Making connections

School was a struggle for Bennett Walker when he started first grade in the fall of 2012. Bennett’s parents were surprised and worried.

They knew their 7-year-old was bright: April Walker had started reading to Bennett when he was an infant, and he began memorizing children’s books at 14 months. When he was 2, he soaked up information about World War II, learning facts about military machines and details of key battles. (Bennett and his family are identified by pseudonyms in this story.)

“He has an amazing ability to focus for long periods of time on a topic, and then, for reasons unbeknownst to us, he switches and starts drilling in on a new topic,” said his mother. Every weekend, she took him to their local public library and they brought home 30 to 50 books. At 3, he was reading to her.

But in the first weeks of first grade, Bennett’s teachers said something was wrong.

“He was getting bullied,” his mother said. “They asked us, and we said, ‘He’s fine at home, we don’t have any problems at home.’ But he was acting out at school.” When she and her husband asked Bennett what was going on, their son told them, “Nobody cares about what I do or who I am.”

“He was desperately unhappy,” she said.

Seeking more answers, the Walkers arranged for their son to have a clinical evaluation that included several types of cognitive testing. The results held a shock: Though his symptoms were of mild severity, Bennett had autism.

“We took about a week to process and grieve that his test results meant the death of a future that didn’t exist anymore,” said his mother. Then she and her husband, Jacob, began aggressively pursuing interventions for their son: speech therapy, occupational therapy, academic tutoring and participating in clinical trials of autism treatments.

“Jacob and I are both very much boots-on-the-ground type of people,” Walker said. “We were taking any and every action we could find.”

A social gap

The Walkers found themselves facing a challenge that confounds parents and researchers alike: Bennett struggled to navigate social situations.

Medications for the disorder’s core features, including social problems, are high on the wish list of autism experts, and Stanford scientists are working to address that. In particular, they’re enthusiastic about two hormones: oxytocin and vasopressin.

Bennett’s social struggles didn’t stem from lack of intelligence. Some aspects of his cognitive abilities were almost off the charts — his vocabulary test scores were in the 97th percentile for a child his age.

But social logic eluded Bennett. For instance, the last two weeks of the elementary school year — when classroom routines gave way to a frenzy of field trips, pool parties, movies and kickball games — were confusing and overwhelming for him. With buy-in from school officials, Bennett’s parents took to keeping him home in early June. Though a workable coping strategy, this didn’t explain why Bennett’s brain was overloaded by activities his classmates enjoyed.

“At least some individuals who have mild symptoms of autism say, ‘I really want friends, I really miss this,’ and have depression and anxiety that are attributable — through their eyes — to not being able to connect socially.” 

The mystery of why children with autism struggle socially has been equally challenging for researchers. Scientists and clinicians know what autism looks like from the outside, what behaviors fit the disorder’s core features of social and communication difficulties, as well as restricted and repetitive interests or behaviors. They know that 1 in 59 children are affected, with four or five boys diagnosed for every girl, and that the disorder is on the rise. But autism’s underlying biology is still mysterious, which makes it hard to treat.

“At least some individuals who have mild symptoms of autism say, ‘I really want friends, I really miss this,’ and have depression and anxiety that are attributable — through their eyes — to not being able to connect socially,” said Karen Parker, PhD, associate professor of psychiatry and behavioral sciences.

The best available treatments consist of behavioral therapies to teach specific skills, such as understanding facial expressions or using words to express one’s wants and needs.

To try to develop medications that could add to the treatment options, Parker and her colleagues are studying the actions of hormones that regulate sociability. A recent pilot study, in which Bennett participated, showed improvements in social abilities in 30 children who were given vasopressin. They’re now testing whether the results can be repeated in a larger group.

“If we have a neuropeptide that we could administer to allow people to understand social cues, or that is socially motivating, maybe it would work for children who have these social impairments,” Parker said.

Questioning the ‘love hormone’

Oxytocin and vasopressin are tiny, nearly identical hormones, each made of nine amino acids. Manufactured by the hypothalamus, a small region at the base of the brain, the hormones have similar three-dimensional shapes.

Oxytocin release aids many types of social behavior in animals and people, including mother-infant bonding and bonding between mates.

Starting in the 1990s, small studies suggested that deficiency of oxytocin, sometimes called the “love hormone,” might explain autism in children. Through subsequent research, Parker and her colleague Antonio Hardan, MD, professor of psychiatry and behavioral sciences, have shown that reality is more complicated. In addition to his research role, Hardan directs the Autism and Developmental Disorders Clinic at Lucile Packard Children’s Hospital Stanford, where he treats children and teens with autism.

