Humankind has always sought ways to treat illness, injury, and pain. For example, the first known brain surgeries occurred about 6,000 years ago in Asia Minor. Also, archaeologists have found skulls of ancient Incas of Peru with small pieces of skull carefully removed (a process called trepanation) to treat head wounds, or possibly to cure epilepsy or infections. The earliest of these Incan skulls did not show any healing, indicating that the patients soon died. But by the 1400s, about 90 percent of the ancient skulls discovered showed bone regrowth.
How did those patients survive and how did they deal with the pain? It is likely that herbs like tobacco and coca leaves, and corn beer might have been consumed to provide some relief. As you learn about brain tumors, head trauma, pain management, and other problems caused by disease processes, remember that neuroscience seeks to understand the roots of these issues. Such insights will ultimately advance the medical field, enabling more effective treatments and therapies for the future.
BRAIN TUMORS
Each year, more than 79,000 people in the United States are likely to be diagnosed with a tumor that originates in their brain — a primary brain tumor. An estimated 26,000 of these tumors will be malignant (cancerous), and 53,000 will be benign (noncancerous). In addition, more than 200,000 people will be diagnosed with brain tumors that develop when cancer cells from other parts of the body travel through the bloodstream to the brain. Called metastatic brain tumors, these cancers typically spread from tumors of the lung, breast, skin, colon, or kidney. Regardless of its origin, a tumor, or any space-occupying lesion in the brain, can be lethal — thus surgical removal is required for survival.
Types of brain tumors are named according to the kind of cell from which they arise and the brain area where they develop. For example, many brain tumors are called gliomas — a general term for tumors that arise from the glial cells that support and protect neurons in the brain. The most common form of brain cancer is a glioblastoma — a proliferation of immature glial cells. The most common type of primary brain tumor is a meningioma: a benign tumor arising in the meninges, thin layers of tissue that cover the brain.
Symptoms of a brain tumor vary with its location and size and also differ among people. In some cases, a tumor causes general symptoms such as headache, due mainly to the pressure a tumor exerts on the brain. Or, a tumor located in a part of the brain controlling vision can cause difficulties with sight. In other cases, a tumor can damage healthy tissue as it grows. For example, as gliomas grow, they release toxic amounts of glutamate, which can destroy nerve cells near the tumor and cause seizures.
Several treatments — including surgery, radiation, targeted treatments, and chemotherapy — can be used alone or in combination to treat brain tumors. The goal of the treatments is to remove or shrink brain tumors to relieve pressure on the brain, as well as eliminating or reducing symptoms such as seizures and headaches.
If a tumor can be accessed without injuring nearby areas of the brain, surgery is usually the first step. Brain tumors can be removed with conventional techniques such as a craniotomy, in which the skull is opened and as much tumor as possible is removed. Another type of treatment for some tumors uses radiation. For this technique, called stereotactic radiosurgery, a high dose of radiation is aimed precisely at the tumor. A few radiation treatments can reduce or eliminate the tumor while sparing healthy tissue nearby. More recently, tumors are treated by multiple beams of ultrasound focused precisely to intersect exactly at the site of the tumor. These interventions can be carried out painlessly in awake patients inside imaging machines that visualize the tumor in the brain.
National Cancer Institute.
This brain scan shows a tumor in the brain’s left occipital lobe, seen here in bright blue. Knowing exactly where a tumor is located can help doctors start the proper treatment.
Following conventional surgery, doctors usually prescribe steroid medications to reduce swelling in the brain. Reduced swelling helps alleviate symptoms such as seizures, memory problems, or confusion that can occur after brain surgery. In patients with cancerous brain tumors, radiation may be administered to surrounding brain areas to help eliminate any cancer cells that remain in the brain after surgery. People with cancerous brain tumors can also be given chemotherapy to prevent growth or regrowth of their tumors. In the past decade, researchers have developed new ways to administer chemotherapy that allow medication to be delivered directly to the brain (tumor), rather than traveling through the body before reaching the brain. For example, after surgical removal of a brain tumor, small wafers containing anticancer drugs can be implanted in the space previously occupied by the tumor. Over time, the wafers slowly dissolve and release the chemotherapy drugs to nearby areas.
Researchers have also been studying various promising treatments that target specific cell mechanisms thought to be important to cancer cell growth. These targeted treatments zero in on genes and other cell mechanisms that fuel cancer cell growth, while sparing healthy tissues and causing less severe side effects than those that occur with conventional radiation or chemotherapy. For example, medications that help block formation of blood vessels are already being used to treat glioblastomas. Blocking tumor blood vessel formation is a key strategy in treating glioblastomas, because these tumors form strong networks of vessels that feed tumor growth.
