Brain Facts: A Primer on the Brain and Nervous System

Like many health conditions, psychiatric disorders can be caused by multiple factors. Genes often play a role, with many psychiatric disorders tending to run in families. Yet having a close relative with anxiety, schizophrenia, depression, or another psychiatric condition does not mean that you will develop the same problem. Many environmental effects, including life circumstances, medical conditions, and personal relationships, also have an influence. Environmental factors can be negative — like the death of a loved one, poverty, addiction, or being exposed directly to violence such as military combat — or they may be protective. These so-called resilience factors include a strong support system of family and friends, good coping skills, being physically active, and involvement in a range of activities.

ANXIETY DISORDERS AND POST-TRAUMATIC STRESS DISORDER

Everyone feels anxious at times, and worrying is a normal and healthy response to uncertainty or potential danger. But unhealthy, uncontrollable anxiety is the common thread in a variety of psychiatric disorders: post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), and panic attacks. Collectively, anxiety disorders are the most common mental disorders experienced by Americans. They are more common in women, for reasons that are not clear but likely include both sex differences (biological) and gender differences (psychosocial).

Medications used to treat most anxiety disorders work by altering the levels of neurotransmitters that carry signals between brain regions. Selective serotonin reuptake inhibitors (SSRIs) raise serotonin levels, which are known to be deficient in many psychiatric conditions. Benzodiazepines (such as diazepam, or Valium) were once the standard medication for anxiety because they boost levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GABA acts like a “brake pedal” on neurons, helping to decrease their activity, especially in areas of the brain important in anxiety. However, because of the risk of dependence, benzodiazepines are no longer the first choice for treatment of anxiety.

Obsessive-Compulsive Disorder

OCD is a common, chronic condition aptly named for its symptoms: uncontrollable, recurring thoughts (obsessions) and repeated, ritualistic behaviors (compulsions) to banish, relieve, or compensate for the obsessions. OCD affects about 1 percent of U.S. adults, with an average age of 19 at diagnosis. Obsessions vary widely: A person may, for example, worry about getting sick from a contaminated object, or feel the need to be “perfect” all the time. Compulsions attempt to counteract those thoughts behaviorally — for example, by excessive hand washing, or constantly checking for mistakes or problems such as leaving appliances on. Another type of OCD is hoarding, provoked by the fear of losing or forgetting important information after discarding something. People with OCD are burdened by their obsessive thoughts and, although compulsive behaviors can provide relief, they do not bring pleasure.

Research studies that examine the brain with powerful imaging tools have enabled neuroscientists to define the brain regions involved in obsessions and compulsions. One such region, the basal ganglia, connects with the cortex to help control our ability to move and think, but it also helps us conduct routine behaviors that we call habits. The basal ganglia are also involved in the brain’s reward system, our ability to feel good, and in learning and memory; these functions are mediated by the neurotransmitters dopamine, serotonin, and glutamate, respectively. Reward systems are often dysfunctional in people with psychiatric disorders, addiction, or both.

Researchers suspect that disrupted signaling between the basal ganglia and the cortex could set the stage for ritualistic behaviors. Studies of repetitive behaviors in mice have revealed electrical activity that starts and ends in nerves that connect these two brain regions. The ability to manipulate, or “override,” those circuits may point the way to breaking the obsession-compulsion cycle in people with OCD.

About 70 percent of people with OCD obtain limited relief with medication, primarily SSRIs, but at higher doses than are used for depression therapy. If SSRIs do not work to control OCD, other approaches include medications such as the tricyclic antidepressant clomipramine and neuroleptic (tranquilizing) drugs, both of which have significant side effects. Cognitive behavioral therapy, a form of counseling, can also be useful. Deep brain stimulation (DBS) is a therapeutic approach used for people with OCD who do not respond to standard drug or behavioral treatments. DBS was first used about 30 years ago to treat movement disorders like Parkinson’s disease, but is now being investigated for other uses. In DBS, electrodes implanted at specific brain locations emit high-frequency electrical pulses intended to reset abnormal neuronal firing. Scientists are beginning to explore the use of DBS in the basal ganglia and several other brain regions to alleviate the symptoms of OCD.

Panic Disorder

Panic disorder is a type of anxiety disorder characterized by sudden, unexpected bouts of intense, irrational fear and frightening physical symptoms such as difficulty breathing, a racing heart, sweating, and dizziness. It is more common than OCD, affecting 2.7 percent of U.S. adults and about the same proportion of teens. Panic attacks typically last several minutes or sometimes longer. Because the attacks occur unpredictably, people who experience them often live in fear of having an attack in public or while driving — further increasing their anxiety. About half of people with panic disorder also have mood disorders such as depression or bipolar disorder, as well as other psychiatric illnesses like OCD, phobias, and schizophrenia. Panic disorder is usually treated with psychotherapy, medications, or a combination of these. SSRIs are the primary drugs used for panic disorder, although benzodiazepines can be used in an emergency situation.

