Developing Neuroscience Tools to Improve Treatments

Developing Neuroscience Tools to Improve Treatments

Posted: July 19, 2017
Developing Neuroscience Tools to Improve Treatments

Psychiatry, says Dr. Daniel Pine, is at a crossroads. The two crossing paths can be labeled “clinically-focused diagnosis” and “patient-oriented biological understanding” of mental illness. Beginning in the 1970s, psychiatrists embraced the important goal of achieving greater consistency in making diagnoses. They achieved this through a massive multi-year effort to base patient evaluations on what could be observed consistently in each of the many brain and behavior disorders, in the clinical setting of doctors’ offices and hospital inpatient units.

It was vitally important that a person diagnosed with major depression by a psychiatrist in, say, Detroit, would be likely to receive the same diagnosis, made according to the same set of agreed-upon criteria, in Los Angeles or New York or Peoria, Illinois. The famous “DSM” manual (Diagnostic and Statistical Manual, now in its 5th edition) is the product of this effort by mental health professionals to achieve greater consistency and precision in their diagnoses.

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A longtime leader of mood and emotion research at the National Institute of Mental Health explains why psychiatry is at a crossroads. The overwhelming challenge says Dr. Daniel Pine, is to take the great insights generated in recent years by neuroscience and make them relevant in the clinic. One thing is clear in his mind: “we’ve come about as far as we can by simply observing the range of behaviors exhibited by patients.”

“The current crossroads,” says Dr. Pine, has been reached after a sobering realization: “The major advances in diagnosis and treatment that we all want are going to be difficult to achieve as long as we remain solely focused on what can be observed in the clinic.” His own career, which spans some 25 years and over 500 published research papers, exemplifies a transition that is under way. It involves taking the great insights generated in recent years by neuroscience “and making them clinically relevant,” Dr. Pine says. In his view, we have come about as far as we can by simply observing—albeit very accurately and consistently—the range of behaviors exhibited by patients.

Dr. Pine is among the world’s leading experts in childhood disorders. He spent the first decade of his career, the 1990s, performing what he calls “bread-and-butter” research on pediatric mood and anxiety disorders, hoping to learn three things. One was “what happens to kids with these disorders as they grow up? Which kids will overcome it, and which will not? Who will go on later in life to develop mood or other psychiatric disorders?” A second question concerned families with a parent suffering from a mood or anxiety disorder: was it possible to understand why one child would be affected and another would not? A third objective was to determine what treatments were most effective for these disorders. When he began his research around 1990, very little was known about treatments in young patients.

In the last years of the 1990s Dr. Pine and colleagues conducted a clinical trial that resulted in a 2001 paper in the New England Journal of Medicine. It had broad impact in the world of patient care. While anxiety disorders were well known to be “extremely common” in childhood, in Dr. Pine’s words—they are the most prevalent of the childhood psychiatric disorders— very little of the research on popular SSRI antidepressants had considered whether they were safe or effective in children, particularly anxious children; most of the work had been based only in adults. His team and other collaborating teams worked together to demonstrate that the SSRI medicine fluvoxamine (Luvox) was an effective treatment for children and adolescents with social phobia, separation anxiety disorder, or generalized anxiety disorder, and caused few side effects.

The following year, Dr. Pine’s interest shifted to a related question: “for how long is SSRI treatment appropriate” in a young patient? His review of published data led to valuable suggestions for clinicians. He recommended they consider trying a period off the medication in young patients who had been helped by them in a first round of treatment.

While proud of this research, Dr. Pine says he has long yearned to go beyond it. For the truth remains that we still know relatively little about the precise biological causes of mental illnesses, including those on which he focuses. He says he had a “lifechanging” realization around the year 2000—when his very successful work on SSRIs in young patients was progressing quite well.

“I was spending a lot of time with neuroscientists around then and was so impressed by the level of detail and experimental control that they had in their research, compared to what we [behavioral researchers] had. But something else really shook me up. I started to learn about unpublished evidence from large scale clinical trials, discussed in regulatory committees beginning around 2002, which suggested that the efficacy data on pediatric conditions including depression and anxiety really wasn’t as strong as we had initially thought.”

