Brain-Imaging Study Links Cannabinoid Receptors to Post-Traumatic Stress Disorder—Findings Bring First Pharmaceutical Treatment for Ptsd Within Reach—

In a first-of-its-kind effort to illuminate the biochemical impact of trauma, researchers at NYU Langone Medical Center have discovered a connection between the quantity of cannabinoid receptors in the human brain, known as CB1 receptors, and post-traumatic stress disorder, the chronic, disabling condition that can plague trauma victims with flashbacks, nightmares and emotional instability. Their findings, which appear online today in the journal Molecular Psychiatry, will also be presented this week at the annual meeting of the Society of Biological Psychiatry in San Francisco.

CB1 receptors are part of the endocannabinoid system, a diffuse network of chemicals and signaling pathways in the body that plays a role in memory formation, appetite, pain tolerance and mood. Animal studies have shown that psychoactive chemicals such as cannabis, along with certain neurotransmitters produced naturally in the body, can impair memory and reduce anxiety when they activate CB1 receptors in the brain. Lead author Alexander Neumeister, MD, director of the molecular imaging program in the Departments of Psychiatry and Radiology at NYU School of Medicine, and colleagues are the first to demonstrate through brain imaging that people with PTSD have markedly lower concentrations of at least one of these neurotransmitters —an endocannabinoid known as anandamide—than people without PTSD. Their study, which was supported by three grants from the National Institutes of Health, illuminates an important biological fingerprint of PTSD that could help improve the accuracy of PTSD diagnoses, and points the way to medications designed specifically to treat trauma.

“There’s not a single pharmacological treatment out there that has been developed specifically for PTSD,” says Dr. Neumeister. “That’s a problem. There’s a consensus among clinicians that existing pharmaceutical treatments such as antidepressant simple do not work. In fact, we know very well that people with PTSD who use marijuana—a potent cannabinoid—often experience more relief from their symptoms than they do from antidepressants and other psychiatric medications. Clearly, there’s a very urgent need to develop novel evidence-based treatments for PTSD.”

The study divided 60 participants into three groups: participants with PTSD; participants with a history of trauma but no PTSD; and participants with no history of trauma or PTSD. Participants in all three groups received a harmless radioactive tracer that illuminates CB1 receptors when exposed to positron emissions tomography (PET scans). Results showed that participants with PTSD, especially women, had more CB1 receptors in brain regions associated with fear and anxiety than volunteers without PTSD. The PTSD group also had lower levels of the neurotransmitter anandamide, an endocannabinoid that binds to CB1. If anandamide levels are too low, Dr. Neumeister explains, the brain compensates by increasing the number of CB1 receptors. “This helps the brain utilize the remaining endocannabinoids,” he says.

Much is still unknown about the effects of anandamide in humans but in rats the chemical has been shown to impair memory. “What is PTSD? It’s an illness where people cannot forget what they have experienced,” Dr. Neumeister says. “Our findings offer a possible biological explanation for this phenomenon.”

Current diagnostics for PTSD rely on subjective measures and patient recall, making it difficult to accurately diagnose the condition or discern its symptoms from those of depression and anxiety. Biological markers of PTSD, such as tests for CB1 receptors and anandamide levels, could dramatically improve diagnosis and treatment for trauma victims.

Among the 1.7 million men and women who have served in the wars in Iraq and Afghanistan, an estimated 20% have PTSD. But PTSD is not limited to soldiers. Trauma from sexual abuse, domestic violence, car accidents, natural disaster, violent assault or even a life-threatening medical diagnosis can lead to PTSD. The condition affects nearly 8 million Americans annually.

These findings were made possible through the collaborative efforts of researchers at NYU School of Medicine, Yale School of Medicine, Harvard Medical School, the Department of Veterans Affairs National Center for PTSD and the University of California at Irvine.

(Image caption: Hypothetical cannabinoid receptor CB1 binding to anandamide)

Research identifies co-factors critical to PTSD development

Research led by Ya-Ping Tang, MD, PhD, Associate Professor of Cell Biology and Anatomy at LSU Health Sciences Center New Orleans, has found that the action of a specific gene occurring during exposure to adolescent trauma is critical for the development of adult-onset Post-Traumatic Stress Disorder (PTSD.) The findings are published in PNAS Online Early Edition the week of April 1-5, 2013.

