The Mind at Work: Kay Tye on unlocking the grip of negative emotions

There has perhaps never been a better time to be a neuroscientist. For decades, the field has focused on mapping the functional architecture of the brain in higher and higher resolution, both spatially and temporally. We’re now able to see how different parts of the brain literally light up during particular activities and thought patterns. And there are theoretical frameworks, most notably Karl Friston’s free energy principle, that mathematically describe the simultaneous dynamics of brain systems at different scales.

At the other end of the microscope, we now have increasingly precise and powerful tools to investigate the circuits created by individual neurons. Improvements in what is called two photon imaging now have sufficient resolution and sensitivity to observe individual neurons in living tissue. And optogenetics can turn genetically modified neurons on and off with light, allowing us to substantiate causal factors behind these observation. So far, these techniques have mainly been used in experiments with mice, but are likely to have direct application to treating human diseases in the years ahead.

Neuroscientist Kay Tye represents a new generation of brain researchers taking full advantage of these new tools. Tye won the Society for Neuroscience Young Investigator Award in 2016, and earlier this year moved her lab from MIT to the Salk Institute in San Diego, where I talked with her recently. She explores “motivated behaviors such as social interaction, reward-seeking and avoidance,” mainly in the context of diseases related to the dysfunction of these behaviors. But these same types of behaviors, when dysfunctional, generate the stressful dynamics of the 21st century workplace. Tye’s work may hold a key to understanding these dynamics, and, as she writes, “selectively enhance learning about rewards but not threats.”

It’s hard to separate her palpable enthusiasm for research from the evident pleasure she takes in training and mentoring young scientists. Most people try to fill their lab or startup team with like-minded people they think will be more likely to enjoy working together. “I’m literally doing the opposite,” say Tye. “I’m trying to find the most diverse group possible.” In her case, this not only means economic, racial, and geographic diversity, but also scientific and emotional. She’s filled her lab with computer scientists, chemists, virologists, behaviorists, not just people who identify as neuroscientists—or people as extroverted as she is. “If you have more diversity, not everybody sees things the same way. There will be more conflicting viewpoints. I like to have people who are going to disagree, and then in those rare moments that everybody agrees—it must be really true,” she explains.

It’s hard not to draw a parallel between the way Tye runs her lab and the discoveries it’s making. Their recent findings point to a diversity of neuronal function masked by the statistical averaging of larger-scale brain imaging. Most of what we think of as higher intelligence is the product of the cerebral cortex, which has a very uniform structure made up of consistent layers of different types of neurons and cortical columns assigned to very specific functions. In contrast, Tye investigates the neuronal circuits that mediate emotional responses, connecting the cortex to the older and more anarchic amygdala, midbrain and brainstem regions.

Whenever a structure is genetically conserved over a long period of time, scientists look to see what positive evolutionary function it could have. This is the case with the amygdala, a bi-lateral pair of small regions deep in the middle of the brain associated with the reward system. In the amygdala, which has been a particular focus for Tye and her PhD advisor, Patricia Janak, the diverse functions of adjacent neurons within it seem to be a feature, not a bug. When you dig into how the amygdala works, its informal structure facilitates the lightning fast responses necessary to avoid predators or take advantage of opportunistic rewards. It also seems to facilitate plasticity of learning, allowing creatures to quickly integrate new information critical to their survival.

As is often the case in neuroscience, pathologies often motivate exploration of underlying functions. In the case of both Tye and Janak’s research, understanding the mechanisms behind substance abuse involves decoding the brain’s basic reward and punishment circuits—which appear to run through the amygdala. Tye is also investigating the related and often simultaneously occurring pathologies of depression, anxiety, and attention-deficit disorder, which also seem to be caused by the maladaptive function of these same circuits.

In a paper just published in Science, Tye’s lab documents one of these circuits to predict compulsive drinking in mice. In contrast to previous research that has looked at brain changes caused by binge drinking, this study shows distinctive differences in neuron activity between healthy mice and those predisposed to compulsive drinking—from the first drink. These differences involve a circuit between a region involved in behavioral control and another that responds to adverse events. The susceptible mice will continue to drink alcohol even after it is combined with a bitter taste that inhibits other mice from drinking. Tye considers these differences a biomarker that allows us to “look into the brain and find activity patterns that predict if mice will become compulsive drinkers in the future, before the compulsion develops.” Even more intriguing is the possibility, which they will be testing in further research, that the “same circuit is involved in multiple different compulsive behaviors such as those related to other substances of abuse or natural rewards.”

In other words, it could be that one of the reasons for the co-morbidity of conditions like depression and substance abuse is that they both emerge from imbalances in the brain’s basic valence systems. Serious and prevalent as these neuropsychiatric disorders are, these systems that encode the positive or negative interpretation of stimuli also underlie every aspect of our conscious experience. What we’ve come to see as the psychopathologies of the workplace—stress, loneliness, and burnout—may also feed off misfirings of valence. 

