Rodolfo A. Llinas, M.D., Ph.D.
Professor & Chair of Physiology and Neuroscience
New York University School of Medicine
Q: You have spent much of your career studying brain rhythms—the patterns of nerve-cell activity that underlie various behaviors or mental states—and how disrupted rhythms contribute to neurological and psychiatric problems. How is it that such a seemingly simple problem, an abnormal rhythm, can produce such diverse symptoms?
A: The idea has always been that psychiatric and neurological conditions are very different. But if one looks carefully at these disorders, one finds that a very similar cellular mechanism—an abnormality in the rhythms of neuronal firing—can generate many different types of symptoms depending on where in the brain the abnormal activity is located.
One example is the aura that sometimes occurs before an epileptic seizure. The aura can be of any type: auditory, where you hear sounds or words; visual, where you see things; motor, where you move; psychomotor, in which you begin to think desperately about certain things, or any number of other kinds of auras. This would suggest that the mechanism underlying these auras must be very different, yet there is but one mechanism: an abnormal rhythm that precedes the seizure. The same cellular mechanism can produce a variety of functional conditions depending on the type of the abnormal rhythm and its location in the brain.
Rhythm abnormalities can happen anytime a group of nerve cells in the thalamus or cortex begin to generate oscillatory [firing] activity at a lower frequency than is normal in the alert, awake brain. Specifically, the cells fire coherently and at slower wavelengths in discrete areas of the brain. A similar pattern occurs throughout the brain when you fall asleep. When that type of pattern occurs outside of sleep, the part of the brain affected functions abnormally: it becomes fixed at a low frequency and does not respond correctly to external inputs. It becomes disconnected and non-responsive, similar to what happens under general anesthesia, where low-frequency brain activity correlates with loss of responsiveness to external pain and other sensory inputs.
There is also a phenomenon we call the “edge effect” associated with the area of low-frequency activity. Cellular activity at the edge of low-frequency activity can be altered in an opposite pattern, producing ongoing high-frequency activity. These alterations produce what are known as “positive” symptoms, which are continuously “on.”
For example, deafness due to low-frequency activity in the auditory system would be considered a negative symptom, whereas a continuous sound associated with such deafness, a tinnutis, is a positive symptom; it is accompanied by high-frequency gamma bands in the cortex due to a failure of inhibitory mechanisms [that would normally tamp down the firing]. In Parkinson’s disease, difficulty moving or partial paralysis are negative symptoms, whereas ongoing uncontrollable tremor is a positive symptom. Both types of symptoms are produced by the same mechanism: abnormal rhythms.
This is beginning to be called “thalamocortical dysrhythmia,” defined as a set of neurological and psychiatric conditions produced by abnormal oscillatory activity in the major neural circuit that links the brain’s thalamus and cortex. Different symptoms are produced depending on where in the brain the rhythm disruption is occurring, but the neuronal mechanisms are the same.
Q: How do these understandings help explain the success of deep brain stimulation?
A: This the most plausible explanation for why we are seeing such success with deep brain stimulation (DBS.) There is no question in my mind that DBS is one effective way to make progress in treating brain rhythm disorders.
It’s interesting that electrical brain stimulation has been developed through years of trial and error. The concepts behind it are not new; the effects of stimulating the brain have been known for a long time. The first serious DBS was done in Switzerland in the 1930s and 40s, and actually was the subject of a Nobel Prize given to Rudolph Walter Hess in 1949 for work in animals. The technology so far is not that innovative.
We have been very interested in using electrical brain stimulation as a therapy for thalamocortical dysrhythmia, and are pursuing various strategies aimed at improving the technologies and the techniques that are used. We have developed patents for the use of nanowires as both stimulating and recording probes, for example.
Q: To date, DBS has largely been used in Parkinson’s disease and other movement disorders. Do you see this changing?
A: DBS is now also being considered for depression, obsessive-compulsive disorder, and other neuropsychiatric conditions. There is the fascinating case reported by Columbia and Cleveland Clinic neuroscientists Nicholas Schiff and Ali Rezai, who treated a fire fighter who had been in a coma for nine years. They targeted the midline thalamus (intralaminar nucleus), and the man recovered consciousness as well as memories from decades before. We have to pay attention to these cases because they are giving us important clues about brain function.
