Scientists' Understanding of Anxiety is Radically Evolving—But How Long Will it Take for Treatments to Catch Up?


If you think we live in anxious times now, the neuroscientist Joseph LeDoux suggests you consider what life must have been like in the Middle Ages. "That was probably a pretty lousy time to live," LeDoux, author of the 2015 book Anxious and one of the foremost experts on the neuroscience of fear, told Newsweek. "Disease, poverty and just the stress of life."

LeDoux was making a point he also makes in his recent book: Every age thinks it's "the Age of Anxiety."

"We love our anxiety and because it's ours, we think it's so special," he said. "But that's the nature of anxiety—it's all-consuming in your mind. If my mind is charged with anxiety, I can't imagine other people could've felt this bad in their lives."

It was a fair point, but I wasn't entirely convinced. I'd arrived at his office early and, while waiting for the eminent researcher, took a quick peek at my cellphone, which revealed the following news stories: The Amazon rainforest—the "lungs of the world"—was on fire, which could accelerate global warming. The trade war between the U.S. and China had escalated and the Dow Jones Industrial Average had plunged 600 points. There'd been two random mass shootings in recent weeks.

As I contemplated what all this might mean for my children, the planet and my 401k, a text message arrived from my editor at Newsweek. Could I deliver my story on anxiety a week early—say, in three days? If this wasn't the "Age of Anxiety," then what was it?

LeDoux was right about one thing. I am certainly not the only one living in the present who is grappling with fear of the future, even if it sometimes feels like it.

In May, the American Psychiatric Association reported that for the second year in a row, two out of three Americans say they are "extremely or somewhat anxious" about their health, paying bills and keeping themselves and their family safe. The problem is most pronounced for younger adults—70 percent of those between 18 and 34 report anxiety about paying bills and keeping their families safe, and two out of three are also anxious about relationships (compared with 40 percent for those over 55). About one in five has sought professional care.

College graduates are the most anxious of all, surveys suggest. Last fall, members of Generation Z (those born after 1996) reported the worst mental health of any generation, with 91 percent saying they had felt physical or emotional symptoms associated with stress, such as depression or anxiety, according to the American Psychological Association. Meanwhile, more than 60 percent of college students said they had experienced "overwhelming anxiety" during the previous year, and the number of students who visited campus counseling centers increased by more than 30 percent between the fall of 2009 and 2015.

A high school student and former patient of “Delete,” a therapy group for children with “nomophobia” (fear of being left without a mobile phone). MAURO PIMENTEL/AFP/Getty

Many researchers think that the internet and social media have contributed to this trend. "The constant access to news—and the constant warnings on news sites—is incredibly stressful and can create a sense of panic," says Jenny Taitz, a Los Angeles-based author and therapist who specializes in treating anxiety. "There's a shooting here, there is this break-in there, all this information that we have access to puts danger at the forefront of our mind. How can you relax when you have access to all the bad news that's happening right at your fingertips?"

When I mentioned this to LeDoux, he conceded that we live in "a particularly complex time." He added: "Other generations didn't have the internet, which has turned out to be one of the worst things that's ever happened to us as a species."

Luckily, the spike in anxiety comes at a time of incredible discovery for brain science. Advances in brain imaging and other techniques in recent years have vastly increased our knowledge of the neurological basis of anxiety and led to widespread optimism about the future of the field. Researchers have found that anxiety is a whole-brain phenomenon that involves the activity of complex neuronal circuits. As they proceed in identifying these circuits, they expect to uncover targets for new drugs and treatments. "I think we are on the cusp of a mental health treatment revolution," says Kay Tye, a neuroscientist at the Salk Institute for Biological Sciences. "It's an extremely exciting time."

For many of us, the revolution can't come soon enough.

Follow the Brain Circuits

Few scientists have contributed more to our understanding of fear and anxiety than Joseph LeDoux. When he began working on the problem in the 1980s, scientific dogma held that the emotional processing areas of the brain relied on signals that must first pass through the neocortex, the thinking part of the brain—suggesting that emotional reactions come after, and are caused by, our conscious thoughts about a situation.

