The bomb that shattered Travis Adams's peace of mind never actually exploded. Its timer went off, but the bomb malfunctioned. Still, the 25-year-old U.S. marine remained haunted by the memory of an explosive device diabolically concealed beneath a tempting array of cookies and candies. Whoever had set it that day in Iraq must have planned to blow up children. “People are evil if they're willing to do that,” he recalls thinking.
Adams had his share of close calls during his nine years of active duty, including a mortar that landed 50 yards from his bed one night. But he could not shake off his horror of the candy bomber, which soon metastasized into a broader distrust of his superiors and even himself. By the time Adams returned home to San Diego four years later in 2012, he was drinking heavily, irritable and prone to fits of anger. He spent most of his time alone, playing video games. People told him he had changed. He ignored them. It was not until later that same year, when his older brother, also a former marine, pressed him to get help that he visited the local Department of Veterans Affairs center. There he received a diagnosis of post-traumatic stress disorder (PTSD).
Adams's story is all too familiar. After two protracted military conflicts in Iraq and Afghanistan, American mental health experts are seeing an epidemic of PTSD among returning soldiers. Between 10 and 20 percent develop symptoms of the disorder, which include agitation, irritability, disturbing and intrusive imagery, and difficulty sleeping. This poses a tremendous burden on the soldiers themselves and on society at large, costing billions of dollars in treatment and lost productivity. In 2012, 500,000 veterans sought medical attention for PTSD, nearly three times the number requesting help a decade earlier.
Given such proportions, there is considerable urgency to discover the sequence of biological events that causes PTSD and to learn why some soldiers succumb and yet others do not. Such an understanding may yield better interventions in the form of new medicines and therapies and even allow for prevention. Finding ways to forestall the damage done by extreme stress would benefit not just service members: nearly one in 15 Americans acquire symptoms of PTSD following a traumatic life experience.
To that end, the overseas deployment of 2.7 million Americans since 2001 has afforded scientists a unique research opportunity. Clues are starting to emerge from a number of studies looking at soldiers before and after their exposure to war zones. Investigators have, for example, uncovered measurable differences in brain structure and function that appear to predict vulnerability to the disorder. Perhaps most intriguing, heightened immune reactivity seems to both increase the likelihood of developing PTSD and mark its onset. What is more, changes in the brain and in the immune system may reinforce one another.
Studies show that experiencing trauma early in life seems to increase the chance of suffering from PTSD years later—perhaps because these early traumas alter the expression of genes involved in how the body responds to stress, threats, injury and infection. Although the finding is contested, some researchers argue that American soldiers are more likely to have experienced childhood abuse and adversity than the general population, and some recruits may enlist just to escape harrowing environments. Thus, the military may count in its ranks a greater than average ratio of people prone to PTSD—upping the imperative to understand how the disorder unfolds and how it might be prevented.
Renegade inflammation
Terror in any form involves an immediate physical reaction: your stress hormones rise; adrenaline floods your body; your heart rate accelerates; and blood shunts away from nonessential functions, such as digestion, to more essential ones, such as powering the muscles needed to move. For years scientists suspected that this fight-or-flight response somehow got stuck in the “on” position in PTSD—a theory supported by studies showing that patients with PTSD have disturbed cycles of stress-related hormones such as cortisol and altered expression of genes involved in the fight-or-flight response. But scientists had also noted odd signs of inflammation in the blood serum of PTSD patients. And animal studies suggested that chronic stress could activate the immune system, inducing low-grade but persistent inflammation. So one outstanding question that arose in PTSD research was: Is inflammation an unimportant sideshow, or does it somehow contribute to psychiatric symptoms?
Results corroborating the latter idea are beginning to surface from the Marine Resiliency Study at the VA's San Diego facility, among other places. This investigation took a variety of measurements from some 2,600 marines before and after deployment. In 2013 Stephen J. Glatt, a neuroscientist at SUNY Upstate Medical University in Syracuse, and his colleagues examined the data and found that just by looking at the expression of certain genes, many involved in inflammation, they could predict with 70 percent accuracy who would develop PTSD after exposure to battlefield trauma. The more these genes cranked out inflammatory signals before combat, the greater the risk of PTSD later. A subsequent study on the same cohort, conducted by Satish Eraly of the University of California, San Diego, and his colleagues, reported that troops showing the highest levels of C-reactive protein, a marker of systemic inflammation, before deployment were also those most susceptible to PTSD afterward.