"This is the first study to show that a timely manipulation of a certain neurotransmitter system in the brain during the stage of trauma exposure is potentially an effective strategy to prevent the pathogenesis of PTSD," notes Dr. Tang.

The research team conducted a series of experiments using a specific strain of transgenic mice, in which the function of the gene can be suppressed, and then restored. The model combined exposure to adolescent trauma as well as an acute stressor. Clinically PTSD may occur immediately following a trauma, but in many cases, a time interval may exist between the trauma and the onset of disease. Exposure to a second stress or re-victimization can be an important causative factor. However, the researchers discovered that exposure to both adolescent trauma and to acute stress was not enough to produce consistent PTSD-like behavior. When exposure to trauma and stress was combined with the function of a specific transgene called CCKR-2, consistent PTSD-like behavior was observed in all of the behavioral tests, indicating that the development of PTSD does not depend only on the trauma itself.

As a predominant form of human anxiety disorders, PTSD affects 7.8% of people between 15-54 years in the United States. PTSD can cause feelings of hopelessness, despair and shame, employment and relationship problems, anger, and sleep difficulties. Additionally, PTSD can increase the risk of other mental health conditions including depression, substance abuse, eating disorders, and suicidal thoughts, as well as certain medical conditions including cardiovascular disease, chronic pain, autoimmune disorders, and musculoskeletal conditions.

A favored current theory of the development of anxiety disorders, including PTSD, is a gene/environment interaction. This study demonstrated that the function of the CCKR-2 gene in the brain is a cofactor, along with trauma insult, and identified a critical time window for the interaction in the development of PTSD.

"Once validated in human subjects, our findings may help target potential therapies to prevent or cure this devastating mental disorder," Dr. Tang concludes.

(Image: canstockphoto)

Study indicates reverse impulses clear useless information, prime brain for learning

When the mind is at rest, the electrical signals by which brain cells communicate appear to travel in reverse, wiping out unimportant information in the process, but sensitizing the cells for future sensory learning, according to a study of rats conducted by researchers at the National Institutes of Health.

The finding has implications not only for studies seeking to help people learn more efficiently, but also for attempts to understand and treat post-traumatic stress disorder—in which the mind has difficulty moving beyond a disturbing experience.

During waking hours, brain cells, or neurons, communicate via high-speed electrical signals that travel the length of the cell. These communications are the foundation for learning. As learning progresses, these signals travel across groups of neurons with increasing rapidity, forming circuits that work together to recall a memory.

It was previously known that, during sleep, these impulses were reversed, arising from waves of electrical activity originating deep within the brain. In the current study, the researchers found that these reverse signals weakened circuits formed during waking hours, apparently so that unimportant information could be erased from the brain. But the reverse signals also appeared to prime the brain to relearn at least some of the forgotten information. If the animals encountered the same information upon awakening, the circuits re-formed much more rapidly than when they originally encountered the information.

"The brain doesn’t store all the information it encounters, so there must be a mechanism for discarding what isn’t important," said senior author R. Douglas Fields, Ph.D., head of the Section on Nervous System Development and Plasticity at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the NIH institute where the research was conducted. "These reverse brain signals appear to be the mechanism by which the brain clears itself of unimportant information."

Their findings appear in the Proceedings of the National Academy of Sciences.

The researchers studied the activity of rats’ brain cells from the hippocampus, a tube-like structure deep in the brain. The hippocampus relays information to and from many other regions of the brain. It plays an important role in memory, orientation, and navigation.

The classic understanding of brain cell activity is that electrical signals travel from dendrites—antenna-like projections at one end of the cell—through the cell body. From the cell body, they then travel the length of the axon, a single long projection at the other end of the cell. This electrical signal stimulates the release of chemicals at the end of the axon, which bind to dendrites on adjacent cells, stimulating these recipient cells to fire electrical signals, and so on. When groups of cells repeatedly fire in this way, the electrical signals increase in intensity.