Freud had famously established the notion of "unconscious factors" that play a role in anxiety, but there was no solid science to support the idea—until LeDoux came along. Working with rats, he discovered a new pathway that operates independent of conscious thought. Sensory stimuli could travel directly to a part of the brain known as the amygdala, a primitive structure that serves as the seat of the emotions. The implications were profound. It helped to explain how emotions can overpower our rational minds, why we are sometimes captive to irrational phobias and the mechanism by which it is possible to feel overcome by a deep sense of foreboding and anxiety or "gut feeling" without knowing why.

The amygdala was evolution's way of allowing humans to gain a few precious extra seconds in dodging an attacking lion or jumping out of the way of an oncoming car. There was a "slow" or "high road" to the mind, which ran through the cortex, the more reasonable part of the brain. And there was a "fast" or "low road" that traveled directly to the defensive and survival oriented areas of the brain, which allow us to react instantaneously—the "fight-or-flight" reflex.

The amygdala helped explain how the human brain processes fear, which is generally triggered by an immediate threat in one's environment. But it didn't entirely explain anxiety, which is what we feel when we are worried about the possibility of misfortune or personal injury at some point in the future.
In the 1990s, researchers identified a tiny structure that played a key role in how rodents dealt with "ambiguous threats"—ones that didn't place them in immediate danger. Called the Bed Nucleus of the Stria Terminalis (BNST), it was about the size of a sunflower seed and located near the amygdala. While the amygdala appears to be the brain area primarily involved in activating the fight-or-flight response, the BNST kicks in when we have reason to remain hypervigilant—that hormone-driven state of hyperarousal we feel in our bodies when we are tense in the face of uncertainty.

"What the amygdala is to fear, the BNST is to anxiety," LeDoux says.

A machine measures variations in the brain’s magnetic field. BSIP/Universal Images Group/Getty

In a neuroimaging lab at the University of Louisville, Brendan E. Depue, a psychology professor, has shown how these findings in rodents manifest in humans. Placing students one by one in an fMRI machine, Depue simulated fear conditions by showing subjects images of fearful faces and playing them sounds of human screams. To simulate ambiguous threats, he simply projected a blank screen and informed subjects that a scream or fearful face could occur at any time, but the subject might also at any time be shown a neutral face and hear indistinct coffee shop chatter instead. Under these conditions, the amygdala consistently activated when the screams and scared faces appeared and the BNST was more engaged with the ambiguous threats.

"Mostly people who complain, or go into counseling, or seek therapy are really not there for a reaction to a fear stimulus," Depue says. "They're there because they're tormented by anticipation of an unpredictable event. It's just in their mind. It causes them to develop a chronic and maladaptive vigilance to the environment. We think that can be attributed more to the BNST than the amygdala."

But the hormonal cascade engineered by the amygdala and the BNST, it turns out, is only one piece of the puzzle. In recent years, new techniques have come online that have allowed researchers to begin to trace the "circuits" of the brain in even greater detail and to better understand how disparate parts of the brain interact—creating both widespread excitement and the sense that there is a lot more to learn. Since 2011, Tye, of the Salk Institute, has been using genetically-modified light-sensitive proteins to turn neurons on and off, and systematically tracing the connections between different parts of the brain involved in fear and anxiety.

Her work has added to a growing body of evidence that brain structures other than the amygdala and BNST play a role in anxiety. These include the prefrontal cortex, the hippocampus, the cingulate gyrus and a number of other areas.

"If you think of an analogy of the brain being like the world, and neurons being like people, and you want to understand how information is propagated across the world, you would say, 'yeah, it's important to know where someone lives, I guess,'" she explains. "But it's way more important to know what they're saying, who they're saying it to, who's listening and how do the people that are listening respond? How are those messages sent and filtered to different corners of the brain?"

These findings make the focus on the amygdala and even the BNST seem outdated. LeDoux, the scientist many credit with establishing the importance of the amygdala, is quick to agree. Like Nixon in China, LeDoux has been proselytizing his colleagues to pay more attention to the contributions of the higher-order structures in the anxiety circuit. What parts of the brain the amygdala and BNST are "talking to" may eventually prove crucial in finding more effective ways of treating anxiety.

