Wednesday, August 11, 2010

Amygdalar and hippocampal substrates of anxious temperament differ in their heritability

So here's a recent bit of sad silliness from the Davidson crew.

I wrote to the author of the release asking about a couple things. My letter follows the release.
Public release date: 11-Aug-2010

Contact: Susan Lampert Smith
ssmith5@uwhealth.org
608-262-7335
University of Wisconsin-Madison
Inherited brain activity predicts childhood risk for anxiety

MADISON – A new study focused on anxiety and brain activity pinpoints the brain regions that are relevant to developing childhood anxiety. The findings, published in the Aug. 12 edition of the journal Nature, may lead to new strategies for early detection and treatment of at-risk children.

"Children with anxious temperaments suffer from extreme shyness, persistent worry and increased bodily responses to stress," says Ned H. Kalin, chair of psychiatry at the University of Wisconsin-Madison School of Medicine and Public Health, who led the research. "It has long been known that these children are at increased risk of developing anxiety, depression, and associated substance abuse disorders."

The new study by Kalin and colleagues demonstrated that increased brain activity in the amygdala and anterior hippocampus could predict anxious temperament in young primates.

"We believe that young children who have higher activity in these brain regions are more likely to develop anxiety and depression as adolescents and adults and are also more likely to develop drug and alcohol problems in an attempt to treat their distress," says Kalin.

Previous research led by Kalin established that anxious young monkeys are similar to children who are temperamentally anxious. In the current study, researchers examined the extent to which genetic and environmental factors influence activity in the anxiety-related brain regions that may make children vulnerable.

In the largest imaging study of nonhuman primates, the researchers at UW-Madison scanned the brains of 238 young rhesus monkeys, all of which belong to the same extended family. The monkeys underwent a positron emission tomography (PET) scan, which in humans is used to understand regional brain function by measuring the brain's use of glucose.

Key findings of the study include:

* Young rhesus monkeys from a large related family showed a clear pattern of inherited anxious temperament.
* Monkeys with anxious temperaments had higher activity in the central nucleus of the amygdala and the anterior hippocampus. In addition, researchers could predict an individual's degree of anxious temperament by its brain activity.
* Genes and environmental factors affected activity in the amygdala and hippocampus in different ways, providing a brain-based understanding of how nature and nurture might interact to determine an individual's vulnerability to developing common psychiatric disorders.

First author Jonathan Oler, associate scientist at the UW-Madison Department of Psychiatry, says the findings were a surprise.

"We expected that all of the brain regions involved in anxious temperament would be similarly affected by genes and environment, but found that activity in the anterior hippocampus was more heritable than in the amygdala," says Oler.

The new discovery may ultimately lead to new ways to detect anxiety in children, says Drew Fox, a graduate student working with Kalin and a co-author on the study.

"Markers of familial risk for anxiety could be identified by understanding alterations in specific genes that influence hippocampal function," says Fox.

The study suggests that there is a tremendous opportunity to modify the environment to prevent children from developing full-blown anxiety.

"My feeling is that the earlier we intervene with children, the more likely they will be to lead a happy life in which they aren't as controlled by anxiety and depression," says Kalin, who is also director of the UW-Madison HealthEmotions Research Institute. "We think we can train vulnerable kids to settle their brains down."

Under Kalin's leadership, researchers at the HealthEmotions Research Institute are translating these findings to humans by measuring amygdala and hippocampal function in young children who have early signs of anxiety and depression.

Kalin emphasizes that the research could not have been accomplished without the important contributions of collaborators including Steve Shelton, Richie Davidson and Terry Oakes of UW-Madison; Tom Dyer, Wendy Shelledy and John Blangero of the Southwest Foundation; and Jeff Rogers of Baylor University.

###

Dear Ms Smith,

I am writing in regard to the recent news release you wrote announcing the publication of Oler et al's new paper in this week's Nature.

I am particularly interested in your quote from Dr. Kalin: "It has long been known that these children are at increased risk of developing anxiety, depression, and associated substance abuse disorders."

In the paper, Amygdalar and hippocampal substrates of anxious temperament differ in their heritability, the authors write: "Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse." They cite Biederman J et al Further Evidence of Association Between Behavioral Inhibition and Social Anxiety in Children. Am J Psychiatry. 2001.

This seems to be the bedrock justification for Kalin et al's many years of papers on temperament in monkeys, which might have begun with their publication of Lateralized response to diazepam predicts temperamental style in rhesus monkeys. Davidson RJ, Kalin NH, Shelton SE. Behav Neurosci. 1993.

But Biederman et al, 2001, doesn't support Kalin's or Oler et al's claim. You can review Biederman et al, 2001 here.

Biederman et al, 2001 makes no mention of substance abuse and mention of depression occurs only in describing the parents of the children being studied.

In the nine categories of anxiety disorders looked at by Biederman et
al, (see http://ajp.psychiatryonline.org/content/vol158/issue10/images/large/J722F2.jpeg) most were unrelated to children's parents' own anxiety disorders, suggesting that - in humans - most anxiety disorders are not heritable. The authors conclude: "Behavioral inhibition in children was selectively associated with a higher risk for avoidant disorder and social phobia and a lower risk for disruptive behavior disorders. No association was detected between behavioral inhibition and other disorders, which suggests that behavioral inhibition may have specific associations with social anxiety in children."

Interestingly, they also call attention to a previous study that found that "behavioral inhibition protected both disruptive and nondisruptive boys against delinquency;" apparently at odds with the claims made by Oler et al if delinquency includes substance abuse. I have not reviewed the referenced paper.

In any case, the work cited by Oler et al and the claim made by Kalin do not appear to be supported by the paper they cite for evidence.

Genuine beneficial results of Oler et al, and Kalin et al's previous work in this area are difficult to point to. In your release, you write: "Under Kalin's leadership, researchers at the HealthEmotions Research Institute are translating these findings to humans by measuring amygdala and hippocampal function in young children who have early signs of anxiety and depression."

Following Roger N. Rosenberg's scathing editorial, Translating Biomedical Research to the Bedside A National Crisis and a Call to Action, JAMA. 2003, "translation" has become a buzz word in basic biomedical science. Numerous "Centers" and "Institutes" for the translation of basic research have been started around the country, as if doing so will improve the translation rate. The UW Institute for Clinical and Translational Research, created in 2007 apparently, is a local example. See too: Evolution and translation of research findings: from bench to where? Ioannidis JP. PLoS Clin Trials. 2006.

In your statement, the use of "translating" is misleading and probably stems from the increased use of the term. "Measuring" (what does that even mean?) amygdala and hippocampal function in young children who have early signs of anxiety and depression is not a translation of Oler et al or Kalin et al's work. In fact, similar work in children has been ongoing since at least 2000. See for instance A pilot study of amygdala volumes in pediatric generalized anxiety disorder. DeBellis MD, Casey BJ, Dahl RE, Birmaher B, Williamson DE, Thomas KM, Axelson DA, Frustaci K, Boring AM, Hall J, Ryan ND. Biol Psychiatry. 2000.

Learning that certain areas of the brain are associated with particular mental affect or defect has not led to ways to fix them. This is the heart of the translation problem and why Oler et al and Kalin et al's past work in monkeys does not warrant the ballyhoo you made of it.

Sincerely,

Rick Bogle

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