Dr. Bukalo and her team examined electrical signals that traveled in reverse—from the cell’s axon, to the cell body, and out its many dendrites. This reverse firing happens during sleep and at rest, appearing to reset the cell, the researchers found.

After first stimulating the cells with reverse electrical impulses, the researchers next stimulated the dendrites again with electrical impulses traveling in the forward direction. In response, the neurons generated a stronger signal, with the connections appearing to strengthen with repeated electrical stimulation.

This pattern appears to underlie the formation of new memories. A connection that is reset but never stimulated again may simply fade from use over time, Dr. Bukalo explained. But when a cell is stimulated again, it fires a stronger signal and may be more easily synchronized to the reinforced signals of other brain cells, all of which act in concert over time.

Portion of Hippocampus Found to Play Role in Modulating Anxiety

Columbia University Medical Center (CUMC) researchers have found the first evidence that selective activation of the dentate gyrus, a portion of the hippocampus, can reduce anxiety without affecting learning. The findings suggest that therapies that target this brain region could be used to treat certain anxiety disorders, such as panic disorder and post-traumatic stress syndrome (PTSD), with minimal cognitive side effects. The study, conducted in mice, was published in the online edition of the journal Neuron.

The dentate gyrus is known to play a key role in learning. Some evidence suggests that the structure also contributes to anxiety. “But until now no one has been able to figure out how the hippocampus could be involved in both processes,” said senior author Rene Hen, PhD, professor of neuroscience and pharmacology (in psychiatry) at CUMC.

“It turns out that different parts of the dentate gyrus have somewhat different functions, with the dorsal portion largely dedicated to learning and the ventral portion dedicated to anxiety,” said lead author Mazen A. Kheirbek, PhD, a postdoctoral fellow in neuroscience at CUMC.

To examine the role of the dentate gyrus in learning and anxiety, the investigators used a state-of-the-art technique called optogenetics, in which light-sensitive proteins, or opsins, are genetically inserted into neurons in the brains of mice. Neurons with these genes can then be selectively activated or silenced through the application of light (via a fiber-optic strand), allowing researchers to study the function of the cells in real time. Previously, the only way to study the dentate gyrus was to silence portions of it using such long-term manipulations as drugs or lesions, techniques that yielded conflicting results.

In the current study, opsins were inserted into dentate gyrus granule cells (the principal cells of the dentate gyrus). The researchers then activated or silenced the ventral or dorsal portions of the dentate gyrus for three minutes at a time, while the mice were subjected to two well-validated anxiety tests (the elevated plus maze and the open field test).

“Our main findings were that elevating cell activity in the dorsal dentate gyrus increased the animals’ desire to explore their environment. But this also disrupted their ability to learn. Elevating activity in the ventral dentate gyrus lowered their anxiety, but had no effect on learning,” said Dr. Kheirbek. The effects were completely reversible — that is, when the stimulation was turned off, the animals returned to their previous anxiety levels.

“The therapeutic implication is that it may be possible to relieve anxiety in people with anxiety disorders by targeting the ventral dentate gyrus, perhaps with medications or deep-brain stimulation, without affecting learning,” said Dr. Hen, who is also director of the Division of Integrative Neuroscience, the New York State Psychiatric Institute, and a member of The Kavli Institute for Brain Science. “Given the immediate behavioral impact of such manipulations, these strategies are likely to work faster than current treatments, such as serotonin reuptake inhibitors.”

According to Dr. Hen, such an intervention would probably work best in people with panic disorder or PTSD. “There is evidence that people with these anxiety disorders tend to have a problem with pattern separation — the ability to distinguish between similar experiences,” he said. “In other words, they overgeneralize, perceiving minor threats to be the same as major ones, leading to a heightened state of anxiety. Such patients could conceivably benefit from therapies that fine-tune hippocampal activity.”

Dr. Hen and his team are currently exploring strategies aimed at modulating the activity of the ventral dentate gyrus by stimulating neurogenesis in the ventral dentate gyrus. “Indeed the dentate gyrus is one of the few areas in the adult brain where neurons are continuously produced, a phenomenon termed adult hippocampal neurogenesis,” added Dr. Hen.