Researchers are also testing ways to stimulate the ability of the body’s own immune system to stop tumor growth — an approach called immunotherapy. For example, promising research is using substances called checkpoint inhibitors, which interfere with the signals some tumors send to inhibit the immune system’s ability to block tumor growth.
Another promising area of research involves gene therapy. This technology identifies the genetic components that promote tumor growth and then interferes with their ability to work. Research is currently underway on a number of different gene therapies aimed at killing tumor cells and suppressing their growth-promoting genes.
Other approaches also under development focus on targeted delivery of antibodies, toxins, and growth-inhibiting molecules that can attach specifically to tumor cells and interfere with their growth. Researchers are also exploring the role of stem cells in both the development and treatment of brain tumors. Stem cells are undifferentiated, or unspecialized, cells with the potential to develop into any of a number of specialized cells, such as neurons. Normally, regulatory processes prevent mature, specialized cells from dividing and spreading; cancer cells escape these regulations. Understanding the normal processes that allow stem cells to mature will allow researchers to understand what might be going awry in cancer cells.
NEUROLOGICAL TRAUMA
Traumatic brain and spinal cord injuries can lead to significant disabilities and death. In the United States, an estimated 1.7 million people sustain traumatic brain injuries (TBI) each year. Of those, 275,000 are hospitalized, and about 52,000 will die as a result of TBI. Falls are the leading cause of all traumatic brain injury, and motor vehicle/traffic injury is the leading cause of TBI-related death. The direct medical costs and indirect costs of TBI, such as lost productivity, are estimated to be more than $60 billion a year in the United States.
Understanding the normal processes that allow stem cells to mature will allow researchers to understand what might be going awry in cancer cells.
Each year, about 17,000 people suffer spinal cord injuries in the United States, and an estimated 282,000 people currently live with spinal cord injuries. Vehicle crashes are the leading cause of spinal cord injury, followed by falls, acts of violence (primarily gunshot wounds), and injuries due to participation in sports and recreational activities. Death rates among people with spinal cord injuries are significantly higher during the first year after the injury, especially people whose injuries cause severe neurological impairments.
Few effective remedies have been found to repair damage incurred by head and spinal cord injuries; however, new methods have come to light for preventing damage that develops after the initial injury. In addition, there are ongoing efforts to support better rehabilitation techniques as well as research into the regeneration and repair of injured tissue.
Traumatic Brain Injury
Widespread use of computerized tomography (CT) and magnetic resonance imaging (MRI) techniques has afforded opportunities to observe the extent of tissue damage in TBI and determine its medical management. Traumatic brain injuries are caused by bumps, blows, or jolts to the head that cause multiple minuscule bleeds or by penetrating head injuries that directly destroy brain tissue. TBI can be “mild,” such as concussion — a temporary disruption in brain activity — or “severe.” TBI can cause bruises in the brain, massive bleeding inside the brain, cuts in the brain tissue, direct nerve damage, and death of nerve cells. Brain injury can trigger swelling, fever, seizures, and other neurological impairments. Even mild TBI can cause damage to neurons, which release pro-inflammatory factors that initiate and sustain an inflammatory response.
People such as professional football players or boxers, who sustain repeated concussions and other brain trauma, might develop a progressive degenerative brain disease called chronic traumatic encephalopathy (CTE). CTE occurs when repeated head trauma triggers degeneration of brain tissue; this process includes a buildup of abnormal proteins, which can begin months, years, or even decades after the last brain trauma. Symptoms associated with CTE include memory loss, confusion, impaired judgment, impulse control problems, aggression, depression, and, eventually, progressive dementia.
Most people with mild brain injuries, such as concussions, recover fully in a short period of time. Yet a study of college ice hockey players who had concussions showed that their brain volume had decreased two weeks after the concussion, a change that lasted at least two months. Rest and avoidance of physically demanding activities give the brain time to heal and are key aspects of recovery. People who arrive in the emergency department with a severe head injury are carefully monitored for bleeding or swelling that puts pressure on the brain. Treatments for increased pressure inside the skull include removing an amount of water fluid from injured and inflamed brain tissue.
Severe TBIs can cause bruising on the surface or within the brain. The bruising might cause blood to leak from vessels and contact brain tissue directly, which can be toxic to brain cells. Pressure often increases in the injured area, compresses the blood vessels, and reduces critical blood flow to the injured tissues. If fluid removal and medications fail to decrease pressure on the brain, part of the skull can be drilled open or removed to relieve pressure on the brain. In extreme cases of TBI, bruising in the brain can contribute to development of a seizure disorder called post-traumatic epilepsy.
