Day 3: Saturday, September 25, 2010

Session IV: Clinical Trials of Neural Prosthetics

Research in Human Electrocorticography and Neuroprosthetic Implications

E.C Leuthardt ^1,2

¹Department of Biomedical Engineering, Washington University in St. Louis, St Louis, MO
²Department of Neurological Surgery, Washington University in St. Louis, St Louis, MO

High frequency oscillations, known as gamma rhythms, have become an important indicator of focal, event-related cortical activity. This has also become an important signal used for ECoG derived brain computer interface (BCI) control To date, the majority of studies have treated amplitude changes in frequencies above 30 Hz as a uniform phenomenon. We hypothesize that gamma rhythms are heterogeneous. In several studies we have defined the effect that cognitive task and anatomic location have on gamma changes in human cortex. Using simple speech and motor tasks in humans, we show that high frequency electrocorticographic (ECoG) signals (30-530Hz) have distinctly non-uniform behavior. For a given cortical task, there were power changes in distinct frequency bands for each cognitive task performed. Additionally, for the same cognitive task, there were also power changes in separable frequency bands that distinguished the cortical region. These task and anatomy dependent power changes were present at single cortical sites and across multiple sites within individual subjects. Moreover, when these task and location dependent frequency specific phenomena were assessed across all the subjects, there were trends that were consistent across the population. Taken together, the independence and non-uniformity with which power changes occur in narrow bands throughout the 30-530Hz range suggest that a new approach is necessary to evaluate cortical activity. In addition to time and location, these findings show that frequency is another fundamental dimension of cortical activation and feature space for BCI operation.

Clinical Trials Of An Intracortical Neural Interface System

Leigh R. Hochberg, M.D., PhD^1,2,3 and John P. Donoghue, Ph.D.^1,4
1Rehabilitation Research & Development Service, Providence VA Medical Center, Providence, RI
²Stroke and Neurocritical Care Services, Massachusetts General, Brigham and Women’s, and Spaulding Rehabilitation Hospitals, Harvard Medical School, Boston, MA
³Engineering and ⁴Neuroscience, Institute for Brain Science, Brown University, Providence, RI

For people with cervical spinal cord injury, pontine stroke, amyotrophic lateral sclerosis and other neurologic illnesses, currently available assistive and rehabilitation technologies are inadequate. In severe brainstem stroke and advanced ALS, patients may suddenly or progressively enter a locked-in state of being awake and alert but unable to move or communicate. Through clinical translation based on decades of fundamental neuroscience research, intracortically-based “brain-computer interfaces” are poised to revolutionize our ability to restore lost function. Over the past decade, neurotechnologies to record the individual and simultaneous activities (action potentials, multi-unit activity, and local field potentials) of dozens to hundreds of cortical neurons have yielded new understandings of cortical function in movement, vision, cognition, and memory. This preclinical research, generally performed with healthy, neurologically intact non-human primates, has demonstrated that direct neural control of virtual and physical devices can be achieved. Recently, this exciting research has been translated into initial pilot clinical trials (IDE) of an intracortically-based neural interface system (BrainGate), seeking to determine the feasibility of persons with tetraplegia controlling a computer cursor or other devices simply by imagining movement of their own hand. A variety of methods for decoding brain signals are now being tested with the hope of not only restoring communication, but also providing a control signal for the reanimation of paralyzed limbs. In related research, it is hoped that this first glimpse into the activities of dozens of individual cortical neurons in humans might provide new diagnostic and therapeutic modalities for our patients with epilepsy.

Interfacing Brain To Machine For Restoration And Enhancement Of Human Functionality

Philip R. Kennedy, MD, PhD
Neural Signals Inc., Duluth, GA

Brain implants for communication purposes can achieve two main goals: neural prosthetics and brainenhancement. Successful requires a stable connection between brain and machine for the lifetime of the recipient of the brain implant. One solution to forming a stable connection between brain and machine is to grow neuropil into the electrode, rather than poking a sharp electrode tine into the neuropil. The Neurotrophic Electrode (NE) has been shown to provide a stable signal over many years. In our efforts to develop a speech prosthetic, the NE has recorded useful signals five years after implantation. This electrode consists of a hollow glass cone in which Teflon insulated gold wires are fixed, with neurites being enticed into the tip using trophic factors. The trapped neurites become myelinated over a few weeks and the wires record action potentials travelling along these myelinated neurites. The neural signals thus recorded have most recently been used to produce vowel phonemes with 80% accuracy in a locked-in subject.After successful development of neural prosthetics, these technologies will likely become consumer devices that enhance brain function. These devices will operate like a cell phone, enhance memory and perform higher order calculations. These applications will be primarily restricted in their development by our lack of understanding of which brain pathways will provide access and process such large loads of information. Hence, basic neuroscience is a key to the development of these devices.

