Advances in neuroscience technology may capture the zeitgeist of brain research for the next decade. Solving the riddle of why electrical stimulation works in the brain and how to harness it could radically improve the treatment of many neurological disorders, including Parkinson’s disease.

Imagine being a concert violinist and losing your ability to control your hand movements. It would end your career. That is precisely what one musician was facing when Kendall Lee, MD, PhD, a neurosurgeon, researcher and director of the Neural Engineering Laboratory at the Mayo Clinic in Rochester was recommended to consult on the case. The patient’s diagnosis was essential tremor. Following deep brain stimulation (DBS) surgery, the violinist was able to play again and return to his vocation. The procedure seems miraculous but the mechanisms at work remain an enigma.

On a cold January day in 2004, Charles B. Blaha, PhD, an internationally published neuroscientist and expert in the field of neurochemistry and development of neurotransmitter recording techniques at the University of Memphis, received a phone call from Lee. Lee had Googled “dopamine,” a neurotransmitter in the brain involved with movement, and Blaha’s website popped up. That connection was the genesis of a ‘dream team’ for studying deep brain stimulation - a procedure that holds the potential for dramatically changing the lives of many suffering from a range of neurological and psychological disorders.

As part of the Deep Brain Stimulation Consortium formed later in 2004, Blaha, Lee and colleagues Kevin Bennet, MBA, Paul Garris, PhD, and Pedram Mohseni, PhD, have collaborated to advance the knowledge, technology and efficacy of DBS. Based at Mayo, the DBS Consortium members represent four institutions. A five year $2.1 million grant from NIH was awarded to Blaha and Lee to continue their study of the neural mechanisms of DBS in the non-human primate model, already proven to produce therapeutic results in humans. Blaha and Lee are hoping to unravel the mystery of how and why DBS works.

“There are three aims of the project: using functional Magnetic Resonance Imaging (fMRI) to identify the areas of the brain activated by therapeutically effective DBS; to identify the neurochemical correlates of DBS; and to implant the recording electrodes chronically (fixed to the skull) and record from them while the primate model is undergoing fMRI,” said Blaha.

What is DBS?

Deep brain stimulation is a neurosurgical procedure which involves implanting a device with three parts: a neurostimulator (similar in size to a pacemaker) that is placed under the skin of the upper chest, a lead (the stimulating electrode), and insulated wire that connects the neurostimulator to the lead that runs under the skin. The lead is placed by the surgeon in a specific location in the brain that, when activated, provides symptom relief to the patient. For patients suffering from Parkinson’s Disease (PD), this is typically in the subthalamic nucleus (STN). Once the system is in place, the neurostimulator is turned on and adjusted until motor symptoms disappear. The patient is awake to help the surgeon guide the positioning of the electrode into the target area.

DBS has been in use therapeutically in the U.S. since 1997 for PD, essential tremor, dystonia, epilepsy and more recently for OCD (obsessive-compulsive disorder). Identifying the neural mechanisms is needed to improve and optimize therapeutic outcome. “The practical application of our studies on DBS mechanisms is to guide the research in the right direction,” added Blaha.

Michael J. Fox, who established a foundation for PD research following his own diagnosis, commented recently on the susceptibility for developing the disease, “The genes load the gun but the environment pulls the trigger.” The etiology of the disease is yet to be fully understood but is thought to be the result of a combination of genetic and environmental factors leading to the loss of dopamine neurons in the brain. Exactly what triggers the death of these neurons is vigorously being investigated.

A chronic and progressive disease, PD worsens over time and affects almost a million people in the U.S alone. Recent estimates note that PD occurs in only 5 percent of older people but in those over 85, 50 percent have symptoms associated with the disease. With no known cause or cure, treatment options consist of medication, surgery or combination therapy to manage symptoms.

Parkinson’s patients lose dopamine over time, so they are given L-dopa, its precursor to reduce their symptoms. “Over time, the drug loses its effectiveness,” said Blaha, “so they need an alternative. That alternative is deep brain stimulation.” And that’s where Lee and Blaha hope to improve outcomes.

A major hurdle for advancing knowledge and understanding of how DBS works is the difficulty of combining methodologies which measure neural activity with techniques that allow one to detect which neurotransmitters - such as dopamine, adenosine or glutamate - are being released in the brain during DBS. Originally it was thought that the benefit was “lesioning” (ablating) the neurons with DBS but that theory has been replaced by an “axonal activation” theory (activating the neurons to produce neurotransmitter release).

Using a combination of fMRI to identify the areas in the brain that are activated by DBS and neurochemical recording techniques to simultaneously measure neurotransmitter release in those areas has been an exciting breakthrough methodology that Blaha and Lee have applied for the first time. “The basics…is using fMRI to identify the specific areas of the brain activated by therapeutically effective DBS,” said Blaha, “and once identified, to use that information to place neurotransmitter recording electrodes into those sites.” Blaha claimed, “…this study is so unique because we are combining very powerful brain imaging techniques with neurochemical recordings. No one has ever done that before.”

WINCS (Wireless Instantaneous Neurotransmitter Concentration System, patent pending) was developed by Lee and Blaha working closely together with their DBS Consortium colleagues, Paul Garris, an electroanalytical chemist, and Kevin Bennet, chair of engineering at Mayo, and is a device which pairs digital telemetry with electrochemical (neurochemical) recording capabilities. This facilitates the measurement of dopamine and other neurotransmitters in real time and is being used in the primate model for their study.

The DBS study plans to take the technology a step further. Blaha is known internationally for developing in vivo electroanalytical techniques that can be used to measure neurotransmitters. “What we want to do is improve (the current stimulation device) by...incorporating measurement of neurotransmitter release during DBS to optimize therapeutic efficacy and to ‘know’ when to turn DBS off and on (stimulate), depending on the level of neurotransmitters.” In addition to providing a more complete understanding of the mechanisms at work, the hope is that their investigations will lead to the development of a “smart” implantable DBS system that utilizes neurochemical feedback control. A key task for the Consortium’s electrical and software engineers is to further improve and “micro-miniaturize” the WINCS system to a microchip and battery unit no larger than 2 x 2 mm fixed to the surface of the skull.

Given the depth of experience and expertise in their respective fields, Lee and Blaha are poised to further understanding of DBS mechanisms. Regarding their effective teamwork, Blaha declared, “It’s a match made in heaven to tackle a project as demanding and complex as this one.” Blaha, who has been in the OR for many of the procedures, added, “Seeing the faces of Dr. Lee’s patients when they realize that they can move like they used to before the disease, is an incredibly satisfying feeling.”

Tags:

Related:

Bookmark:

Digg

Facebook

Technorati

Newsvine

Google