In the 1970s, the hit sci-fi television drama The Six Million Dollar Man envisioned a brave and futuristic new world for medical science. Now, nearly 30 years after the show's protagonist Steve Austin-the "bionic man"-completed his last assignment, it is reality. A new wave of implantable technologies is promising to profoundly impact neurology practice and bring the notion of bionic men and women into everyday life. The neurodevices currently on the market or in clinical trials represent a new paradigm in patient care that is revolutionizing delivery of treatment for many neurologic disorders. Neurostimulators modulate brain circuitry; infusion pumps deliver drugs or other therapies directly to disease targets; and sensors record, stimulate, and analyze activity inside the 3-lb universe of the brain. These neurotechnologies generally take the form of battery-powered electronic devices. Designed to be surgically implanted in discrete areas of the body, the devices feature wire leads and electrodes that are routed through the body and emplaced in specific areas of the brain or nervous system to improve function and, in some cases, provide a complete restoration of a deficit. "Given the rapid advances in neuroscience and clinical and biomedical engineering, neurotechnologies have tremendous potential to help people with neurologic diseases and injuries," said Leigh Hochberg, MD, PhD, associate neurologist at Brigham and Women's Hospital and an instructor in neurology at Harvard Medical School in Boston. The study of neurodevices is still in its infancy, but the prospects are looking good, and the market is waiting. "The CNS and nervous system disorders represent the largest and fastest growing unmet medical market: 1.5 billion people worldwide," according to a market analysis and investment report issued earlier this year.1 According to the report, neurodevices already account for $2.6 billion of the $110 billion neurotechnology industry, which also includes neuropharmaceuticals and neurodiagnostics. Moreover, companies addressing CNS-related markets have "the greatest potential for major scientific discoveries, commercial success, and sustainable investment opportunities," according to the report. "On a social scale, implants are becoming very commonplace if you consider all types of implants-intraocular lenses, orthopedic implants, pacemakers, and defibrillators," observed Reese Terry, cofounder, chairman of the board, and executive vice president of Cyberonics, a medical device manufacturer based in Houston. "We are coming up on the 'bionic man' and the next frontier is neurologic implants." MAKING SCI-FI REALITY The notion of modulating the nervous system dates back thousands of years. "In mosaics found in the ruins at Pompeii, there are depictions of people using torpedo fish, which have electrical properties, [to treat] headaches and gout," noted Ali R. Rezai, MD, surgical director of the Center for Neurological Restoration at the Cleveland Clinic. "It was a very crude form of neuromodulation. Now we have the tools to implement neuromodulation in the most optimal fashion." Although development of modern neurotechnology got under way in the 1960s, the new wave of commercial implantable neurodevices took shape in the 1980s. By 1983, Medtronic, which began by manufacturing cardiac pacemakers in 1949 in Minneapolis, received FDA approval for the Itrel nerve stimulator, the first implantable spinal cord stimulator for chronic pain. On the academic front, Jacob Zabara, PhD, a neurophysiologist then conducting research at Temple University in Philadelphia, was developing an electronic device for the treatment of epilepsy that involved wrapping a wire lead around the vagus nerve and sending a 30-second signal to the brain to interrupt seizures.2 The Vagus Nerve Stimulator (VNS), as it came to be called, was licensed to Cyberonics. By the mid-1990s, the neurotechnology wave was gaining significant momentum. The FDA approved Cyberonics' VNS for treatment of medically refractory partial-onset seizures. In addition, Medtronic secured agency approval of another first-of-its-kind device, a deep brain stimulation system called Activa Tremor Control Therapy for treatment of essential tremor. The company followed it with the Activa Parkinson's Control Therapy, which gained FDA approval in 2002. Meanwhile, new companies were emerging. Among them Advanced Neuromodulation Systems of Plano, Texas, introduced a line of spinal cord stimulators for pain management as well as drug infusion pumps; NeuroPace, of Mountain View, California, designed the