What Do White-Matter Changes Have to Do With Anxiety?

When people are anxious by nature, could it be due to a major disruption in white matter—that is, in the bundles of nerve axons wiring the brain? It's a possibility, a new study suggests.

Subjects who scored high on the temperament trait of anxiety had fewer white-matter connections in the amygdala and other anxiety-processing brain areas than did subjects who scored low on this trait.

Credit: Lars Westlye, Ph.D.

The study was headed by Lars Westlye, Ph.D., a postdoctoral fellow in the Center for the Study of Human Cognition at Norway's University of Oslo. Results were published in the April Archives of General Psychiatry.

In recent years, considerable evidence has emerged that anxiety-related personality traits are important predisposing factors to anxiety and depressive disorders. Emotional processing is known to rely on the structural and functional integrity of distributed neuronal circuits in the brain. Therefore Westlye and his colleagues wondered whether anxiety-related personality traits and an associated increased risk of anxiety and depressive disorders might be rooted in aberrations in white matter in areas of the brain crucial for anxiety processing, such as the amygdala, hippocampus, thalamus, subgenual cingulate, and orbitofrontal cortices.

The study sample consisted of 263 volunteers with no evidence of psychiatric disease ranging in age from 20 to 85. Subjects' tendency to be anxious was evaluated with the "harm avoidance" subscale of the Temperament and Character Inventory. Individuals who score high in harm avoidance are characterized as fearful, tense, worried, cautious, shy, and easily fatigued. Individuals who score low on harm avoidance are characterized as optimistic, confident, carefree, outgoing, uninhibited, and energetic.

New Neuroimaging Method Used

The scientists then used a relatively new neuroimaging method called diffusion tensor imaging (DTI) on the subjects. DTI makes it possible to map the organization and strength of white matter—that is, its integrity—in the human brain. Finally they assessed whether there were any significant differences in white-matter integrity between subjects who scored high on anxiety and those who did not, while taking possibly confounding factors—age, gender, years of education, alcohol consumption, IQ, and Mini-Mental State Examination results—into consideration.

The researchers found that subjects who scored high on anxiety had decreased white-matter integrity in precisely those brain areas anticipated—the amygdala, hippocampus, thalamus, subgenual cingulate, and orbitofrontal cortices—as well as in the areas connecting them.

Whether decreased white-matter integrity actually contributes to anxiety and depressive disorders remains to be seen. But if it does, there might be clinical implications for such a finding.

Future Research Implications Cited

"I doubt that a drug targeting the mechanisms for the decreased white-matter integrity observed in our study alone would suffice to treat symptoms of anxiety and depression, but it could perhaps be used successfully in conjunction with psychological therapeutic interventions and other pharmacological substances," Westlye told Psychiatric News. "I am not aware of any scientists looking for such a drug, but since decreased white-matter integrity has been found in many neurodegenerative and psychiatric disorders, including Alzheimer's disease and schizophrenia, I would not be surprised if this is an active area of research in the pharmaceutical industry."

Westlye also pointed out that while the specific gene variants coding for the harm-avoidance personality trait have not yet been identified, "it is very likely that some of these variants have their impact on harm avoidance via defects in the brain's white matter." Indeed, he and his team are collecting genetic data from their subjects in this study to see whether they can "detect gene variants involved in both anxiety-related personality traits and white-matter integrity."

"This study has been thoughtfully designed and has dealt with most of my criticisms about much research into personality characteristics such as harm avoidance," Anne Farmer, M.D., a professor of psychiatric nosology at the Institute of Psychiatry in London, England, told Psychiatric News. Farmer published a study on a related subject—the personality trait of harm avoidance as a predisposing factor to major depression—in the May 2003 Archives of General Psychiatry. "The results … point to disruption in the architecture of [nerve axons], which certainly makes sense in terms of current theories about the etiology of depression and anxiety."

The study was funded by the Research Council of Norway and the University of Oslo.

An abstract of "Linking an Anxiety-Related Personality Trait to Brain White Matter Microstructure" is posted at <http://archpsyc.ama-assn.org/cgi/content/abstract/68/4/369>.