Commonly used functional MRI protocols are not suitable for directly measuring blood oxygen level-dependent responses from very small brain structures that are of interest to neuroscientists, particularly the brain stem nuclei of the dopamine, norepinephrine and serotonin systems. Imbalances in these systems, which play a critical role in the regulation of brain function, have been linked to most major psychiatric disorders, including addiction and schizophrenia, and to Parkinson’s disease.To study the dopamine system with MRI, scientists previously had to examine other more accessible parts of the brain, such as the ventral striatum. According to Kimberlee D’Ardenne, a doctoral student at Princeton University in New Jersey, this approach is problematic because other neuromodulators affect the same brain areas as dopamine, making it impossible to link a response to one neuromodulator.Using a combination of MRI techniques, scientists have directly imaged the ventral tegmental area, capturing activity related to dopamine neurons in the brain stem. They used the substantia nigra, depicted in relation to other parts of the midbrain in the illustration, as a landmark to locate the ventral tegmental area (a). The midbrain, shown outlined in the box and expanded at right, was clearly visualized on proton-density-weighted images. In the expanded view, the ventral tegmental area is outlined with a wedge-shaped solid line (b). Slices were centered on the ventral tegmental area and tilted to include as much of the substantia nigra and ventral striatum as possible (c). Data analysis showed that blood flow increased in dopamine centers of the brain stem when an unexpected reward was received, as shown on the normalized proton-density-weighted (left) and T1-weighted (right) images (d). Reprinted with permission of Science.D’Ardenne and a team of scientists from the university have succeeded in directly imaging the ventral tegmental area, the brain stem structure that houses dopamine neurons. Imaging this very small area, which measures about 60 mm3 in volume, or roughly the size of two voxels at the resolution common in functional MRI studies, presents a challenge. The structure also pulsates with the heartbeat, causing distortions in the magnetic field that decrease the detected signal.The team of scientists addressed these challenges by employing a combination of well-established imaging techniques in a classical conditioning experiment based on the “reward prediction error” theory of dopamine function. This theory states that the firing rate of dopamine neurons encodes the difference between expected and received reward.Thirsty participants were trained to expect a reward of squirts of juice or water delivered at a fixed interval after display of a visual cue. The researchers delayed delivery of the reward in a subset of trials and tracked changes in blood flow using MRI. They found that blood flow increased in dopamine centers of the brain stem when participants received a reward they didn’t expect.Images were acquired using a 3 T Siemens head-only MRI system with a circularly polarized head volume coil. Standard high-resolution T1-weighted structural images were acquired with an MP-RAGE pulse sequence at the beginning of the scanning session.The team gathered functional data using a high-resolution echo-planar imaging pulse sequence that is ideal for measuring blood oxygen level-dependent responses from small subcortical structures. Using the cardiac cycle of the participant to trigger functional image acquisition minimized motion artifacts and reduced the cardiac noise in the brain stem. The amount of data acquired was intentionally limited to the duration of one heartbeat. The scientists applied an algorithm to normalize the data, improving the overlap of participants’ brain stems, an important step for group analysis of data. After functional scanning, a whole-brain functional image was acquired to facilitate image registration to the functional data. Finally, they acquired proton-density-weighted anatomical images, which enabled the researchers to clearly visualize the substantia nigra, helping them to pinpoint the ventral tegmental area located in between.According to D’Ardenne, although they decreased the signal-to-noise ratio by using smaller voxels measuring 1.5 × 1.5 × 1.9 mm, they gained the ability to calculate statistics in small regions such as the ventral tegmental area. Because they acquired data in a small part of the brain, the scientists had to place slices precisely to include as much of the midbrain and the striatum as possible.The team’s methods can be used to study other functions of the dopamine system, such as its role in addiction, disease and mental health disorders, and it could be adapted for studying the norepinephrine and serotonin systems. Science, Feb. 29, 2008, pp. 1264-1267.