If You Give a Mouse a Xanax


A white rat with an electrode implanted in its brain as part of a study at the National Institutes of Health, 1976.

A white rat with an electrode implanted in its brain as part of a study at the National Institutes of Health, 1976.


Corbis Images

Joseph LeDoux is worried. The prominent cognitive neuropsychologist feels his field is at an “impasse.” He takes some of the blame: His own “work and writings,” he confesses, “are in part responsible for these misconceptions” about the workings of fear in the brain. He wants to “straighten out the story before it goes further off track.”

With such a provocative introduction, I thought Mr. LeDoux’s new book, “Anxious: Using the Brain to Understand and Treat Fear and Anxiety,” might contain disturbing news about the hugely popular neuroscience of emotions. Could there have been ethical lapses or technical failures or maybe oversold theories about the role of the amygdala or brain neurotransmitters? And, if so, what would be the impact on how we understand, experience, diagnose and treat anxiety disorders?

But this is not a whistleblower’s book. Instead, Mr. LeDoux offers a careful tour through the current neuroscience of fear and anxiety, and he largely extols the edifice created by decades of painstaking laboratory work with rats. The basic model has shown that fearful behaviors, learned through negative, punitive experiences—in the lab rat’s case, often shocks to the feet from electrified cage floors—persist because of physical changes in brain architecture and chemistry. Such behaviors can be eliminated by new experiences that rewire the relevant parts of the brain. Mr. LeDoux reviews years of experiments that led us to this current juncture, often using clever college-textbook-level charts and diagrams.


By Joseph LeDoux
Viking, 466 pages, $28.95

So the edifice is impressive, and we seem to know a lot about the neural bases of fear and anxiety. But Mr. LeDoux is having second thoughts. Human feelings, he has begun to suspect, are not the same thing as animal reactions. “After 30 years,” he said in an interview a few years ago, “I’ve decided that I haven’t been studying fear or emotion at all. This is an issue within the field . . . I’m not studying feeling. I’m studying the way the rat brain detects and responds to danger.” Jumping around and squealing and defecating and cowering—rat reactions to pain—tell us nothing about what the rodent is experiencing. Nor do they tell us how interventions that change rat behavior might affect what human beings experience in scary circumstances. The author, the director of the Emotional Brain Institute at NYU, wants his colleagues to stop using the language of feelings to describe animals’ behavior and brain circuitry, and to reserve language such as “fear” and “anxiety” for human conscious experience.

Mr. LeDoux’s linguistic quibbles might seem mere semantics to some, but they could be momentous in his field. One implication could be to challenge the dominance of animal models of human brain function in research on drugs for anxiety disorders. If the important role of anti-anxiety medications is to diminish “the essence of anxiety,” which is worried and fearful feelings and thoughts, then we may need a new set of methods that target human language capacities and the ability that consciousness gives us to remember the past and project the future, rather than relying on the types of evidence provided by research on the rat brain. “Failure to make such distinctions accounts for poor outcomes of studies that have attempted to develop new pharmacological treatments for fear and anxiety,” he claims.

What have commonly been called “fear circuits” in the animal brain (especially when that much-publicized small subcortical region called the amygdala is involved) are not substrates for feelings of fear at all, Mr. LeDoux repeatedly points out. “We have not inherited feelings like fear or anxiety from animals; we have instead inherited mechanisms that detect and respond to threats,” he insists. “When these threat-processing mechanisms are present in a brain that can be conscious of its own activities, conscious feelings of fear or anxiety are possible; otherwise threat processing mechanisms motivate behavior but do not necessarily result in or involve feelings of fear or anxiety.”

Why is this important? Because research on these threat-processing circuits may not be dealing with aspects of fear and anxiety that most trouble and even disable people. Developing drugs that reduce fearful behaviors in rats and saying, therefore, that rats became less fearful has misled us, Mr. LeDoux suggests, into thinking that the drugs would reduce the experience of fear in humans. Many drugs sedate, for example, rather than calming or sidelining the mind’s worried chatter and hypervigilance. If we knew more about where and how in the brain these elements of worry operated, drug development might make more progress.

Taking a fresh look at what we can and can’t learn from animal laboratory research leads Mr. LeDoux to resist anthropomorphism outside the laboratory, too. He tells us that he loves his cat, Petey, and acts as if Petey “has self-awareness and feelings,” but his scientist brain knows that he cannot really know. He further argues against a “The Cambridge Declaration on Consciousness” signed in 2012 by prominent neuroscientists that concluded, “the weight of evidence indicates that humans are not unique in possessing the neurological substrates that generate consciousness.” Mr. LeDoux firmly and repeatedly disagrees, insisting that consciousness requires language and a kind of self-awareness that integrates past, present and future. He sees no persuasive evidence of this in nonhuman animals. Stay tuned for a continuing contretemps.

“Anxious,” which is more than 300 pages of text and more than 100 pages of footnotes, will reward the informed reader. But it will overwhelm the curious amateur and disappoint the help-seeker who picked up this book to learn about the second half of the title: “Using the Brain to Understand and Treat Fear and Anxiety.”

Mr. LeDoux does discuss psychotherapies for anxiety, but we are far from identifying their underlying neuroscience. For example, “exposure” therapy is a popular behavioral treatment wherein a person repeatedly encounters fear-provoking situations—“Here I am flying in an airplane and nothing bad is happening to me”—breaking the connection between fearful stimuli and responses. Cognitive behavior therapy introduced in the 1970s, added an analysis of underlying beliefs to the exposure—“I will believe that I am a good person who can change my behavior and that traveling by airplane can become a positive experience”—greatly enhancing the treatment by recruiting human capacities for explanation, justification and hope.

But Mr. LeDoux acknowledges that the operations of the brain involved in such therapies differ from those involved in extinguishing defensive behaviors in rat laboratory research and are far more complex. He speculates that psychotherapy for anxiety freed from an overreliance on rat brain models might end up requiring an array of office, lab and real world interventions to address all the neural components, dramatically changing psychotherapy.

And what about directly intervening in the brain? Mr. LeDoux ends his book by reviewing recent experiments on erasing memories or easing anxiety through injecting protein synthesis blockers or using “electroceuticals,” such as deep brain and vagus nerve stimulation. These high-tech developments seem very far from using electrical shock-boxes to study the defensive circuitry of the rat brain, but this seems to be where clinical neuroscience is heading. Unfortunately, there’s only a brief reference to issues of overdiagnosis and overtreatment, which, for me, have been the elephants in the room in recent media coverage of neuroscience and mental illness. (Mr. LeDoux generously concludes the book with a hymn to the virtues of meditation and breathing techniques for coping with anxiety. But of course these were not developed by neuroscientists, nor does neuroscience offer much to explain why they work.)

I was left with a disquieting feeling after studying “Anxious.” On the one hand, acknowledging the qualitative differences between human and rat mental life does seem like an overdue course correction for laboratory researchers, and it offers a welcome opportunity for interdisciplinary dialogue. On the other hand, the seductions of this newest age of reductionism are hard to curtail when their promise seems so boundless. Despite decades of research and theory, although neuroscience has not produced many practical solutions, more than a course correction will be required to slow this steamroller.

Source: If You Give a Mouse a Xanax

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