The Brain - What Causes Anxiety: Anxiety Disorder

Content provided by the Faculty of the Harvard Medical School

The brain

For decades, scientists have believed that anxiety results from abnormalities in brain chemistry. They base this conviction on the effects of drugs that reduce anxiety by increasing the availability of certain neurotransmitters in the brain. The first anti-anxiety drugs were benzodiazepines, which raise levels of the neurotransmitter gamma-aminobutyric acid (GABA). Later, drugs that increase serotonin levels and affect norepinephrine and other neurotransmitters associated with mood also proved effective. But these findings have raised even more questions. For example, what brain structures are involved? What malfunctions in the brain induce anxiety? And what role do neurotransmitters play?

Regions that influence anxiety

Brain imaging technologies have begun to answer some of these questions. Positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and other tools have allowed scientists to observe brain activity even while an anxiety attack is occurring. These images have helped identify the structures and circuits that are active when an anxiety attack strikes. Here's a summary of what has been discovered.

Amygdala. The amygdala, a small structure deep in the brain (see Figure 1), coordinates the body's fear response. The amygdala is part of the limbic system, a complex group of structures associated with emotions.

Figure 1: The brain and anxiety Several regions of the brain influence anxiety. The amygdala is associated with emotions and coordinates the body's response to fear. The cerebral cortex evaluates data about a perceived threat and forms judgments about it, shaping the response to fear. The hippocampus processes emotions and long-term memories. The locus ceruleus helps determine which stimuli deserve attention.

In the face of danger, two brain circuits become active. One circuit feeds sensory information about the danger — the sight and smell of a fire, for example — to the cerebral cortex, the thinking part of the brain. The cerebral cortex evaluates this information and makes a rational judgment about it. For example, that judgment may determine that the fire is small, but tell you to get out of the house anyway and call the fire department.

The other circuit relays the sensory information to the amygdala, which sends impulses to the autonomic nervous system. This system triggers the "fight-or-flight" response even before the cerebral cortex has made sense of the information. Once activated, it increases heart rate, routes blood to muscles, releases stress hormones and glucose into the bloodstream, and spurs other responses to help you respond quickly to the danger.

The amygdala stores memories of frightening events and other emotional experiences. In people with anxiety disorders, the amygdala may be so sensitive that it overreacts in situations that aren't threatening. Research on animals suggests that different parts of the amygdala are activated for different anxiety disorders.

Hippocampus. Another brain structure in the limbic system, the hippocampus has a central role in processing emotions and long-term memories. Research has found that the hippocampus is smaller than normal in some people with post-traumatic stress disorder. It's also smaller in some women who were abused as children, an experience that increases the risk for post-traumatic stress disorder and other anxiety disorders. But it's unclear whether the response to the trauma makes the hippocampus smaller, or whether certain individuals start out with a small hippocampus whose size predisposes them to anxiety disorders.

Locus ceruleus. The locus ceruleus is an area of the brainstem that helps determine which brain stimuli are worth paying attention to. In experiments with animals, when the locus ceruleus was electronically stimulated, the animals displayed anxiety-like symptoms. Some researchers speculate the same may be true in humans.

Brain cell communication

Understanding the intricate workings of neurons and neurotransmitters can help identify the sources of anxiety disorders and may lead to the development of treatments.

How neurotransmitters work. If you trained a high-powered microscope on a slice of brain tissue, you might be able to see a loosely braided network of neurons, or nerve cells, that send and receive messages. Stretching from each neuron are short, branchlike fibers called dendrites and one longer, more substantial fiber called the axon. The end of the axon is called the axon terminal.

A combination of electrical and chemical signals allows communication within and between neurons (see Figure 2). When a neuron becomes activated, it passes an electrical signal called an action potential down the axon to the axon terminal, where chemical messengers known as neurotransmitters are stored. The electrical signal prompts the axon terminal to release neurotransmitters into the space (synapse) between it and the dendrite of a neighboring neuron. As the concentration of a neurotransmitter rises in the synapse, the neurotransmitter molecules begin to bind with receptors embedded in the membranes of both the original neuron and its neighbor.

Figure 2: How neurons communicate Electrical signal travels down axon. Chemical neurotransmitter is released. Neurotransmitter binds to receptor sites. Signal is picked up by second neuron and is either passed along or halted. The signal is also picked up by the first neuron, causing reuptake to occur; neurotransmitter is transported back into the cell that released it.

The release of a neurotransmitter from one neuron can activate or inhibit a second neuron. If the signal is activating, or excitatory, the message continues to pass farther along that particular neural pathway. If it's inhibitory, the signal will be suppressed. The neurotransmitter also affects the neuron that released it. Once a certain amount of the chemical has been released, a feedback mechanism instructs the neuron to stop pumping it out and to start bringing it back into the cell. This process is called reabsorption or reuptake. Enzymes break down the remaining neurotransmitter into smaller molecules.

When the system fails. At optimal levels, the neurotransmitters of the central nervous system enable people to feel, learn, and move — in general, to function properly. But these complex systems can go awry. For example, receptors may be oversensitive or insensitive to a specific neurotransmitter. The response to its release, therefore, could be excessive or inadequate. The supply of a neurotransmitter may be insufficient if a neuron pumps out too little or an overly efficient reuptake mops up too much before the molecules have the chance to bind to the receptors on other neurons (see Figure 3). Any of these system failures can significantly affect mood and anxiety.