Indeed, LeDoux believes that a true understanding of anxiety lies in an exploration of one of the most complex subjects left in neuroscience: The nature of consciousness (the subject of his recent book, The Deep History of Ourselves).

While the amygdala or the BNST prime our bodies to react defensively by activating hormonal cascades and defensive behaviors, our minds—the higher-level processing areas of the brain—give meaning to what we are experiencing. In a way, what we call "fear" and "anxiety" are manifestations of our consciousness. Any truly effective treatment for anxiety, LeDoux argues, will require a better understanding of processes beyond the ancient brain structures that trigger behaviors and release hormones, extending to what creates our awareness of self.

We all have an anxiety "set-point," a state we are likely to return to throughout life. Although this is partially genetically determined, a growing body of research suggests that it can be molded by life experience. In one 2011 study, for instance, Virginia Commonwealth University psychiatrist Charles Gardner and his collaborators examined nine data sets of longitudinal studies of 12,000 twins across three continents, and examined self-reported symptoms of anxiety and depression at different stages of their lives. While the set points for 10-year-old identical twins were the same or very close to one another, they diverged sharply as the twins moved through adolescence and into adulthood, which suggests that genetic predisposition played only a part.

LeDoux argues individual experience exerts its influence on the set point in part through the development of "mental schema," sets of memories organized around a topic that are activated every time you're in a potentially fear- or anxiety-inducing situation. We might "fear" failing an exam at school because our parents told us that we would never succeed, or we heard the exam was hard or perhaps we failed a previous one. Each time we walk into an exam room, we carry a sense of anxiety into it. Even were it possible to deactivate the BNST and amygdala with a drug, LeDoux says, these mental schema would still interfere with our taking the test.

Bad Treatment

The new emphasis on brain circuits and the newly emerging tools available to study them have electrified neuroscientists and researchers working in the lab. But they haven't yet been translated into new treatments that might relieve anxiety. The last big anti-anxiety medication was Prozac and other selective serotonin reuptake inhibitors, or SSRIs, which came out in the 1980s.

"The field has been sort of stagnating for quite a while, actually," says Stefan Hofmann, a professor of psychology and director of the Psychotherapy and Emotion Research Laboratory at Boston University's Center for Anxiety and Related Disorder. "SSRIs came on the market a couple decades ago with big hype. But since then, not much else really happened and I think people are more or less desperate."

The awkward truth about current anxiety treatments is that they are for the most part unproven. Although 75 percent of patients who seek help for debilitating anxiety get "substantially better" during the course of treatment, medical scientists don't know to what extent these improvements are due to the treatments themselves or to the placebo effect. Drugs that are effective in tamping down anxiety tend to have many unwanted side-effects. Why 25 percent of patients fail to respond to any treatment at all is another mystery.

One problem is that mental-health clinicians don't have good ways of diagnosing and classifying mental disorders. For almost 70 years, the diagnostic bible for clinicians treating anxiety and other psychiatric disorders has been the Diagnostic and Statistical Manual of Mental Disorders (DSM), which assigns symptoms to different classifications of various conditions. As brain science has advanced, the DSM has come to be seen by many in the field as an increasingly antiquated and blunt tool that doesn't fully help define what is wrong with a patient.

"The problem is, you have a list of some 30, 40 different symptoms for any given disorder, and often you have to only meet four or five of them to get a diagnosis," says BU's Hofmann, who helped revise the latest edition, the DSM-V. "You get an astounding number of possible combinations that all would be described as depression and generalized anxiety disorder. So you have this wide array of people that are assigned to the same diagnostic category. Even though they seem to have similar problems on the surface, they might have very different problems that give rise to these problems."

There is widespread agreement among mental health professionals, says Hofmann, that the system needs to change. But reaching consensus and rewriting the approach is still likely years away.

Eventually, clinicians will have more measures from genetics, neuroscience, neural imaging and other disciplines that would help shape the clinician's ability to pick a treatment applicable to individual patients, says Daniel Pine, chief, section on development and affective neuroscience, in the National Institute of Mental Health Intramural Research Program. Finding new and more specific ways to classify patients who are experiencing symptoms is an important initial step.