Once a person with a brain injury is stable, the long road to recovery begins. Physical and occupational therapy are used to help people regain lost functions such as speech and movement. A wide variety of medications can be used to treat other symptoms of TBI such as pain, seizures, muscle spasms, sleep disorders, depression, and anxiety.
Spinal Cord Injury
Like TBI, spinal cord injuries (SCI) can permanently damage nerve cells and cause a wide range of disabilities — including various degrees of paralysis. Methylprednisolone, a steroid drug, is the only treatment for SCI currently approved by the U.S. Food and Drug Administration (FDA). This medication appears to reduce damage to nerve cells and decrease inflammation near the site of the SCI. If administered within eight hours of injury, it can be effective in treating spinal cord injuries in some people.
There is no cure for spinal cord injuries, but scientists are investigating new ways to repair damaged spinal cords. These include protecting surviving nerve cells from further damage, replacing damaged nerve cells, stimulating the regrowth of axons and targeting their connections, and retraining nerve circuits to restore bodily functions. In addition, scientists constantly search for new methods for rehabilitating patients with SCI and improving their quality of life. Rehabilitation focuses on physical therapy to strengthen muscles and improve mobility. Occupational therapy focuses on enhancing fine motor skills, such as the skills needed to write or type. Electrical stimulation is sometimes used to help restore function to muscles affected by the injury.
Scientists have also discovered that new nerve cells can be born in an adult brain. However, these new cells do not seem to help an injured brain repair itself, so studies are ongoing to determine how to jumpstart the pathway that stimulates the birth of new nerve cells. Stem cells, some even derived from a patient’s own tissues, might be able to start a new population of cells that are able to produce many cell types, nerve cells among them. Researchers are also working to understand how certain neurochemical and cellular barriers that prevent regrowth and repair can be overcome and how the newly born cells can be induced to integrate into the injured circuit.
NEUROLOGICAL ACQUIRED IMMUNE DEFICIENCE SYNDROME
In 2015, about 2.1 million people worldwide became infected with the human immunodeficiency virus (HIV), the virus that causes acquired immune deficiency syndrome (AIDS). Currently, an estimated 37 million people worldwide live with HIV. The vast majority live in eastern and southern Africa, and about 40 percent of people living with HIV are unaware that they are infected with the virus. From 2008 to 2014, the estimated number of new HIV diagnoses in the U.S. fell by 18 percent, possibly due to targeted prevention efforts.
Globally, the number of people receiving treatment for HIV has increased dramatically in recent years, particularly in developing countries. In 2015, 17 million people living with HIV were receiving life-prolonging antiretroviral treatment. In 2010, only 7.5 million people were receiving this treatment.
Although HIV targets the immune system, the nervous system can also be affected. More than half of people with HIV develop HIV-associated neurocognitive disorders (HAND). HAND causes mental problems ranging from mild difficulty with concentration, memory, coordination, and complex decision-making to progressive dementia, called AIDS dementia. Even people who receive antiretroviral treatments can develop mild symptoms of HAND.
The mechanism behind the development of HAND is unclear. Most scientists speculate that certain proteins in the virus itself, or proteins released by cells infected with HIV, cause nerve damage leading to the disorder. Whatever the mechanism, HIV infection appears to be the key player in HAND, because antiretroviral treatment may prevent or reverse it in many people.
Mild forms of HAND have been reported in about one-third of people with HIV infection who have no other symptoms. In advanced disease, people can develop increasing problems with concentration and memory as well as an overall slowing of their mental processes. At the same time, they might experience leg weakness and loss of balance. MRI and CT scans show brain shrinkage in people with HAND. Examination of the brains of people who die with AIDS sometimes reveal loss of nerve cells, white matter abnormalities, and damage to cellular structures involved in cell-to-cell communication. Inflammation and vessel disease can also be present.
Recently, research has indicated that “cocktails” of three or more antiretroviral (ARV) drugs active against HIV can reduce the incidence of AIDS dementia. These treatments can also reverse brain abnormalities caused by HIV.
Another neurological problem commonly developed by people with HIV is peripheral neuropathy. Peripheral neuropathy involves injury to the nerves of the extremities and causes discomfort ranging from tingling and burning to severe pain. HIV is believed to trigger the injury, and certain ARVs can cause the neuropathies or make them more frequent and serious. More than half of people with advanced AIDS have neuropathy.
Despite remarkable advances in new therapies, AIDS cannot be cured, and some of its neurological problems do not respond to treatment. In addition, people living with HIV are particularly vulnerable to certain infections and cancers because the virus weakens their immune system. Fortunately, combination ARVs have greatly reduced the incidence of most of these infections, as well as some of the neurological problems associated with AIDS.
