The brain is the last and grandest biological frontier, the most complex thing we have yet discovered in our universe. It contains hundreds of billions of cells interlinked through trillions of connections. The brain boggles the mind.

James D. Watson, 1992

Imagine agreeing to have an electrode implanted in your brain. You are wide awake in the operating room while the neurosurgeon implants it and asks you to hold out your hands to help him pinpoint the sweet spot. Bingo! He teases it with pulses of electricity and, before your eyes, your tremor simply stops. The procedure, an approved treatment for patients with Parkinson’s disease and tremor, is called Deep Brain Stimulation (DBS). Neurosurgeons know that it works but little about how it does so. Uncovering these mechanisms is the quest of the Mayo-based Deep Brain Stimulation Consortium — a team of scientists and engineers from four research institutions. Their goal to develop a “smart” DBS — something like a thermostat for the brain — boggles the mind.

An early fascination with consciousness

Since his college days, Kendall Lee, M.D., Ph.D., has yearned to understand the mind. In the early nineties, he was studying electrophysiology mechanisms that influence sleep and wakefulness for his Ph.D. thesis at Yale when the concept of DBS began to be noticed. After participating in Dartmouth Hitchcock Medical Center’s first case of DBS, during his neurosurgical residency, he was hooked. Soon afterward, Dr. Lee came up with an idea that has the potential to open a new era in medical diagnosis, intervention, and treatment for neuropsychiatric disorders. However, to bring it to fruition, he knew he needed a team of neuroscientists and engineers.

In January, 2004, Dr. Lee googled “dopamine” and the website of Charles Blaha, Ph.D., popped up. People with Parkinson’s disease have low dopamine levels due to damage of the brain cells that produce it. Dr. Blaha is a neuroscientist at the University of Memphis. He specializes in unraveling the labyrinth formed by the 100 billion nerve cells that make up the brain. Dr. Blaha is internationally known for developing in vivo, electroanalytical techniques to measure neurotransmitters, including dopamine. He was in his office when Dr. Lee called.

“Dr. Lee was surprised to hear that we had done DBS studies stimulating the subthalamic nucleus (STN),” says Dr. Blaha. “Half an hour after I sent him our data, he was back on the phone asking if he could fly to my lab the next day. We’ve been friends and collaborators ever since.”

Later that year, Dr. Lee published one of the first papers to show that neurotransmitters were being released by DBS (Journal of Neurosurgery, 2004). Drs. Lee and Blaha now have a patent pending on their idea for technology that can regulate neurochemical levels in the brain.

What is Deep Brain Stimulation?

In conventional DBS treatment of Parkinson’s disease, an electrode is surgically implanted in an area of the brain called the STN. The DBS system consists of the electrode wire; a neurostimulator (electronics and battery), which is a bulky device implanted under the skin in the chest or the abdomen; and an extension wire to connect the two. The electrode emits electrical pulses which, like a heart pacemaker, has an immediate effect.

Precise electrode placement is difficult to achieve. Preoperatively, MRI, a medical imaging technique, is used to identify a trajectory for the electrode to access the STN. Following the groundwork, the patient is moved to the OR where neurosurgeons insert a recording electrode to identify the STN, but must remove it before sliding in the stimulating electrode. These complexities result in multiple post-op appointments to adjust the frequency and magnitude of stimulation.

A “smart” upgrade

For the patient’s optimal treatment, safety and comfort, an ideal DBS device would include an electrode that not only stimulates but also accurately measures several chemical concentrations in the brain at the same time. The “smart” feature would sense when it needs to fire off stimulation and when to hold back. In addition, it would be wireless and the battery unit and circuit chip tiny enough to be embedded directly in the bone of the skull.

Assembling the rest of the team

In 2006, after completing his extensive training, Dr. Lee joined Mayo Clinic where he now directs the Neural Engineering Laboratory. He is thrilled with Mayo’s friendly, team-enhancing environment. He was amazed at the enthusiastic response of the engineering team in getting behind a newcomer with a novel idea.

“Engineers here have a unique perspective,” says Dr. Lee. “They collaborate with physicians and scientists to make a difference in people’s lives.”

Kevin Bennet is a chemical engineer and chair of Mayo’s Division of Engineering. He is now one of the group’s directors and is excited about the possibilities and successes of the DBS research program.

