Tracing Familial Risk of Mental Illness

Ask anyone, from Sophocles to Freud: Family ties are a mixed blessing. We can thank our parents, in large part, for our intelligence, our resilience, our sense of humor. But their gifts don’t always merit our gratitude—including, as they may, such dubious boons as the relentless qualms of anxiety and the shadowy dreads of depression.

Transmission of mental illness risk has been subject to increasing scientific scrutiny. What part of this legacy is due to the genes our parents handed down to us, what part to how and where they brought us up?

Substantial progress has been made toward answering such questions; studies with twins, extended families, and large populations indicate that 40-50 percent of the tendency toward depression, for example, can be traced to genes, and even suggest which may be involved.

But just how parents’ mental difficulties are visited on their sons and daughters remains a mystery. “We know that that children born to depressed mothers are at risk for depression” says Deanna Barch, chair of psychological & brain sciences at Washington University of St. Louis. “The question is why, by what pathway familiality contributes to risk.”

Anxiety in the Family Tree

Seeking the story beneath the surface, neuroscientists have looked within for links between heredity and brain differences associated with mental troubles.

In a recent animal study, researchers at University of Wisconsin did PET scanning on nearly 600 young rhesus monkeys and tested them for a primate behavioral equivalent of anxious temperament.

In a 2015 PNAS paper, the investigators reported an association between anxiety and metabolism in a brain circuit linking the amygdala, brain stem, and prefrontal cortex. The finding is “consistent with what is seen in human studies,” says Ned Kalin, chair of psychiatry at University of Wisconsin and senior author of the paper. “That we saw this very early in the life of the primate suggest these alterations are not the result of long-term disease, but more likely set individuals up for vulnerability to develop problems.”

Because Kalin and his colleagues have studied this colony of monkeys over a period of years, they could trace kinship networks linking parents, offspring, and collateral relatives, and analyze the transmission patterns of both anxious temperament and the “anxiety circuit.”

“We found that function in this brain circuit falls through the family tree in the same way as anxious temperament,” Kalin says. A predisposition to anxiety and variation in the amygdala-brain stem-prefrontal cortex network were “coheritable,” in the words of the paper: “Metabolism within this tripartite neural circuit is likely to share a genetic substrate with anxious temperament” through which risk of psychopathology is passed down.

Because rearing and living conditions were more controlled and less variable in this primate colony than they would be among people, the observed pattern was more likely due to genetic process than to “environmental noise,” Kalin says.

He is now following a group of 200 human children with anxious temperaments into adolescence. By tracking metabolism within the brain network identified in the primate study, via fMRI, they hope to see whether changes over time will indicate which children will remain highly anxious, who will develop full-blown anxiety or depressive disorder, and who will find ways to manage their temperament.

Intergenerational Neuroimaging

While extended pedigree studies like Kalin’s suggest how traits like anxious temperament are transmitted, other researchers are taking a more direct approach: The emerging field of intergenerational neuroimaging explores structural and functional patterns in parent-offspring pairs.

In a 2016 study reported in Developmental Neuroscience, Stanford University researchers scanned, via MRI, mothers who had had repeated bouts of depression and their early-adolescent daughters who had, as yet, no signs of mood disorder. The researchers compared this group to mother-daughter pairs with no depression history.

Both the depressed mothers and their daughters showed signs of cortical thinning, relative to controls, in one specific area: the fusiform gyrus. What was more, says senior author Ian Gotlib, there was concordance in the depressed mother-daughter pairs: The extent of thinning in the mother’s cortex predicted the degree of abnormality in the daughter’s.

“We’re doing other studies now, looking at functional concordance during a reward processing task,” says Gotlib, who is chair of the psychology department at Stanford. An earlier study of cortisol levels in a group that included these mother/daughter pairs found a similar concordance, suggesting that stress reactivity is also passed down from parent to offspring. “It’s another piece of the puzzle,” he says.

