Exercise prescription

From Wikipedia, the free encyclopedia

Exercise prescription commonly refers to the specific plan of fitness-related activities that are designed for a specified purpose, which is often developed by a fitness or rehabilitation specialist for the client or patient. Due to the specific and unique needs and interests of the client/patient, the goal of exercise prescription should be focused on motivation and customization, thus making achieving goals more likely to become successful. The prescription of exercise came about because of the major impact that exercise can have on our health and the many benefits it brings to our body. Exercise benefits our mind, body and emotional state. It can also benefit our social life as well. Exercising daily can help to prevent various illnesses, which is another reason why physicians prescribe exercise to their patients. Many people don't get the adequate amount of exercise or don't exercise at all which leads to them contracting harmful ailments.

Patient referral

In the United Kingdom there is a scheme called "Exercise on prescription" in which doctors are able to prescribe exercise to those with conditions that benefit from it, such as asthma, depression, or obesity. The initiative particularly aimed to lower the rate of heart disease. National standards for such initiatives from doctors were established by the Department of Health in 2001. Exercise on prescription aims to prevent deterioration of conditions, and views exercise as a preventative health measure. Fitness classes or a course at the local gym are available on prescription at a reduced rate to people who might benefit from them. It aims to make it easier for people to follow their doctors' advice about taking more exercise or losing weight. Such preventative measures hope to lead to savings for the National Health Service.

Researchers in New Zealand have also discussed the benefits of exercise referral by medical practitioners there. In New Zealand it is known as a green prescription, while in the United States a similar initiative is known as Exercise is Medicine. A green prescription is a referral given by a doctor or nurse to a patient, with exercise and lifestyle goals written on them. The term, used by health practitioners in New Zealand draws parallel to the usual prescriptions given to patients for medications, and emphasises the importance of exercise in improving their condition, and not relying on drugs. The green prescription is written after discussing the issues and goals in the consultation. Studies have shown that an increase in exercise, better sense of well-being, and a decrease in blood pressure results from using the method. A decreased risk of coronary heart disease has not been shown. This was shown in two studies, one by Swinburn (1998), that surveyed patients in Auckland and Dunedin. The other was Elley (2003) and was done in 42 practices in the same region of New Zealand.

General practitioners like the idea as it formalises what they are telling the patient about how their lifestyle changes are necessary (Swinburn 1997).

Research in Australia has suggested that an exercise prescription program would be very beneficial and many ICU physiotherapists are already performing this practice, however there is no national standards to govern how this practice is administered so there is great variety in the ways this is administered therefore more research is needed.

Mental and Emotional Benefits

Exercise is a great stress relief whether you go for a jog or hit the gym. Both physical and mental stress are reduced by daily exercise. Working out can also make you feel happier and more joyful due to the fact that endorphins are released which create feelings of jubilation. The release of endorphins can alleviate symptoms of depression and anxiety. Even just exercising for 30 minutes a few times a week can enhance overall mood. Self-confidence and self-worth can also be enhanced with exercise by promoting self-love and taking care of ones health. Exercising outdoors can also increase self-love even more by getting much needed vitamin d, getting fresh air, and enjoying the beautiful outdoor scenery. People start to gain a more positive mood and outlook on life through working out and become more emotionally stable. They become more emotionally stable because they are less consumed by responsibilities and commitments while enjoying their physical activity. 

As humans age and get older, their brain cells start to shrink and people start to lose many important brain functions. Exercise can't cure decline in functions of the brain but it can prevent degenerations of cognitive processes that usually occur after age 45. Studies have also demonstrated that cardiovascular exercise can improve brain performance and enhance levels of a brain-derived protein that assist with decision-making, higher thinking, and learning. Regular physical activity can also sharpen memory, assist in controlling addiction, and increase levels of relaxation. Memory is sharpened because there is an increase in production of cells in the hippocampus, which is responsible for memory and learning. For example, a study demonstrated how running sprints improved vocabulary retention among healthy adults. Some people can become addicted to the chemical dopamine and the substances that produce it such as drugs and alcohol. Physical activity can help addicts recover by distracting them from their addictions and make them think less about their cravings. Physical activity restarts the circadian rhythm and allows addicts to fall asleep at the right time and stay up all night. While working a few hours before bedtime raises body temperature, then few hours later the body temperature cools down and signals to the body that its time to relax and fall asleep which initiates better relaxation and fulfilling sleep.

