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