That the fusiform cortex is the locus of mother-child concordance is especially interesting, says Deanna Barch. “It suggests that whatever is causing intergenerational correspondence is going through [this area] rather than, for example, the amygdala. If [the finding] were confirmed and replicated, the importance of the fusiform for face processing points research in a slightly different direction than if it were the whole brain.”

A next step will be predicting the onset of depression. Researchers in the Gotlib lab have been following the girls who participated in these studies for some 10 years. “At this point, 60 percent have now had episodes of depression,” he says. “We’re re-imaging as many as we can, looking not only at changes associated with depression but at what can protect against it. Is there a trajectory associated with the onset of the disorder vs. resilience?”

To better dissect depression precedents from consequences, Gotlib has begun a long-term scanning study beginning with 6-month-old infants of depressed mothers.

The Stanford study chose mothers and daughters because earlier evidence links transmission more closely to mothers than to fathers, and girls are more likely to develop depression in adolescence than boys. A study reported in Journal of Neuroscience in 2016, examined questions of sex-specificity more systematically, performing MRIs of non-depressed parent-offspring pairs in all permutations: mothers and daughters, mothers and sons, fathers and daughters, fathers and sons.

“We found matrilineal transmission patterns in the corticolimbic system, which is important in emotional regulation and in depression and anxiety,” says Fumiko Hoeft, director of BrainLENS (Laboratory of Educational NeuroScience) at University of California, San Francisco, and senior author of the study. “Not mother to [all] offspring, but mother to daughter specifically.”

Their findings need to be replicated, Hoeft says, but if the pattern holds up, “it gives us lots of ideas where to go next in exploring possible mechanisms, [which might involve] mitochondria, prenatal hormone effects, or postnatal environment.”

Dissections and Connections

“Parent-to-child correspondence by itself doesn’t prove heritability…there may be similar environmental effects operating for both,” Barch notes. “Genetic factors might contribute to an environment that leads to the same outcome as genetics itself; a daughter raised with a depressed mother might have increased post-natal stress. It’s hard to tease them apart.”

Epigenetic effects—modifications in genes expression—are one possible mechanism of mental illness risk transmission. Repeated animal studies have demonstrated that early maternal care helps shape neural circuits that regulate their offsprings’ stress reactivity, learning and memory, and that altered gene activity may play a central role. Other research suggests that parents’ life experiences can change gene expression in ways that are passed on to their offspring: One generation’s stress may make the next vulnerable to PTSD.

A study that Hoeft has recently embarked upon may extend insights into such mechanisms to humans. “We’re looking at different kinds of in vitro fertilization (IVF) families,” comparing surrogacy, when another woman carries the baby, and IVF, using donor eggs and the woman’s own. By correlating brain structures and behavior in parents and offspring within the different groups, this “naturalistic cross-fostering experiment” could begin to disentangle prenatal, postnatal, genetic, and epigenetic influences, Hoeft says.

In an age of increasing scientific teamwork, intergenerational neuroimaging research may gain power through collaboration with other approaches.

Lianne Schmaal, co-chair of the major depression working group of ENIGMA [Enhancing Neuro Imaging Genetics through Meta Analysis], an international consortium of researchers that looks for brain patterns linked to mental and neurological illness, thinks that their huge data set “might inform smaller studies by helping them prioritize regions of interest, functionally and structurally, rather than looking across the entire brain.”

Another ENIGMA project explores associations between age and brain structure. “Mothers and daughters are in different developmental stages,” Schmaal says. By providing “normative data,” ENIGMA could help researchers make more meaningful interpretations of intergenerational similarities and differences.

Ultimately, Hoeft says, a better understanding of familial transmission could help identify high-risk children earlier, and trigger preventive strategies such as parental nutrition boosters and programs to increase maternal responsivity.

Ian Gotlib is already testing one such intervention. “We’re training daughters of depressed mothers to use neurofeedback to change patterns of activation, and seeing if that can delay or prevent the onset of depression,” he says.