Post-Traumatic Stress Disorder

PTSD is somewhat unique among psychiatric disorders because it has a well-defined cause: a harrowing, traumatic event such as military combat, a natural disaster, a terrorist attack, a serious accident, or physical or sexual assault as a child or adult. PTSD can arise quickly after the distressing event, but sometimes it can take months to years for symptoms to emerge. Symptoms are often severe enough to interfere with relationships or work. Some people have PTSD for many years, experiencing flashbacks and nightmares, intrusive memories of the traumatic event, and hyperarousal — feeling on edge and/or angry. To compensate, individuals with PTSD try to avoid trigger situations but nonetheless may experience memory loss, feelings of blame, and decreased interest in everyday activities. Currently, cognitive behavioral therapy is thought to be the most effective treatment for PTSD.

Neuroscientists have discovered physiological changes in people with PTSD. These changes include increased heart rate and heightened electrical sensitivity throughout the skin and on the face in response to audio or video triggers of traumatic scenes like gunfire or other violence. Simply recalling the initial traumatic event can also bring on these symptoms. Another hallmark of PTSD is shallow sleep with increased periods of rapid eye movement, which can lead to sleep deprivation over time. The body’s general response to stress is maximal in PTSD, with altered levels of hormones such as cortisol and norepinephrine, the primary fuels in the fight-or-flight response to danger or fear. Not surprisingly, PTSD treatment includes drugs that block norepinephrine, such as the blood-pressure medication prazosin and beta-blocker drugs like propranolol. Scientists have also detected low levels of other neurotransmitters, such as serotonin, in people with PTSD, leading to the use of SSRIs for treatment. The neurotransmitter neuropeptide Y also appears to offer some protection against developing PTSD.

Neuroimaging studies have begun to reveal the neurobiological signatures of PTSD, including changes in brain structure. Many people with PTSD have a smaller hippocampus (the brain region integral for learning and memory) and a smaller prefrontal cortex (the part of the brain that helps control thinking, emotions, and behavior). In contrast, the brain’s emotional center, the amygdala, is apparently overactive in responding to stimuli in people with PTSD. Genes are involved in PTSD susceptibility, but research results are not yet conclusive regarding the importance of their role or which genes are involved. What is clear, however, is that genes affecting PTSD risk also affect the risk for major depression, generalized anxiety disorder, and panic disorder — suggesting common biological components of these psychiatric conditions. Neuroimaging studies that pinpoint brain regions disrupted in PTSD support the development of new drugs targeting neural function in those regions. Among these drugs are cannabinoids, glutamate, and oxytocin — the latter, sometimes called the “love” or “happiness” hormone, is released by both men and women during orgasm and is secreted by mothers during childbirth and breastfeeding.

Neuroimaging studies have begun to reveal the neurobiological signatures of PTSD, including changes in brain structure.

MOOD DISORDERS

Mood is a vague term describing a person’s general state of mind. You can easily recognize someone in a good mood and, likewise, in a not-so-good mood. Your moods change frequently with your emotional state, and such changes are normal when they suit your context and surroundings. Mood disorders, on the other hand, are mood changes that become longer lasting and independent of what is going on around you. The two main mood disorders are major depression and bipolar disorder. In recent years, neuroscientists have made major progress in linking genetic and other biological contributors to mood disorders and to disorders of cognition, like schizophrenia. Hopefully, their findings will lead to better treatments for people with more than one such condition.

Major Depression

Diagnosis of major depression is based on a set of criteria (at least four must be met) that have persisted for at least two weeks. These criteria include feeling empty or sad, loss of appetite, irritability, problems with sleep, and changes in appetite or weight. Like anxiety, major depression is a common psychiatric disorder that contributes to considerable disability and death worldwide. Often, depression is accompanied by other diseases. Various medical and psychiatric conditions (for example, diabetes, cancer, heart disease, and addiction) are common in people who are depressed, and depression can make the other problems worse. Nearly 7 percent of American adults — about 16 million people — have experienced at least one major depressive episode in the past year, and 7 out of 10 of these are likely to be female. This striking sex imbalance is not thoroughly understood, but is an area of active research.

Several factors combine to cause depression: genes, biological risk factors, environmental triggers, and psychological influences. Many people develop depression in response to the stress of a difficult life experience or a disabling medical problem such as cancer or chronic pain. Inside the brain, depression appears to disrupt the hypothalamus. This region secretes a hormone that, via the pituitary gland, tells the adrenal cortex to produce more of the stress hormone cortisol. The monoamine neurotransmitter systems, which include dopamine and serotonin, are also disrupted. Some cases of depression — typically those evoked by a stressful incident, situation, or short-term illness — respond to treatment, and symptoms go away. In many cases, though, depression becomes a chronic condition and depressive symptoms persist without any outside influence.

As was also observed in people with PTSD, people with depression tend to have a smaller hippocampus and prefrontal cortex. These two brain areas help manage stress, but can be damaged by excessive stress. When researchers showed negative pictures to depressed individuals and looked for brain activation, they noted activity in parts of the cortex linked to the limbic system. Even though the burst of activity soon died down, individuals who showed greater activation were more likely to have worse depression 18 months later. Such imaging techniques may help identify individuals at risk for relapse.

