New research shows that there are crucial periods of early life in which a stressful event can reduce hippocampal volume in adolescence. In a study presented at the 2016 meeting of the Society of Biological Psychiatry, Kathryn L. Humphreys and colleagues found that children who experienced a significant stressor before age 8 had smaller hippocampi in early adolescence than children who did not have a significant stressor early in life.
The severity of the stressors that occurred when children were between the ages of 0 and 2 predicted the volume of the hippocampus later in life. This was true to a lesser extent for stressful events that occurred between the ages of 3 and 5. No effect was seen for stressful events that took place between the ages of 6 and 8.
The period of sensitivity to stressful events between ages 0 and 2 and its effects on hippocampal volume could influence a variety of psychiatric outcomes in conditions such as depression and post-traumatic stress disorder (PTSD).
In new research presented at the 2016 meeting of the Society of Biological Psychiatry, researcher Tracy Barbour and colleagues revealed that youth with a family history of depression showed more amygdala activation in response to a threat than people without a family history of depression. This amygdala hyperactivity was linked to low resilience to stress and predicted worsening depressive symptoms over the following year.
In the study, 72 non-depressed youth were shown images of cars or human faces or cars that seemed to loom in a threatening way. Brain scans showed increased amygdala activity in participants with a family history of depression compared to those without such a history.
The amygdala is an almond-shaped part of the brain in the temporal lobe that has been linked to emotional reactions and memory, decision-making, and anxiety.
Rodents who are repeatedly defeated by larger animals often exhibit depression-like behaviors. In new research that researcher Georgia E. Hodes presented at the 2016 meeting of the Society of Biological Psychiatry, animals who are susceptible to these social defeat stress behaviors showed immune irregularities, including high levels of the inflammatory marker interleukin-6.
An intervention to prevent the mice from secreting interleukin-6 in blood and bone marrow took away their susceptibility to social defeat stress. When bone marrow from rodents with no interleukin-6 was transplanted into susceptible mice, the recipients showed resilience to social defeat stress. Conversely, a transplant from susceptible mice to those mice without IL-6 led to social defeat stress in the previously “immune” mice.
This research shows that the peripheral immune system, including blood and bone marrow, plays an important role in depression-like behaviors in mice.
Telomeres are repeated DNA sequences that sit at the end of chromosomes and protect them during cell replication. Shorter telomeres are associated with aging and an increase in multiple medical and psychiatric disorders, while some healthy behaviors including exercising, eating healthy, meditating, and avoiding smoking can help maintain telomere length. Lithium treatment also increases telomere length.
Recent research by Mateus Levandowski and colleagues found that people who were dependent on crack cocaine had shorter telomeres than elderly women without psychiatric illnesses, particularly if the crack cocaine users had also experienced stress early in life, such as maltreatment or neglect.
Since short telomeres are associated with a variety of medical and psychiatric problems and premature aging, the combined effects of drug use and early life stressors are likely to have an adverse impact on people who have experienced both.
Stress is a risk factor for depression and other mental health disorders. Researchers are currently working to clarify how stress leads to depression, anxiety, and post-traumatic stress disorder, and why trauma early in life has lasting consequences.
Two recent studies in mice examined whether just witnessing a stressful event leads to depression-like behaviors. In one, adult female mice watched a male mouse as it was repeatedly attacked by a larger mouse. After ten days of this, the female mice were socially withdrawn, had lost interest in drinking sucrose, and gave up more easily during a physical challenge. They also lost weight and showed higher levels of the stress hormone corticosterone in their blood. The researchers, led by Sergio Iniguez, believe their study clarifies how witnessing traumatic events can lead to stress-induced mood disorders.
In the other study, by Carlos Bolanos-Guzman, adolescent male mice witnessed another mouse being attacked. Both the mice that went through the physical stress of being attacked and the mice that went through the emotional stress of watching the attacks occur showed similar depressive behaviors to the mice in the previous study—social withdrawal, loss of interest in sucrose, decreased food intake and exploration of the environment, and decreased motivation in physical challenges. These behaviors persisted into adulthood. Both groups of mice also had increased levels of corticosterone and reduced expression of a particular protein in the ventral tegmental area, a part of the brain linked to stress response. Bolanos-Guzman suggests that both physical and emotional stress have lifelong consequences in mice.
