It’s every psychiatrist’s dilemma: Two patients sit in front of you, displaying the same symptoms and the same diagnosis. After going through the same treatment, one recovers and one doesn’t. What’s the difference?
It very well could be inside the brain itself. Scientists have learned a lot about the brain in the last few decades, but mental illnesses are still diagnosed based on symptoms—the visible tips of a tower hidden in fog. But for each person a different part of the tower may be broken.
“The standard of care in psychiatry is symptoms-based diagnosis. But anyone who treats patients knowns there’s some serious limitation with this kind of approach,” said Noah Philip, associate professor of psychiatry at Brown University and director of psychiatric neuromodulation at the Providence VA Medical Center in Rhode Island. “Ultimately it’s someone telling us what they are feeling, which is important but it doesn’t necessarily map on to what’s going on in the brain.”
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That’s why Philip and many others are now looking past the symptoms and diagnostic labels and into the underlying brain networks to find what drive a patient’s symptoms, how these network vary among individuals and how they can be directly targeted to help those patients who don’t improve with traditional treatments.
One of the conditions showing benefits from such targeted approach is post-traumatic stress disorder, or PTSD. After being through an extremely traumatic or terrifying event, people who develop PTSD experience persistent frightening thoughts, recurring flashbacks or nightmares, and crippling anxiety that impairs their everyday life. Psychotherapy is the most effective treatment, but only works for about half of the patients. Medications are even less effective and come with physical side effects.
Emerging research suggests the variation in treatment response may have something to do with biological variability inside the brains of people with PTSD, said Amit Etkin, associate professor of psychiatry at Stanford University and an investigator at the Palo Alto VA in California. In a study presented this month at the annual meeting of the Society of Biological Psychiatry in New York, Etkin and his colleagues analyzed brain activity in 106 people with PTSD and found they show four distinct patterns, corresponding to different clinical symptoms.
In other words, patients grouped under the same diagnostic category may be quite different from each other and require tailored treatments.
“The actual diagnosis you’re given has relatively little predictive value for the specific brain regions involved,” Etkin told the Daily Beast. Etkin received the NIH Director’s Pioneering award last year for his “brain circuit first” approach to psychiatric research. “What we are essentially trying to do in the lab now is to understand biology at the level of the individual patient and develop personalized interventions.”
Putting the brain’s own power into motion
Psychotherapy is currently the most effective treatment for PTSD; one approach is cognitive behavioral therapy, which aims to help a trauma victim change how they think of the traumatic event. Another is exposure therapy, which involves gradually exposing someone to the things or situations they fear, but in a safe environment so they have a chance to reinterpret fearful triggers and lower their stress response. But even as an effective treatment, psychotherapy works for only about half of the people with PTSD, and scientists don’t quite know why.
“There are many medications out there, but none of them works as well as psychotherapy. And yet we don’t understand how psychotherapy actually works,” Etkin said. “It's long been a mystery, even though we’ve realized for over a hundred years that this is an effective intervention.”
Recently, Etkin found the success of exposure therapy depends on the strength of brain networks underlying how an individual recognizes and regulates response to frightening stimuli. It’s been known that PTSD is partly a result of inadequate control of the brain’s frontal regions over limbic regions that process fear and emotions: When people with PTSD are reminded of the trauma or face threats, they tend to have an underactive prefrontal cortex and an overactive amygdala. But patients appear to show different degrees of this problem, Etkin found.
In a study published in the American Journal of Psychiatry in December, Etkin and his colleagues asked 66 people with similar levels of PTSD symptoms to complete tasks that required them to manage their emotional response. For example, one task involved watching fearful faces but focusing on identifying the skin hue or gender of the faces. Meanwhile, the researchers monitored their brain activity using functional magnetic resonance imaging (fMRI).
After the brain scans, the participants were randomly assigned to receive 9 to 12 sessions of exposure therapy over a few weeks or to join a waiting list.
At the end of the study, the researchers went back to the initial brain scans. Patients who had the largest reductions in symptoms after treatment had shown greater activity in prefrontal regions and lesser activity in the amygdala in response to fearful faces. This meant these people were less emotionally reactive and better able to activates their prefrontal cortex to regulate their emotional response.
Even healthy people are variable in their ability to unconsciously bring on brain’s frontal circuits to control amygdala activity—and PTSD patients are no different, Etkin said. “We saw these capacities are latent and sitting there. And they matter for your ability to respond to treatment, but they don’t directly dictate your current level of symptoms.”
An old-timed treatment armed with new tech
There may be a way to make psychotherapy successful for the other half as well: by stimulating and “conditioning” the brain networks, Etkin said.
Other research has shown zapping the brain to stimulate the frontal regions, using a noninvasive technique called transcranial magnetic stimulation, or TMS, can improve the connection between the frontal regions and the amygdala. The TMS device is an electromagnetic coil that is placed over the skull and can boost or lower the activity in a targeted brain region. The effect is temporary and reversible, but thanks to brain’s plasticity, repeated stimulation can lead to lasting changes in neuronal activity. In 2008, TMS was approved by the U.S. Food and Drug Administration as a treatment for some forms of depression.
In a study published in the Journal of Affective Disorders in April, Philip and his colleagues had 35 people with PTSD and depression undergo 40 daily sessions of TMS. The treatment reduced the symptoms of both conditions, enough that half of the patients were no longer experiencing symptoms severe enough that required further treatment.
Several other groups have seen PTSD patients benefits from TMS, raising the idea that the brain stimulation techniques could be coupled with existing treatments, such as psychotherapy.
“It is difficult to talk to someone right when they are undergoing TMS—it feels like a angry woodpecker on your forehead,” Philip said. “But the future of getting people better is combining treatment modalities. After psychotherapy we expect to see better control of prefrontal cortex over the amygdala. Maybe we can prime that circuit with psychotherapy and then stimulate it or the other way around. The two together, I would expect, will have the best outcome.”
To test that idea, Philip is running a VA-funded clinical trial in which veterans undergo exposure therapy inside virtual reality and simultaneously receive brain stimulation.
There’s still more research to be done to better identify brain targets for personalized PTSD treatments. But ultimately, translating the research to the clinic is very doable, Etkin said. It is impractical to run fMRI scans on every PTSD patient to see if they need a TMS boost, so his team is working on sophisticated methods for analyzing brain activity using EEG devices instead, which are widely available in the clinics. TMS devices, too, are now exist in many clinics for depression treatment. “There’s an infrastructure across the country that this could be plugged into,” he said, “It’s not like inventing something from scratch.”