Figure 3: Failures in neuron communication Too little neurotransmitter released Reabsorbs too much neurotransmitter Failures in the way neurons communicate can affect mood and anxiety. There are several causes of such failures, including the two shown here. As the first illustration reveals, sometimes the cell that is releasing the signal doesn't release enough of the neurotransmitter (A). Or, as the second illustration shows, the neuron releases enough of the neurotransmitter, but reabsorbs too much of it too quickly, so it doesn't bind adequately to the receptor sites of the neighboring cell (B).

Neurotransmitters and anxiety. The following neurotransmitters are known to play a role in anxiety.

Gamma-aminobutyric acid (GABA) is an amino acid known as an inhibitory neurotransmitter because it's thought to hinder the activity of other neurotransmitters; it may help quell anxiety.

Serotonin helps regulate mood, sleep, and appetite, and inhibits pain; people with anxiety are believed to have low levels of serotonin in the brain. Low levels of serotonin are also linked to depression.

Norepinephrine constricts blood vessels and raises blood pressure; it plays a role in sensitization, fear conditioning, and stress response. Excess norepinephrine may trigger anxiety. Most neurons that release norepinephrine are located in the locus ceruleus, a part of the brain that may induce anxiety when it malfunctions.

Dopamine is perhaps best known for being essential to movement. A lack of dopamine leads to the movement difficulties characteristic of Parkinson's disease. Dopamine also seems to influence motivation and reward. Although there's little evidence linking dopamine to anxiety in people, some research suggests a connection to social phobia. For one thing, people who take medications that block dopamine sometimes develop social phobia. In addition, dopamine-enhancing antidepressants, such as monoamine oxidase (MAO) inhibitors, are more effective in treating social phobia than tricyclic antidepressants, which have little effect on dopamine. On the other hand, too much dopamine may contribute to obsessive-compulsive disorder in some patients. The anti-anxiety drug buspirone (BuSpar), which blocks dopamine slightly, has been helpful for some people with obsessive-compulsive disorder.

Hormones and the HPA axis

While neurotransmitters help transmit signals along nerve pathways, other chemicals, called hormones, carry messages to organs or groups of cells throughout the body. Imbalances of certain hormones increase the risk for anxiety and may induce anxiety symptoms.

These hormones circulate in a pathway called the hypothalamic-pituitary-adrenal (HPA) axis, which influences mood. The hypothalamus is a part of the brain located above your brainstem, the pituitary gland sits below your brain, and the adrenal glands are located atop your kidneys. Together these bodies govern a multitude of hormonal activities in the body and may play a role in anxiety disorders. The autonomic nervous system, which triggers the fight-or-flight response and directs functions throughout the body, is responsible for the HPA axis (see Figure 4).

Figure 4: Understanding the HPA axis When you're faced with a threat, the HPA axis allows you to respond quickly. However, in some people with anxiety disorders, this system remains in overdrive. The hypothalamus secretes the hormone corticotropin-releasing factor (CRF), which rouses the body. CRF travels to the pituitary gland. The pituitary gland secretes adrenocorticotropic hormone (ACTH). ACTH circulates in the bloodstream, traveling to the adrenal gland. The adrenal gland releases cortisol, another hormone. Cortisol stimulates many reactions in your body, including a rush of energy and alertness.

The hypothalamus secretes corticotropin-releasing factor (CRF), a hormone vital to rousing your body when a physical or emotional threat looms. This hormone follows a pathway to your pituitary gland, where it stimulates the secretion of adrenocorticotropic hormone (ACTH), which pulses into your bloodstream. When ACTH reaches your adrenal glands, it triggers the release of cortisol, a steroid hormone. The rise in cortisol prompts a cascade of reactions in your body, including a rush of energy and alertness. This enables you to respond quickly to a threat. Normally, a feedback loop allows the body to disable these defenses when the threat passes. But in some cases, the floodgates never close properly, and cortisol levels rise too often or simply stay high.

Research suggests that having the HPA axis in persistent overdrive may lay the groundwork for depression as well as anxiety. Evidence points to excess CRF as the main culprit. Some studies have found that people with anxiety disorders have increased levels of CRF in the cerebrospinal fluid, a clear liquid surrounding the brain and spinal cord. Research sponsored by the National Institute of Mental Health found that individuals with post-traumatic stress disorder have above-average levels of CRF. One study found higher-than-normal levels of pituitary and adrenal stress hormones, such as cortisol and ACTH, in the bloodstreams of women who had been physically or mentally abused as children. The levels were especially high in women who were experiencing symptoms of anxiety and depression at the time of the study.

This research suggests a biological explanation for why early stress or trauma increases the risk of developing an anxiety disorder in adulthood. Early trauma may cause a lasting increase in CRF and other stress hormones, and the pumped-up levels of these hormones may keep the HPA axis and the autonomic system in a state of alert (see Figure 5). These findings also point to a possible treatment: Drugs that block CRF receptors may help relieve or even prevent anxiety disorders related to early stress. Some such drugs are in development.

Figure 5: Early emotional trauma may alter hormone levels Some research has found that individuals with anxiety disorders have increased corticotropin-releasing factor (CRF) levels. Scientists believe that an emotional trauma during childhood can cause a lasting increase in CRF, which may keep the body in a heightened state of alert.

Last updated:	September 05, 2008