Specifically, the left PFC is instrumental in producing what Davidson calls "pre-goal attainment positive affect," what you and I call eagerness, the emotion that arises as we approach a desired goal. The depressed can't mentally hang on to goals or stay attuned to rewards. Result: lowered capacity for pleasure, lack of motivation, loss of interest.
But the left PFC doesn't just activate positive feelings. Davidson finds that it is also crucial in inhibiting negative emotion that gets in the way of focusing on positive goals. In this, the left PFC draws on its links to the amygdala, an almond-shaped structure in the center of the brain that pumps out negative feelings.
By placing subjects in a functional magnetic resonance imager to measure brain activity while showing them emotionally laden pictures—photographs of starving children, for example—Davidson has graphically confirmed what many scientists have suspected: that the amygdala scans incoming experience for emotional significance, puts a flag on negative feelings such as fear, and sends out notice of threat, information we could not survive without.
If the PFC masterminds depression by failing to activate, the amygdala controls the severity of depression by its negative output. Along with the University of Pittsburgh's Wayne C. Drevets, Davidson has found that blood flow in the amygdala is greater the more depressed a person is. Moreover, studies show that the amygdala is highly active during states of helplessness, as when people face an insoluble problem. Amygdala activity also determines how firmly a negative event is held in memory.
Ordinarily, as the left PFC turns on, it simultaneously shuts off the amygdala and dampens the flow of negative emotions from it. But among the depressed, the general failure of activation of the left PFC leaves the amygdala running unchecked, overwhelming them with dread, fear and other negative feelings.
Individuals normally differ in the degrees of neural activation of the left and right sides of the PFC in response to emotional messages. That difference may help account not only for a person's vulnerability to depression, Davidson says, but also for variations in personality. A peppy left PFC underlies extraversion, while a relatively more active right PFC is linked to inhibition and anxiety.
It isn't clear how asymmetries in prefrontal activity get established to begin with. "Although these characteristics of brain function are very stable in adults," Davidson says, "they are much less so in children." That suggests to him that activation levels of this circuit are set early in life, certainly by puberty.
One clue may be that differences in PFC activation go hand in hand with differences in brain levels of the stress-related hormone cortisol. When the left PFC is highly active, not only do people have a sunny outlook, but levels of cortisol are low. Cortisol patterns suggest that stress had a hand in there somewhere.
No Glee Over Glia
Some years ago, Wayne Drevets, then at Washington University, discovered that depressed persons not only have altered PFC activity, but their prefrontal cortex is actually smaller than in the nondepressed. It is one thing to find abnormalities in the way the brains of the depressed function—but structural abnormalities? Anatomical ones?
Drevets found that depressed patients have a drastically smaller volume of a section of the left PFC that sits about two and a half inches behind the bridge of nose and is called the ventral anterior cingulate. Drevets calls it the subgenual prefrontal cortex because it sits beneath the genua, or knee, of the corpus callossum, the Continental Divide of the brain. The little site was 40 percent smaller in the depressed.
The subgenual cortex is vastly important: it is one of the few cortical regions connecting to the hypothalamus, a deep-brain structure that instigates the body's stress response. The subgenual cortex also helps orchestrate the body's hormonal response to stressful stimuli.
Taking their cue from Drevets' findings, colleagues at Washington University began searching for what could account for the cortical shrinkage. They examined tissue that, at autopsy, had been collected from the brains of normal individuals and those with bipolar or unipolar depression.
At a meeting of the Society of Neuroscience, graduate student Dost Ongur reported startling findings. He had expected to see a decrease in the number of neurons, what he calls "the business end of the brain in terms of processing information and generating actions." Instead he found a dramatic loss in the number of glia, small cells that perform important—maybe critical housekeeping functions for the more patrician neurons. The loss of glia was seen only in those with a family history of depression.
Glut of Glutamate
The glia are known to nourish neurons by assuring a steady supply of glucose, their preferred food. They also protect neurons by stabilizing levels of the neurotransmitter glutamate. Glutamate is the main transmitter in the cortex that activates cells. But too much glutamate can overstimulate neurons, causing collapse of the branches by which they communicate with other cells.
The glia also play a big role in the development of the serotonin neurotransmitter system, which, everyone now knows, also functions abnormally in depression. "It could be," Drevets says, "that some defect in the neural development of the prefrontal cortex could be the initial abnormality in depression that starts a cascade of changes in other systems."
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