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Optogenetics: Noninvasive brain control using Jaws, a light-sensitive protein

Noninvasive brain control is big news because the new light-sensitive protein enables simpler, more powerful optogenetics, which is a technology that allows scientists to control brain activity by shining light on neurons, says a new study, "Noninvasive brain control: New light-sensitive protein enables simpler, more powerful optogenetics," published June 29, 2014 in the journal Nature Neuroscience. The noninvasive technique relies on light-sensitive proteins that can suppress or stimulate electrical signals within cells. Other techniques require a light source to be implanted in the brain, where light can reach the cells to be controlled. Optogenetics gives researchers the ability to restore and enhance brain function. The noninvasive technique using light generated from a protein known as Jaws, is becoming a reality.

Optogenetics: Noninvasive brain control using Jaws, a light-sensitive protein.
Optogenetics: Noninvasive brain control using Jaws, a light-sensitive protein.Photo by China Photos/Getty Images

Massachusetts Institute of Technology (MIT) engineers have now developed the first light-sensitive molecule that enables neurons to be silenced noninvasively, using a light source outside the skull. This makes it possible to do long-term studies without an implanted light source. The protein, known as Jaws, also allows a larger volume of tissue to be influenced at once.

This noninvasive approach could pave the way to using optogenetics in human patients to treat epilepsy and other neurological disorders, the researchers say, although much more testing and development is needed. Led by Ed Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT, the researchers described the protein in the June 29, 2014 issue of Nature Neuroscience.

Optogenetics, a technique developed over the past 15 years, has become a common laboratory tool for shutting off or stimulating specific types of neurons in the brain, allowing neuroscientists to learn much more about their functions

The neurons to be studied must be genetically engineered to produce light-sensitive proteins known as opsins, which are channels or pumps that influence electrical activity by controlling the flow of ions in or out of cells. Researchers then insert a light source, such as an optical fiber, into the brain to control the selected neurons.

Such implants can be difficult to insert, however, and can be incompatible with many kinds of experiments, such as studies of development, during which the brain changes size, or of neurodegenerative disorders, during which the implant can interact with brain physiology. In addition, it is difficult to perform long-term studies of chronic diseases with these implants.

Mining nature's diversity

To find a better alternative, Boyden, graduate student Amy Chuong, and colleagues turned to the natural world. Many microbes and other organisms use opsins to detect light and react to their environment. Most of the natural opsins now used for optogenetics respond best to blue or green light.

Boyden's team had previously identified two light-sensitive chloride ion pumps that respond to red light, which can penetrate deeper into living tissue. However, these molecules, found in the bacteria Haloarcula marismortui and Haloarcula vallismortis, did not induce a strong enough photocurrent — an electric current in response to light — to be useful in controlling neuron activity.

Chuong set out to improve the photocurrent by looking for relatives of these proteins and testing their electrical activity

She then engineered one of these relatives by making many different mutants. The result of this screen, Jaws, retained its red-light sensitivity but had a much stronger photocurrent — enough to shut down neural activity.

"This exemplifies how the genomic diversity of the natural world can yield powerful reagents that can be of use in biology and neuroscience," says Boyden, according to the June 29, 2014 news release, "Noninvasive brain control." Boyden is a member of MIT's Media Lab and the McGovern Institute for Brain Research.

Using this opsin, the researchers were able to shut down neuronal activity in the mouse brain with a light source outside the animal's head. The suppression occurred as deep as 3 millimeters in the brain, and was just as effective as that of existing silencers that rely on other colors of light delivered via conventional invasive illumination.

Restoring vision

Working with researchers at the Friedrich Miescher Institute for Biomedical Research in Switzerland, the MIT team also tested Jaws's ability to restore the light sensitivity of retinal cells called cones. In people with a disease called retinitis pigmentosa, cones slowly atrophy, eventually causing blindness.

Friedrich Miescher Institute scientists Botond Roska and Volker Busskamp have previously shown that some vision can be restored in mice by engineering those cone cells to express light-sensitive proteins. In the new paper, Roska and Busskamp tested the Jaws protein in the mouse retina and found that it more closely resembled the eye's natural opsins and offered a greater range of light sensitivity, making it potentially more useful for treating retinitis pigmentosa.

Restoring the vision in mice using a noninvasive optogenetics technique could take researchers a step closer to treating diseases such as epilepsy in humans

This type of noninvasive approach to optogenetics could also represent a step toward developing optogenetic treatments for diseases such as epilepsy, which could be controlled by shutting off misfiring neurons that cause seizures, Boyden says, according to the news release. "Since these molecules come from species other than humans, many studies must be done to evaluate their safety and efficacy in the context of treatment," he says, according to the news release.

Boyden's lab is working with many other research groups to further test the Jaws opsin for other applications. The team is also seeking new light-sensitive proteins and is working on high-throughput screening approaches that could speed up the development of such proteins.

