快猫短视频

A REVOLUTION in neuroscience seems to be under way. It has allowed a 13-year-old autistic boy to speak for the first time. It has freed people with Tourette鈥檚 from physical tics so severe that they broke bones. It has stopped people with obesity from overeating and prevented those with anorexia from eating too little.

The revolutionary therapy is deep brain stimulation, a treatment that uses electrodes implanted in the brain to bring problematic behaviours under control. It established its bona fides by releasing people with Parkinson鈥檚 disease from some of its most debilitating symptoms, and over the past decade or so the range of mind and brain disorders for which it has been used has been widening steadily. Its dramatic successes have led to calls to extend its use still further, perhaps even to curb paedophilic or psychopathic desires (see 鈥�The off-switch for desire鈥�).

Recently, however, this wonder treatment has been dealt a grievous blow. Two failed clinical trials have left neuroscientists at an impasse about how widely the treatment should be used, and brought ethical questions from the periphery into the spotlight.

As surgeries go, deep brain stimulation is fairly straightforward. A rigid frame is attached to the patient鈥檚 head, and then two holes are drilled into the skull. Through these, the surgeon pushes two metal electrodes, each about the diameter of a piece of spaghetti, to the region of the brain responsible for the symptoms. 鈥淪tick a knitting needle through a piece of butter and it鈥檚 exactly the same feeling,鈥� says Thomas Schl盲pfer, a neurosurgeon at University Hospital Bonn in Germany. In a second operation, a pulse generator about the size of a stopwatch is implanted under the collarbone and connected up to the electrodes by a lead beneath the skin. Over the following couple of weeks, a technician will adjust the flow of electricity into the brain by tweaking parameters like voltage and pulse frequency, until it hits a sweet spot.

Pacemakers for the brain

It is hard to overstate the effects. Tremors disappear . A person who could not hold a cup of tea can suddenly keep their hands motionless. Since the treatment was approved in Europe and the US in the mid-1990s, more than 100,000 鈥渂rain pacemakers鈥� have been implanted to mitigate the disabling muscle spasms of people with Parkinson鈥檚, essential tremor and dystonia. For these, large-scale trials backed the treatment鈥檚 efficacy.

On the back of such successes, in 1999, researchers at the Catholic University of Leuven (KUL) in Belgium offered it to four people with severe obsessive-compulsive disorder. For three of them, . Since then, small trials involving ailments ranging from anorexia to tinnitus, and even drug addiction, have followed in rapid succession (see chart).

For most of these conditions, deep brain stimulation has so far been approved only on an experimental basis, for use in small studies, typically without a control group. Although there is much anecdotal evidence of its ability to treat psychiatric conditions, there has never been any large-scale proof that it works well for anything other than Parkinson鈥檚 and other motor disturbances.

Two major trials looked poised to change that, testing deep brain stimulation鈥檚 apparently great promise in reining in treatment-resistant depression. 鈥淲e see this as a malignant form of depression, with suicide being a major risk,鈥� says Helen Mayberg at Emory University School of Medicine in Atlanta, Georgia. Hers is one of several research groups who have been working in this area for more than a decade. Twenty small trials had recorded improvement rates as high as 60 or 70 per cent. 鈥淧eople come out of that very dangerous state, and stay well,鈥� says Mayberg. 鈥淭hey just get back on the bus.鈥�

These results convinced equipment manufacturers St Jude Medical and Medtronic to invest millions of dollars in setting up two large-scale controlled trials. Judging by the positive results of the smaller trials, these should have been a slam dunk. Instead, they failed.

There were no warning signs. 鈥淚 was quite surprised,鈥� says Darin Dougherty, director of the Division of Neurotherapeutics at Massachusetts General Hospital, who was involved with the Medtronic trial. The published results show that (Biological Psychiatry, vol 78, p 240). St Jude Medical has not yet made its trial data available, but told 快猫短视频 that its decision to end the trial was 鈥渂ased on a low 鈥�. Not only was stimulation , but some of their symptoms got worse 鈥� and a few people developed new ones.

St Jude Medical says it is still investigating the use of deep brain stimulation for treating depression, but Medtronic has formally withdrawn from commercialising the therapy.

鈥淢edtronic and St Jude have spent millions and millions of dollars to have two negative trials,鈥� says Dougherty. And it鈥檚 not just the device-makers who have been stung. The failed trials have highlighted some troubling realities about deep brain stimulation. Knowledge is improving, but we still don鈥檛 really know how it alters people鈥檚 minds.

鈥淲e鈥檝e learned a tremendous amount about the biology,鈥� says Michael Okun, a neurologist at the University of Florida in Gainesville, who has overseen more than 800 implants for Parkinson鈥檚. The electrodes have the effect of inhibiting some neurons and exciting the fibres that link one neuron to another. Neurochemicals like adenosine and glutamate are released. Stimulation also has effects on the whole brain, affecting the rhythmic activity of its neurons. But working out which of these effects, singly or in combination, results in tremors stopping or OCD symptoms lifting 鈥� 鈥渢hat鈥檚 tricky,鈥� says Okun. This hasn鈥檛 mattered too much with Parkinson鈥檚 and tremor; the stimulation just works. But it assumes new significance if the goal is to expand adoption to conditions that affect the brain in more subtle ways.