How to model emotions has been an area of contentious debate in psychology, though most researchers have long agreed that valence, the polarity of an emotion, and arousal, the bodily activation associated with an emotion, are the two most important dimensions. But to understand how we determine our feelings about something that happens, it also matters in which order our brains get there. The two factor theory of emotion explains that we evaluate the salience of an event—its raw intensity—before we label it as good or bad. This chronology explains why we can experience intense emotional states without knowing the immediate cause, leaving us to construct an explanation on the fly, often erroneously.

Our experience of emotion is mediated, in other words, by many factors besides the stimulus that arouses them. In different strands of her research, Tye has identified both hunger and social status as factors that can cause the same stimuli to evoke very different behaviors. In the case of hunger, Tye has shown that after just one day of fasting mice will shift the balance of their behavior. “If you make an animal really hungry,” she says, “then not getting the reward becomes an equal threat to their survival as being eaten by the predator.” Transpose this situation to the office and you can see how people hungry for status can shut their colleagues down through behavior that turns out to be predatory.

Tye hypothesizes that the diversity of neurons within the amygdala’s different nuclei facilitate this rapid plasticity through selective local inhibition and excitation. Compared to the cortex, she says, “The amygdala is much more of a self-sufficient system where you can put information in, things will be weighted, and then it all dukes itself out locally. For example, if there’s some sort of predator trying to kill you, there are systems in the brain to silence all the other things while you escape.” Fortunately, these same systems help you shut out all distractions and focus when you have an impending deadline.

These findings support other research that shows just how fast our brains code valence. The speed of these responses can have big consequences in the workplace. “A huge thing that I think about when I’m running my own lab is that there’s a lot of emotional contagion,” Tye says. “If one person is stressed, it can stress out the whole group.” She emphasizes the importance of counteracting this contagion by making stressful events positive instead of negative. “If you have lots of stressful things but you always make people feel good when they’re over, and you celebrate and reward people, then you can make people thrive.” The secret for leaders, Tye explains, is to help their teams “develop really good habits for coping with stressful situations and thriving under pressure.”

You can use social solutions, like big parties, to combat social contagion, but social isolation and disengagement require a more individualized approach. Tye is working on a new concept called social homeostasis that shows the impact of social isolation on behavior and decision making. Each person has a social set point, an amount of social contact that feels comfortable and natural for them. Similar to hunger, Tye is finding that even a single day of social isolation can cause changes in animal behavior. 

“The breakthrough that we had,” Tye says, “is we found the neurons that are necessary for the isolation-induced rebound of social interaction and also these neurons that track social isolation and social contact. This represents the first cellular substrate of anything within a social homeostatic circuit.” To do science at the cellular level you need to have a starting point. “Now we can trace their outputs, trace their inputs, what is connected to these cells,” she continues. “You just need to follow the wires wherever they take you.”

Where the wires seem to go is that social factors, like rank and isolation, have a big impact on how we respond to events in the world. This may partially explain why the 21st century workplace, with its flattened hierarchies and geographically distributed workforce, is seeing an epidemic of loneliness and disengagement. The initial research by Norwegian zoologist Thorleif Schjelderup-Ebbe, who coined the term “pecking order” in 1921, described the adaptive effect of social hierarchy as reducing the overall energy expenditure of the whole flock because less is devoted to conflict. Yet, on the individual level, it forms the basis of inequality. Low social status in humans is not only associated with poverty, but also higher incidence of depression and other major diseases.

If you’re a boss, people are always coming to your meetings. That feeling of having a table full of eager reports is good for your self esteem, so much so that you grow to expect it. For people working their way up the corporate ladder, on the other hand, big team meetings can be a source of anxiety and boredom. They may feel, often correctly, that the meeting is more about making the boss feel in control than about spending people’s time effectively. Unfortunately, the same drive that makes the manager push for social cohesion can lead employees towards social isolation. Although this may seem to be just a problem of ineffective management, we can see now that it’s rooted deep in the brain’s emotional circuits.

An awareness of social status exists in most creatures, from mice to human children as young as two. Hailan Hu, of Zhejiang University in China, who Tye describes as “one of my favorite scientists in the world,” has done pioneering research identifying neurons in the brains of mice that encode rank. By manipulating these neurons with optogenetics, her lab has been able to literally change the pecking order among groups of mice, as if flipping a switch. Social status is an important components of social homeostasis, another set point that we monitor and take actions to maintain. 

Part of the complexity of interpersonal communication is trying to understand and take into account other people’s set points. Emotional reactions happen quickly, and people with a predisposition to depression or related disorders may be more likely to interpret ambiguous evidence negatively. Particularly in the workplace, chronic misunderstandings can degrade job performance and diminish the confidence of those least likely to speak up. Even something as simple as making the subject line of an email, “Thanks for your hard work” rather than “Post mortem for the project,” can make the difference between a positive impact and an anxiety attack.

The immediate goals of Tye’s research are to find neuronal targets for medical interventions that prevent or reverse disease states like depression, anxiety, and substance abuse. But as we understand these brain mechanisms better at a cellular level there’s the prospect that they will inform our wider understanding of emotion in our everyday lives. Tye sees the brain as a collection of systems working in parallel at different levels of cognition. “Things that are more important can break through when you use your emotional memory systems,” she says. “It’s a different circuit than other memory systems, so you can have access to more power and increase your bandwidth.”