The research at MIT was funded by Jerry and Marge Burnett, the Defense Advanced Research Projects Agency, the Human Frontiers Science Program, the IET A. F. Harvey Prize, the Janet and Sheldon Razin '59 Fellowship of the MIT McGovern Institute, the New York Stem Cell Foundation-Robertson Investigator Award, the National Institutes of Health, the National Science Foundation, and the Wallace H. Coulter Foundation.

Putting magnets around your head is in the news again

Duke University researchers have developed a method to record an individual neuron's response to transcranial magnetic stimulation therapy. What methods do researchers use to record an individual neuron's response during transcranial magnetic stimulation? Certain types of magnets are used to stimulate the neurons in the head, at least in new research with nonhuman primates.

The advance will help researchers understand the underlying physiological effects of TMS -- a procedure used to treat psychiatric disorders -- and optimize its use as a therapeutic treatment. You may wish to check out the abstract of the new study, "Optimization Of Transcranial Magnetic Stimulation And Single Neuron Recording Methods For Combined Application In Alert Non-Human Primates," published online June 29, 2014 in the journal Nature Neuroscience. Or see, "Watching individual neurons respond to magnetic therapy."

New technique could show transcranial magnetic stimulation (TMS) treating depression and other disorders. Engineers and neuroscientists at Duke University have developed a method to measure the response of an individual neuron to transcranial magnetic stimulation (TMS) of the brain.

The advance will help researchers understand the underlying physiological effects of TMS -- a procedure used to treat psychiatric disorders -- and optimize its use as a therapeutic treatment. TMS uses magnetic fields created by electric currents running through a wire coil to induce neural activity in the brain.

With the flip of a switch, researchers can cause a hand to move or influence behavior

The technique has long been used in conjunction with other treatments in the hopes of improving treatment for conditions including depression and substance abuse. While studies have demonstrated the efficacy of TMS, the technique's physiological mechanisms have long been lost in a "black box." Researchers know what goes into the treatment and the results that come out, but do not understand what's happening in between.

Part of the reason for this mystery lies in the difficulty of measuring neural responses during the procedure; the comparatively tiny activity of a single neuron is lost in the tidal wave of current being generated by TMS. But the new study demonstrates a way to remove the proverbial haystack.

"Nobody really knows what TMS is doing inside the brain, and given that lack of information, it has been very hard to interpret the outcomes of studies or to make therapies more effective," said Warren Grill, according to the June 29, 2014 news release, "Watching individual neurons respond to magnetic therapy." Grill is a professor of biomedical engineering, electrical and computer engineering, and neurobiology at Duke University. "We set out to try to understand what's happening inside that black box by recording activity from single neurons during the delivery of TMS in a non-human primate. Conceptually, it was a very simple goal. But technically, it turned out to be very challenging."

First, Grill and his colleagues in the Duke Institute for Brain Sciences (DIBS) engineered new hardware that could separate the TMS current from the neural response, which is thousands of times smaller. Once that was achieved, however, they discovered that their recording instrument was doing more than simply recording.

Magnetic fields created by an electric current measuring neurons in the brain

The TMS magnetic field was creating an electric current through the electrode measuring the neuron, raising the possibility that this current, instead of the TMS, was causing the neural response. The team had to characterize this current and make it small enough to ignore.

Finally, the researchers had to account for vibrations caused by the large current passing through the TMS device's small coil of wire -- a design problem in and of itself, because the typical TMS coil is too large for a non-human primate's head. Because the coil is physically connected to the skull, the vibration was jostling the measurement electrode.

The researchers were able to compensate for each artifact, however, and see for the first time into the black box of TMS

They successfully recorded the action potentials of an individual neuron moments after TMS pulses and observed changes in its activity that significantly differed from activity following placebo treatments. Grill worked with Angel Peterchev, assistant professor in psychiatry and behavioral science, biomedical engineering, and electrical and computer engineering, on the design of the coil. The team also included Michael Platt, director of DIBS and professor of neurobiology, and Mark Sommer, a professor of biomedical engineering.

They demonstrated that the technique could be recreated in different labs. "So, any modern lab working with non-human primates and electrophysiology can use this same approach in their studies," said Grill, according to the news release.

The researchers hope that many others will take their method and use it to reveal the effects TMS has on neurons

Once a basic understanding is gained of how TMS interacts with neurons on an individual scale, its effects could be amplified and the therapeutic benefits of TMS increased. "Studies with TMS have all been empirical," said Grill, according to the news release. "You could look at the effects and change the coil, frequency, duration or many other variables. Now we can begin to understand the physiological effects of TMS and carefully craft protocols rather than relying on trial and error. I think that is where the real power of this research is going to come from."

Authors of the study are Mueller, J.K., Grigsby, E.M., Prevosto, V., Petraglia III, F.W., Rao, H., Deng, Z., Peterchev, A.V., Sommer, M.A., Egner, T., Platt, M.L., and Grill, W.M. This research was supported by a Research Incubator Award from the Duke Institute for Brain Sciences and by a grant from the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (grant R21 NS078687).

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