There is also the intriguing possibility that brain stimulation over the long-term may result in secondary changes related to plasticity. We are just beginning to understand these changes and what their implications may be.
Q: Do you encounter resistance to the concept of electrically stimulating the brain?
A: Sometimes, mostly because people don’t understand what brain rhythms are all about. They think you just stick electrodes into the brain and look for a “sweet spot” and see if the patient gets better. There is a perception out there that we really don’t know anything about how electrical brain stimulation works. But we know that such stimulation works by changing brain rhythms, at least for the acute results. The only thing that this electrical stimulation can do to neurons, especially in cases when patients respond immediately to stimulation, is to modify their firing patterns.
I believe people’s views are beginning to change, in part due to the simple fact that brain stimulation has been so totally successful. Indeed, people who are completely paralyzed, who couldn’t do anything, suddenly are able to be constructive members of society and to take care of themselves and so on, all as a result of targeted stimulation of the brain. It is amazing. At the National Institutes of Health, such results have been considered among the most important breakthroughs in 20th century neuroscience.
But it really goes beyond electrical brain stimulation. There is growing evidence that localized microlesions in the brain can help modify dysrhythmias in certain cases, and there are drugs that can help as well. The fact is that now that we have a target—abnormal brain rhythms—we can address that target through whatever means we have. We have something that can be localized, measured and understood at the single-cell level and at the level of channels and of circuits and so on. It is very exciting. It is interesting to me that it has taken the success of electrical brain stimulation to validate this long history of basic research on abnormal rhythms, which people had really not paid much attention to previously.
Q: Basic scientists and clinical scientists have historically occupied different worlds, with cross-fertilization the exception rather than the rule. Do you see this changing at all?
A: Yes, I think the relations between basic science and clinical science are changing very rapidly. This is a touchy issue, because clinical scientists are mostly interested in basic science only when the implications of the basic science research are clear and the applications are mature. On the other hand, it may have taken basic scientists decades of hard work to understand the principles, so they are cautious to take the same care to show how something is clinically relevant.
You have this situation where the clinical scientists look at the basic scientists and say, “Yeah, but is it relevant?” and, the basic; scientists look at the clinical scientists and wonder if they understand the implications of the basic finding, or if they even care. It has been a difficult situation; people know what they know and want to stay in the areas that are familiar to them. Venturing into areas that may be outside the norm must be done with extreme care, and one has to be ready to be criticized by both sides.
That said, it is indeed time for change. More and more these days, basic and clinical scientists are taking the extra step and trying to communicate. There is this new willingness to educate one another.
Q: You have told the story of using your technique for detecting abnormal brain rhythms on a skeptical neurosurgeon from New York University, who was “stunned” that you were able to diagnose his tinnutis and describe it just by recording brain rhythms with MEG. Are you finding more acceptance these days for your ideas about the clinical implications of your basic research on abnormal brain rhythms?
A: The case of Dr. [Patrick] Kelly was a very good case in point. He was basically saying, “Look, I’ve been hearing about this research for so many years; can you guys really offer me something that will help my patients?” In some ways, the question he asked typified the attitude of many clinicians: “Are you coming here to tell us something that we can use or what?”
I had been discussing this research with Dr. Kelly for many years, and the feeling he had was that there was not very much that this kind of interaction could generate. Since the tinnutis incident with Dr. Kelly, which happened just last summer, I’ve been talking to my colleagues in the department of neurosurgery all the time, and many people are coming to find out what is going on. So things like that do help change attitudes, and slowly it is beginning to percolate.
Q: What has driven your interest in bridging the divide between clinical and basic science? Why care?
A: Well, it is true one is not required to do any of this. We basic scientists have our labs, our grants and areas of studies and so forth. But on the other hand, one may also wonder if understanding the clinical implications of what one does should not also be part of the process.
Personally, the issue centers on whether there is more to basic scientific work than the immediate knowledge that it generates. It is clear that we are at a time in history when the nervous system is seriously beginning to be understood. For those of us in basic research, it is a given that the basic knowledge we are generating is crucial and essential. The question then becomes: Is it sufficient?