The studies were presented at a scientific meeting in December.
Stress increases the risk of psychiatric illnesses such as major depression and post-traumatic stress disorder. Not everyone who experiences stress goes on to develop these illnesses, though. Researchers are currently trying to find out why, exploring treatments that might increase resilience and prevent mental illnesses.
Animal research is often used to study depression. Mice exposed to certain stressors behave in ways that resemble human depression—like giving up faster when they’re forced to tread water, or withdrawing from activities they once enjoyed, like eating sucrose. In a recent study by researcher Christine Denny and colleagues, mice were injected with either saline or ketamine, a rapid-acting antidepressant, and one week later they were exposed to triggers that typically produce a depressive response. Mice who received the saline injection still got depressed when, for example, they were repeatedly forced to confront a dominant mouse. But mice who received ketamine injections did better, maintaining their motivation and not showing signs of depressive behavior following the stress. The researchers concluded that ketamine may have a protective effect against stress.
Editor’s Note: These results are remarkable because ketamine’s effects are typically short-lived.
At the 2015 meeting of the American Academy of Child and Adolescent Psychiatry, researcher Charles Popper reviewed the literature to date about broad-spectrum micro-nutrient treatments for psychiatric disorders in young people, concluding that these formulations of vitamins and minerals can reduce symptoms of aggressive and disordered conduct, attention deficit hyperactivity disorder, mood disorders, anxiety, and stress. Four randomized controlled trials showed that micronutrient formulas reduced violence and major misconduct in children.
Popper warned that while these micronutrients can be helpful in treating children who have never been prescribed psychiatric medication, they can interact dangerously with psychiatric medications in children who do take them.
At the same meeting, researcher Bonnie Kaplan reported that six randomized controlled trials of broad-spectrum micro-nutrients and B-complex vitamins in adults with and without psychiatric disorders showed that both of the formulas reduced anxiety and stress following natural disasters (which are associated with the development of post-traumatic stress disorder (PTSD)).
A collaboration between Norwegian and French researchers led by Bruno Etain has clarified the pathway by which childhood trauma is linked to worse outcomes among people with bipolar disorder. The researchers, who presented their work in a poster at the 2015 meeting of the Society of Biological Psychiatry, replicated earlier findings by this editor (Robert Post) that patients who experienced trauma as a child had a more adverse course of bipolar disorder. Etain and colleagues found a link between childhood trauma and an earlier age of onset of bipolar disorder, rapid cycling, suicide attempts, and cannabis misuse.
The researchers identified more than 550 patients with bipolar disorder, who answered questionnaires about their history of bipolar disorder and childhood trauma. Their DNA was also analyzed, and the researchers found that the effect of childhood trauma on age of onset was mediated by the presence of common genetic variants in proteins related to stress (the serotonin transporter) and immune function (Toll-like receptors). They also found that the traits of mood lability (or moodiness) and impulsivity mediated the effects of trauma on clinical outcomes.
The lasting epigenetic effects of child maltreatment and adversity noted in the above abstract are consistent with a large literature showing more epigenetic effects in these individuals than in controls. While genetics are important, the impact of the environment is also substantial.
Studies of primates suggest that the amygdala plays an important role in the development of anxiety disorders. Researcher Ned Kalin suggested at the 2015 meeting of the Society of Biological Psychiatry that the pathology of anxiety begins early in life. When a child with anxiety faces uncertainty, the brain increases activity in the amygdala, the insula, and the prefrontal cortex. Children with an anxious temperament, who are sensitive to new social experiences, are at almost sevenfold risk of developing a social anxiety disorder, and later experiencing depression or substance abuse.
A study by Patrick H. Roseboom and colleagues presented at the meeting was based on the finding that corticotropin-releasing hormone (CRH) plays a role in stress and is found in the central nucleus of the amygdala (as well as in the hypothalamus). The researchers used viral vectors to increase CRH in the central nucleus of the amygdala in young rhesus monkeys, hoping to determine what impact increased CRH has on a young brain. Rhesus monkeys and humans share similar genetic and neural structures that allow for complex social and emotional functioning.