Both findings imply that a tendency toward inflammation can predispose someone to PTSD and that the immune system may be causally involved in the disorder. This observation aligns with parallel research showing that people with PTSD have an elevated risk of other diseases associated with inflammation, including cardiovascular disease, metabolic syndrome, diabetes, autoimmune diseases, preterm birth in women and dementia in old age. To date, it remains unclear whether they have an underlying propensity to become inflamed or whether trauma-induced inflammation increases the risk of these other conditions.
The link between PTSD and immune activation fits with a growing body of research connecting inflammation and psychiatric illnesses—especially depression. Psychiatrist Andrew H. Miller of Emory University was among the first to explore this relation more than a dozen years ago. He studied cancer patients receiving infusions of a protein called interferon-alpha to activate their immune systems. These patients often reported feeling down, and about 30 to 45 percent of them fell into a deep depression that usually lifted when treatment ceased. Inflammation, Miller had observed, could trigger profound feelings of despair and even suicidal thoughts.
A flurry of animal research, meanwhile, began to unveil how the brain and immune system interact. Historically, scientists viewed the two as entirely separate, assuming that the blood-brain barrier shielded the brain from any potential damage caused by an immune response to infection or injury. What they discovered is that neurons themselves actually secrete and respond to immune system signaling proteins and that white blood cells—the warriors of the immune system—can cross from brain to body and back. A T cell in your intestine today might be in your brain tomorrow. Moreover, roughly half of the volume of the brain consists not of neurons but of glial cells, which help to maintain synaptic connections and prune unneeded ones. Glial cells act very much like white blood cells, and they are exquisitely sensitive to inflammation elsewhere in the body.
Thus, one way inflammation may influence our mental state is by modifying the activity of glial cells, disturbing how they maintain neuroplasticity and prompting a decline in their production of proteins, such as brain-derived neurotrophic factor, necessary for learning and memory formation. Both these functions are thought to go awry in PTSD and depression. More recently, Miller and his colleagues have observed another way in which inflammation may impact the brain and adversely affect mood. They took functional MRI scans of patients treated with interferon-alpha for hepatitis C infection and found reduced activity in a brain region called the basal ganglia. This reduction correlated with an inability to feel pleasure after a rewarding activity—in this case, winning a simulated card game, played inside the scanner and rigged in their favor. Additional positron-emission tomography scans revealed that the subjects' brains were producing lower than normal levels of dopamine, the neurotransmitter that, among other things, makes us feel good.
Considering these results together, Miller proposes that immune activation mutes the neural circuitry responsible for pleasure and motivation, and he offers an evolutionary explanation: if you are genuinely fighting some pathogen, inflammation signals to your brain that it is time to hunker down, rest and take it easy to aid recovery. Clinical depression, he thinks, occurs when this signal starts blaring in the absence of ongoing infection or injury—say, in response to extreme stress of the kind that provokes PTSD. Indeed, those suffering from PTSD often report profound feelings of depression, suggesting shared biological underpinnings. Maybe more pertinent, some patients receiving interferon-alpha infusions also display hostility and aggression akin to that seen in PTSD.
Miller sees all these behaviors as a kind of survival instinct, conserved across many species. “If you ever see a dog hit by a car on the street, everyone knows that the last thing you should do is go poke the dog,” he says. It is liable to take your finger off.
Hair-trigger fear
A few years before Glatt found that inflammation levels before deployment could predict which soldiers might later succumb to PTSD, Roee Admon, a neuroscientist now at Harvard University, was looking at another way to detect who was vulnerable. The amygdala—two almond-shaped regions deep in the brain—coordinates the fear response, considered central to PTSD. Admon began examining these areas in Israeli soldiers and military paramedics using fMRI. He found that the recruits whose amygdala reacted most forcefully, meaning with the greatest blood flow, to images of potentially threatening soldiers before service were the most vulnerable to PTSD after combat stresses.
Later studies revealed that hyperactivity in both the amygdala and the immune system might be related. In 2012 neuroscientist Naomi Eisenberger and her colleagues at the University of California, Los Angeles, began exploring this connection by provoking inflammation in healthy volunteers with infusions of a bacterial by-product called endotoxin. Then, using fMRI, the researchers observed amygdala activity when participants were shown pictures of frightening faces. Sure enough, individuals inflamed by the endotoxin showed significantly more blood flow in the amygdala than control subjects did.
