial to move stem cells to the clinical realm.
 
This presentation will focus on our clinical experience on fetal cell transplantation in patients with Parkinson's disease. Particular emphasis will be giving to neurosurgical techniques aimed at the safe and precise cell delivery to the human brain. Innovations on cell preparation methodology, immunosuppression and the role of stem cells in the future of brain repair for neurodegenerative diseases will also be discussed.

Keynote Address — A Retinal Prosthesis: from Idea to Clinical Approach
Robert Greenberg, MD, PhD, Alfred E. Mann Foundation

In the early 1990s, a team at Johns Hopkins demonstrated that electrical stimulation of the retina produced the perception of light in individuals who were completely blind from retinitis pigmentosa. Since then, that initial team and a group of many more dedicated engineers, surgeons, and scientists, have worked to bring to market a fully-implantable retinal prosthesis. Their goal was finally achieved in 2013, when the Argus II Retinal Prosthesis System became the first visual prosthesis to be approved by the FDA for commercialization in the United States. It had been approved two years earlier in Europe.
 
The Argus II System consists of a receiver coil, a hermetically-sealed electronics case, and a thin-film electrode array with 60 platinum-based electrodes, which are implanted in and around the eye. Externally, the System comprises a pair of glasses with a miniature video camera and transmitter coil, and a small wearable computer.
 
The safety and probable benefit of the System have been demonstrated in a clinical trial; reliable function has been shown in over 125 cumulative patient-years. A total of 56 people have been implanted with the Argus II System to date. The success of this technology is bringing hope to thousands of blind people who previously had no treatment options.

*Additional abstracts coming soon.

Travel & Lodging

Event Location

Aspen Meadows Resort
845 Meadows Road
Aspen, CO 81611

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