Taking on Depression via Electrodes and the Brain's Secret Calcium Signals

New research uncovers a mechanism behind the success of transcranial direct current stimulation.

Mar 23 2016, 10:00am

Astrocyte. Image: Wikipedia

It's become increasingly clear that transcranial direct current stimulation (tDCS) works, at least some of the time. The therapy, which applies very low electrical currents to the brain via electrodes placed on the scalp, has show the most promise for treatment-resistant depression, but little is known about how it actually works deep down.

From the high-level perspective, we can say that it increases or decreases the long-term electrical potential between neurons—depending on the polarity of current applied. How it does this has been difficult to judge.

Now, researchers from RIKEN Brain Science Institute in Japan have shown that the changes may not have to do directly with neurons at all. Instead, the group has found that tDCS induces waves of calcium to be released from cells called astrocytes, which provide a large number of support functions in the brain and spinal cord, including signaling. It seems likely that these waves function as signals that result in the increases in neuroplasticity required for long-term changes to occur in the brain. The RIKEN group's work is described in a paper published Tuesday in Nature Communications.

The neuroscientists were able to reach this conclusion thanks to transgenic mouse models. In these models, both astrocytes and a subset of neurons were made to secrete a green fluorescent protein called G-CaMP7. Via this protein, they observed the rodents' neurological activity as they received various sensory inputs.

With their mice cortices sufficiently buzzing, the researchers used G-CaMP7 to observe the subjects' neurological activity both before and during tDCS. Not only did they find relative increases in cortical activity following tDCS, when subject to sensory inputs in the forms of puffs of air directed at the mice's whiskers or flashes of light, they observed accompanying surges in calcium being produced by astrocytes.

That astrocyte-based calcium surges have a role in the process by which neurons establish connections with each other is not in itself a new thing, and it's been suggested that astrocytes are a routine part of the brain's information processing functions. Neurons signal each other using electrical impulses, but astrocytes in turn regulate this signaling using their own calcium-mediated form of signaling. The signaling interactions between astrocytes and neurons are together known as gliotransmission.

A 2014 perspective in the journal Neuron declared the identification of gliotransmission processes to be "a paradigm shift in our thinking about brain function."

What the RIKEN group wanted to explore is how and if this extra layer of signalling is impacted by tDCS. Indeed, the astrocyte response to tDCS was quick and synchronized across the entire cerebral cortex, rather than just the region responsible for processing the whisker- and flash-related sensory input.

The researchers then went on to explore the relationship between the observed calcium surges and known depression models in mice. tDCS has been shown to be effective in such models, generally, so the group attempted tDCS on mice who had their astrocyte-produced calcium channels blocked. Without the calcium surges, the stimulation proved to be ineffective.

We may be onto something pretty important here. If depression can be better treated by manipulating astrocytes and calcium levels, together with neural activity, we have a new and very different approach to an illness in dire need of new and very different approaches.