What was the problem? Dr. Pine explains that the problem has many components. One facet is particularly important. “Scientists like me are trained to look at behaviors, whether in people or in mouse models of human illness. But let’s consider the anxious child who refuses to raise their hand in class. That’s a ‘behavior.’ What we’ve learned from neuroscience is that when you look in the brain, there can be many different changes that can give rise to that very same behavior. As a result of this complexity, one would expect that different treatments might have different effects in children with problems classified based only on their behavior.”

That was one issue. A related issue, Dr. Pine says, was that “neuroscience experiments teach us that we can manipulate the brain in two different animals, and with the same manipulation we can induce the animals to express their behaviors in different ways!”

This is not to minimize the value of these experiments. They help teach scientists about how the brain works. What they cannot do, at least with our current level of knowledge, is tell us definitively why certain constellations of behavior occur in any one particular patient, even in two different patients with the same diagnosis.

Realizing these things was “humbling,” Dr. Pine says, but it was also a powerful motivation to move forward in new ways. He modestly describes much of his research in the last 17 years as a “retooling,” by which he means an extended period in which he and colleagues have worked to develop powerful new tools grounded in neuroscience and sought to begin to use them in ways that may eventually influence clinical practice.

What happens in the clinic, when doctor meets patient, has motivated him from the beginning of his career. “When I went into medicine,” he recalls, “it was almost entirely because I wanted to help people. That’s why I did it. I love science, and I’m really interested in it. But it has always been about helping people, most of all.”

Some examples of Dr. Pine’s recent work show how his love of science intersects with this strong desire to have an impact on patient care. In a November 2016 “Commentary” published in Biological Psychiatry , he proposed how “computational approaches” could hasten our journey toward advances in the clinic. “Some patients with anxiety disorders benefit from cognitive behavioral therapy, others benefit from medication, and still others require both,” he noted. How might doctors, then, “better tailor available treatments” to specific patients, and how might scientists go about discovering new therapies with similar specificity?

The image on the next page depicts how a computer-based approach might enable researchers to understand particular sets of defensive behaviors in children asked to perform a fear-conditioning task. In this task, children learn about aversive events that might happen after the child sees one or another face. The goal in this research is to “understand particular sets of defensive behaviors, which researchers can then use to elucidate mechanisms” underlying complex, hard-to-pin-down clinical features, such as the various ways anxious children report what they are feeling as they are learning. “We want to quantify factors that tightly link behaviors to brain function,” Dr. Pine says—which takes researchers an important step beyond simply observing and grouping those behaviors.

The idea behind the experiment shown is to get behind that baffling complexity that led Dr. Pine to “retool.” Different patients will report different responses to a sequence of faces displayed on a computer monitor. Some of the faces are neutral in expression; others show faces of people who are surprised, horrified, afraid. Some of the faces might predict an aversive event, and others will not. During this stream of events, the experiment can measure bodily responses of the participants as they respond to the faces, their skin response (“skin conductance”) registered with electrodes slipped over two fingers. At an entirely different level, the activity of key brain areas involved in the fear response also can be recorded via functional magnetic resonance (fMRI) imaging scans.

The various streams of hard data generated in such a computer-directed experiment “address the fundamental challenge made so difficult by the complex nature of brain-behavior relationships,” Dr. Pine says. The data offer views at different levels about what is happening as fear conditioning proceeds. Responses to both conditioned and intentionally ambiguous stimuli presented to research subjects via the computer reveal their startle responses, their tendency toward avoidance of danger, and at the same time, makes possible cross referencing these to specific responses within the circuitry in the brain’s amygdala as all of these “behaviors” are being manifested.

There is much to be learned when data is compared from young people without anxiety disorders and those who have been diagnosed with them. Hard data—beyond mere surface observation of behavior—helps elucidate mechanisms in the brain “that allow healthy people to adapt to aversive events.” This becomes a basis for understanding what is going on in the brains of different people suffering from anxiety—people, for example, who have a too-strong reaction to potential ambiguity or even actual danger. Fear is useful to us, but excessive fear is problematic—it can lead to excessive inhibition, which can impair a child’s social relationships, for example, or prevent him or her from raising their hand in class.

