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“IT’S going to help millions of people. Patients are going back to school, to work, getting married and reintegrating into society, instead of being isolated as a result of their disease.” It’s hard to overstate neurosurgeon Ali Rezai’s enthusiasm for the therapy he is helping to develop. He believes it will revolutionise the treatment of intractable diseases such as depression and obsessive-compulsive disorder.

Rezai, of the Cleveland Clinic in Ohio, is talking about brain stimulation, the use of electric current to alter the workings of the brain. His focus is a technique called deep brain stimulation (DBS), which involves installing electrodes deep inside the brain, but that is just one technique among several. Others involve placing electrodes just under the skull; some rely on applying magnetic fields to patients’ heads.

All these are at different stages of development and each has its own benefits and drawbacks. The basic idea uniting them all is that certain illnesses are caused by aberrant activity in particular brain circuits, which can be corrected with electricity.

If Rezai comes across as evangelical, it’s not hard to see why. Trials in patients whose depression or obsessive-compulsive disorder (OCD) had resisted all other forms of treatment and left them suicidal and profoundly disabled are now able to go out, hold down jobs and form relationships. Buoyed by this success, researchers are now starting to test brain stimulation for other conditions, such as drug addiction, anorexia and stroke. “There’s an explosion of these new techniques,” says clinical psychiatrist Mark George of the Medical University of South Carolina in Charleston.

As with every promising new treatment there are potential pitfalls. Neuroscientists do not yet fully understand how brain stimulation works, nor how best to deploy it. Some are calling for caution, arguing that going too far ahead of the science could harm the technology’s potential and ultimately short-change patients. There is also the possibility – albeit a remote one – that brain stimulation could be hijacked as an enhancement tool for healthy brains. “This a bombshell of an area,” says Thomas Schlaepfer, who works on brain stimulation at the University of Bonn, Germany.

The use of brain implants has its roots in a cruder surgical treatment for Parkinson’s disease, whose symptoms include muscle tremors and stiffness caused by overactivity in some parts of the brain that control movement. In the 1950s, surgeons tried to help the most severely affected patients by destroying, or “lesioning”, parts of these movement-control centres.

While this was often effective, it was also risky – the death rate was up to 1 per cent – and was a dauntingly permanent step. Surgeons later found that the movement-control centres could also be stifled by inserting a hair-thin electrode that delivered a high-frequency current, powered by a generator implanted under the collarbone. The surgery is still risky with a death rate of up to 0.5 per cent, but crucially, it is reversible: simply turn off the current and you’re back where you started. It can also be fine-tuned to changes in a patient’s symptoms.

Ritual obsessions

Today DBS is used to treat Parkinson’s disease, another movement disorder called essential tremor, and dystonia, which involves disabling muscle spasms. About 35,000 people have received implants worldwide.

Now neuroscientists are expanding the technique into the realms of psychiatry. The first such foray was for OCD, in which people are plagued by intrusive thoughts and feel compelled to endlessly repeat rituals such as washing their hands or turning off light switches. OCD is usually treated with psychotherapy or anti-anxiety drugs but these tend to give only limited help.

As with Parkinson’s, there was a surgical precedent: a few people with severe OCD had shown improvement after lesioning an area of the brain called the anterior capsule. In 1999, researchers at the University of Leuven in Belgium tried DBS of this area in four people with severe OCD (). Three reported some improvement, and in the patient with the most dramatic changes this persisted when the DBS was tested “blind” – in other words, when she did not know whether the device was switched on or off.

Since then, Medtronic, the Minneapolis-based manufacturer of the device used in the trial, has funded further trials that suggest the benefits are long lasting. In an unpublished study of 26 people, the team team found that seven years later nearly two-thirds of them were still experiencing a significant reduction in symptoms.