It鈥檚 also unclear what causes the side effects. Some could almost be considered endearing: while being treated for OCD, one man in the Netherlands suddenly . After he was 鈥渄eeply affected鈥� by a chance encounter with the song Ring of Fire, all other artists were 鈥渂anned鈥� while the brain stimulation was working. Not all side effects are so benign. People with deep brain stimulation implants to stop Parkinson鈥檚 symptoms have reported an increase in impulse control disorders, . Treatments for other conditions have resulted in similar symptom 鈥渟pillovers鈥�. In the St Jude trial, reports of side effects were in keeping with these accounts. The published report on the Medtronic trial states that the 鈥減sychiatric adverse events鈥� included worsening depression and suicidal thoughts.

The side effects of deep brain stimulation have always been recognised, and that鈥檚 why it has largely been considered a treatment of last resort. But now it looks as if we need to rethink the cost-benefit analysis for using electricity to treat psychiatric conditions. While it would be easy to conclude that the treatment should be put on hold as we ponder the ethical dilemmas it raises, withholding it could have worse consequences. 鈥淚t would be almost unethical, if you think you could improve this patient鈥檚 poor quality of life, to not offer a treatment,鈥� says Dirk De Ridder, a neurosurgeon at the University of Otago in New Zealand.

鈥淔ailed trials show that we don鈥檛 really know how the treatment alters minds鈥�

For some people, deep brain stimulation can be a godsend. 鈥淚鈥檝e seen patients in the open-label trials who were considerably ill who improved and got their lives back,鈥� says Dougherty. Could something other than the treatment account for this? 鈥淚t would be hard to explain the improvements we have seen over seven years by placebo,鈥� says Schl盲pfer.

In light of these inconsistencies, many neuroscientists say the failed trials are not an indication of a failed treatment, but may point the finger at the way they were set up and run. 鈥淏oth of these trials had lots of problems with protocol design鈥�, says Schl盲pfer. For starters, the initial trial periods (four months in the Medtronic trial and six in the case of St Jude) were simply too short to reveal subtle improvement in symptoms.

That gets to the issue of proof. In Parkinson鈥檚, the success of a treatment is obvious 鈥� the tremors cease. But with the complex collection of symptoms that characterise a mental illness such as depression, the effects of treatment are less obvious and more subjective. 鈥淎re you better if your sleep, appetite and libido improve, but you still feel disinterested and suicidal?鈥� says Mayberg. She also wonders whether some gains may have been masked by reliance on subjective, rather than quantitative, assessments.

Real-time insights

Mayberg thinks the trials highlight the importance of finding measurable biological markers of depression. New technology may help. She is one of a handful of researchers to whom Medtronic have given prototype pulse generators that give live readings of electrical activity in the tissue surrounding the electrodes during brain stimulation. The idea is to identify which changes in brain activity signify that deep brain stimulation has defeated depression. 鈥淲e鈥檙e learning for the first time what we are doing in real time when we are stimulating,鈥� says Mayberg.

But there may be a more general problem with using existing forms of deep brain stimulation to treat mental illness. Many of the disorders in neuroscientists鈥� cross hairs occur in intermittent episodes, so perhaps delivering electricity constantly isn鈥檛 the best approach.

It鈥檚 a subtlety that Dougherty is trying to address. As part of the BRAIN Initiative in the US, he is aiming to treat post-traumatic stress disorder, characterised by episodic anxiety and panic attacks. His group has a $30 million grant to develop a more responsive kind of deep brain stimulation. Instead of simply delivering continual current, this would monitor specific brain regions for the telltale oscillations of an impending episode. Only then would a sensor flick on the electricity. He thinks it is the key to unlocking deep brain stimulation for mental illnesses, including depression and substance abuse.

All of this work will begin to provide a 鈥渃artography鈥� of mental illness, a map of the parts of the brain that give rise to specific symptoms. That would revise our understanding of mental illness, says , a medical ethicist at Weill Cornell Medical College in New York. For example, depression might be split into different subtypes, each linked to a different network of the brain, and each treated by electrically stimulating these specific regions.

For now, however, we still have much to learn about deep brain stimulation, as the failed trials showed. A note of caution is warranted, especially as the treatment is beginning to make headlines, prompting people to look to it for things other than actual illness. Over the past two years, Okun says he has had enquiries from people who have no psychiatric problems and simply want their memory or mood enhanced. 鈥淭his is a horizon we鈥檙e going to have to watch,鈥� he says.

Dougherty agrees. 鈥淵ou don鈥檛 want to get into the mentality of putting the first flag on the moon, where you just grab a patient with a disorder that hasn鈥檛 been studied yet and say, 鈥榟ey, we did the first one鈥�,鈥� he says. 鈥淧eople do that, it鈥檚 amazing.鈥�

Okun has a self-imposed ethical principle: 鈥淲e will apply the technology only for one reason, and that is to alleviate human suffering.鈥�

(Image: Living Art Enterprises/SCIENCE PHOTO LIBRARY)

This article appeared in print under the headline 鈥淪hort circuit鈥