I was sitting at dinner a few nights ago next to a very bright guy (not in medicine or science), and he asked me what I did. When I told him I was a neurologist, he said, “Working on the brain these days must be very exciting. What’s the most interesting thing that is happening?” We were on our first course, and I wondered if my answer might not last until dessert. His question did get me thinking, and that leads to this month’s column.
The answer to my dinner companion’s question as a clinical neurologist, is that the advances in imaging, of our ability to see the structure and activities of the brain, have opened up whole new opportunities to determine how the normal and abnormal brain is working. But that’s where we are now. What’s next? I have chosen two examples: optogenetics and tau imaging.
I base my answer, to some extent, on the article in The Wall Street Journal entitled “Scientists Cast Light Onto Roots of Illness Deep in the Brain,” by Robert Lee Hotz. This article refers to a relatively new field of research called optogenetics, a technique that relies on the use of light-sensitive proteins that can change the behavior of neurons. These proteins, naturally occurring in single cell organisms such as bacteria or algae, are responsive to light at very specific wave lengths. The breakthrough that opened up this field of research was to link these light-sensitive proteins to a virus, and to introduce the proteins into brain cells by infecting these cells with the virus. Depending on the protein introduced, exposure to light at specific wave lengths lead to neurons being turned on (made to fire) or turned off (made unresponsive). Those neurons with their new proteins are the only ones to respond; other neurons are unchanged.
Since the technique was invented in 2005, the field has exploded. Optogenetics has not yet been used on humans, but investigators are getting close, working on monkeys. The ability to activate, or shut off, specific neurons that are part of a brain circuit allows questions to be asked that were not even feasible a few years ago. In his article Hotz mentions how optogenetics has provided new information about mechanisms of fear, desire for cocaine, control of seizures, and modification of depression. Studies of memory, learning, motor control, and response to injury are also in progress.
Every so often a technique comes along that makes a jump in our knowledge about the brain. Certainly the histological description of neurons by Cajal, the demonstration of patterns of brain electrical activity by electroencephalograpy, the non-invasive delineation of brain structure by CT and MRI scanning and the use of PET scans to define brain activity, all fall in this category. Perhaps optogenetics will be next.
I have written previously about chronic traumatic encephalopathy (CTE), the pathological disorder which occurs in people with head injuries, such as football players or those in the military injured by roadside bombs. The pathology is quite distinctive, with accumulations of a protein: tau, which also is present in those with Alzheimer’s disease. In a previous column, I mentioned the need for the ability to image tau—that is to be able to determine if tau is present in the brain by non-invasive methods, as we can with amyloid in Alzheimer’s. There is now a preliminary report involving former football players who were all having some degree of cognitive and behavioral problem. All were shown to have tau on brain scanning, in the same distribution in the brain as those with pathologically proven CTE. The study involved only five subjects, but it’s a start.
The implications of being able to detect tau early, by brain scanning, are enormous. All kinds of questions are waiting to be addressed: How early is tau there? Does it gradually accumulate? Are there genetic factors in its occurrence? If there are no further head injuries, will it gradually go away? Are there people walking around with tau in their heads who are perfectly normal? Most importantly, should the presence of tau in a person’s head influence subsequent participation in activities with a risk of head injury?
I could go on and on, but like at my recent dinner, I want my dessert.