DBS is also being tested in clinical depression, a poorly understood disease in desperate need of better treatments. Numerous ideas have been put forward to explain depression, involving several different neurotransmitters and brain regions. One such is the subgenual cingulate – there is some evidence that it is metabolically overactive in people with severe depression. In 2005, Helen Mayberg at the University of Toronto reported that DBS of this area can treat depression. She found significant improvement that lasted for at least six months in four out of six patients whose depression had resisted all other treatments ().

In 2007, Schlaepfer and his colleagues reported targeting a different area, the nucleus accumbens, in three depressed patients (). Severely depressed people lose the ability to experience pleasure, suggesting that their reward systems are faulty. The nucleus accumbens was an attractive target for DBS because it is involved in processing reward and pleasure, as well as mediating motivational behaviour. What’s more, the nucleus accumbens receives input from, and sends output to, many different brain circuits. Many of these circuits are involved in processing emotions, including the area Mayberg’s team targeted. The idea is that stimulating this area can somehow restore normal activity to faulty circuits.

The improvements in symptoms were immediate. Schlaepfer is at pains to warn that DBS is not a panacea, but he says: “These are patients who did not respond to anything beforehand, which makes it really remarkable.” Medtronic is now gearing up for a large trial with more than 100 patients.

“These are patients who do not respond to anything, which makes it remarkable”

If OCD was proof of principle that DBS could work in psychiatric disorders, then depression is the business opportunity, says Keith Mullett, research director at Medtronic. Depression is the number one cause of disability in developed countries.

Another, more contentious, use of DBS is in the treatment of drug addiction. Neurosurgeon Bomin Sun of Shanghai Jiao Tong University in China has found that destroying areas of the nucleus accumbens in heroin addicts can completely relieve their drug cravings. However, all six people who had this surgery have experienced undesirable side effects such as apathy and inactivity, so Sun has moved on to DBS.

So far he has treated two addicts. The results are still unpublished, but Sun says the patients experienced few side effects and one was freed of their drug cravings, while the other has been able to reduce their dependency on a heroin substitute.

Sun and his team have also tested DBS in people with anorexia nervosa, again targeting the nucleus accumbens on the basis that lesioning has been effective in some cases. In a small preliminary study, he found that a combination of lesioning and DBS produced an improvement both in the eating disorder and in other psychiatric symptoms.

It seems the only limit to the number of different ways that DBS is being tested lies in the ingenuity of the neurosurgeons involved. Yet researchers such as George warn against what they see as the overenthusiastic deployment of DBS.

A key bone of contention is that no one is exactly sure how DBS works. It was originally thought that stimulation “stuns” neurons into silence, an idea bolstered by the fact that it mimicked the effects of a lesion. But some now argue that DBS does the exact opposite: it mimics lesions by activating neurons.

According to this idea, diseases such as Parkinson’s and OCD result from abnormal oscillating bursts of neuronal activity. DBS works by causing neurons to fire constantly, producing a stream of activity that eliminates the harmful oscillations. The brain gets used to the constant firing and ignores it as background noise, behaving as though the neurons were not there.

Cameron McIntyre, a biomedical engineer at the Cleveland Clinic, heads one of the teams trying to understand how stimulation works. In computer simulations of DBS, the team has found that whether a neuron is activated or silenced depends on its position relative to the electrode. “There are many different things going on,” says McIntyre. “And it certainly isn’t clear right now in DBS which of these various things is the fundamental mechanism.”

All of this matters, because if DBS does stimulate rather than inhibit neurons, it might be possible to use it to induce permanent changes. Stimulating neurons can encourage them to form new connections, a phenomenon known as plasticity. If DBS could be tweaked to produce plastic changes, it might mean that patients would only have to have their implants in place temporarily, says George. “That’s the real dream.” McIntyre agrees. “I think it’s a very exciting concept,” he says. “The next big challenge is figuring out how we are going to do it.”