MULTIPLE SCLEROSIS
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, usually diagnosed in people between 20 and 40 years of age. For unknown reasons, the immune system of a person with MS launches an attack against its own central nervous system, including the brain, spinal cord, and optic nerves. The target of this attack is the myelin sheath, a fatty substance that forms a protective coating around nerve fibers; the nerve fibers themselves can also be affected. As a result of the attack, the damaged myelin and the accompanying inflammatory cells form lesions, patches of scar tissue that look like sclerosis.
In MS, the patches of disease activity appear in multiple areas of the central nervous system, which is why the disease is called multiple sclerosis. Damage to the myelin sheaths and nerve fibers interferes with transmission of nerve impulses within the brain and spinal cord, as well as their communication with other body areas. The effects of MS are often compared to the loss of insulation around an electric wire and damage to the wire itself, interfering with signal transmission. Damage can occur in the white (myelin) and gray (nerve cell bodies, glia, etc.) matter of the brain.
The cause of MS is unknown, but there are some hints that a genetic factor is involved. Siblings of people with MS are 10 to 15 times more likely to develop MS than people with no family history of the disease. The risk is particularly high for an identical twin of someone with MS. Oddly, the disease is as much is five times more prevalent in temperate climates, such as the northern United States and northern Europe, than in the tropics. Although Caucasians run a higher risk than other races of developing MS, the prevalence of MS indicates that risk is shaped by both genetic and geographical factors.
Damage to the nervous system in people with MS can cause a wide array of symptoms. The spinal cord, cerebellum, and optic nerve are commonly affected by MS, so problems often arise in functions controlled by those areas. Symptoms include numbness, clumsiness, and blurred vision. Other symptoms are slurred speech, weakness, pain, loss of coordination, uncontrollable tremors, loss of bladder control, memory loss, depression, and fatigue.
At the location of an injury, the body produces prostaglandins, which increase pain sensitivity. Aspirin blocks the production of prostaglandins, thus preventing pain. Opiate drugs act in the brain and spinal cord to block pain signals.
When a person is diagnosed with MS, treatment options depend on the type of disease that is present. Specialists classify MS as one of three categories: relapsing-remitting MS, characterized by flare-ups of new or worsening symptoms followed by complete or partial remission of symptoms; primary-progressive MS, defined by progressive worsening of symptoms after disease onset; and secondary-progressive MS, in which relapsing-remitting disease has transitioned into a progressive form of disease that worsens over time.
Within each category, MS is further classified as “active” or “not active.” While the categories refer to the progression of symptoms, the classification refers to presence (“active”) or absence (“not active”) of new areas of inflammation, seen on MRI scans. In some cases, MS is defined as “stable,” meaning that symptoms are stable and no activity appears on routine MRI scans.
MS has no cure, but an increasing number of medications are becoming available or are under investigation. Since 2010, six new or revised disease-modifying therapies have been approved for use in people with MS. In addition, several medications can now help control the inflammation and immune system attacks in relapsing-remitting MS. Steroid drugs, specifically glucocorticoids, reduce the inflammation and might also help shorten acute attacks. Medications and therapies are also available to control symptoms such as muscle stiffness, pain, fatigue, mood swings, and bladder, bowel, or sexual dysfunction.
CHRONIC PAIN
Pain can be acute — a short-lived side effect of injury or disease — or a chronic condition that persists for weeks, months, or even years. For some people, pain is the disease itself. Pain affects more Americans than diabetes, heart disease, and cancer combined, afflicting the lives of approximately 100 million Americans. Back pain, severe headache or migraine pain, and facial ache are the most common culprits. In the US, the cost of healthcare, disability, and lost productivity due to pain ranges from $560 billion to $635 billion annually. Chronic pain can trigger a cascade of psychological processes that lead to changes in perception, attention, mood, motivation, learning, and memory. Increasing evidence indicates the value of a combination of treatments involving drugs, behavior, physical therapy, and other modalities to fully manage chronic pain.
Treating Pain
Anesthesia is used to prevent pain during a wide variety of medical procedures and surgery. Local anesthetics work by temporarily blocking pain receptors. Commonly used anesthetics include procaine (Novocain) and lidocaine.
Once pain occurs, four main types of painkillers may be used to relieve it: aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen; opioids (powerful drugs that act directly on the nervous system) such as morphine and codeine; antiepileptic agents such as gabapentin; and antidepressants such as amitriptyline.
