MIEKO had no quality of life any more, says her surgeon Ali Rezai from the Cleveland Clinic in Ohio. For 15 years, she’d coped with Parkinson’s disease, but then her medication began to fail her, and she found herself alternating between the uncontrollable wild movements created by her drugs and being locked motionless.
For Antonia it was a different story. She had endured agonising pain around her face for seven years since an operation to relieve the pressure of a blood vessel against a nerve. Drugs did nothing. Last month, both found instant relief when Rezai implanted a small electronic pacemaker-like device deep inside their brains.
Such devices appear to work by interrupting the excessive neuronal firing that causes chronic pain or by smoothing out the strange rhythmical brain activity that causes rigidity and tremors, much as a heart pacemaker flattens the unusual beat rhythms of a fibrillating heart. They aren’t a new way of dealing with pain or Parkinson’s disease-stimulating the spine to interrupt pain signals was first used in the 1960s. But, if a controversial new theory is correct, surgeons like Rezai may soon be getting ready to fit these “pacemakers” in a whole new group of patients with psychiatric conditions such as obsessive compulsive disorder (OCD) and depression, or desperately distracting sensations such as ringing in the ears (tinnitus) or schizophrenic hallucinations.
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According to Rodolfo Llinàs, a neuroscientist at the New York Medical Center, and Daniel Jeanmonod, a neurosurgeon at the University Hospital in Zurich, these conditions are united by a common feature. The researchers believe that they are all characterised by strange, slow rhythms of neural activity originating in a walnut-sized brain region called the thalamus.
This activity, they say, looks just as though one tiny part of the brain has fallen asleep. The resulting disruption in the flow of signals to the rest of the brain would produce the abnormal patterns of activity that could account for bizarre perceptions and neurological symptoms as wide-ranging as tinnitus and depression.
Until recently, the thalamus was considered to be no more than a simple relay station sitting at the top of the brainstem, controlling the flow of information from our senses to the brain’s outer cortex. But interest in the region has grown since neuroscientists discovered that when we’re awake, it is working overtime, passing on and modifying fast “gamma” rhythms of activity to the cortex that seem to equate to conscious perception (New Scientist, 30 October 1999, p 28).
It’s by no means a one-way flow of information. Within milliseconds of receiving information from the thalamus, the cortex returns a signal indicating which information might be worth dealing with. The thalamus filters out what appears irrelevant and reinforces the relevant by sending more signals back to the cortex. “You can’t think thalamus without cortex, or vice versa,” says Jeanmonod, “It’s a recurrent interplay between the two.”
The two-way flow depends on bundles of neurons that send slender processes back and forth between the thalamus and the cortex, forming “thalamocortical loops” (see Diagram). Different loops carry different information-visual, auditory, touch, and so on-and damage to any particular set of loops can have serious consequences. Damage from a stroke in the bundles carrying visual information can cause blindness, for example, even though the region of the cortex responsible for analysing vision is intact.
But it is not only the physical connections between the thalamus and cortex that guide the passage of sensory infomation. The different activity patterns of sleep or waking states are also important. Llinàs describes the thalamus as a “central switch” for sending the brain to sleep. When we fall asleep, the thalamus lets very little information through. It becomes less excitable, lowering its level of activity to a slow, rhythmical pattern-the “theta” and “delta” rhythms-and effectively disconnects us from the outside world.
Llinàs was one of the first to detect the switch from waking to sleeping rhythms in individual thalamocortical neurons, back in 1982. He discovered that the switch could be triggered by altering the chemical environment or the electrical charge of the outer membrane of the cell. More recently, he wondered what effect switching from fast to slow rhythms would have if it occurred at the wrong time: “It would be like having one part of your brain asleep,” he says. But what would this then do to the cortex? How might this alter people’s perceptions of the outside world, and their health? “It would be terrible if you got stuck in any one of these situations.”
One of the first groups of patients Llinàs looked at with these ideas in mind were people with Parkinson’s disease, who were experiencing limb tremors. He noticed that their muscles were twitching in time to a theta rhythm-between three and six twitches every second. At the same time, he was able to record electrical activity across the brain using a technique called magnetoencephalography, or MEG, and found the same rhythmic activity appearing in the areas of the cortex that were responsible for initiating and sensing movement. He suspected that the rhythms originated in the region of the thalamus connected to these cortical areas (Neurology, vol 46, p 1359).
This set him wondering whether something similar could occur in parts of the thalamus related to other areas of the nervous system, such as the visual, auditory and emotional areas, and not just in those regions responsible for movement.
Meanwhile, Jeanmonod had been recording electrical activity directly in the brains of patients with Parkinson’s disease and chronic pain who had been referred to him for brain surgery because they had failed to respond to normal drug treatment.
Like many surgeons, Jeanmonod routinely destroyed small parts of the thalamus in order to bring Parkinson’s tremors under control-a common alternative to implanting a pacemaker. This approach was decades old, even though surgeons had only the vaguest idea of how it could relieve symptoms. The problem, however, was that some patients suffered severe side effects, ranging from defects in language and analytical thinking to paralysis, when surrounding brain tissue was damaged. Jeanmonod hoped that by recording the activity in the thalamus, using tiny electrodes implanted during exploratory surgery, he would be able to pinpoint exactly which areas were abnormal, and so target his surgery more precisely.
He found the sleep-like theta rhythms in the thalamus in patients with Parkinson’s disease and chronic pain when they were awake. Just as Llinàs had suspected, Jeanmonod managed to pin the rhythms down to two neighbouring regions of the thalamus, which together are responsible for passing on movement and pain sensations. By destroying only the affected part of the thalamus, Jeanmonod was able to considerably improve the outcome of his surgery, and has now operated on more than 50 people with Parkinson’s, and more than 100 with chronic pain, using theta rhythms for guidance.