In research published in 2014, Parker and Hardan compared blood oxytocin levels in three large groups of children: those with autism, their siblings without autism, and unrelated typically developing kids who had neither an autism diagnosis nor an autistic sibling.

Blood oxytocin levels varied within each of the three groups, with some children having low, medium and high levels. Overall, children with higher oxytocin had greater social abilities.

“It didn’t matter if you were a typically developing child, a sibling or an individual with autism: Your social ability was related to a certain extent to your oxytocin levels, which is very different from what people have speculated,” Hardan said.

“The previous hypotheses saying that low oxytocin was linked to autism were maybe a little bit simplistic. It’s much more complex: Oxytocin is a vulnerability factor for social functioning that has to be accounted for, but it’s not the only thing leading to the development of autism.”

The team followed up with an oxytocin treatment trial in which they gave daily doses of intranasal oxytocin or a placebo to 32 children with autism. In the study, which was published in 2017, the hormone modestly improved social behaviors, but only in children with low initial oxytocin levels.

“It didn’t matter if you were a typically developing child, a sibling or an individual with autism: Your social ability was related to a certain extent to your oxytocin levels, which is very different from what people have speculated.”

Research published this year by the Stanford researchers adds another interesting wrinkle to the story. Yawning in response to another person’s yawn is thought to be an indicator of empathy, but studies of whether the contagious yawn response was absent in people with autism had mixed results. The Stanford team found that children with autism failed to yawn contagiously only if their oxytocin levels were low.

“These findings suggest that only a biologically defined subset of children with autism spectrum disorder exhibits reduced empathy, as measured by the impaired contagious yawn response,” the scientists reported.

Parker and Hardan have collaborated for more than 10 years on applying basic laboratory research to clinical investigations. Their recent oxytocin research underscores the idea that the disorder is not one autism but many autisms.

“Because of the heterogeneity of the disorder, we need to start doing clinical trials not to see if there will be a response, but more to see who will respond to possible treatments,” Hardan said.

The National Institutes of Health is funding a large, multicenter oxytocin treatment trial, which is expected to publish soon. Parker and Hardan weren’t involved in that study but are eager to see its findings. If their pilot study results are replicated, it will suggest that clinicians should check oxytocin levels in kids with autism and consider prescribing the hormone if baseline levels are low.

Oxytocin’s fraternal twin

Alongside the team’s oxytocin work, Parker has been following a hunch that stemmed from her dissertation research. As a graduate student in the late 1990s, she studied social behavior in tiny mammals called meadow voles. Parker discovered that vasopressin helps facilitate pair-bonding and fathering behavior in the males. Meanwhile, other scientists had shown that the females’ pair-bonding and mothering requires oxytocin release, a finding that holds in many mammalian species.

As she considered autism, Parker wondered if the vole findings held a clue to the disorder’s biology.

“I was thinking that maybe there are things that protect females or make males vulnerable,” she said. “We didn’t find that oxytocin was a smoking gun for autism; it looked like a universal regulator of social function, not an indicator of whether you have autism or not. Since autism is strongly male-biased, I wanted to go back and look at vasopressin.”

The highlights of her findings include a 2015 paper seeking a link between vasopressin levels in children with autism and performance on a test of theory of mind, the ability to recognize that other people’s thoughts differ from one’s own. Autistic children with lower vasopressin scored worse on the theory-of-mind test.

In a study published in 2018, Parker’s team based at the California National Primate Research Center at UC-Davis investigated what male rhesus monkeys could reveal about vasopressin signaling. Monkeys that were naturally the least social had less vasopressin in their cerebrospinal fluid — which bathes the brain — than the most social monkeys.

A comparison of vasopressin levels in the fluid from human boys, using samples from seven children with autism and seven without, uncovered a similar vasopressin deficit in children with autism. A follow-up study of 36 children with autism and 36 non-autistic children found that lower vasopressin levels in the spinal fluid were associated with more severe autism symptoms among children with the diagnosis.

“Karen has really rolled up her sleeves and done the hard work of trying to understand the biological baseline.”

The vasopressin research was pain-staking work: Collecting cerebrospinal fluid requires invasive lumbar punctures. But Parker knew it was important to measure the hormone’s levels in the fluid that bathes the brain because it has different roles and potentially different regulation in blood.

