Researchers and Clinicians Participate at First Mechanisms of Action Conference

by James Cavuoto, editor
March 2014 issue

Nearly 200 clinicians, researchers, and neuromodulation industry representatives attended the first World Congress on Mechanisms of Action, held in Orlando, FL earlier this month. The meeting, sponsored by Neurovations and the Napa Pain Institute, was devoted to elucidating the biological mechanisms underlying electrical stimulation of the nervous system. Elliot Krames, former president of the International Neuromodulation Society, served as cochair of the meeting, along with Eric Grigsby of Neurovations.

Most of the conference dealt with mechanisms of spinal cord stimulation and deep brain stimulation, though there were also sessions on peripheral nerve stimulation, cardiac neuromodulation, and visceral disorders.

During the meting, Robert Levy from University of Florida spoke on the levels of evidence for different forms of neuromodulation, noting that there were only a small number of randomized control trials gauging the effectiveness of SCS. That said, Levy argued that RCTs we’re not all that was needed in the treatment of diverse populations of pain sufferers.

Krames gave a background on dorsal root ganglion stimulation for treating neuropathic pain, pointing out the critical role that T-junctions play in the therapy. Because of their location between DRG axons and the spinal cord, T-junctions are able to pass, block, or enhance pain signals traveling to the brain. Krames explained that there was no direct neuronal communication within the DRG, although there was local communication between glial cells surrounding the neurons. Cytokines released by glial cells in response to injury also play a key role in pain, he said.

In a lengthy session devoted to mechanisms of DBS, Paul Stypulkowski from Medtronic gave a historical account on the evolution of our thinking on treatment of Parkinson’s disease. In early models, the subthalamic nucleus was thought to be overactive so stimulation of STN would achieve the same effect as lesioning it. Later, a network oscillation model emerged that focused on network synchrony. Researchers observed that sinusoidal oscillatory activity in the beta frequency band corresponded to Parkinson’s symptoms and DBS was seen as a way to suppress that beta band activity.

Stypulkowski described Medtronic’s efforts to explore DBS mechanisms using its “Brain Radio” device, which can both stimulate and sense signals continuously. Researchers have used the device to gather more than three years worth of data from sheep within a circuit containing anterior thalamus and hippocampus. By stimulating and recording in hippocampus, they found a profound difference in effect of a 50 Hz, 10-second burst of stimulation when they varied the voltage from 0.9 to 1.3 volts. They found another noticeable difference by changing frequency from 20 to 40 Hz. Aside from stimulation parameters, investigators could also test the effect of changing the contact from the four available on the lead.

Konstantin Slavin from University of Illinois Chicago discussed mechanisms of DBS for treatment of epilepsy. He mentioned early research on cerebellar stimulation for epilepsy and reviewed clinical trial data from NeuroPace’s RNS device and Medtronic’s SANTE trial. Slavin observed DBS-induced GABA inhibitory post synaptic potentials and enhanced slow after-hyperpolarization. He suggested that there might be more than one mechanism involved and proposed that treatments be tailored for the individual epilepsy patient.

Kelly Foote from University of Florida described his and other institutions’ efforts at reverse engineering the brain. He likened action potentials to binary computer code, whereas aggregate signals like local field potentials or EEGs were analogous to high-level computer languages. Foote also stressed the importance of topography in analyzing DBS mechanisms, noting that when you stimulate axons you get an increase in neuronal activity whereas stimulating cell bodies does not achieve that effect. Addressing the apparent conflict that stimulation of STN—with its plethora of cell bodies—produces the most robust beta suppression, he suggested that perhaps the highest concentration of fibers is what’s important and that stimulating at boundary areas might be most fruitful.

Foote described his lab’s use of the NeuroPace RNS device to record LFPs after stimulation of individuals with Tourette’s syndrome. Looking for neural correlates of the premonitory urge that precedes a Tourette’s tic—referred to as a”psychic itch” by some patients—Foote discovered a change in activity in the central medial thalamus about three seconds prior to the tic that acted as a biomarker. Increased thalamic gamma correlated with tic suppression, whether voluntary or induced by stimulation. Subjects reported a sense of calm that accompanied the tic suppression. A scheduled regimen of 16 seconds on 120 seconds off produced good results, causing Foote to speculate that continuous stimulation might be disruptive, while burst stimulation might be more effective.

Kendall Lee from Mayo Clinic described his institution’s use of the Harmoni device to study neurotransmitter/DBS interactions [NBR Nov13 p1]. He believes that high-frequency stimulation increases calcium ion concentration in astrocytes, which is the source of DBS-evoked glutamate. Glutamate depolarizes neurons and abolishes network oscillations.

Cameron McIntyre from Case Western Reserve University described efforts he and Helen Mayberg of Emory University have undertaken to compare and contrast the difference between therapeutic and non-therapeutic stimulation of individuals with depression. It’s not where you put the electrode, but the selection of stimulation parameters that is most important in driving the right pathways, he said.

Andres Lozano from the University of Toronto summarized his Phase II study of 40 patients with Alzheimer’s disease using DBS of the fornix. The goal is to change the structure of the circuits, not just neural activity, he said. His team has found a three-fold increase in neurogenesis after stimulation. Lozano is also working with pulsed ultrasound and after stimulation of 30 patients the results look like those from pallidotomy, he said.