(Image: Catherine E. Myers, Memory Loss and the Brain)

Threat bias interacts with combat, gene to boost PTSD risk

Soldiers preoccupied with threat at the time of enlistment or with avoiding it just before deployment were more likely to develop post-traumatic stress disorder (PTSD), in a study of Israeli infantrymen. Such pre-deployment threat vigilance and avoidance, interacting with combat experience and an emotion-related gene, accounted for more than a third of PTSD symptoms that emerged later, say National Institutes of Health scientists, who conducted the study in collaboration with American and Israeli colleagues.

“Since biased attention predicted future risk for PTSD, computerized training that helps modify such attention biases might help protect soldiers from the disorder,” said Daniel Pine, M.D., of the NIH’s National Institute of Mental Health (NIMH).

Pine, Yair Bar-Haim, Ph.D., of Tel Aviv University, and colleagues, report their findings, Feb.  13, 2013, in the journal JAMA Psychiatry.

The Cost of War Includes at Least 253,330 Brain Injuries and 1,700 Amputations

Here are indications of the lingering costs of 11 years of warfare. Nearly 130,000 U.S. troops have been diagnosed with post-traumatic stress disorder, and vastly more have experienced brain injuries. Over 1,700 have undergone life-changing limb amputations. Over 50,000 have been wounded in action. As of Wednesday, 6,656 U.S. troops and Defense Department civilians have died.

That updated data (.pdf) comes from a new Congressional Research Service report into military casualty statistics that can sometimes be difficult to find — and even more difficult for American society to fully appreciate. It almost certainly understates the extent of the costs of war.

Start with post-traumatic stress disorder, or PTSD. Counting since 2001 across the U.S. military services, 129,731 U.S. troops have been diagnosed with the disorder since 2001. The vast majority of those, nearly 104,000, have come from deployed personnel.

But that’s the tip of the PTSD iceberg, since not all — and perhaps not even most — PTSD cases are diagnosed. The former vice chief of staff of the Army, retired Gen. Peter Chiarelli, has proposed dropping the “D” from PTSD so as not to stigmatize those who suffer from it — and, perhaps, encourage more veterans to seek diagnosis and treatment for it. (Not all veterans advocates agree with Chiarelli.)

The congressional study also brings to light the extent of one of the signature injuries of the post-9/11 wars, Traumatic Brain Injury (TBI), often suffered by survivors of explosions from homemade insurgent bombs. From 2000 (a pre-9/11 year probably chosen for inclusion for control purposes) to the end of 2012, some 253,330 troops have experienced TBI in some form. About 77 percent of those cases are classified by the Defense Department as “mild,” meaning a “confused or disoriented state lasting less than 24 hours; loss of consciousness for up to thirty minutes; memory loss lasting less than 24 hours; and structural brain imaging that yields normal results.”

More-severe TBI is measured along those metrics, lasting longer than a day. Nearly 6,500 of of those cases are “severe or penetrating TBI,” which include the effects of open head injuries, skull fractures, or projectiles lodged in the brain.

Like with PTSD, the TBI diagnoses scratch the surface. The military’s screening for TBI is notoriously bad: One former Army chief of staff described it as “basically a coin flip.” Worse, poor military medical technology, particularly in bandwidth-deprived areas like Iraq and Afghanistan, have made it uncertain that battlefield diagnoses of TBI actually transmit back to troops’ permanent medical files.

Amputations are a feature of any prolonged war. Almost 800 Iraq veterans have undergone “major limb” amputations, such as a leg, and another 194 have experienced partial foot, finger or other so-called “minor limb” losses. For Afghanistan veterans, those numbers are 696 and 28, respectively.

The Iraq war is over for all but a handful of U.S. troops and thousands of contractors. The Afghanistan war is in the process of a troop drawdown through 2014 of unknown speed and will feature a residual troop presence of unknown size. Even if the U.S. deaths and injuries in those wars may almost be over, the aftereffects of the wars on a huge number of veterans will not end.

Study Seeks Biomarkers for Invisible War Scars

Over the past decade, about half a million veterans have received diagnoses of post-traumatic stress disorder or traumatic brain injury. Thousands have received both. Yet underlying the growing numbers lies a disconcerting question: How many of those diagnoses are definitive? And how many more have been missed?

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