x Abu Dhabi, UAEMonday 24 July 2017

Do rat brains hold the key to understanding deep-brain stimulation?

Deep-brain stimulation offers a better way of treating diseases like Parkinson's - but no one knows quite why.

A rat brain that underwent deep-brain stimulation in research conducted at UAE University in Al Ain shows a patch of inactivity – the area without black dots – near the spot that was stimulated, seen in yellow. Courtesy Safa Shehab
A rat brain that underwent deep-brain stimulation in research conducted at UAE University in Al Ain shows a patch of inactivity – the area without black dots – near the spot that was stimulated, seen in yellow. Courtesy Safa Shehab

AL AIN // For decades doctors have drilled wires through skulls to shoot electric currents into the brain.

The treatment, however much it may sound like science fiction or torture, has been shown to ease the incessant shaking caused by Parkinson's disease, some of the disruptive symptoms of epilepsy, muscle spasms, chronic pain and even obsessive-compulsive disorder and depression.

Yet even while experts install "brain pacemakers" inside patients' heads and upper chests, they are not exactly sure why deep-brain stimulation works.

Does it excite cells or inhibit them? Does it succeed by stimulating the targeted area or another region that is connected to it? And what side effects might result?

In the middle of the 20th century, doctors treated Parkinson's by "lesioning", or permanently damaging, the part of the brain that caused the shaking.

Killing the cells that were causing the shaking stopped it. To work out which parts of the brain to lesion, doctors first used electric currents, stimulating the area they believed was causing the shaking to see if it stopped.

But the lesioning was irreversible, so if an intervention caused intolerable side effects or was simply ineffective, there was nothing to be done.

Other scientists, meanwhile, were using the same type of electrical stimulation to figure out the connections between brain activity and motor function.

Stimulate a particular area, and the patient's foot, for example, would twitch.

In the 1970s and '80s, it was realised that the stimulation itself could be used as a treatment, rather than merely an investigative tool. While it was unclear whether the current was exciting or inhibiting the brain cells, it worked.

And it had a crucial advantage over lesioning. Although both required surgery to implant an electrode, the stimulation needed to be administered constantly. That meant it could be turned up or down, to heighten or reduce the effects. Switch it off, and those effects ceased.

Electric stimulation, then, has the potential to be a better solution. Still, the exact mechanism of its effects remains opaque.

"Despite the fact that there's huge work on the brain, we still know very little," says Safa Shehab, a neurosurgeon-turned-professor at UAE University in Al Ain who has specialised in the brain and nervous system since 1981.

"The more I investigate it, the more I learn, and the more intriguing it becomes. What exactly is direct brain stimulation doing to the area connected, at the area being stimulated, and where is the connected area?"

He is working to shed light on exactly that, using rats as a model for the effects of deep-brain stimulation, with the same type of electric current that has been found to be effective for people.

"If I were to do all frequencies it might take five years," he said. "But here I use what they use for humans, because that's what helps humans."

He is two years into a three-year Dh750,000 research grant from the university, which has allowed him to use top-notch equipment that he says has made all the difference. "I am better off this year than before with the financial support."

The experiments begin with "stereotaxic neurosurgery" - the inserting of tiny electrodes into the rats' brains. Probes are implanted under general anaesthesia, using a dental drill to poke through the skull and a detailed brain "atlas" to find the right spot. Once in place, the electrodes are cemented to the skull to keep them there.

After the rat is awake and recovered, the stimulation starts, delivering current for half an hour. Ninety minutes later, the rat is put down.

Its brain is finely sliced using a "Vibratome" - a vibrating platform attached to a razor that creates slivers just a sixteenth of a millimetre thick.

The transparent slices float into a surrounding moat of water, then are slipped into a bottle filled with an antibody that serves as a stain. They sit on a vibrating machine for a day, to let the stain set in, then are photographed under a microscope.

The resulting images give a precise snapshot of what was going on in the rat's brain before it died. Active areas appear as dark dots of stain amid the palish tissue.

The most recent series of images, published last June in the journal Neurobiology of Disease, show small areas of inactivity - that is, areas without dark dots - extending around each stimulation point in the areas of the brain linked to epilepsy.

That suggests those areas are being inhibited.

"When you put the current [in that area], there is no activity around the electrode," says Dr Shehab.

He has found the same effect in the parts of the brain associated with Parkinson's and has produced a set of images that will be presented later this year.

Next he will turn to other major unknowns surrounding the mechanics of stimulation: how do different sections of the brain relate to one another, and how do severed connections affect disease?

Studies of Parkinson's patients have shown, for example, that stimulation may inhibit the direct area targeted but excite neighbouring fibres; it is possible, too, that a lower frequency of current might excite the neurons, rather than inhibiting them.

Other scientists have investigated the potential of deep-brain stimulation in treating other conditions.

But they have found it can come with troubling side effects.

Patients can become manic or hypersexual. Others cravesweets, and still others swing into depression orlose motivation.

"It's still a big mystery," said Christelle Baunez, the head of research at the National Institute for Scientific Research in France, who focuses on the subject.

There are a number of side effects, she says,but little way of predicting which patients will suffer them.

In her experiments, rats that liked alcohol showed even greater interest after undergoing treatment. That suggests humans with a history of addiction should be careful.

And electrode placement remains a matter of trial and error, especially with non-motor diseases like obsessive-compulsive disorder and depression.

"People tend to try everywhere. Sometimes you wonder what was the rationale behind their decision," said Dr Baunez. Tackling these questions is valuable, however, because more patients are using deep-brain stimulation.

"People are happy.They can go back to their life, they can go to work, they can do sports. It's really an amazing treatment."

 

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