“It’s an incredibly high energy group,” says Mr. Bennet. “We are committed to collaboration by sharing our areas of competence and building new capabilities of the technology by incorporating the ideas and discoveries of the group.”

Dr. Lee is astounded by the progress since coming to Mayo.

“In only one year, we took the concept of a new DBS system from an idea to an operational device and multiple publications,” says Dr. Lee. “There is absolutely no way this could have been done anywhere else.”

Besides Mr. Bennet and Drs. Lee and Blaha, the Mayo-based DBS Consortium is co-directed by Paul Garris, Ph.D., an electroanalytical chemist from Illinois State University, Normal, IL and Pedram Mohseni, Ph.D., an electrical engineer from Case Western Reserve University, Cleveland, OH.

WINCS: a giant step toward a smart DBS

So how does DBS work? Does it act like a lesion and silence neurons at the site of stimulation? Does the effect of DBS extend beyond the site of stimulation? If so, what brain structures are affected by DBS? Does it activate neuronal terminals in various ways to engage neurotransmission in order to normalize brain activity?

In 2009, the Mayo-based DBS Consortium received national and international attention (MIT Technology Review, US News & World Report) for developing a sensor electrode system that can wirelessly measure the concentration of neurotransmitters in real time (Pub online: Journal of Neurosurgery, May 2009). The device, called Wireless Instantaneous Neurotransmitter Concentration System (WINCS), combines digital telemetry (remote measurement) with fast-scan cyclic voltammetry and fixed-potential amperometry, electrochemical techniques for which Dr. Garris and Dr. Blaha are respective experts. Dr. Garris also developed the prototype to WINCS for laboratory animals.

“WINCS will help us identify the pattern of chemical activity in the brain during DBS,” says Dr. Blaha. “We can measure dopamine as well as other molecules such as adenosine, glutamate, serotonin, and norepinephrine in real time.”

So far, they have successfully tested WINCS with various types of chemical recording electrodes to measure dopamine, glutamate and adenosine, both in vivo and in vitro, and it is already increasing the understanding of how DBS works. They now use a pig model, which has very similar neural systems to humans, but on a smaller scale.

Future projects

The group has planned a series of projects on their path to the next generation smart DBS system. In the fall of 2009, Dr. Blaha spent three months at Mayo as a visiting professor to oversee animal studies and collaborate more closely with Dr. Lee’s lab. Dr. Garris also recently spent a sabbatical at Mayo with Dr. Lee testing and developing WINCS. He also helped to establish a large-animal, mock-human DBS surgery with the engineering and laboratory staff using the pig model.

One project is to develop a single wire to be surgically placed in the STN. Along its shaft, in addition to the stimulating electrodes, they are strategically placing areas of dopamine, glutamate and adenosine sensors at depths that correspond to areas of the brain where the corresponding neurochemical is released during DBS. They can then stimulate between different pairs of contacts on the electrode to learn more about the link between DBS stimulation and neurotransmission in specific areas of the brain. They are also comparing dopamine levels following DBS with and without the presence of the drug L-dopa, the gold standard drug for Parkinson’s disease.

In another project, the group is using functional MRI (fMRI), an imaging technique that measures changes in blood flow. “The brain nuclei show up as red areas on the fMRI image in response to DBS,” explains Dr. Blaha. “That gives us a global anatomical picture of the brains’ response to DBS. We have done a preliminary pig study that suggests DBS activates different regions of the brain.”

Dr. Mohseni is directing another project area. His expertise includes developing integrated circuits that can be linked to tiny implantable sensors. His task is to reduce the size of WINCS.

In 2009, the DBS group published 14 peer-reviewed papers and Dr. Lee’s vision is well on the way to fulfillment. The team is energized by the enormous therapeutic potential of DBS for other neurological and psychiatric disorders, such as epilepsy, chronic pain, cluster headache, craniofacial pain, depression, Tourette's syndrome, and obsessive-compulsive disorder.

“You know, some people are overcome with emotion in the OR because they are so joyful to have immediate relief of their symptoms,” says Dr. Lee. “That’s a very powerful incentive.”

— Yvonne Hubmayr, December 2009