Written By Peter Tarr, Ph.D.

Click here to read the Brain & Behavior Magazine's July 2017 issue

Developing Neuroscience Tools to Improve Treatments Wednesday, July 19, 2017

Psychiatry, says Dr. Daniel Pine, is at a crossroads. The two crossing paths can be labeled “clinically-focused diagnosis” and “patient-oriented biological understanding” of mental illness. Beginning in the 1970s, psychiatrists embraced the important goal of achieving greater consistency in making diagnoses. They achieved this through a massive multi-year effort to base patient evaluations on what could be observed consistently in each of the many brain and behavior disorders, in the clinical setting of doctors’ offices and hospital inpatient units.

It was vitally important that a person diagnosed with major depression by a psychiatrist in, say, Detroit, would be likely to receive the same diagnosis, made according to the same set of agreed-upon criteria, in Los Angeles or New York or Peoria, Illinois. The famous “DSM” manual (Diagnostic and Statistical Manual, now in its 5th edition) is the product of this effort by mental health professionals to achieve greater consistency and precision in their diagnoses.

“The current crossroads,” says Dr. Pine, has been reached after a sobering realization: “The major advances in diagnosis and treatment that we all want are going to be difficult to achieve as long as we remain solely focused on what can be observed in the clinic.” His own career, which spans some 25 years and over 500 published research papers, exemplifies a transition that is under way. It involves taking the great insights generated in recent years by neuroscience “and making them clinically relevant,” Dr. Pine says. In his view, we have come about as far as we can by simply observing—albeit very accurately and consistently—the range of behaviors exhibited by patients.

Dr. Pine is among the world’s leading experts in childhood disorders. He spent the first decade of his career, the 1990s, performing what he calls “bread-and-butter” research on pediatric mood and anxiety disorders, hoping to learn three things. One was “what happens to kids with these disorders as they grow up? Which kids will overcome it, and which will not? Who will go on later in life to develop mood or other psychiatric disorders?” A second question concerned families with a parent suffering from a mood or anxiety disorder: was it possible to understand why one child would be affected and another would not? A third objective was to determine what treatments were most effective for these disorders. When he began his research around 1990, very little was known about treatments in young patients.

In the last years of the 1990s Dr. Pine and colleagues conducted a clinical trial that resulted in a 2001 paper in the New England Journal of Medicine. It had broad impact in the world of patient care. While anxiety disorders were well known to be “extremely common” in childhood, in Dr. Pine’s words—they are the most prevalent of the childhood psychiatric disorders— very little of the research on popular SSRI antidepressants had considered whether they were safe or effective in children, particularly anxious children; most of the work had been based only in adults. His team and other collaborating teams worked together to demonstrate that the SSRI medicine fluvoxamine (Luvox) was an effective treatment for children and adolescents with social phobia, separation anxiety disorder, or generalized anxiety disorder, and caused few side effects.

The following year, Dr. Pine’s interest shifted to a related question: “for how long is SSRI treatment appropriate” in a young patient? His review of published data led to valuable suggestions for clinicians. He recommended they consider trying a period off the medication in young patients who had been helped by them in a first round of treatment.

While proud of this research, Dr. Pine says he has long yearned to go beyond it. For the truth remains that we still know relatively little about the precise biological causes of mental illnesses, including those on which he focuses. He says he had a “lifechanging” realization around the year 2000—when his very successful work on SSRIs in young patients was progressing quite well.

“I was spending a lot of time with neuroscientists around then and was so impressed by the level of detail and experimental control that they had in their research, compared to what we [behavioral researchers] had. But something else really shook me up. I started to learn about unpublished evidence from large scale clinical trials, discussed in regulatory committees beginning around 2002, which suggested that the efficacy data on pediatric conditions including depression and anxiety really wasn’t as strong as we had initially thought.”