Surgeons faced with desperate patients in the grip of intractable and life-threatening illnesses may be less worried about the precise mechanics of DBS than whether or not it works. Yet, while safer than a surgical lesion, DBS is far from risk-free. For a condition such as Parkinson’s disease, the benefits have been shown to outweigh the risk, but for the new conditions the risk-benefit ratio is still not clear. “I do think we need more data before we release this onto the market,” says George.

Medtronic has made researchers such as George uneasy by trying to hasten the approval process for DBS in OCD under a US Food and Drug Administration scheme that allows life-saving medical devices for rare diseases to be sold without full clinical trials. This strategy was successful in getting the company approval for the treatment of dystonia. George says: “My response to that as a scientist is we need double-blind data before we put a potentially life-killing technology into people’s brains.”

“I would like to see it as a life-potentiating therapy, although it is one that we have to apply with great caution,” counters Mullett. Medtronic is obtaining double-blind data, he says, adding that the FDA requires that proper safeguards are in place.

Burying an electrode deep in the brain is not the only way to manipulate it. Seattle company Northstar Neuroscience has developed a patch of electrodes designed to stimulate small areas of the cerebral cortex, which lies at the outer surface of the brain. The patch, about the size of a postage stamp, is placed inside the skull on top of the tough membrane that encases the brain. The surgery is much less invasive, and therefore safer, than implanting a DBS electrode.

Research on animals suggests that such “cortical stimulation” encourages neurons to fire, which over time makes them form stronger connections. Northstar has begun testing the device in people who have had strokes, with the aim of helping areas of the brain surrounding the damaged one to compensate. “Even if they are not totally cured, it can make a big difference in their ability to get by and have their independence back,” says John Bowers, president of Northstar ().

As with DBS, cortical stimulation is moving into psychiatry, again starting with depression. Northstar is investigating placing the device on the dorsolateral prefrontal cortex, another brain area that has been associated with depression.

As well as DBS and cortical stimulation, there is a third way to give the brain a buzz – transcranial magnetic stimulation, or TMS. In this, a powerful magnet flicking on and off many times a second is held against the outside of the head. This induces an electrical current that penetrates a couple of centimetres into brain tissue. Depending on factors such as the magnetic field’s intensity and frequency, this can either enhance or suppress activity in that area of the brain.

The overwhelming appeal of TMS is that it requires no surgery, but it remains the dark horse of brain stimulation. Numerous research groups are investigating it as a treatment and many claims have been made, but most are based on small studies that have proved hard to replicate. Opinion is divided as to whether TMS can produce worthwhile clinical effects.

Vincent Walsh, a neuroscientist who works with TMS at University College London, is a sceptic. “The ultimate problem for TMS is that its effects are so short-term,” he says.

George, who has been treating depression with TMS, disagrees. His team recently reported the results of a double-blind trial of TMS on 301 patients. They found a significant improvement in symptoms, at least for the duration of the trial (). “In my opinion, TMS’s antidepressant effects are as good as any medication that we have,” says George.

Other conditions that are being investigated using brain stimulation include epilepsy, tinnitus, chronic pain and migraines. Last year, a team at Weill Cornell Medical College in New York even reported using DBS to rouse a man who had been in a minimally conscious state for six years (91av, 1 August 2007, p 14).

As brain stimulation becomes safer, less invasive and more accessible, could it one day be used to enhance the performance of a healthy person’s brain? There are precedents, notably the stimulant Ritalin and the wakefulness promoter Modafinil. Could brain stimulation be turned to similar ends? “We certainly would not do that, but if there are neuroenhancing effects you bet there will be a market and an interest,” says Schlaepfer.

The days of recreational DBS are a long way off – it’s hard to envisage anyone risking highly invasive neurosurgery on the unproven promise of boosting their mental powers. But therapeutic brain stimulation is here, in a big way. “We’re on the edge of a vast sea trying to understand what electricity does when you apply it to brain cells and how to use that therapeutically,” says George. “We’re at the very beginning.”

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