P. Hunter Peckham, PhD
Case Western Reserve University and Veterans Administration Medical Center

Clinical Translation of a Motor System Neuroprosthesis

Major advances have been made over the past decade in use of neuroprostheses for restoration of motor function. These advances have been built on the fundamental science of neural excitation and the technologies for implantable stimulation and control. The technologies have advanced to provide operational systems that function in the human body for decades, and include implantable electrodes, stimulation devices, and sensors. The neural interface between the excitable tissue and the delivery electrode are enabling evermore powerful control and precision in the delivery of stimulation, not only providing for excitation but also blocking of neural activity (e.g. for annihilation of pain or spasticity) and selective stimulation. Distributed implantable systems and brain control interfaces are currently in development that will provide greater flexibility in implementation and performance.

The clinical manifestations of these findings are the available systems that have been created, and are being developed, to restore function. These include many areas of the body for people with spinal cord injury, including hand grasp, standing and walking, breathing, and bladder and bowel control. Several patients have benefited from systems that enable more than one function (e.g. hand function and bladder control). The presentation will provide examples of both upper and lower extremity neuroprostheses to restore full arm mobility and levels of standing and ambulation. Several areas where future advances are likely to meet clinical challenges will be discussed.

Brain-Computer-Interfaces In Paralysis: Applications In Locked-In Syndrome, Chronic Stroke And Emotional Disorders

Niels Birbaumer, PhD
University of Tuebingen, Institute of Medical Psychology and Behavioral Neurobiology, Germany

Little is known about efficacy of invasive and non-invasive BCIs in clinical populations. Large controlled clinical trials do not exist. About 50 cases of patients with amyotrophic lateral sclerosis -- most from our laboratory -- at different stages of their disease including locked-in patients using EEG-BCI for verbal communication were documented in the literature. The data demonstrate successful, albeit slow communication up to and in the locked-in-state. BCI-use in the completely locked-in was difficult to show: first data using classical EEG-conditioning in this population are presented as a solution to the problems of the completely locked-in. Motor restoration of chronic stroke using MEG- and EEG-BCI in proof of principle studies showed promising results in the laboratory but lack of generalization to the home environment. Finally, a series of experiments with healthy participants, chronic schizophrenics, criminal psychopaths and drug addicts with surprisingly fast voluntary control of BOLD in different cortical and subcortical brain areas and strong specific effects on behavior.

Supported by the DFG (Deutsche Forschungsgemeinschaft), BMBF (Bundesministerium für Bildung und Forschung), Bernstein Center on Computational Neuroscience, European Research Council (ERC)

Session V: Translating Neural Prosthetic Devices to the Clinic

A Better Way To Read From The Brain

Philip Low, PhD^1,2,3,4
1NeuroVigil, Inc, La Jolla, CA
²Stanford University School of Medicine, Stanford, CA
³MIT Media Lab, Cambridge, MA
⁴Crick-Jacobs Center, Salk Institute for Biological Studies, La Jolla, CA

High-resolution brain scanning is currently limited to a laboratory environment, and tends to rely on methods which are costly, stressful and impair normal functioning. Here we present alternative methods which pair advanced single-channel EEG analysis, including SPEARS, to create dynamic maps of brain activity (Low Thesis, 2007) with non-invasive single-channel recording devices, including an affordable single-channel home-based brain recording device (iBrain). We present non-invasively collected biomarkers in both humans and animals and discuss the implementation of these techniques to obtain additional information on pre-market drugs in clinical trials.

Spinal Cord Injury is a Multifaceted Problem

Jacqueline C. Bresnahan, PhD
University of California, San Francisco

Spinal cord injury induces a wide variety of changes in a number of body systems. The most obvious change is loss of locomotor control and this is the function that receives the most attention. However, spinal cord injury interrupts signals from the spinal cord to the brain encoding sensory information from both somatic structures and autonomic structures. Similarly, loss of descending input to the spinal cord affects somatic and autonomic motor function. In addition, direct damage to the spinal cord circuits in the gray matter at the lesion site will affect local processing of afferent, integrative and efferent signals as well as short and long relays. Thus, the SCI syndrome encompasses a wide variety of functional loss including somatic motor, sensory (tactile, proprioceptive, temperature, pain), autonomic (respiratory, cardiovascular, gastrointestinal, eliminative, and sexual) functions and their interactions.