What was the problem? Dr. Pine explains that the problem has many components. One facet is particularly important. “Scientists like me are trained to look at behaviors, whether in people or in mouse models of human illness. But let’s consider the anxious child who refuses to raise their hand in class. That’s a ‘behavior.’ What we’ve learned from neuroscience is that when you look in the brain, there can be many different changes that can give rise to that very same behavior. As a result of this complexity, one would expect that different treatments might have different effects in children with problems classified based only on their behavior.”

That was one issue. A related issue, Dr. Pine says, was that “neuroscience experiments teach us that we can manipulate the brain in two different animals, and with the same manipulation we can induce the animals to express their behaviors in different ways!”

This is not to minimize the value of these experiments. They help teach scientists about how the brain works. What they cannot do, at least with our current level of knowledge, is tell us definitively why certain constellations of behavior occur in any one particular patient, even in two different patients with the same diagnosis.

Realizing these things was “humbling,” Dr. Pine says, but it was also a powerful motivation to move forward in new ways. He modestly describes much of his research in the last 17 years as a “retooling,” by which he means an extended period in which he and colleagues have worked to develop powerful new tools grounded in neuroscience and sought to begin to use them in ways that may eventually influence clinical practice.

What happens in the clinic, when doctor meets patient, has motivated him from the beginning of his career. “When I went into medicine,” he recalls, “it was almost entirely because I wanted to help people. That’s why I did it. I love science, and I’m really interested in it. But it has always been about helping people, most of all.”

Some examples of Dr. Pine’s recent work show how his love of science intersects with this strong desire to have an impact on patient care. In a November 2016 “Commentary” published in Biological Psychiatry , he proposed how “computational approaches” could hasten our journey toward advances in the clinic. “Some patients with anxiety disorders benefit from cognitive behavioral therapy, others benefit from medication, and still others require both,” he noted. How might doctors, then, “better tailor available treatments” to specific patients, and how might scientists go about discovering new therapies with similar specificity?

The image on the next page depicts how a computer-based approach might enable researchers to understand particular sets of defensive behaviors in children asked to perform a fear-conditioning task. In this task, children learn about aversive events that might happen after the child sees one or another face. The goal in this research is to “understand particular sets of defensive behaviors, which researchers can then use to elucidate mechanisms” underlying complex, hard-to-pin-down clinical features, such as the various ways anxious children report what they are feeling as they are learning. “We want to quantify factors that tightly link behaviors to brain function,” Dr. Pine says—which takes researchers an important step beyond simply observing and grouping those behaviors.

The idea behind the experiment shown is to get behind that baffling complexity that led Dr. Pine to “retool.” Different patients will report different responses to a sequence of faces displayed on a computer monitor. Some of the faces are neutral in expression; others show faces of people who are surprised, horrified, afraid. Some of the faces might predict an aversive event, and others will not. During this stream of events, the experiment can measure bodily responses of the participants as they respond to the faces, their skin response (“skin conductance”) registered with electrodes slipped over two fingers. At an entirely different level, the activity of key brain areas involved in the fear response also can be recorded via functional magnetic resonance (fMRI) imaging scans.

The various streams of hard data generated in such a computer-directed experiment “address the fundamental challenge made so difficult by the complex nature of brain-behavior relationships,” Dr. Pine says. The data offer views at different levels about what is happening as fear conditioning proceeds. Responses to both conditioned and intentionally ambiguous stimuli presented to research subjects via the computer reveal their startle responses, their tendency toward avoidance of danger, and at the same time, makes possible cross referencing these to specific responses within the circuitry in the brain’s amygdala as all of these “behaviors” are being manifested.

There is much to be learned when data is compared from young people without anxiety disorders and those who have been diagnosed with them. Hard data—beyond mere surface observation of behavior—helps elucidate mechanisms in the brain “that allow healthy people to adapt to aversive events.” This becomes a basis for understanding what is going on in the brains of different people suffering from anxiety—people, for example, who have a too-strong reaction to potential ambiguity or even actual danger. Fear is useful to us, but excessive fear is problematic—it can lead to excessive inhibition, which can impair a child’s social relationships, for example, or prevent him or her from raising their hand in class.

Written By Peter Tarr, Ph.D.

Click here to read the Brain & Behavior Magazine's July 2017 issue