In a subsequent experiment, the same group tested the effects of stress on the immune system. They first recorded interviews with 31 healthy female volunteers. During fMRI scans, the women then watched what they were told was a real-time evaluation of their personality made by another study participant (in actuality, a researcher). The assessments included words such as “annoying,” “arrogant” and “boring.” Women who became the most stressed, reflected by greater activity in the amygdala, also became the most inflamed, as measured by blood tests.
The research raises the classic chicken-or-egg question: Do differences in neural architecture—such as having a hyperreactive amygdala—dictate your immunological response to upsetting stimuli, or do tendencies in immune function increase the risk of brain dysfunction after trauma? The answer may be all of the above; there may be several paths to what we consider to be a single disorder. That does not mean we should throw our hands up in despair, says Dewleen Baker, lead scientist for the Marine Resiliency Study. To the contrary, it could imply that multiple intervention points exist. “Anywhere you can break into this disordered system and make it right—that would be a good way to go,” she says.
Preemptive therapeutic strikes
The best time to intervene in PTSD may be years—perhaps decades—before the trauma that precipitates it actually takes place. A consistent finding is that early-life adversity increases the risk of PTSD many years later. In the Marine Resiliency Study cohort, the relationship was dose-dependent. The soldiers who reported having the greatest number of childhood hardships—such as physical or emotional abuse or neglect—have triple the risk of developing PTSD compared with those with the least distressing upbringings, even when controlling for alcohol and tobacco use.
This may be because childhood adversity seems to modify the same immunological pathways implicated in PTSD. An ongoing prospective study of more than 14,500 families in the Avon region in England showcases this link. Epidemiologist Natalie Slopen, now at the University of Maryland, and her colleagues examined these data and reported that youths who faced difficult circumstances before age eight had higher levels of the inflammatory proteins interleukin-6 (IL-6) and C-reactive protein at age 10 and of C-reactive protein at age 15. Psychiatrist Golam Khandaker of the University of Cambridge and his colleagues found that elevated levels of IL-6 and C-reactive protein at age nine predicted psychiatric disorders, such as depression and psychosis, at age 18. Chronic stress may rev up immune function, and that modification may increase the risk of psychiatric problems.
Early life struggles may also alter the amygdala and other brain areas associated with PTSD. Studies indicate that children reared in orphanages and otherwise deprived of affection from caretakers—an extreme stress—display an enlarged, overactive amygdala that responds more readily to threatening images. Making matters worse, maltreatment also seems to reduce volume, and presumably functionality, in regions such as the insula, the dorsal anterior cingulate cortex and the prefrontal cortex, involved in self-control, self-awareness and executive function.* These structures may help put the brakes on runaway reactions and emotions. Amit Etkin, a neuropsychiatrist at Stanford University, speculates that when they go offline, as they appear to do in PTSD, other areas are left unchecked, possibly accounting for the disorder's hallmark tendency to obsessively ruminate. “If we're right, resisting inner voices and not being too much in your own head is important for recovering from trauma,” he says.
These twin modifications to the nervous and immune systems may augment each other. Extreme early life stress may change immune function, producing a permanently elevated immunological “idle speed” and a tendency to become rapidly inflamed. And a brain modified by childhood trauma may mount a stronger and faster fear response, more likely to trigger a proinflammatory cascade in the face of some stressor. “It's like an orchestra,” Baker says. “If it isn't playing quite right, it's easier to flip into a chronic condition like PTSD.”
Sandro Galea, dean of Boston University's School of Public Health and one of the first to note immunological abnormalities in PTSD, argues that more comprehensive social welfare policies aimed at improving the health and well-being of vulnerable groups, such as poor children, might serve to reduce the overall incidence of stress-induced psychiatric disorders. Barring that, he says, the next best fix is to ensure robust social support for returning soldiers and others exposed to trauma. Research by him and others suggests that social support, including group therapy–like models and assistance to manage military personnel's affairs during deployment, can help stave off PTSD even after trauma has occurred. The idea is to prevent an already battle-strained soldier from coming home to more stress—for example, back rent or a repossessed car. “I am convinced that that's the best approach to help as many people as possible as much of the time,” he says. It is worth noting that strong social networks also help ward off other disorders associated with chronic inflammation, such as heart disease and dementia.
When Adams sought help at the San Diego VA center, he was put on antidepressant medication. Then he began cognitive-behavior therapy—a kind of mental training that taught him to question and assess his own thoughts and beliefs and, ultimately, to change them. The incremental improvements he saw motivated him to work harder. And he recovered, he says, after just a few months. Now he works for the San Diego VA center, helping other veterans with PTSD.
