Psychiatric disorders such as depression, anxiety and schizophrenia have long been something of a mystery, but new research is identifying the brain circuits and chemicals that are involved in such illnesses.
This opens the doors to many possibilities for new treatment, but it also shows that one thing is sure: early life exposure to depression and anxiety permanently changes the structure of the developing brain.
"If we can fully understand the roots of mental illness in brain circuitry and systems, we may be able to develop better treatment targets for the millions suffering from these diseases," said Carol Tamminga, MD, of the University of Texas Southwestern and an expert on schizophrenia.
Science is only recently beginning to understand the underlying physical causes of such mental illnesses such as schizophrenia, major depression, and bipolar disorder. With one in 17 Americans suffering from such serious mental illness, it is one of the leading causes of disability in this country. But researchers are making serious strides into understanding how these illnesses develop physically, particularly in early development of the brain.
Childhood Anxiety and Depression
Recent psychological research has shown that childhood exposure to trauma, grief or abuse has prolonged effects, leading to higher rates of emotional and psychiatric problems later in life. But new medical research has demonstrated a physical result of early life depression and anxiety in brain development. Shaozheng Qin, PhD, of Stanford University and colleagues scanned the brains of 60 children between seven and nine years old.
The children were also given an assessment to measure their levels of depression and anxiety. Those who were the most anxious and depressed had increased activity between the amygdala, the part of the brain that processes negative emotions, and the other parts of the brain involved in emotional processing and regulation. The study is the first to show that anxiety and depression problems in childhood alter the intrinsic function of the way the brain connects during development.
"Understanding the effects of childhood anxiety and depression on the amygdala is particularly important, as the amygdala has been found to be a key center governing the behavior of teenagers," says Barbara Long, M.D., Ph.D. "The amygdala, one of the oldest centers of the brain from an evolutionary standpoint, is involved in instinctive, gut-level, risk-taking behaviors. As normal teens mature, the brain center governing behavior shifts from the amygdala to the frontal cortex, which applies reason and restraint to help teens understand the possible consequences of their actions." If the normal neural connections from the amygdala have been disrupted because of childhood mental disorders, it could have significant adverse effects on the maturational process in teens.
Prenatal Infection and Schizophrenia
For schizophrenia, the development causes may go back even farther than childhood. Prenatal infection in the womb has been shown to be a risk factor for the mental disorder, causing changes in the brain chemistry vital for long-term memory, which could create schizophrenic behavior.
At McGill University in Canada, a team of researchers led by Melissa Burt simulated prenatal infection by administering a bacterial toxin to pregnant rats. When the offspring reached adolescence, they showed reduced function in brain cell communicators called N-methyl-Daspartate receptors (NMDAR). The animals also had deficits in spatial memory, a trait common in people with schizophrenia. Burt says the findings suggest that prenatal infection could lead to schizophrenia by decreasing NMDAR function.
"Understanding how specific environmental factors, like prenatal infection, increase the risk for schizophrenia is necessary in order to devise preventive strategies for this serious disorder," Burt said.
The most common medication currently used are antipsychotic drugs, which often cause adverse side effects without improving cognition. Also, many people show resistance to such drugs; but a potential new avenue for drug treatment has been uncovered.
People who suffer from schizophrenia have higher levels of a brain enzyme called striatal-enriched tyrosine phosphatase (STEP). These elevated levels of STEP lower the levels of important NMDAR cells, which are necessary for communication between neurons and many aspects of cognition.
At Yale University, researchers led by Nikisha Carty, PhD, bred mice without any STEP, and gave them a drug that causes schizophrenia-like symptoms. But without STEP, the mice did not develop any schizophrenic behaviors and showed increased amounts of NMDAR. Carty called the results promising, and indicative of possibly STEP-related drugs that could be a more effective strategy in dealing with schizophrenia.
Brain Chemicals as Protection
Conversely, certain chemicals in our brains could act as a buffer against depression. A brain chemical called fibroblast growth factor-2 (FGF2) supports the growth of certain brain cells called glia. Animal studies have shown that a loss of glia cells can trigger depression.
A team led by Maha Elsayed of Yale University exposed mice to natural stressors until they showed depressive behaviors. Some of the mice were then given FGF2, which produced new glia cells. Afterward, these mice behaved in tests as if they were not depressed. The findings suggest a new mechanism to explore in creating faster, more effective antidepressant medications.
"Our study confirms that FGF2 can alleviate symptoms of depression in animals, and goes one step further in providing a new targeted mechanism for treating depression," said Elsayed. "Our results show that FGF2 promotes the formation of new glia cells, restoring the glia deficits triggered by stress."
Another way to affect depression at the brain chemical levels is by activating certain neurons. Stimulating a particular brain circuit produced antidepressant effects for Melissa Warden, PhD, of Stanford University. Her team injected rats with a substance designed to turn on specific neurons in the brain circuit that connects the prefrontal cortex and the dorsal raphe nucleus. The neurons would activate when the rats were exposed to blue light from a mini-fiberoptic laser.
When the neurons were activated, an immediate antidepressant effect occurred. When rats are put into a tank of water, passively floating indicates a depression-like state. But when the rats' neurons were activated with the blue laser light, they spent more time trying to escape the water, rather than just floating. The researchers also recorded the rats' neural activity, and identified neurons that only turned off when the rats were floating. But the neurons were active when the rats were trying to escape the water or were engaged in normal activity in their cages.
"These findings help pinpoint the dysfunctional circuitry underlying depression and will likely reveal new avenues for therapeutic intervention," Warden said."