People with SCI when asked what functions they were most interested in having return to normal to improve the quality of their lives (Anderson, 2004), chose sexual function followed by bladder and bowel function if paraplegic, and hand function followed by bladder a bowel function if quadruplegic. Respiratory function if a high quad, and chronic pain was also a significant problem for a large subset of spinal cord injured people. Thus, multiple opportunities exist for neural prosthetic approaches to improving function beyond locomotion after spinal cord injury. We hope that turning attention to these understudied issues will yield enhanced recovery and improvement in the quality of life for the nearly 1.275 million people surviving this devastating injury.

The Argus Ii – A 60 Electrode Neural Interface

Robert J. Greenberg MD, PhD
Second Sight Medical Products, Inc., Sylmar, CA

Methods: All subjects were implanted with a Second Sight™ Medical Products, Inc. Argus® II implant and had bare light perception or worse due to retinitis pigmentosa (clinicaltrials.gov NCT00407602). Visual function was evaluated by grating visual acuity, assessing the ability to determine the direction of motion of a line and the location of a square on an LCD screen, letter reading and orientation and mobility tests.
Results: 32 subjects have been implanted at 11 centers and all use the system at home. In the O&M tests, subjects were able to successfully navigate to the door and to the end of the line more often with the System ON vs. OFF. At the most recent follow-up visits, 96% (26/27) of subjects show a significant improvement in accuracy and 93% (25/27) show a significant improvement in repeatability with the system on compared with off (p<0.05, Student’s t-test) in the square localization test, and 58% (14/24) perform Direction of Motion tests better with the System ON vs. OFF. 40% of subjects in the most recent Argus II cohort (6/15) have statistically measurable grating visual acuity better than 2.9 logMAR (Snellen 20/15900) with System ON in their implanted eye and the best subject measured 1.8 logMAR (20/1260). Subjects were able to correctly identify letters in a closed set 73% of the time with the System ON vs. 17% with the System OFF (n=22 subjects).
Conclusions: With up to 3.2 years follow-up on 32 subjects, this is the largest and longest study of a visual prosthesis to date and CE Mark is expected this year. The results confirm previous reports on the ability of the Argus prosthesis to provide visual function over the long-term. This is further validation for the Argus platform’s high reliability.

Reflections On Architecting Practical Interfaces to the Nervous System

Tim Denison PhD
Medtronic, Inc., Minneapolis, MN

This talk will present reflections on designing neural interface (NI) technology from a "translational" perspective. Historically, a NI has often had one of two pathways: one inserting therapeutic or sensory information to modulate the nervous system, and the other sensing information from neural circuits. Due to key translational constraints, the majority of initial implantable devices focused on making a robust link to the nervous system through the first pathway. The flexibility of these systems allowed researchers to cross-leverage and develop solutions for a wide variety of therapeutic applications. The second pathway, sensing information chronically from the brain, has not yet reached this maturity. Lack of translation is due in part to the ongoing challenge of aligning technological capabilities with requirements in the scope of targeted applications like motor prosthesis. However, new research is suggesting that adding embedded sensors and algorithms could potentially improve the performance of existing therapeutic stimulation systems. This motivates the exploration of a merged, bi-directional NI architecture that takes advantage of technically feasible sensing modalities that are well-aligned with unmet needs. A flexible and robust bidirectional device, architected to serve a broad set of neurological conditions, would help catalyze a new era of research focused on better understanding and treating neurological disease while also providing a key milestone for translating brain sensing technology into clinical practice.

Can Cognitive Neural Prosthetics be used to treat Alzheimer’s disease?

Howard Fillit, MD
Alzheimer's Drug Discovery Foundatio, New York, NY

Alzheimer’s disease is a chronic progressive and ultimately fatal disorder that affects essentially all systems of cognition and emotion in the end-stages. The cause is unknown, but many approaches to treatment are currently under investigation. In the early phases of the disease, memory and learning, language, aspects of judgment and reasoning, the ability to “recognize,” the ability to execute complex tasks, and other cognitive functions, may be impaired. These deficits are likely related to the “disconnection” of various centers in the brain. Dysfunction of neural networks connectivity in Alzheimer’s disease can be demonstrated by various imaging techniques. Some have suggested cognitive neural prosthetics could be employed for the treatment of Alzheimer’s disease. The outlook for the potential use of cognitive neural prosthetics for Alzheimer’s disease, and how such high risk work might be funded through philanthropy, will be discussed.