Adams's treatment regimen is among the best currently available for PTSD [see “Using Virtual Worlds to Heal Real Wounds” at bottom]. But the emerging biomarkers of PTSD—the differences observed in brain and immune function—may one day yield therapies that complement, or even supplant, talk therapy–based approaches. Last year Miller and his colleagues published a small randomized, placebo-controlled trial in which he gave infusions of a drug called infliximab to depressed subjects, some of whom showed signs of inflammation. The medication, normally used to treat autoimmune disorders, blocks a proinflammatory protein: tumor necrosis factor–alpha. Miller found that among patients with higher baseline levels of inflammation, those who took infliximab responded more readily to treatment, suggesting that calming the immune system can sometimes improve mood. Now he aims to test the drug on subjects with PTSD.
Other researchers are considering less conventional ways to curb inflammation and possibly prevent PTSD. These range from dietary interventions to developing drugs based on curcumin, a nutrient derived from turmeric that has neuroprotective and anti-inflammatory properties, to inoculating subjects with what some call a “dirt vaccine.” The concoction, derived from soil-dwelling bacteria—Mycobacterium vaccae—stimulates an arm of the immune system that counteracts inflammation, says neuroendocrinologist Christopher A. Lowry of the University of Colorado Boulder. If it works in people as well as it works in mice, he can imagine immunizing soldiers before they head to the battlefield. “You should be able to prevent PTSD,” he says, by strengthening soldiers' own ability to regulate inflammation.
Our understanding of PTSD has advanced dramatically since World War I, when physicians first described it as shell shock. Because the condition occurred without obvious wounds, some thought that afflicted soldiers had weak dispositions or that they faked their problems to avoid fighting. “It was blaming the victim,” says Irina Komarovskaya, a psychiatrist at New York University. Views have changed, but many of those struggling with the disorder still feel stigmatized. For them, the emergence of biological markers for PTSD may be important for reasons beyond the hope for better therapies. Understanding the disorder in solidly biological terms may finally erase the lingering shadow of shame.
Using Virtual Worlds to Heal Real Wounds
Breakthroughs may one day emerge from recent discoveries about the roots of post-traumatic stress disorder. But for now most patients get talk-based treatments such as cognitive-behavior therapy and drugs such as serotonin reuptake inhibitors, originally developed to treat depression. That does not mean that there is nothing new under the sun for PTSD. Increasingly, therapists are working with innovative technologies, including virtual reality, to augment treatment.
One long-standing treatment, often called exposure therapy, involves asking the afflicted to mentally revisit the trauma. The idea is to help them gradually reprocess it so that lingering symptoms—agitation, avoidance and panic—subside. This approach does not work for everyone, but it helps about half of the patients who try it, which is roughly the same success rate as cognitive-behavior therapy.
Albert Rizzo, director for medical virtual reality at the Institute for Creative Technologies at the University of Southern California, thinks that virtual reality can improve results. As computer-processing power has grown, he and his colleagues have designed ever more intricate war zone experiences, replete with sights, sounds, vibrations and smells—diesel fuel, sweat, burning plastic—that can boost the reexposure process. “Instead of watching Band of Brothers, they're in a Band of Brothers episode,” Rizzo says.
These episodes have been tested at more than 50 hospitals and clinics around the U.S. They usually feature some catastrophe—an improvised explosive device (IED) detonating or a squad leader getting killed. But unlike real life, the soldier can hit pause and, aided by a therapist, talk about what is happening. When asked about traumatic events, soldiers with PTSD cannot always recall their feelings. They appear stricken by an emotional numbness. Rizzo thinks his scenarios can accelerate the deconditioning process that is at the heart of exposure therapy because they appeal directly to sensory memory and may trigger memories that are otherwise inaccessible.
Other researchers are testing tech-enhanced versions of an older technique called biofeedback, which gives patients real-time readouts of heart rate and other physiological functions. Instructors demonstrate breathing methods and, in some cases, visualization practices for regulating these functions. The theory is that, armed with such tools, patients can learn to calm themselves when the panicky sensations of fight or flight kick in.
Carmen Russoniello, a professor at East Carolina University and a former marine himself, is teaching biofeedback techniques to soldiers suffering from PTSD by way of video games. Participants directly control avatars in games such as Pac-Man using their physiological responses. The calmer they are, the better they fare. “How do you turn yourself into a meditator in a couple of hours?” he asks. “This is one way to do it.”—M.V.-M
*Editor's Note (7/24/15): The original sentence from the magazine article was edited online after posting to correct an erroneous description of the prefrontal cortex.