To understand anxiety, scientists need to explore not only what brain structures are activated during anxiety but also how they communicate with one another. Daniel Pine, a neuroscientist at the National Institute of Mental Health Intramural Research Program. Courtesy of Dr. Daniel Pine

When it comes to finding new drugs to treat anxiety, the pharmaceutical industry has yet to incorporate the new science into its drug discovery methods that might target specific circuits or parts of the circuit. Instead, says the Salk Institute's Tye, they have relied largely on trial and error—"shooting into the dark." In recent years, many pharmaceutical companies, discouraged by the complexity of the mechanisms of anxiety in the brain, have reduced spending on R&D for anxiety medications.

"We're just bathing the brain and body in these drugs," she says. "And, when you take a drug systemically, it's going to go through your circulatory system. It's going to pass through the blood brain barrier. And it's going to bathe the entire tangled mess of wires that is our brain in a soup."

This, she notes, will activate a wide array of circuits, including those that have opposite functions. "And then, that has two results. Number one, you get zero sum effects, because the neurons that have opposing effects cancel each other out, and that's probably why it doesn't work on some people," she says. "And number two, we have nonspecific effects, where you're targeting a bunch of neurons that do something totally different than what you wanted to target, and that give you undesirable side effects."

Tye points to benzodiazepines, like Klonopin, Xanax and Valium, as a prime example of the pitfalls of this approach. The benzos suppress activity in the fear centers of the brain by downregulating key neurotransmitters, but also suppress them everywhere else. Thus they can cause sedation, locomotor suppression, respiratory suppression and cognitive impairments, among other things.

Despite this critique, Tye is optimistic. Once all of the circuits involved in anxiety and other disorders are identified, she says, the circuit-specific neural machinery can be genetically sequenced to identify unique characteristics. And once that happens, drugs can be developed that are more directed. But it may take five to 10 years for scientists to map out, characterize and sequence the majority of circuits of the brain.

Beyond Medicine

Drugs are only one way to treat anxiety, exercise and mindfulness can also help reduce anxiety. fizkes/Getty

Those of us who can't wait that long have some options. In addition to medications like SSRIs and benzodiazepines, psychotherapeutic approaches such as Cognitive Behavioral Therapy help patients learn how to identify—and then change—the thoughts that feed negative behaviors and emotions. And there are other remedies that are not necessarily medical, such as exercise, which studies have shown is particularly helpful for anxiety.

Ironically, many clinicians say one of the most exciting trends in mental health in recent years is the rise in the use of a technique that is thousands of years old and actually predates many of the current treatments: mindfulness. Using techniques that help patients to focus on the present moment can often serve as a potent tool to help them manage overwhelming fears about the future.

"Uncertainty is absolutely central to anxiety," says Jack Nitschke, a psychology professor at the University of Wisconsin and a practicing psychotherapist. "Anxiety is about being concerned about something that might happen in the future." Often, this worry turns out to be impractical and a waste of time—nine in 10 things people most frequently worry about never come to pass.

"If we're living in some sort of future, what-if scenario about something bad that might happen, if we can realize that we're off there and actually I'm sitting in a chair in a room, here many days in advance of this future event that I'm imagining, that point right there is a kind of mindfulness," Nitschke explains. "We've just gotten back into the present moment, realizing where we were and seeing where our mind has gone. And that can indeed be helpful for people with worries."

It makes an odd sort of sense that the most promising technique in a time of technological-influenced advances in brain science dates back thousands of years, especially considering the technologies that bombard us with information and take us out of the present.

So if you're feeling anxious, perhaps there is something you can do while you're waiting for science to come up with the next great pill to help you relax: Put down your cell phone, turn off the cable news and try to be present in the moment. Listen to the sounds around you. Take a walk with a loved one and feel the sun on your face. Above all, don't look at social media or read the news. Except perhaps Newsweek, of course.

Correction (9/6 12.45 p.m.): A previous version of this article did not include Jack Nitschke's expertise. He is a psychology professor at the University of Wisconsin, and a practicing psychotherapist.