Identifying the underlying biological features of depression will help in the development of personalized therapy. Currently, approved antidepressant medications raise the levels of norepinephrine, serotonin, and dopamine in nerve cell synapses. Among the most widely used medications are SSRIs, which block serotonin reuptake and are also used to treat other psychiatric conditions. These molecules work by reshaping synapses, and usually require a few weeks to take effect. Cognitive behavioral therapy, often in combination with medications, is also effective in people with depression. This type of counseling works to change thought patterns and reroute negative, dysfunctional thinking. Treating people with depression can be challenging, as medications affect individuals differently. Sometimes, two or three tries are needed to find an effective treatment plan.

Unfortunately, for some people with depression, neither medication nor psychotherapy works. Researchers are actively investigating other approaches to treating depression, such as deep brain stimulation (DBS). Some promising studies have found that DBS can relieve intense depressive episodes that were resistant to other forms of treatment.

Bipolar Disorder

Like most people, you probably have good days and bad days, days when everything goes well and days when the whole world seems against you. But people with bipolar disorder (formerly called manic-depressive illness) experience very intense mood changes. Their moods swing between extreme highs and severe lows, each lasting anywhere from a few hours to several months. High, or manic, episodes involve boundless energy, racing thoughts, and insomnia; they may also involve substance abuse and harmful behaviors like risky sex or other unsafe activities. During low, or depressive, episodes, people with bipolar disorder feel very sad and hopeless, worried, and sometimes suicidal. Some individuals with bipolar disorder are hypomanic; they are highly productive, feel great, and function better than normal. These changes may be outwardly subtle — only noticed by a friend or family member — but can be a clue to more intense developing mania.

Bipolar disorder is difficult to diagnose. No specific tests, other than a set of symptoms medical professionals use, differentiate it from other psychiatric disorders such as depression, psychosis, or schizophrenia. Researchers don’t understand what causes bipolar disorder, although many individuals have a family history of a mood disorder or psychotic illness. Some people with depression may be at higher risk for bipolar disorder if a relative is bipolar or has another psychiatric illness like schizophrenia or autism. Studies analyzing the genomes of thousands of people with diseases like bipolar disorder have identified genetic changes that appear to be involved, but more research is needed to understand how and why these DNA misspellings cause serious brain dysfunction.

Kim, et al. PLoS One, 2010.

Brain imaging can reveal how the brains of individuals with schizophrenia function differently. In this image, the areas shown in orange were found to be less active in people with schizophrenia compared to healthy controls.

Bipolar disorder is notoriously hard to treat. Psychiatrists typically prescribe separate drugs to lessen the highs and stabilize the lows. Medications such as anti-epilepsy drugs, lithium, or so-called atypical antipsychotics are used for manic periods, and antidepressants or cognitive behavioral therapy during depressed periods. Most treatments have significant side effects and, unfortunately, up to one-third of people with bipolar disorder do not respond to treatment at all, creating enormous hardship for the affected individuals as well as their family and friends.

DISORDERS OF COGNITION

Schizophrenia

Schizophrenia is a lifelong, severe psychiatric disorder that seriously disturbs thinking, emotion, and behavior. People with schizophrenia appear to have lost touch with reality. They experience “positive” symptoms such as hallucinations, delusions, and confused thinking, and “negative” ones, including an inability to experience pleasure and a severe lack of motivation. Like many psychiatric disorders that first emerge when the human brain matures in the late teens and early 20s, schizophrenia usually appears between ages 15 and 25. This time period corresponds to development of the brain’s prefrontal cortex.

Although no cure exists for schizophrenia and many symptoms do not respond to treatment, some people can pursue personal and professional life goals with the help of medications, behavioral therapy, or a combination of these. Chlorpromazine, the first antipsychotic drug, was developed in the 1950s as an anesthetic for surgery but was soon employed to calm people with psychiatric disorders including schizophrenia. Since then, more than 20 similar antipsychotic drugs have been developed. Most of these drugs work by damping the dopamine response, which is thought to drive schizophrenia’s “positive” symptoms. For that reason, these medications may cause tremors and other movement-related side effects resembling Parkinson’s disease, which involves low dopamine activity. The most recently developed drugs also suppress some serotonergic activity, which seems to help with the negative symptoms of schizophrenia.

Scientists have known for many years, through studying twins and extended families in which schizophrenia is common, that this condition is highly influenced by heredity. Only recently, however, with the emergence of powerful tools that scan massive amounts of DNA information, have scientists identified more than 100 common genetic misspellings and at least 11 rare ones in the DNA of people with schizophrenia. Current research is focused on learning more about these genes, which affect nerve cell growth as well as development, learning, and memory. Genes having a proven relationship to schizophrenia are potential targets for new medications.

Recently, research has uncovered a new and unusual perspective for thinking about schizophrenia therapies. Previous studies had noted that nearly 90 percent of people with schizophrenia smoke cigarettes, possibly to provide relief for their symptoms. Researchers have learned that nicotine seems to relax rigid nerve-cell shape and function in areas of the brain affected by schizophrenia. Thus, drugs containing nicotine may prove to be useful as future treatments for schizophrenia.