Session VI: Promising New Applications of Neural Prosthetics

The Development of Deep Brain Stimulation for Depression

Helen Mayberg, MD
Emory University School of Medicine, Atlanta, GA

Critical to the development of deep brain stimulation (DBS) as a novel therapy for patients with treatment resistant depression has been the characterization of brain systems mediating normal and abnormal mood states as well as those mediating successful and unsuccessful response to various antidepressant interventions using functional neuroimaging. Building on converging evidence implicating the subcallosal cingulate as a critical node within an imaging-based, putative depression network model, the subcallosal cingulate white matter was targeted for initial proof-of-principle testing of DBS in patients with treatment resistant major depression, adopting neuromodulation techniques routinely used to treat Parkinson’s disease and other movement disorders. The theoretical and data-driven foundation for this new treatment strategy as well as results from ongoing experimental studies will be presented.

Deep Brain Stimulation For Epilepsy

Robert S. Fisher, MD, PhD
Department of Neurology, Stanford University School of Medicine, Stanford, CA

Deep brain stimulation (DBS) is a promising new therapy for epilepsy. Two general strategies have been employed: stimulation on a cycling schedule and stimulation of a seizure focus in response to detection of a seizure. Brain regions stimulated include cerebellum, caudate, brainstem, hippocampus, hypothalamus, subthalamus, centromedian thalamus, anterior thalamus and the cortical seizure focus. Stimulation of the vagus nerve is an approved therapy for epilepsy. A trial entitled SANTE, for stimulation of the anterior nucleus of thalamus for epilepsy, recently implanted electrodes into bilateral anterior thalamic nuclei, attached subcutaneously to a dual-channel programmable stimulator on the chest. The 110 participating subjects had frequent and unmanageable partial-onset seizures. After postoperative recovery for a month, subjects were randomized to 5V or 0V (placebo) using 90 microsecond pulses at 145 per second, cycling on for one minute and off for five. Over a three-month blinded phase, seizures were fewer in the stimulated group (40 vs. 15% reduction, p=0.038). Severe seizures and injuries were reduced. At month four, all patients received 5V stimulation. Seizure improvement increased over the next two years, with 14% becoming seizure-free for 6 months. Adverse events were as expected for implanted brain electrodes, generally well-tolerated. DBS appears effective for refractory partial-onset seizures. Many questions are unanswered, including how DBS works, best stimulation methods, the best patient populations and target sites, why benefits increase over time, whether adverse events will emerge, how to predict good responders, and where in the spectrum of epilepsy treatment to use this new therapy.

Session VII: Ethical and Regulatory Issues

Overview of FDA Medical Device Regulation

Kristen A. Bowsher, PhD
Food and Drug Administration, Center for Devices and Radiological Health, Office of Device Evaluation

The United States Food and Drug Administration (FDA) is charged with assuring the safety and effectiveness of a variety of medical products and the FDA’s Center for Devices and Radiological Health (CDRH) is responsible for premarket and postmarket regulation of medical devices. Since many new and innovative medical device uses and technologies are rapidly emerging it is increasingly important for sponsors to gain an increased understanding of the regulatory process and engage in early interaction with the FDA. One of the main responsibilities of CDRH’s Office of Device Evaluation (ODE) is to develop and interpret regulations and guidelines regarding medical devices. There are several paths to market for medical devices: Premarket Notification (510(k)), Premarket Approval Application (PMA), and Humanitarian Device Exemption (HDE). Medical devices are classified based on risk into Class I, II, and III. Clinical data is required for Class III PMA devices and some class II 510(k) devices. In order to study a significant risk device (whether an unapproved device for an unapproved indication or an approved device for an unapproved indication) in human subjects, a sponsor must receive approval from the FDA of an investigational device exemption (IDE) application prior to beginning the investigation. Review of an IDE is focused on determining whether the sponsor has demonstrated that there is a reasonable assurance of safety and that the anticipated benefits to health, from use of the device for its intended uses and conditions of use, outweigh the probable risks.

When Ethics Become Prosthetic: Bringing Context To The Neural Interface

Joseph J. Fins, MD
Weill Cornell Medical College, New York, NY

Although prostheses work within individuals, communication with others occur in a societal context. Because of this larger frame of reference, ethical analysis of neuroprosthetic devices meant to facilitate communication -- and foster interaction with others -- must take account of broader contextual issues, including how clinicians, caregivers and the courts might view the patient’s contemporaneous assisted communication in light of prior wishes and preferences. Using the example of passive and active communication with neuroimaging methods being studied in patients with disorders of consciousness, I will consider the impact of imperfect channels of communication upon patient rights and how the ambiguity of prosthetic output might be understood in light of a fuller patient narrative. Absent this ethical contextualization, prosthetic tools meant to foster autonomy might inadvertently undermine self-determination by giving undue primacy to that what was said and not that which was meant.