Electrodes implanted in the brain could transform the lives of psychiatric patients. Alison Abbott watched an operation to release a man from his obsessive thoughts.
“What are you thinking about?” Clamped to the operating table with his skull drilled through to expose a patch of brain, Herr Z. answers his psychiatrist anxiously: “I'm still thinking about the bad impression I must have made on the former colleague I met in the supermarket.”
It is close to midday and his brain surgery — which began at 8 am and will continue until 5 pm — has only partially distracted Herr Z. from this incessant, hammering thought.
Herr Z., now being operated on by Volker Sturm, a neurosurgeon at the University of Cologne, suffers from obsessive-compulsive disorder (OCD), which makes him unemployable. He rarely goes out, because he fears contamination from anything he touches. Twenty years of therapy have not helped.
An experimental surgical technique called deep brain stimulation (DBS) is currently the only hope for people like Herr Z. Having proved its value in the treatment of advanced Parkinson's disease, neurosurgeons are now keen to try DBS to treat one of the world's biggest health burdens — psychiatric disorders. Controlled clinical trials are under way in several centres in Europe and the United States to see if it can help with OCD and major depression. “The early results are very encouraging,” says Ali Rezai, a neurosurgeon at the Cleveland Clinic in Ohio.
DBS involves the insertion of electrodes deep in the brain to hit a precise neuro-anatomical target that is believed to be central to the disease being treated. The electrodes are connected to a battery-driven stimulator that sends pulses of current to the target neurons and normalizes their activity. The stimulator is sewn into the belly or chest and can be switched on or off remotely through the skin.
The use of the technique has exploded since 1993, when Alim-Louis Benabid from the Grenoble University Hospital in France reported results from more than 80 patients with Parkinson's disease1. Around 30,000 similar operations have now been carried out worldwide. The success rate is high, and gratifyingly visible: a pulse of current through a correctly placed electrode instantly stops the tremors and releases the frozen muscles characteristic of the disease. The most common targets in Parkinson's disease are the subthalamic nucleus and the globus pallidus, components of the brain's motor circuitry whose signals are known to be distorted in Parkinson's disease.
The motor circuit is one of several proposed neural pathways that circulate sensory information received from the outside world, by sight and touch for example, through the thalamus into the cortex, the ‘thinking’ part of the brain (see Graphic, below). Having ‘decided’ how best to respond, the cortex returns response signals through the thalamus: signals to move away from something, or to feel good or bad about something, are shunted on to appropriate subcortical parts of the brain that arrange for the commands to be executed.
Surgeons wondered whether other, less well defined cortico-thalamic circuits could be targeted by DBS. The subcortical limbic system is especially interesting as it is associated with emotion and may be central to certain psychiatric conditions. Andres Lozano, a neurosurgeon at the University of Toronto who recently published results of the first trial of DBS in severe depression2, makes no bones about it. “Our greatest opportunity is in the field of psychiatry.”
Surgeons are still not agreed about where best to strike with their electrodes. They realize that targeting one point will affect an entire circuit — and one modified circuit is likely to affect information flow through others. No one knows exactly how these various circuits, with their positive and negative feedback components, might weave through different anatomical structures.
But there are some pointers. In people who have suffered very localized brain damage, often following a stroke, behaviour can change in a very precise way. Neurosurgeons have often taken a lead for DBS from such observations and created carefully controlled damage, or lesions, in these areas to treat psychiatric diseases, including OCD. Bart Nuttin, a neurosurgeon from the Catholic University of Leuven in Belgium, who pioneered DBS in OCD patients3, targets a small frontal part of the limbic system known as the internal capsule.
Other pointers come from functional magnetic resonance imaging (fMRI) and positron-emission tomography, which enable activity in different parts of the brain to be visualized. Lozano, for example, selected a limbic region known as Cg25 for stimulation after his collaborators found it to be particularly active in depressed patients.
Meanwhile, back on the operating table, Sturm is closing in on his preferred target, a particular section of the outer shell of the nucleus accumbens, a peanut-sized structure directly below the internal capsule.
