Scientists image nuclei of brainstem

The research team included Kimberlee D’Ardenne GS, psychology professor and co-director of the Princeton Neuroscience Institute Jonathan Cohen, co-director of the Neuroscience of Cognitive Control Laboratory Leigh Nystrom and Stanford University associate psychology professor Samuel McClure, who was a Princeton post-doctoral fellow at the time of the study.

Though researchers have developed fairly sophisticated methods for imaging the brain cortex, D’Ardenne said, many brainstem areas have not been imaged successfully. Difficulties scanning brainstem nuclei arise because the nuclei are hard to locate in the brain due to their tiny size and constant shifting caused by blood circulation.

The brainstem, located beneath the cortex, is composed of the medulla, pons and midbrain and connects to the spinal cord, serving as the neural conduit for signals between the body and brain. Neurons in the brainstem also regulate the production and release of neurotransmitters including dopamine, serotonin and norepinephrine.

These neurotransmitters play important roles in a variety of mental disorders and diseases, McClure said. In the past, scientists were only able to study these hormones by observing the effects they have on cortical brain regions and other parts of the body, D’Ardenne added, because it was impossible to image the brainstem nuclei that release them.

“I think a lot of people who wanted to image these areas previously found that their methods were just completely inadequate,” D’Ardenne said. “People did standard experiments and used procedures similar to the ones we use for cortical scanning, but no one corrected for all the problems and challenges associated with these particular regions.”

The Princeton study focused on areas of dopamine production, D’Ardenne said, especially in the clusters of neurons (or nuclei) in the ventral tegmental area of the midbrain.

“There’s a lot of interest in this [tegmental] area because it’s so important for the way people make decisions,” McClure said. “Parkinson’s disease happens because you lose the ability to make decisions and moderate your behaviors. Drug addiction happens because you override your natural decision-making capacities. It’s an area that’s exceedingly important for medical reasons.”

The imaging technique will likely be used to study schizophrenia as well, since dopamine has been linked to this mental disease, D’Ardenne said. The methods developed by the research group may also be applicable to imaging regions of the brainstem responsible for making other hormones, like norepinephrine and serotonin, she added.

The team faced three main challenges, McClure said. The first was interference from the blood vessels surrounding the brainstem, the second was locating and zooming in on the tiny area, and the third was normalizing multiple patients’ brainstem images so that they could be compared against each other.

“All of your blood supply to your brain comes along the brainstem,” McClure said. “So [the brainstem] is surrounded by huge blood vessels, and every time your heart beats the whole brainstem moves because the vessels around it are dilating and contracting. This makes it very difficult to image because you have to account for that movement.”

The researchers linked the scanner to the subject’s heart and took each brain scan at the same point during a heartbeat to minimize the effects of the brainstem’s movement. “That really cleaned up the noise in the data and increased the signal,” D’Ardenne said.

Additionally, the researchers faced the challenge of focusing on and photographing a much smaller region of the brain than is usually imaged, D’Ardenne said. To zoom in closer on the brain at a higher resolution, the team used smaller brain-imaging units, called voxels, which are essentially three-dimensional pixels, she said. While most brain-imaging procedures divide the brain into 3mm cubic voxels, the Princeton group used 1.5 x 1.5 x 1.9mm voxels to improve the resolution and precision of the image.

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Locating the tegmental region inside the brain required special scanning, D’Ardenne said. “The first thing you do in the scanner is to take a whole brain image. Usually it’s a T1-weighted black-and-white image, and you can’t see anything in the brainstem,” she explained. “By taking a proton density-weighted image [instead of a T1-weighted image] we found that [a region of the basal ganglia] popped out which allowed us to navigate the brainstem much more easily.”

Assembling statistics for the study was another challenge because it required a new brain normalization method, McClure said.

“In order to do statistics you need many different samples, and since everyone’s brain is different you have a sample size of one,” McClure said. “So people stretch the brains using mathematical algorithms, called normalization procedures, so the brains overlap, and their functions align.”

Since most normalization procedures focus on aligning images of the cortex, the research group found it needed a new method that would work specifically for the midbrain. The algorithm they settled on was published recently by Massachusetts General Hospital at Harvard Medical School, D’Ardenne said.

The study lasted almost two years, D’Ardenne said, beginning in summer 2005 and concluding in spring 2007. The group presented its work at the Society for Neuroscience meeting in November 2007 and published its findings in the Feb. 28 edition of Science Magazine.