NSAIDs reduce inflammation and are effective for postoperative pain and for pain caused by inflammation such as arthritis. NSAIDs are also useful for treating the mild or moderate pain of headaches, sprains, or toothache. NSAIDs work by inhibiting substances that trigger the synthesis of pro-inflammatory and pain-producing chemicals (such as prostaglandins). Moderate pain is often treated by combining a mild opioid like codeine with aspirin or another NSAID.
Opioids, often used for severe pain, work directly in the central nervous system by attaching to receptors on nerve cells. These drugs not only reduce feelings of pain but also produce feelings of euphoria. While highly effective against pain, opioids do have many serious side effects, such as slowing a person’s breathing. Most importantly, they are highly addictive. The current opioid epidemic in the United States is caused, in part, by the facility to obtain opioid prescriptions and poor pain management of chronic pain. The brain of a person suffering from chronic pain undergoes major changes, and the solution for this complex problem should include more than pharmaceuticals.
A stroke occurs when a blood vessel bringing oxygen and nutrients to the brain bursts or is clogged by a blood clot. Without blood, cells in the brain start to die within minutes. It can also cause dangerous molecules called free radicals to escape, which can further damage brain tissue. The effects of a stroke, such as movement or speech problems, depend on where in the brain the stroke occurs.
Psychological therapies such as cognitive behavioral therapy and biofeedback can also be used to stimulate relaxation and release muscle tension, thereby helping reduce the effects of chronic pain. Psychological treatments can also help people manage changes in mood, perception, memory, and other psychological factors often affected by chronic pain.
Antiepileptic and antidepressant drugs are generally used to treat nerve pain that results from injury to the nervous system. Nerve damage and pain (neuropathy) can be due to chronic high blood sugar levels; viruses, such as shingles; phantom limb pain; or post-stroke pain.
The Body’s Pain Control System
Studies of the body’s pain control system have shown that our bodies produce their own naturally occurring opioids, called endorphins. Scientists have also identified the receptors through which opioids work to decrease pain. The finding that opioid receptors are concentrated in the spinal cord led to the use of injections of morphine and other opioids into the cerebrospinal fluid (CSF) surrounding the spinal cord. Remarkably, these injections enabled profound pain control without causing paralysis, numbness, or other severe side effects. This technique is commonly used to treat pain after surgery. In addition, some patients are given implanted opioid pumps to enable long-term treatment of severe chronic pain.
Scientists have identified many molecules that are involved in the body’s pain response. Developing drugs that target these molecules could have great benefit for treating patients who experience acute or chronic pain.
Advances in brain imaging techniques have also broadened our understanding of how the brain perpetuates chronic pain after a painful stimulus has been removed and injuries have healed. As a result, pain researchers are moving toward a whole-brain approach for their studies, developing new technologies and techniques that could lead to better diagnosis and more effective treatment of chronic pain.
STROKE
Each year, nearly 800,000 people in the United States suffer a stroke — an interruption in blood flow to the brain due to a ruptured blood vessel or a blood clot. Of these, about 600,000 are first strokes. Strokes are a leading cause of long-term disability in the United States, costing about $33 billion each year, including the costs of health care services and medicines to treat stroke, and missed days of work. More than 130,000 Americans die of a stroke each year.
Risk factors for stroke include obesity, physical inactivity, and heart disease. Controlling these factors by maintaining a healthful weight, exercising, avoiding excessive alcohol intake, and taking medications for stroke-related physical problems such as high blood pressure, can reduce the risk of having a stroke. There is also a genetic component in stroke risk, especially evident if a parent has suffered a stroke by age 65. To date, several candidate genes have been suggested, but increased stroke risk is most likely due to multiple genetic factors.
Until recently, treatments for a stroke did not go far beyond physical or speech therapy. Today, however, clot-dissolving medications are a standard treatment. Tissue plasminogen activator (tPA), a clot-dissolving drug approved by the FDA in 1996, helps to break down blood clots and open blocked blood vessels. tPA can restore circulation before oxygen loss causes permanent brain damage; given within three hours of a stroke, its use often limits brain damage. In addition, surgery to clear clogged arteries and other treatments targeting heart disease can help prevent strokes. Anticoagulant drugs also help by reducing the likelihood of clots forming elsewhere in the body and traveling to the brain, causing a stroke.
Research is underway to find new methods for preventing and treating strokes. Some drugs have been shown to be effective at preventing damage to the nervous system, including nerve cell death following a stroke. Another promising research area is the use of neural stem cells to improve recovery after a stroke. Preliminary research suggests that injection of stem cells helps promote recovery, even when given several days after a stroke. Administering growth-stimulating substances along with the stem cells might enhance the benefits of the stem cell transplant. 