fMRI, Optogenetics Research on Brain Activity Yields Clues into Neural Circuitry

The noninvasive technology offers a view into the physiology of human cognition and emotion, but--without a real clarification of how some common fMRI signals are produced--the ability of researchers to draw conclusions has been limited.

Now a Stanford University School of Medicine (Stanford, CA, USA)-led team has solved the mystery, and in doing so has discovered a new way to make fMRI signals based on increased blood flow even more useful when combined with optogenetics (a technology developed at Stanford that employs genes from microbes to allow neurons to be controlled with pulses of light).

The team's research was published May 16, 2010, in the online version of the journal Nature. The study is the first to validate what neurologists could only hope was true: that fMRI signals based on heightened levels of oxygenated blood in specific parts of the brain are caused by an increase in the excitation of specific kinds of brain cells. For example, in the past investigators could only assume that when they showed subjects a picture of someone they knew, stronger fMRI signal in a part of the brain that perhaps deals with face recognition was caused by the excitation of neurons, rather than some other factor.

These signal increases are measured using the blood oxygenation level-dependent (BOLD) technique. Because researchers have published more than 250,000 articles utilizes or building upon the BOLD technique, clarifying its true meaning is very important, according to senior author Karl Deisseroth, M.D., Ph.D., associate professor of bioengineering and of psychiatry and behavioral sciences. "It was often assumed that a positive fMRI BOLD signal can represent increased activity of excitatory neurons, but this was never really known and, in fact, became much more controversial over the years,” said Dr. Deisseroth. Now, the new study confirms those earlier suppositions.

The key experiment involved turning on genetically engineered excitatory neurons in an experimental group of rats in the presence of blue light delivered via a fiberoptic cable. The researchers then anesthetized the rats and looked at their brains with fMRI. They discovered that exciting these defined neurons with the optogenetic light generated the same kind of signals that researchers see in traditional fMRI BOLD experiments--with the same complex patterns and timing. In the control group of rats, which were not genetically modified, no such signals occurred. This showed that true neural excitation indeed produces positive fMRI BOLD signals.

To see what else this new understanding of optogenetically-enhanced fMRI BOLD might produce, the researchers took the research a few steps further, led by co-first authors Remy Durand, a Stanford bioengineering graduate student, and Jin Hyung Lee, Ph.D., a University of California Los Angeles (UCLA; USA) assistant professor and alumna of Deisseroth's lab at Stanford. They found that they could use optogenetics to produce activity in specific kinds of cells in neural circuits, and then read out the far-reaching effects with fMRI BOLD over a substantial distance in the brain.

In one experiment, for example, the investigators could see how activity they stimulated in the thalamus, a major relay center deep in the brain, could affect circuits stretching into the somatosensory cortex, a surface brain region important in processing sensation. "We can now ask what the true impact of a cell type is on global activity in the brain of a living mammal,” Dr. Deisseroth concluded. "A key to scientific inquiry is developing tools that allow us to intervene and experiment with brain circuits--engineering a reversible gain or loss of function--rather than simple observation of correlations. This points to new approaches for understanding and treatment.”

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