Truly Translational: Louis Sokoloff and PET Brain Imaging

By Susan Speaker

Twenty-first century medical practitioners have many ways of making images of the inside of the body, including x-rays, ultrasound, magnetic resonance imaging (MRI), computerized axial tomography (CT scan), and positron emission tomography (PET). These technologies allow physicians to “see” structural abnormalities, and in the case of functional MRI and PET, can show which tissues are active, by showing their level of blood flow or energy consumption (metabolism). This is very useful if you want to see, for example, what specific area of the brain is stimulated by a certain drug, or track a tumor’s response to chemotherapy. We’re familiar with these images, especially the colorful CT and PET brain scans, and it’s easy to think of them as just pretty color photos taken with a giant camera. In truth, the pictures are the product of a complex system that includes the scanner, sophisticated computer programs, and radioactive tracer substances (in the case of PET). The accurate clinical information conveyed by these images derives from decades of painstaking basic research by scientists such as Louis Sokoloff, who was born 95 years ago today.

Dr. Sokoloff (1921–2015), the focus of NLM’s newest Profiles in Science collection, worked in the Laboratory of Cerebral Metabolism at the National Institute of Mental Health from 1953 until his retirement in 2004. During that time, he used his extensive knowledge of medicine, biochemistry, physiology, neuroscience, mathematics, and kinetic modeling to transform the study of brain structure and function. And he was able to “translate” his laboratory discoveries into a clinical technology—PET scanning—that could show the human brain working in real time.

When Sokoloff began his research career, one of the central problems in neuroscience was how to find out when things are happening in the brain, and where they’re happening—initiation of movement, response to stimuli, thought, emotion, and so on. It was a difficult problem—after all, how can one watch the brain at work, when a) it’s hidden inside the skull, and b) even if it were visible, it doesn’t actually move? One of Sokoloff’s mentors, Seymour Kety, had developed a technique using nitrous oxide (N₂O) to measure blood flow in the brain, and used this and blood oxygen levels as indirect measures of activity. But many brain phenomena couldn’t be detected with such a general method.

In the 1950s, Sokoloff and his NIMH team began using radioactive tracers to track blood flow in specific parts of the brain, using experimental animals. For these studies, they infused a tracer solution into a living animal’s vein for about one minute, continuously sampling the arterial blood to monitor the tracer concentration in the blood. To measure the concentrations of the tracer in particular parts of the brain at a particular moment, the animal was humanely killed and its head frozen in liquid nitrogen. The frozen brain was cut into thin cross-sections, and the sections placed on x-ray film. When the film was developed, the image (called an autoradiogram) showed the distribution of the radioactive tracer in the structures of the brain. The darker the film, the greater the concentration of the tracer in the tissue. The investigators could then use a densitometer (an instrument that measures the degree of darkness in film) to relate the darkness in a given region of the film image to the concentration of the tracer in the tissues shown. The autoradiograms clearly showed the anatomical components of the brain, and demonstrated significant differences in blood flow rates to them. Because the concentrations of tracer in the various tissues were closely related to the rates of blood flow to them, the autoradiograms were essentially pictures of the relative rates of blood flow in those tissues at a given moment. The group’s 1955 report, which described images obtained from the brains of cats with eyes open or closed or stimulated with light flashes, was the first published demonstration of functional brain imaging.

Images of blood flow to specific brain regions helped researchers learn much more about brain structure and function, but blood flow was still an indirect measure. Sokoloff believed that measuring the brain’s use of glucose—its metabolism—would be a better way to track its activity. During the 1960s and ‘70s, he developed a technique using radio-labeled 2-deoxyglucose (2-DG), a glucose analog that is taken up by brain tissue in the first step of glucose metabolism, and then retained there so that it can be detected in autoradiograms. As in the blood flow studies, the images were analyzed with densitometers to determine the relative concentrations of tracer in the tissues. Doing this manually was tedious and time-consuming, so the team collaborated with several computer scientists at NIMH to develop an image-processing program that could scan and reconstruct the radiographic images, and assign different colors to the different levels of metabolic activity. With the 2-DG method, Sokoloff and his team proved that functional activity levels in specific brain regions were linked to metabolic levels in those areas.  Their work sparked a rapid expansion in brain mapping research.

The final step of the bench-to-bedside process was to adapt the 2-DG method for use with human patients. This required only a non-invasive scanning device and a 2-DG tracer modified so that the device could detect it. Positron emission tomography (PET) technology was newly available by the late 1970s, and Sokoloff worked with a team at UCLA to finish the translation. This achievement earned Sokoloff a Lasker Award in 1981.

PET imaging made it possible to map all kinds of activity in the human brain with greater certainty, from the processes of thinking, sleeping, dreaming, and physical movement, to the actions of drugs and hormones. It also proved useful in clinical diagnosis, e.g., for Alzheimer’s disease, Huntington’s disease, and seizure disorders, and later, for identifying and tracking the treatment of many types of tumors.

We invite you to explore the Louis Sokoloff papers on Profiles in Science and learn more about Sokoloff’s story through a selection of digitized photos from his childhood and early career, correspondence with colleagues and students, and experimental brain images produced with the tracers he developed.  The full collection of NLM’s Louis Sokoloff Papers is described in the collection finding aid and available to onsite researchers.   NLM is giving special attention to this and all of the Library’s archives and manuscript collections in a number of activities this month in honor of American Archives Month.

Susan Speaker, PhD, is Historian for the Digital Manuscripts Program of the History of Medicine Division at the National Library of Medicine.