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Depression: Major Depression & Unipolar Varieties
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Biology of Depression - Genetics and Imaging

Rashmi Nemade, Ph.D., Natalie Staats Reiss, Ph.D., and Mark Dombeck, Ph.D.

Genetics

For a long time, doctors have known that depression runs in families. Many individuals with depression can name other family members who also struggle with the same or similar illness. Early studies on the genetics of depression were conducted with twins. Identical twins share the same genes, while fraternal twins (and non-twin siblings) share only 50% of their genetic material. Researchers from all over the world have found that when one identical twin is depressed, the other twin will also have depression 76% of the time. With fraternal pairs, the twin of a depressed person experiences depression only 19% of the time. Research studies examining twins raised in different homes have further strengthened the evidence for a genetic link (and not just social-learning) to depression. Among identical twins who were raised in separate homes; when one twin has depression, the other twin also developed the same disorder 67% of the time.

Among the general population, Major Depressive Disorder is 1.5 to 3 times more common among first-degree biological relatives of affected individuals than it is among other less related individuals. In other words, a person who has a parent or sibling with depression is almost three times more likely to develop Major Depression than someone with no history of depression in their parents or siblings. There is also an increased risk for developing depression if someone has a first-degree relative who is alcohol dependent. Dysthymic Disorder is also more common among first-degree biological relatives of people with Major Depressive Disorder than among the general population. The converse is also true; Dysthymic Disorder and Major Depressive Disorder are more common in first-degree relatives of individuals with Dysthmic Disorder.

At the present time, we haven't uncovered specific genes that are responsible for causing depression. Recent research suggests that some types of depression may spring from genes on a specific region of chromosome 15. With additional research, we will probably find additional genes that are related to depressive illnesses. Remember though, that simply having a depressed family member or "depression genes" is probably not enough to cause people to become depressed themselves. As suggested by the diathesis-stress model, it is likely that a genetic tendency or vulnerability to become depressed is actually transmitted from generation to generation. This tendency to become depressed then interacts with particular stressors to ultimately result in Major Depression.

Imaging

While measuring physiological and biochemical changes in the body is a source of important information, brain imaging technology has also yielded significant insights into the causes of depression.

Brain imaging technologies are a group of non-invasive techniques that allow scientists to examine the whole brain or portions of it without having to perform surgery. Imaging procedures provide doctors with information about brain structure (i.e., what different parts of the brain look like) as well as brain function (i.e., how the brain is behaving). Researchers are currently using imaging technology to further understand the biology of depression by comparing the brains of depressed and non-depressed people.

Structural brain imaging techniques include Computed Axial Tomography (CT) and Magnetic Resonance Imaging (MRI). CT imaging uses special x-ray equipment to measure the amount of radiation being absorbed throughout a person's body. This information is translated into two- dimensional or three-dimensional cross-sectional computer images ("slices") of the inside of the body. In contrast, MRI uses radio frequency waves and a strong magnetic field to provide three-dimensional computer images of internal organs and tissues.

Using structural imaging, scientists have discovered that the part of the brain called the ventromedial cortex is much smaller in individuals affected by depression. The ventromedial cortex allows people to switch from one mood to another mood, as well as to experience pleasure and positive reinforcement (i.e. rewards). Researchers have found that this size decrease within the ventromedial cortex of depressed people is caused by a reduction in the number of glial cells in this portion of their brains. The function of certain glial cells is to supply neurons with energy. As a result, if the number of glial cells in parts of the brain decrease, then a decline in the activity of the associated neurons is not surprising.

Structural brain imaging techniques produce still photographs or still models of the brain. In contrast, functional imaging techniques produce "brain movies" that show how the various parts of the brain interact through time. Functional imaging technologies depend upon measurements of brain metabolism (e.g., oxygen and glucose consumption) and blood flow rates to make these movies possible.

Positron Emission Tomography (PET) allows scientists to determine the metabolic rates of the brain by measuring oxygen and blood sugar (glucose) utilization. Areas of the brain that are active use more oxygen and glucose than areas that are not active. Prior to the PET scan, a safe radioactive tracer is attached to glucose and injected into a person's bloodstream. A PET scan then shows where the tracer becomes concentrated in the brain across time. A computer records a three-dimensional image of the brain, and the areas that are actively metabolizing sugar and oxygen "light up" with different colors.

Functional MRI (fMRI) also allows us to determine which parts of the brain are active. Rather than glucose levels, fMRI measures blood flow. Magnets in the fMRI scanner exploit the natural magnetic properties of blood and water in the body, and create a color-coded image on a computer screen. The fMRI image informs researchers which areas of the brain have the highest (more activity) and lowest (low activity) blood flows.

Using these techniques, researchers have found that depressed people have less activity in the prefrontal cortex of the brain, and more activity in the limbic system. (The ventromedial cortex mentioned above forms part of the prefrontal cortex, so the results from functional brain imaging studies confirm results obtained with structural imaging). Scientists think that the prefrontal cortex enables us to regulate emotions, and more specifically, helps us inhibit inappropriate or incapacitating emotions. If our prefrontal cortex is less active, then negative emotions (such as depressed mood) may be expressed more frequently and more intensely. Functional brain imaging also suggests that certain parts of the parietal and temporal lobes of the brain work more slowly in people with depression. The activity in these lobes is connected to our ability to focus on the outside world, and may explain in part, why depressed people are focused more on their own thoughts and internal feelings than their surroundings.

Quite recently, neurosurgeons have reported successful treatment of several patients' severe and treatment-resistant depression by implanting a pacemaker-like device into a particular area of their brains, the subgenual cingulate region (otherwise known as Brodmann's area 25) and a part of the medial (middle) frontal cortex. The device provided continual electrical stimulation to these brain areas, and this stimulation had a pronounced anti-depressant effect. Though the results of this experimental neurosurgery speak for themselves, exactly why this treatment appears to work is not clear. Presumably, stimulation of these regions, which connect limbic (emotion) centers in the brain with the frontal cortex helps the frontal cortex to better manage its emotion regulation job. The frontal cortex may then be able to help reduce depressive rumination (the unending and unwanted repetition of depressive thoughts and feelings that many depressed patients report). Further research will be necessary before a complete understanding of why this treatment works emerges.