Using the Brain to Treat the Body's Diseases

There’s an article in New York Times Magazine about using electrical signals in the nervous system to signal to the rest of the body to somehow alter molecular signaling outside the nervous system. Neuroscientists have known for a while that neurons transmit messages by electro-chemical signals: at each synapse, an electrical impulse arrives from a cell body, is converted to a chemical message via neurotransmitters. The chemical message jumps across the synapse, where it is again converted into an electrical signal at the next (postsynaptic) neuron. For some reason though, the thought that electrical signals interact with non-nervous system elements (like the immune system) has not been very popular; the idea that one could manipulate the electrical signals to “hijack” downstream molecular signaling without affecting neural communication itself seems like magic. The NYT article describes how Kevin Tracey, a neurosurgeon, hooked up stimulating electrodes around a rat’s vagus nerve and injected a toxin that increases tumor necrosis factor (TNF), a cytokine that promotes cell death. He found that stimulating the vagus greatly reduced TNF production in the liver (original paper can be found here) and reduced inflammation. Tracey is currently pursuing clinical therapies using such “bioelectronics” to treat diseases like rheumatoid arthritis, which don’t respond well to drugs (drugs go all over the body and usually act in different tissues, despite being designed to target specific targets).

The bioelectronics approach should be useful because electrodes can be placed directly on the organ that needs intervention. While stimulating the whole vagus nerve, as in the rheumatoid arthritis treatment described in the article, is still a sledgehammer approach, one could imagine more specific stimulation in the future (e.g. targeting a subset of the nerve or its targets or finding better stimulation timing or amplitude). One could record nerve signals while monitoring production of molecules of interest (or patient symptoms) to optimize the stimulation.

Perhaps most exciting is the idea that one could record electrical signals (either in the peripheral nervous system, near the organs, or in the brain itself) and in real time give positive reinforcement in order to reward those signals that produce a desirable outcome. (Such paradigms have been successfully used to examine how the brain can interact with a machine  - researchers from Jose Carmena’s lab at UC Berkeley trained rats to control an auditory cursor using the firing rates of neurons in motor cortex - the higher the firing rate, the higher the pitch of the cursor. The rats quickly learned to adjust the neurons' firing rates in order to receive a food reward.)

Aside from the cool ideas on manipulating neural activity to treat diseases, the article, by Michael Behar, had a funny description of patch clamping, a technique to record potentials and currents from a cell membrane.

In patch clamping, the tip of a glass capillary tube filled with conductive solution is heated and pulled to a sub-micron diameter. This fine electrode is then placed onto the membrane of a neuron to record electric signals either on the surface or inside the cell (“patch” comes from the fact that you’re examining a small area of the membrane; “clamping” means the technique allows one to hold the neuron’s electrical potential at a fixed value while monitoring membrane currents and vice versa). Behar imagines this technique to involve “clamps”:

"The conventional approach to recording neural signals is to use tiny probes with electrodes inside called patch clamps. A prostate-cancer researcher, for example, could attach patch clamps to a nerve linked to the prostate in a healthy mouse and record the activity."

Not a big deal of course. It is somewhat misleading though that Behar goes on to suggest that patching neurons is the only way to record activity. Patching a neuron is indeed a slow process and most setups allow only one neuron to be recorded at a time. Behar gives a shoutout to Adam Cohen in writing that the solution is to record neural activity optically using voltage sensitive dyes (small molecules that fluoresce when a neuron is electrically active) that Cohen is developing. This not only ignores that recording activity using hundreds of metal or silicon microelectrodes is a relatively standard technique (and getting easier for new labs to start, thanks to initiatives like Open Ephys), but that optical techniques to record from hundreds of neurons have been in wide use for years now (of course there’s plenty of room for improvement).

Small details aside, this is a cool article worth reading.