Brain circuitry and mechanisms underlying anxiety uncovered

You’ve probably felt it at one time or another, maybe before a big deadline, a public presentation, or an important job interview: an inner heaviness, possibly followed by a flurry of nervous activity. While some amount of anxiety can be beneficial in certain situations, for some it can be overwhelming and debilitating – and take a major toll on daily life. The US National Institute of Mental Health estimates that 40 million adults, aged 18 and older, have an anxiety disorder.

Dr. Ned Kalin, chair of the Department of Psychiatry at the University of Wisconsin School of Medicine and Public Health in Madison, US, discusses the use of brain imaging in his anxiety research. Image courtesy University of Wisconsin School of Medicine and Public Health.

Ned Kalin, the Hedberg Professor and Chair
 of the Department of Psychiatry at the 
University of Wisconsin School of Medicine and Public Health, has spent 30 years studying anxiety and its underlying mechanisms both in primates and humans. “We’ve now combined studies using Rhesus monkeys with those of young children, to begin to directly translate what we’ve learned from the animal studies,” says Kalin.

“The goal being to develop novel, scientific strategies that are based on the science of alterations of the brain, to create effective treatments for anxiety in young children,” Kalin explains. “We’ve characterized a phenotype – anxious temperament – with components of higher levels of freezing or inhibiting behavior, lower levels of vocalization, and higher levels of stress hormones.”

Kalin has shown for the first time that an anxious temperament is a continuous measure – meaning temperament at one point in life is predictive of temperament at another point, and the temperamental dimension is stable throughout development. After developing the model and phenotype, Kalin’s lab engaged in large-scale imaging studies to try to understand exactly which brain circuit was most predictive for the anxious temperament.

The stria terminalis: an anxiety-related white-matter tract imaged using Diffusion Tensor Imaging (DTI). Image courtesy Ned Kalin.

“After studying 590 animals with imaging and phenotyping, we were able to determine a circuit that is overactive in relation to anxious temperament, and includes a variety of structures known to be associated with anxiety.” Kalin identifies the structures as the amygdala, the hippocampus, and the prefrontal cortex. “There are also regions in the brain stem – the periaqueductal grey matter – that are part of the overactive circuit,” he adds. “What's important is that we've shown that the overactivity is stable with development.”

Not only is the anxious phenotype stable; the brain circuitry underlying it is also stable. Kalin has shown for the first time that if you actually alter the functioning of some of brain regions, in particular a region in the central nucleus of the amygdala, – the central nucleus – the functioning is causally related to anxious temperament. “If we decrease activity in the central nucleus, we can show that the reduction will reduce an individual’s levels of anxiety,” he notes.

The groundbreaking research hasn’t, however, been without its challenges: developing a reliable model in non-human primates being the first, and developing a large database of imaging data being the second. “Most imaging studies in humans, and for sure the few that have been done in monkeys, typically involve only small samples,” says Kalin. “We’re now up to nearly 600 subjects and we have this unbelievable data set in which we can be very confident in that what we see behaviorally is reflected in the brain, and how it is reflected.”

Anxiety-related brain regions rendered on an average brain. Image courtesy Ned Kalin

Talking about brain imaging data means talking about hundreds of thousands of points within the brain of each subject. Analyzing every data point in the brain – both in relation to how alterations in the brain are causally linked to anxiety, and to whether or not they are inherited through a complicated family tree – is not a trivial matter. The scientists are not looking just at 600 different data points; they’re looking at every possible pair of data points and how they are related.

High-throughput computing resources like the Open Science Grid (OSG) will be the future of brain science. Research will require big data and complicated analyses, and OSG infrastructure is going to be critical for analyzing these data sets. Fox, as a single user, has required more computing hours on the OSG than the University of Wisconsin-Madison’s particle physics groups. “Thanks to high-throughput resources, we're able to ask and answer questions that would have taken a few hundred years otherwise,” Fox adds. “It's amazing.”

Most adults that have anxiety, and a considerable number that also have depression, have long histories of these problems, many of which date back to early childhood. Frequently the patients Kalin works with have symptoms dating back to four or five years of age.

The future for the treatment of anyone who suffers from anxiety and depression lies in the work Kalin is doing now. Dedicated to helping young children, his intent is to come up with data that will enable the development of new treatments that can be used very early in life – from toddler through preadolescence; treatments to help not only overcome anxious tendencies, but also reconfigure the brain in a way such that these children are more resilient and more capable of adapting to stress when it occurs later in life.