Roseboom and colleagues compared the temperaments of five monkeys who received injections increasing the CRH in their amygdala region to five monkeys who received control injections. As expected, the monkeys with increased CRH showed increases in anxious temperament. Brain scans also revealed increases in metabolism not only in the central nucleus of the amygdala, but also in other parts of the brain that have been linked to anxiety, including the orbitofrontal cortex, the hippocampus, and the brainstem, in the affected monkeys. The degree of increase in amygdala metabolism was directly proportional to the increase in anxious temperament in the monkeys, further linking CRH’s effects in the amygdala to anxiety.
Dysregulation of the brain in early life can have lasting effects, and the effects of stress and depression can also accumulate. At the 2015 meeting of the Society of Biological Psychiatry, researcher Huda Akil explained that behavioral pathology can “take on a life of its own, leading to deteriorating course of illness and treatment resistance.” She illustrated how preclinical work in animals can help clarify the molecular biology of depression and develop new targets for therapeutics.
Early Life Experiences are Key
Akil discuss studies of rodents in which she used new molecular genetic techniques to increase the number of glucocorticoid receptors in the hippocampus early in life (prior to weaning). Glucocorticoid receptors mediate the effects of the stress hormone cortisol in people and corticosterone in rodents. More receptors help shut off cortisol secretion after a stressful event. People with post-traumatic stress disorder (PTSD) have high levels of glucocorticoid receptors while people with depression have low levels, leading to over-secretion of cortisol in depression.
The increased glucocorticoid receptors led to a long-term increase in anxiety behaviors and response to stimulants. When Akil carried out the same manipulation on rats that had already been weaned, it had no long-lasting effects, showing that there is a vulnerability window for some long-lasting effects on behavior.
CLOCK Genes and Circadian Rhythms
Akil also studied CLOCK genes in rodents. These genes, including BMAL-1, Per 1, Per 2, and Per3, play a role in circadian rhythms, and their transcription induces these 24-hour cycles. In rodents who were induced into a depression-like state, the CLOCK genes were dysregulated and did not correspond to normal circadian rhythms. These data show that depressive states can induce changes in CLOCK genes and circadian rhythms. Others have shown the converse, that abnormal CLOCK genes can induce behavioral abnormalities including mania-like behaviors.
Fibroblast Growth Factor
Levels of fibroblast growth factor 2 (FGF2) in the hippocampus are low in people with depression. In rodents, FGF2 inhibits anxiety. Decreases in FGF2 are seen in the hippocampus of animals in a depression-like state following repeated defeat by a larger animal. It appears that FGF2 is an endogenous antidepressant (i.e. one that is produced by the brain). When the rodent brain is manipulated to eliminate FGF2, the animals become anxious.
In addition, animals bred to have high stress, low social responsivity, and resistance to new learning also have low FGF2. Treatment with FGF2 reversed these behavioral abnormalities and also increased the production of new neurons. For the stressed rats, receiving FGF2 on their second day of life increased new neuron production, decreased anxiety, decreased proneness to social defeat stress and increased the bonding hormone oxytocin in the amygdala into adulthood.
FGF2 had no effect on rats bred for low stress and high social responsivity, indicating that it only worked for the rats that needed it. Akil compared FGF2 to “personalized medicine for rats.”
Defeat stress affects the way genes are transcribed, and FGF2 was able to reverse one of these specific transcriptional effects, suggesting it could potentially ameliorate some of the long-lasting effects of stress and depression.
The Human Brain
Akil also studied the brains of people who had died of depression, bipolar disorder, or schizophrenia. In bipolar disorder, the nucleus accumbens, the reward center of the brain, was enlarged.
In contrast, Akil described the brains of those people who had died with depression as being “low on fertilizer.” That is, they showed less cell growth, less production of new neurons, more abnormalities in cell shape, and more cell death. Akil said that by the time someone is severely ill, the pathology is all over the brain. The changes Akil saw in the brains of people who were depressed are also consistent with data indicating that several neuroprotective factors, including BDNF and VEG-F, are low in the frontal cortex and the hippocampus of depressed people (while BDNF is high in the nucleus accumbens).