Jeanmonod and Llinàs became convinced that the sleep-like rhythms had caused the patients’ symptoms. In 1998, the pair joined forces to try to find out how. Together with Urs Ribary, also from New York Medical Center, they used a more refined version of MEG, which maps activity over the surface of the brain by recording from as many as 148 tiny electrodes placed over the scalp. MEG enables rhythms across the entire brain to be detected at once. Compared with other brain imaging techniques, it is not very good at locating precisely where the different signals are coming from, but it can capture very fast changes in electrical activity, picking up individual bursts occurring only milliseconds apart.
Lack of harmony
At the end of last year, the researchers reported an abnormally high number of slow theta rhythms deep within the brain of four awake patients with Parkinson’s disease, one with tinnitus, two with chronic pain, and two with depression. These, they believe, are originating in the thalamus. At the same time, however, they found what appeared to be an abnormal amount of gamma activity in the cortices of the same patients, breaking the normally harmonious relationship between the two regions. This “dysrhythmia”, as the researchers call it, is what may produce the patients’ symptoms. Llinàs and Ribary have since found similar brain activity in patients with epilepsy, movement disorders and OCD.
Jeanmonod has also extended these findings using electrodes to record slow rhythms directly in the thalamocortical loops of patients with tinnitus, pain, epilepsy, OCD, dystonia and depression. “Eventually it came out that the whole field was related and this led us to this crazy conclusion,” says Jeanmonod. It really looks as though all of the disorders share a common mechanism, he argues.
Jeffrey Schwartz, an OCD specialist at the University of California at Los Angeles, greets the findings enthusiastically. He has found a circuit connecting the cortex and thalamus of OCD patients which, according to electroencephalography recordings, is overactive. This, he believes, accounts for the anxiety and obsessions experienced by patients, as the hyperactivity can be alleviated by behavioural or drug therapy. He says that the theory is consistent with the kind of malfunction he sees. “It’s an extremely coherent working hypothesis,” he says. “Until now there’s been no direct evidence, but this could be viewed as the first set of data to support it.”
Despite enthusiasm from some quarters, the team is causing a stir with such strong ideas. “This is certainly a breathtaking stroke by Llinàs,” says neurophysiologist Roger Lemon from University College London. “I don’t think many clinicians would lump all these conditions together, so if they can find a common mechanism it would be extraordinary.”
But while Llinàs and Jeanmonod are suggesting a common mechanism at the heart of these conditions, they are keen to stress they are not suggesting they all have the same trigger. According to Llinàs, the symptoms seen in different types of patients depend on which part of the thalamus switches into a sleep-like state, as well as the original problem that caused this. He says many things could suppress the activity of a part of the thalamus.
In the case of Parkinson’s disease, it’s well known that dopamine-producing cells gradually die. One of the effects of dopamine is to calm the activity of the globus pallidus, a brain region that sends inhibitor signals to a part of the thalamus. If the loss of dopamine allows the globus pallidus to become overactive, it may inhibit the corresponding thalamocortical loops too much and send them to sleep.
Similarly, in the case of chronic pain, Llinàs suggests, it is a loss of nerve input, perhaps because of a limb amputation, that means the thalamus receives less than its normal amount of sensory input. And in tinnitus, damage to nerves carrying sound may also reduce the incoming signals.
But by far the most daring part of Llinàs and Jeanmonod’s theory is what they call the “edge effect”, to explain how abnormal slow rhythms in the thalamus cause the appearance of fast rhythms in the cortex. It depends on the idea of a type of “neighbourhood watch” system within the cortex, in which each region depends on careful monitoring by the next to maintain a healthy balance of activity. The loss of activity of one neighbour causes the others to compensate by becoming overactive.
Llinàs pictures a central area where the thalamocortical loops are depressed, surrounded by a ring of gamma rhythms. It sounds speculative, but it may explain the strange visual defects of a migraine aura. An underactive region of the visual cortex may produce a scotoma-a temporary blind spot-and a wave of overactivity can produce the characteristic hallucinations.
Llinàs admits that this part is pure guesswork and that more evidence is needed to support such a remarkable claim. So far, he doesn’t know the exact location of the gamma activity in the cortex, and whether it does indeed surround the underactive portions. Until this is clear, there’s no way he can know whether the overactive regions really do account for the particular type of sensory perceptions and emotions that are affected in different patients.
As Lemon and Adam Sillito from the Institute of Ophthalmology in London point out, detecting the abnormal rhythms in patients doesn’t prove that they are responsible for strange perceptions or signals to muscles. They may be a by-product or even pure coincidence, and it will be impossible to say until the precise areas of the cortex involved have been identified. “It’s inspirational and very interesting but it does sit as speculation,” says Sillito.
Undaunted, Llinàs is hopeful that surgery to remove the affected area of the thalamus, as refined by Jeanmonod, could potentially cure all these conditions. Alternatively, he suggests stimulating the thalamus with electrodes, like Rezai’s pacemaker devices, to kick-start it into a faster rhythm of activity.
And while Rezai points out that it may be years before surgeons can begin treating other conditions-depression, OCD or tinnitus-with electrodes, he’s certainly entertaining the possibility. “We are looking for newer and better targets, and as we learn more about the exact location [of the abnormal rhythms] and the mechanism we’ll be able to interfere clinically.”
Meanwhile, Llinàs believes that drugs rather than surgery will be the ultimate answer. If drugs could be developed which selectively alter the firing rhythms of the thalamic cells, the symptoms could be wiped out, reasons Llinàs. “I think that putting holes in people’s heads and making lesions or having them walk around with electrodes are momentary solutions until real solutions are found.”
