Better ways to stimulate the brain

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Sound, light and current help researchers to tweak grey matter function in both health and disease
Deep brain stimulation

Deep brain stimulation, in this case
to address dementia. Photo: CC 3.0/ Wikimedia

Nuance is redefining the art and the evidence-based science of brain stimulation.

That assessment is based partly on a group presentation by a small subset of the researchers at the Society for Neuroscience, held in Washington, DC, November 11-15.

Brain stimulation called only for the use of electricity, the earliest form in modern medical use being electroconvulsive therapy. Newer methods involve such subtler and focused variations as using magnets above the head to produce electrical activity in the areas within it; directly stimulating specific parts of the brain instead of all of it; and using directed sound at a pitch far higher than humans can hear.

Moderator Helen Mayberg of Emory University School of Medicine spoke of how new stimulation techniques not only allowed for ways to treat the brain but also to study thoughts and feelings.

Three of the five presentations focused on different uses of transcranial brain stimulation, the other two on controlling cell activity.

Getting it all back

Transcranial Magnetic Stimulation

Transcranial Magnetic Stimulation.
Photo: CC 4.0/ Wikimedia

John Walker of Northwestern University described how electrical fields can improve memory in senior adults.

The problem the team was addressing was that of declining memory in older adults. One area in the brain strongly linked to memory is the hippocampus, named after the seahorse, because that is what it looks like when when seen along with a nerve bundle called the fornix, which forms the ‘tail.’ It is found in the middle of the brain – behind the eyebrows, level with the temples, and a little above the ears.

The hippocampus is believed to be involved in conscious memory. The hippocampus processes sensory information before sending it for final storage to the outer areas of the human brain, the cortex. Crudely put, this suggests the hippocampus is like a blackboard, which stores information temporarily, and the cortex the book that stores information in the long term. A digital analogy would involve RAM and hard drive. The hippocampus has also been linked to spatial memory, which is why a London cabbie may have a larger hippocampus than you or me.

Mess with this brain area and both storage and retrieval of memory are affected. Diseases linked to memory loss in aging, such as Alzheimer’s and Huntington’s, have been associated with hippocampal damage. But then, older people generally exhibit a decline in memory.

Walker and his team wanted to see if they improve memory in this group, even though the hippocampus is buried deep in the middle of the brain.

The team showed 15 people between the ages of 64 and 81 some novel objects, each against a specific backdrop. During this training phase, the people were also scanned in an fMRI unit. FMRI, or functional magnetic resonance imaging, draws a map of brain activity. For this, it relies on the differences in blood flow in different brain areas (more blood flows past active neurons) and the fact that the oxygen-poor blood in veins is more magnetic than that in the arteries.

Importantly, for five consecutive days during one week, Walker and his team stimulated the hippocampal network during training, using repetitive transcranial magnetic stimulation (rTMS). Another week, they placed the rTMS unit over each subject’s head but relied on stimulation that they had reason to believe was too low to have an effect.

Sure enough, the subjects remembered object-backdrop associations better when they got an effective charge out of the rTMS unit, an effect that lasted a week after treatment. The stimulation made no difference to the mere ability to recognize an object.

Walker said the team’s work showed that medically managed magnetic stimulation of the hippocampus could improve memory.

More reading on the hippocampus and memory.

A really sound control system

High pitch sound far higher than humans can hear has been used to produce images from within the body – such as ultrasound images of babies in the womb. Ultrasound devices focus sound waves into the body and, somewhat like a bat, use the returning sound waves to generate images of what lies within. Since sound shakes things up – whether it be air near your ear or the liquid in the body – it can also be used to stimulate areas in the brain.

Jan Kubanek and his teammates at Stanford wanted to see if focusing ultrasound on areas of the brain could safely affect behavior.

They showed two objects to a macaque one after another and trained it over time to look towards the one that appeared first. In the next phase of the experiment, 100 milliseconds before the first object appeared, they stimulated the left or right side of the frontal eye field, the area of the brain associated with vision. In humans, that is in the back of the head. The left visual field of the eyes is wired to the right side of the brain, and the right visual field to the left.

So when ultrasound was used to stimulate the right eye field, the animal tended to look left, and vice versa. The effect was not seen when the motor cortex, the part involved in directing movement, was stimulated. There was no long-term effect seen after the stimulation was stopped, suggesting the treatment was most likely safe.

