Sodium ions wait outside neurons like knights raring to storm the keep. Man the gates and you can control the castle, or in the case of a neuron, its action potential. However, existing electrical methods require potentially dangerous currents, and the effects can bleed beyond the target nerve to surrounding neurons. In yesterday’s Nature Materials, researchers report on a way to gain subtler control over nerve activity by altering local levels of calcium ions. Using calcium-specific ionophores, they figuratively loosen the gates, making it easier for sodium ions to bust through and the nerve to transmit a signal. In another version, they silence nerves by letting a few sodium ions in, so that there are not enough left outside to mount an action potential. If developed further, this could perhaps become a useful supplement to neuroprosthetics for paralyzed people, or be incorporated into a tunable device to shut off neurons firing in the case of tremors in parkinsonism or neuropathic pain.
“This is a novel way of interfacing with the nerve,” said senior author Jongyoon Han of MIT. He led the study with first author Yong-Ak Song, also at MIT, and co-senior author Samuel Lin of the Beth Israel Deaconess Medical Center in Boston. The researchers inserted a calcium ion-filtering membrane between an electrode and the target nerve to alter the nerve’s threshold for activation, either enhancing or dampening incoming signals.
The study builds on years of work in functional electrical stimulation, in which electrodes near a nerve stimulate action potentials. Electrical stimulation could help paralyzed people move again or still tremors in people with Parkinson’s disease (see ARF news series). What Han and colleagues add, with their membrane-shrouded secondary electrode, is a chemical control mechanism to go along with the electrical one. Electricity, Han noted, cannot be contained; it will spread throughout conductive tissue. That creates side effects. For example, activating one set of motor neurons to create a desired movement might also activate a nearby pain nerve. The new technique minimizes the current required, making it more energy-efficient while keeping the response local, Han said. Plus, Lin added, the new method can also shut down nerves as well as help them activate.
Song worked with dissected frog sciatic nerves, looking for ways to render them more or less sensitive to incoming signals. In the case of paralysis, the scientists would like to lower the threshold of activation, making nerves more likely to fire. Lowering calcium is a well-known method to make nerves hypersensitive, Han said, but usually involves dunking the naked nerve in a calcium-depleted solution. In this case, the researchers brought the low-calcium environment to the nerve instead.
Song used polyvinyl chloride (PVC) as a matrix to support calcium-specific ionophores, and layered this mixture onto an electrode so the ionophores would sit between the nerve and the electrode, which served as the cathode. A separate nearby electrode served as an anode. When Song turned on the juice—at less than one microamp, not nearly enough to stimulate a nerve—it created a membrane potential across the PVC matrix and the ionophores sucked up the nearby calcium. He applied a slightly larger, stimulating current from other electrodes to turn on the nerve. Nerves under the calcium-depletion conditions had a lower threshold of activation, down to 2.2 microamps, as opposed to 7.4 microamps without the calcium-selective membrane. Using the ionophore membrane made the nerves more likely to fire—making the technique of potential future use in people whose nerves do not fire under normal conditions, the authors propose.
Conversely, some people suffer because their nerves fire too much. Tweaking calcium concentrations can fix that problem, too, Lin said. When Song applied a current of 10-15 microamps across the PVC matrix, he altered the sodium ions and gates in a different way. In this case, some of the sodium channels swung open slowly, allowing the ions to seep in and diminish the nerve’s membrane potential. When Song induced an action potential, there were not enough sodium ions to maintain it, and it died. The nerves were in a state similar to the refractory period after an action potential passes, when further action potentials are blocked, Han said. The effect was adjustable and fully reversible, Lin noted, so a person with a nerve-blocking device could tune it so that more or less nerve activity was allowed.
“It looks like a highly innovative approach to modulate threshold,” said Warren Grill of Duke University in Durham, North Carolina, who was not involved in the study. He noted that nerves must remain intact for the stimulation to work, so the technique might not help in cases of neurodegeneration such as amyotrophic lateral sclerosis. The new method of nerve block could be particularly valuable, he said, because current techniques require high-amp currents that could damage tissue as well as leak beyond the desired target nerve.
The study was in vitro but the team hopes to translate their idea into something medically useful. “The proof of principle presented in the paper is promising for future in-vivo studies,” commented Peter Kjall of the Karolinska Institute in Stockholm, Sweden, in an e-mail to ARF. Kjall, who was not involved in the study, predicted the ion-selective technology might become part of many future neuroprosthetics.
The ion-selective membrane technique could supplement regular functional electrical stimulation or act on its own, the authors said. The researchers must take care that the materials are not subject to corrosion by the warm saline in the body, or damage the body in any way, Grill noted. Song’s current electrode is a centimeter square, but he said he could make it smaller—more like a millimeter square—to match up with other electrodes used in neuroprosthetics. They also might design a flexible membrane they could fit to a nerve’s contours, the authors wrote. Ultimately, Lin envisions a self-contained, biocompatible implant that could be recharged across the skin, as some stimulatory systems are.—Amber Dance
- Huang JH, Cullen DK, Browne KD, Groff R, Zhang J, Pfister BJ, Zager EL, Smith DH. Long-term survival and integration of transplanted engineered nervous tissue constructs promotes peripheral nerve regeneration. Tissue Eng Part A. 2009 Jul;15(7):1677-85. PubMed.
- Srivastava AS, Malhotra R, Sharp J, Berggren T. Potentials of ES cell therapy in neurodegenerative diseases. Curr Pharm Des. 2008;14(36):3873-9. PubMed.
- Moritz CT, Perlmutter SI, Fetz EE. Direct control of paralysed muscles by cortical neurons. Nature. 2008 Dec 4;456(7222):639-42. PubMed.
- San Diego: Researchers Rejuvenate Neurons to Bridge Spinal Cord Gaps
- What’s Another Year?—Testing the Limits of Axon Regeneration
- Mind-machine Meld: Brain-computer Interfaces for ALS, Paralysis
- Jumpstarting Axon Regeneration?—Not Such a Stretch
- Spinal Detour—Co-opted Cortical Neurons Control Paralyzed Muscle
- Double Punch Regenerates Injured Spinal Cord, Restores Rat Breathing
- Song YA, Melik R, Rabie AN, Ibrahim AM, Moses D, Tan A, Han J, Lin SJ. Electrochemical activation and inhibition of neuromuscular systems through modulation of ion concentrations with ion-selective membranes. Nat Mater. 2011 Dec;10(12):980-6. PubMed.