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)

Researchers discover the brain origins of variation in pathological anxiety

New findings from nonhuman primates suggest that an overactive core circuit in the brain, and its interaction with other specialized circuits, accounts for the variability in symptoms shown by patients with severe anxiety. In a brain-imaging study published in the Proceedings of the National Academy of Sciences (PNAS), researchers from the University of Wisconsin School of Medicine and Public Health describe work that for the first time provides an understanding of the root causes of clinical variability in anxiety disorders.

Using a well-established nonhuman primate model of childhood anxiety, the scientists identified a core circuit that is chronically over-active in all anxious individuals, regardless of their particular pattern of symptoms. They also identified a set of more specialized circuits that are over- or under-active in individuals prone to particular symptoms, such as chronically high levels of the stress-hormone cortisol.

“These findings provide important new insights into altered brain functioning that explains why people with anxiety have such different symptoms and clinical presentations, and it also gives us new ideas, based on an understanding of altered brain function, for helping people with different types of anxiety,’’ says Ned Kalin, senior author, chair of Psychiatry and director of the HealthEmotions Research Institute.

“There is a large need for new treatment strategies, because our current treatments don’t work well for many anxious adults and children who come to us for help.”

In the study, key anxiety-related symptoms were measured in 238 young rhesus monkeys using behavioral and hormonal measurement procedures similar to those routinely used to assess extreme shyness in children. Young monkeys are ideally suited for these studies because of their similarities in brain development and social behavior, Kalin notes. Variation in brain activity was quantified in the monkeys using positron emission tomography (PET) imaging, a method that is also used in humans.

Combining behavioral measures of shyness, physiological measures of the stress-hormone cortisol, and brain metabolic imaging, co-lead authors Alexander Shackman, Andrew Fox and their collaborators showed that a core neural system marked by elevated activity in the central nucleus of the amygdala was a consistent brain signature shared by young monkeys with chronically high levels of anxiety. This was true despite striking differences across monkeys in the predominance of particular anxiety-related symptoms.

The Wisconsin researchers also showed that young monkeys with particular anxiety profiles, such as high levels of shyness, showed changes in symptom-specific brain circuits. Finally, Shackman, Fox and colleagues uncovered evidence that the two kinds of brain circuits, one shared by all anxious individuals, the other specific to those with particular symptoms, work together to produce different presentations of pathological anxiety.

The new study builds upon earlier work by the Kalin laboratory demonstrating that activity in the amygdala is strongly shaped by early-life experiences, such as parenting and social interactions. They hypothesize that extreme anxiety stems from problems with the normal maturation of brain systems involved in emotional learning, which suggests that anxious children have difficulty learning to effectively regulate brain anxiety circuits. Taken together, this line of research sets the stage for improved strategies for preventing extreme childhood anxiety from blossoming into full-blown anxiety disorders.

“This means the amygdala is an extremely attractive target for new, broad-spectrum anxiety treatments,’’ says Shackman. “The central nucleus of the amygdala is a uniquely malleable substrate for anxiety, one that can help to trigger a wide range of symptoms.”

The work also suggests more specific brain targets for different symptom profiles. Such therapies could range from new, more selectively targeted medications to intensive therapies that seek to re-train the amygdala, ranging from conventional cognitive-behavioral therapies to training in mindfulness and other techniques, Shackman noted. To further understand the clinical significance of these observations, the laboratory is conducting a parallel study in young children suffering from anxiety disorders.

Risk Genes for Alzheimer’s and Mental Illness Linked to Brain Changes at Birth

Some brain changes that are found in adults with common gene variants linked to disorders such as Alzheimer’s disease, schizophrenia, and autism can also be seen in the brain scans of newborns.

“These results suggest that prenatal brain development may be a very important influence on psychiatric risk later in life,” said Rebecca C. Knickmeyer, PhD, lead author of the study and assistant professor of psychiatry in the University of North Carolina School of Medicine. The study was published by the journal Cerebral Cortex on Jan. 3, 2013.

The study included 272 infants who received MRI scans at UNC Hospitals shortly after birth. The DNA of each was tested for 10 common variations in 7 genes that have been linked to brain structure in adults. These genes have also been implicated in conditions such as schizophrenia, bipolar disorder, autism, Alzheimer’s disease, anxiety disorders and depression.

For some polymorphisms – such as a variation in the APOE gene which is associated with Alzheimer’s disease – the brain changes in infants looked very similar to brain changes found in adults with the same variants, Knickmeyer said. “This could stimulate an exciting new line of research focused on preventing onset of illness through very early intervention in at-risk individuals.”

But this was not true for every polymorphism included in the study, said John H. Gilmore, MD, senior author of the study and Thad & Alice Eure Distinguished Professor and Vice Chair for Research and Scientific Affairs in the UNC Department of Psychiatry.

For example, the study included two variants in the DISC1 gene. For one of these variants, known as rs821616, the infant brains looked very similar to the brains of adults with this variant. But there was no such similarity between infant brains and adult brains for the other variant, rs6675281.

“This suggests that the brain changes associated with this gene variant aren’t present at birth but develop later in life, perhaps during puberty,” Gilmore said.

“It’s fascinating that different variants in the same gene have such unique effects in terms of when they affect brain development,” said Knickmeyer.

Doctors have long recognized a link between alcoholism and anxiety disorders such as post-traumatic stress disorder (PTSD). Those who drink heavily are at increased risk for traumatic events like car accidents and domestic violence, but that only partially explains the connection. New research using mice reveals heavy alcohol use actually rewires brain circuitry, making it harder for alcoholics to recover psychologically following a traumatic experience.

“There’s a whole spectrum to how people react to a traumatic event,” said study author Thomas Kash, PhD, assistant professor of pharmacology at the University of North Carolina School of Medicine. “It’s the recovery that we’re looking at — the ability to say ‘this is not dangerous anymore.’ Basically, our research shows that chronic exposure to alcohol can cause a deficit with regard to how our cognitive brain centers control our emotional brain centers.”

The study, which was published online on Sept. 2, 2012 by the journal Nature Neuroscience, was conducted by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and UNC’s Bowles Center for Alcohol Studies.