Responsive Neurostimulator system for treatment of medically refractory epilepsy; and Advanced Bionics, of Sylmar, California, diversified from manufacturing Clarion cochlear implants to developing neurostimulators for chronic pain management. In addition to devices that modulate the brain and nervous system, the neurotechnology revolution also has witnessed the creation of instruments that sense, record, stimulate, and analyze the electrical conversation inside gray matter. Foxborough, Massachusetts-based Cyberkinetics Neurotechnology Systems has introduced an elaborate brain-machine interface system called BrainGate that uses the company's platform technology to sense, transmit, analyze, and apply the language of neurons. It is composed of a sensor implanted on the motor cortex of the brain and a device that analyzes brain signals. The sensor was developed to study how the brain turns thoughts into action. "Now it's setting up a whole new industry of sensing brain activity in a way that had not been tried before," said John P. Donoghue, PhD, cofounder and chief scientific officer of Cyberkinetics and professor of neuroscience at Brown University in Providence, Rhode Island. "It is now technically possible to pick up a 120-Hz cell firing in a particular part of the human brain and monitor it in real time as opposed to using an EEG." CURRENT TRIALS In recent years, neurotechnology has gained more momentum. Cyberkinetics' platform technology-the NeuroPort System, an FDA-approved medical device intended for temporary recording and monitoring of the brain's electrical activity-is currently being evaluated at Columbia University Medical Center in New York City. Meanwhile, the BrainGate system is being tested in 2 human trials, one for patients with spinal cord injury or stroke and another for patients with amyotrophic lateral sclerosis or motor neuron disorders. Medtronic is currently supporting experimental trials of its latest deep brain stimulator systems, Soletra and Kinetra, for the treatment of epilepsy, Tourette syndrome, depression, migraine, obsessive compulsive disorder, addiction, and other psychiatric disorders. It also introduced the first implantable, programmable drug infusion pump system, the Personal Therapy Manager, which the FDA approved last fall. After acquiring FDA approval for the VNS for treatment-resistant depression late last year, Cyberonics engaged in pilot studies to test the therapeutic effectiveness of the VNS system in Alzheimer disease, headache, anxiety disorders, and bulimia. Furthermore, Northstar Neuroscience in Seattle is studying the effectiveness of its cortical stimulation system for stroke recovery in a nationwide trial; Indiana-based Andara Life Sciences is continuing studies with its oscillating field stimulator for sensation and movement recovery after spinal cord injury; and Advanced Bionics is working on a rechargeable neurostimulator so small that it can be injected almost anywhere in the body to treat pain or muscle dysfunction. If all this activity weren't proof enough that implants are becoming a key element in neurology's medicine bag, recent company buyouts and new alliances drive the point home. "Medtronic had the monopoly on pain stimulation systems and then Advanced Neuromodulation Systems came into the arena, and then Advanced Bionics," chronicled Rezai. In 2004, however, Boston Scientific bought Advanced Bionics, and last year St Jude's Medical bought Advanced Neuromodulation Systems. "Now you have 3 big guns, and Johnson and Johnson is looking to come into the field," added Rezai. Despite the big guns, the neurodevice market remains a haven for smaller sharpshooters and start-up companies. "The beauty is that we're applying these [new neurodevices] not only to the brain but also to the entire nervous system," said Rezai. "It really is open territory in terms of the applications for this reversible and dynamically adjustable technology. We are right now in neuromodulation where cardiac pacings were 30 years ago." REFERENCES 1. The Neurotechnology Industry 2005: Strategic Investment and Market Analysis Report of the Global Neurological Disease and Psychiatric Illness Market. San Francisco: NeuroInsights; 2006: Introduction. 2. Zabara J. Neurocybernetic prosthesis. US Patent 4 702 254. October 27, 1987. This 3-part series explores the boom of neurodevices within the neurotechnology revolution now under way. Part I looks at the evolution and current market. Part II will cover application, and Part III will look at the future. AJS RAYL is a freelance writer in Malibu, California.