Brain Modulation

by Guy McKhann, M.D.

August 25, 2014

Over the years neuroscientists have used a variety of approaches to try to figure out how the brain works. I have tried to put these approaches in specific categories:

Studying those with specific injuries to the brain. This is the oldest approach and began with naturally occurring injuries, such as what happens after a stroke. Paul Broca’s studies of a man he called Tan—because this was the only word the man spoke—found that a lesion in the left frontal lobe led to an absence of expressive speech. This area is now referred to as Broca’s area. On the basis of his studies of Tan, and 12 similar cases, Broca made two outstanding conclusions: (1) we speak with the left side of our brain and (2) language is disassociated from memory and intelligence.

Neurologists and psychologists continue to study changes in human behavior in living people who have had strokes and other brain injuries. These modern studies are aided by brain imaging techniques that detail the injuries to the brain and functional imaging studies that can determine how brain function is altered.

Studying the brain after deliberate lesions are made. This approach is used to find out what deficits occur in experiment animals, particularly primates, and to use the lesions as a form of therapy. Often this second usage is based on the results of animal experimentation.

In experimental animals, one is asking two types of questions: If I knock out this specific area of the brain what will happen to the animal’s behavior? If the animal is a model of a human disease, can I modify the disease by making a specific lesion? Nowhere has this latter approach been more successful than in the treatment of Parkinson’s disease. Quite by chance it was discovered that Parkinson’s disease in humans could be induced by the ingestion of a toxin, N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). MPTP was given to monkeys and, presto, an animal model of Parkinson’s was born. As I will discuss next month, these Parkinsonian monkeys were used to determine where in these motor circuits a lesion could alter their symptoms in a favorable way. Several sites were found. Currently, the brains of people with Parkinson’s are not lesioned, but electrodes are placed in these specific areas, stimulating them with electricity. This added approach, called deep brain stimulation, is the modern surgical treatment for Parkinson’s.

Where and how to place lesions. Initially, lesions were placed on the basis of anatomy. Surgeons decided where to lesion by triangulating a spot using various brain landmarks (curves and fissures in the cortex, for example). Those techniques were followed by the use of electrodes which could not only stimulate areas of the brain, but also record from the brain. Different nuclei, collections of nerve cells, often have distinctive firing patterns; when one started recording a specific pattern, the investigator knew the electrode was near a particular nucleus.

What about the future?

We would like to be even more specific, to be able to either excite or inhibit specific collections of nerve cells in a reversible way, and leave the rest of the brain intact. This is now possible in some animals with a technique called optogenetics. In this technique, neurons are sensitized by introduction of light sensitive receptors, tuned to specific wavelengths. The receptors can be either excitatory or inhibitory. This technique was recently used to define specific nerve cells in a part of the brain called the amygdala. As presented by James Gorman in a recent New York Times article, optogenetic techniques were used to define and manipulate a small group of nerve cells to induce a mouse to stop eating. This may lead to the defining of a previously unknown circuit that functions as an appetite control network.

If you want to get some idea of how dynamic neuroscience is becoming, watch this area of modulation of the brain, going from specific cells to neuronal circuits, as we discover neuronal circuits associated with a variety of functions, and how to manipulate them.