“Karen has really rolled up her sleeves and done the hard work of trying to understand the biological baseline,” said John Spiro, PhD, deputy scientific director of the Simons Foundation, which supports autism research and has contributed funding to several of Parker’s vasopressin projects.

The next step was to do a pilot study to see if giving vasopressin to children with autism improved social function. In this initial phase, Hardan and Parker recruited 30 participants, who received daily doses of vasopressin or placebo nasal sprays for four weeks. The children’s social behavior and other autism symptoms were assessed before and after the four-week period.

The trial, which the NIH and the Stanford Maternal & Child Health Research Institute supported, was blinded, meaning the participants, their parents and researchers didn’t know which children were receiving vasopressin and which were receiving a placebo.

April and Jacob Walker heard about the trial from Stanford’s clinical trials registry. “I don’t think we had any reason to think it was going to work,” Bennett’s father said. But they enrolled Bennett, then a third-grader, reasoning that even if the hormone didn’t work, going to Stanford and interacting with the researchers might stretch Bennett’s brain in a positive way.

The Walkers wanted to avoid making him feel stigmatized, so have never told Bennett about his autism diagnosis — but he was enrolled in so many therapies that he didn’t seem surprised to be participating in a Stanford study.

“I saw his brain as an ever-closing door,” said April Walker, who sought as many opportunities as possible to combat this. “The most flexibility he had in rearranging his brain was when he was young, and it went away every single day.”

An open door?

After the treatment period, the Walkers met with Hardan and answered detailed questions about their son’s behavior. Bennett was acting about the same as before the trial, they agreed. Hardan asked the Walkers if they wanted to guess which treatment group they had been in. “We said, ‘Either it doesn’t work or we got the placebo,’” Bennett’s mother recalled.

“That was the placebo,” Hardan told them. As is standard for this type of research, the Walkers were offered four weeks of vasopressin after the blinded phase of the trial ended.

“When he had the real vasopressin, it was stunning — the difference in the amount of eye contact he would make and the initiative he would take,” Jacob Walker said. “The thing that shocked the crap out of me was when he walked up and randomly talked to someone at Safeway. I have never seen that from him, except during that month.”

The Walkers’ experience mirrors the trial results: Compared with children in the placebo group, those receiving vasopressin had more gains in social behavior. They also had less anxiety and fewer repetitive behaviors.

“We saw this across multiple measures independently,” Parker said. “It is really compelling.”

The Walkers believe there was a lasting boost in Bennett’s social abilities after the month of vasopressin treatment. “For about three years, there was a noticeable change,” Jacob Walker said. “That month gave him social gains that did not go away.” They enquired about continuing to give Bennett vasopressin after his monthlong treatment but had difficulty obtaining it. There is no vasopressin nasal spray on the market approved for autism.

“The thing that shocked the crap out of me was when he walked up and randomly talked to someone at Safeway. I have never seen that from him, except during that month.”

Now in eighth grade, Bennett’s social skills are still about two to five years behind his peers, depending on the situation, his parents said. However, Bennett was able to navigate a school trip to Japan last summer without his mom and dad. A teacher chose him for the trip because he’s so organized and reliable.

The Walkers aren’t sure if the social gains from the brief vasopressin treatment have stuck with Bennett. Like all kids, he grows and changes. Now in middle school, he is facing different social challenges than those he encountered when he was taking vasopressin in third grade. “Now he’s adapting to whole new problems,” his mother said.

The researchers are cautiously optimistic about vasopressin’s future as an autism therapy. “We might finally, hopefully, have an agent that will target these core features that are very hard to treat,” Hardan said. “But at the same time, we have to be careful not to get too excited before we finish the larger trial that we are currently conducting.” That trial, also funded by the NIH, is underway now and includes 100 children.

If the findings hold up, the scientists will validate the safety of the hormone in large populations in a multisite trial and then study which aspects of social behavior are most improved by vasopressin, Hardan added. “Is it motivation, affiliation, attachment? Ability to understand others’ mental states or read facial expressions or body language?” he asked.

If treatment continues to show promise, researchers will also face challenging questions about how the hormone might help shape the autistic brain over time. Vasopressin is unlikely to be a magic bullet, they said.

Rather, it may open the door for brain-molding social experiences that come naturally to most kids: giggling at their parents during peek-a-boo, pointing to a sippy cup to ask for water, forming early friendships in preschool, negotiating on-the-fly rules for games with their buddies.

The possibilities are keeping the Stanford team motivated as the work advances. “Our pilot trial showed that vasopressin moves the needle,” Parker said. “Hopefully a large swath of children with autism can benefit.”