Tracing a path
It is now 12:45 pm. Herr Z. began the day having his shaved head firmly clamped, under light anaesthetic, into a plastic stereotactic crown. The crown is now enabling Sturm to guide a 0.8-mm bore along the path he has defined on a computer screen with submillimetre precision. The path must hit the target exactly, without passing through any blood vessels — a haemorrhage could cause brain damage. But getting it right is hard as no two brains are exactly alike and brain-imaging techniques have limitations. After the clamping, Sturm took two different brain images: a computer tomography scan and a structural MRI scan. Sitting at the screen for more than an hour with a physicist and a neuroanatomist, he merged the images, identified his target and traced out the best straight line to its centre.
“I couldn't do this without working closely with basic scientists,” says Sturm, now slowly threading a test microelectrode through Herr Z.'s brain along the set trajectory. The microelectrode converts neuronal activity to sound. Each anatomical structure has its own characteristic song, so this provides Sturm with a second guide. The recording is being carried out by a team of neuropsychologists, who are also taking the opportunity for an experiment of their own — to identify what may be characteristic neuronal firings when OCD patients try to shift their thoughts.
Sturm then inserts the true electrode. It is a hair-thin cylinder 6 mm long, with four 1-mm contacts spaced along it. Each contact can be individually manipulated from outside: its polarity, and the shape, frequency and voltage of the current, can be adjusted. If one contact doesn't have an effect, then the next, 1 mm away, may be in just the right position. An X-ray confirms that its position is spot-on.
1:30 pm. Time for the first test stimulations. Herr Z.'s psychiatrist, Michael Schormann, takes an envelope from his pocket and places it in Herr Z.'s hand. Envelopes upset Herr Z. — they might have been licked. His fingers grip the paper and he reports escalation to 10 on his personal anxiety scale. The test impulse does not reduce it. “It sometimes takes a while to get the effect, but it is psychologically important for patients to take an active part in the procedure,” says Schormann. Relieved of the envelope, Herr Z's hand writhes above the sheet in a washing motion until Schormann wipes it clean with alcohol.
Herr Z. is wheeled out for an fMRI scan which confirms that his brain activity changes appropriately when the electrode is stimulated. Then back for the final sewing up. The long day is over. His stimulator and battery will be put in the next day.
Sturm is part of a small élite group of neurosurgeons in Europe and the United States, including Nuttin, Lozano, Rezai and Benabid. Together, with their teams of basic scientists, they regularly meet to compare techniques and results in order to try to understand scientifically what they are doing.
This isn't simply a question of which anatomical target might be best, and why. The aim is also to understand better what the stimulation itself is doing. The original idea was that it simply blocked abnormal electrical activity, mimicking the effect of a lesion. Indeed, high-frequency pulses do damp down circuits by blocking excitatory neurons. But low-frequency pulses have the same effect by stimulating the inhibitory neurons in these circuits. The group also wants to improve three-dimensional neuroanatomy to help make the positioning of electrodes more accurate and optimize their effects.
The surgeons also want to avoid ethical conflicts. They have occasionally used DBS to treat individual patients with other psychiatric and neurological syndromes, including Tourette's syndrome, epilepsy, minimally conscious state and cluster headaches. And they are thinking about obesity and drug addiction. But they know they must move cautiously.
The controlled OCD and depression trials should first be completed and analysed, says the neurosurgeons, to be absolutely sure that the therapy really works. They don't want to charge blindly on and risk failures and the attendant bad publicity. They also insist that progress in the field should be driven by psychiatrists rather than neurosurgeons, and closely controlled by ethics panels.
Ethicists worry about issues such as truly informed consent. They also debate the concept of personality, and whether it can be changed by DBS. “But patients don't see their obsessions and compulsions as part of their personality,” comments Schormann. “They see them as something imposed on them, that they yearn to be rid of.”
Patients who have been successfully operated on speak of regaining lives they had considered beyond hope. Monsieur F., one of Nuttin's OCD patients, was suicidal before DBS made his obsessive thinking and compulsive behaviour vanish within seconds. “Those who worry about ethics know nothing about it,” he says. Herr Z., fresh off the operating table, hopes for the same freedom. He is a radio ham, and has recently learnt new languages to communicate with the world. He'd like to test out his new skills on a holiday, unconcerned by foreign germs.
Benabid, A. -L. et al. Acta Neurochir. Suppl. 58, 39–44 (1993).
Mayberg, H. et al. Neuron 45, 651–660 (2005).
Nuttin, B. J. et al. Neurosurgery 52, 1263–1272 (2003).
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