The research suggested that noninvasive ultrasound can indeed be used to safely stimulate brain areas.

Those wee twitching lambs

If ultrasound can excite brain areas, could it also suppress activity in them? Also, could an ultrasound unit be worn continually? Seung-Chik Yoo and his team from Harvard University tested that in a few anesthetized sheep, using quarter-pound ultrasound units to focus sounds pulses into the animals’ heads. The units had the added advantage of not influencing the MRI used to monitor change. One unit was made of ceramic, the other of a material (such as quartz) which converts electrical impulses into the mechanical pressure (that is, sound).

No surgery being involved, the area that the sound was focused on was not visible. The team members relied on a software that compared a virtual sheep brain with that of the hapless subject to stay on target.

They learned that tweaking the power, timing and duration of ultrasound pulses could cause either excitation of the brain area or disrupt activity there. The result was that they could focus sound on the area of the brain involved in the leg’s movement.

If you have seen someone wear a horseshoe-shaped Alice headband, that area will be at the center of the head, just in front of the band.

By stimulating this area, the primary motor cortex, the researchers could make a still leg move, or stop a limb from responding to touch.

Despite the confidence generated by the work with macaques, Yoo and his team are yet to confirm that their portable ultrasound unit is safe to use.

The team also has to test the units on awake animals, seeing if they can be made to move when they do not want to, and, perhaps, be unable to when threatened by the local wolf. Of course, the IRB* may not approve of that last wrinkle.

Noah Young from Stanford University and Nicole Swann from the University of California, San Francisco, discussed their different ways of regulating electrical stimulation in real time.

Young and his team wanted to ensure fine control during electrical stimulation, given the errors in data and the fact that too many cells are affected. Their solution: optogenetics.

They have seen the light

Calcium indicators can indicate cellular activity.

Calcium indicators.
Photo: CC 3.0/ Wikimedia

Light can make some proteins, called opsins, change their structure, so as to bind or separate from other biologically active molecules.

The team worked with genetically modified mice with two modified genes. One of these glowed in the presence of calcium ions. Since calcium is an important factor in cellular function, the presence of calcium ions signals increased activity. The glowing patches can highlight which parts of the brain are active during a particular behavior. The other gene, taken from a green algae called Volvox, produces a protein (in technical terms, an opsin) that increases cell activity in the presence of a red laser. The idea is that as cellular activity rises (in this case, in the hippocampus), the light stimulation can be correspondingly reduced, thus maintaining the desired level of activity. Because this happens only on the targeted cells and in milliseconds, it is both focused and quick.

Of course, since it requires light to be directed into the head, this technique is both unwieldy and invasive.

Fine control in Parkinson’s

Deep brain stimulation setup.

DBS setup. Photo: CC 3.0/ Wikimedia

Swann and team members at the University of Oregon, where she earned her PhD, tried to bring fine control to an already invasive technique, deep brain stimulation (DBS).

In this, battery-powered electrodes stimulate the required areas of the brain. It is generally safe, and useful against a variety of brain-related problems – pain, depression, Parkinson’s, etc. But it has a cruder feedback mechanism, often calling on patients themselves to fine-tune the rate and strength of stimuli.

For someone with jerking muscles (dyskinesia), as seen in Parkinson’s, fine control is hard, especially since modifications often have to be made in real time.

The team measured involuntary muscle movements in two people suffering from Parkinson’s disease. It measured activity in the motor cortex – again, a little in front of the Alice headband we had mentioned earlier. It relied on electrocorticography, which involves measuring electrical activity on the surface of the brain.

Swann showed a video of how it helps patients: A DBS patient sitting still suddenly suffers a bout of dyskinesia, which quickly dissipates when a feedback system kicks in, automatically reducing the stimulation.

Now, if the patient had consciously tried to reduce the stimulation it would have taken him longer and called for fine movement he would likely have been incapable of at the time.

Because the unit is not firing all the time, battery consumption also went down 45 percent.

The patients were tested with the unit for 10 minutes to an hour, both indoors and out. The plan is now to keep the units going for a week.

“Our study showed that totally implanted, adaptive deep brain stimulation is feasible and can be used at home in patients,” Swann said. “Adaptive stimulation represents one of the first major advances in DBS technology since this technique was first introduced for the treatment of Parkinson’s disease 25 years ago.”

*Institutional Review Board, a body that gauges all proposed research before deciding if it can go ahead

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