Physical Benefits

Physical activity is a widely known as one of the main ways of losing weight along with a health diet. Certain studies have shown that inactivity played a major role in obesity and weight gain. Frequent exercise increases metabolic rate, which leads to burning more calories and weight loss. Combination of aerobic exercise with strength training can boost fat loss and muscle mass maintenance. Through regular exercise, strong muscles and bones can be developed. It is essential to build bone density when you're younger in order to prevent muscle mass loss and to build and maintain bone density and muscle strength. For some people suffering from severe fatigue such as chronic fatigue syndrome or other illnesses would benefit from regular exercise by increased energy levels. For instance, "a study found that six weeks of regular exercise reduced feelings of fatigue for 36 healthy people who had reported constant fatigue" (Healthline). 

Frequent physical activity decreases chances of getting a chronic disease and decreases belly fat. Frequent physical activity has also been proven to enhance insulin sensitivity, cardiovascular fitness and body composition, while lowering blood pressure and blood fat levels. Exercise boosts the overall health of your skin by reducing oxidative stress in the body. Oxidative stress in the body is when there is an imbalance between free radicals and antioxidants in the body. When the antioxidants are not strong enough to counteract the damaging free radicals then oxidative stress occurs. Moderate exercise increases levels of antioxidants and produces more blood flow, which protects skin and hinders signs of aging. Chronic pain may be controlled and reduced by frequent exercise as well. Physical activity may also increase pain tolerance which will lessen pain interpretation.

For specific diseases

Osteoarthritis

Studies show that exercise prescription aids in both preventing and minimizing the effects of joint disorders such as osteoarthritis. Evidence shows that in addition to the general physiological, psychological and functional benefits gained from exercise, greater quadriceps strength has a mitigating effect on knee joint pain.

Depression

A large body of research indicates that exercise prescription has beneficial effects for patients suffering depression. One study shows a significant improvement for a randomized group of women with major depressive disorder engaging in a twice-weekly resistance training program compared to a control group. The reasons for this marked change is thought to have biochemical, physiological and psychosocial aspects.

Peripheral arterial disease (PAD)

Blockage or closing of the arteries of the lower limbs impairs blood flow to the legs and results in significant reduction in physical capacity. Alternate exercise prescriptions to walking are considered. Aerobic exercises such as arm-cranking or cycling are recommended. Risk factors for disease progression should also be taken into account when aiming to improve waling ability. Functional capacity should be determined prior to commencement of prescribe exercise programs.

Diabetes mellitus

The number of individuals diagnosed with diabetes mellitus are rapidly increasing and a lot of evidence suggests this is due to an insufficiently active lifestyle. Benefits of exercise include stress reduction, reduced risk of heart disease, lowers blood pressure, helps control weight and aids insulin in improving management of diabetes. Exercise that is not too strenuous is recommended. Such activities may include walking, swimming, gardening, cycling or golfing. Incidental activities are encouraged, such as using the stairs instead of an escalator/lift or walking short distances instead of driving. Dr Gebel, who works at James Cook University's Centre for Chronic Disease Prevention conducted a study reporting increased health benefits through incorporation of more vigorous exercise. He stated that this could include 'vigorous gardening', not necessarily meaning going to the gym. Diabetes Australia suggest 30 minutes of exercise daily as a suitable target, which can be divided into three 10-minute sessions throughout the day. Exercise programs however should be tailored and delivered by individuals with appropriate qualifications.

Cancer

According to the Center for Disease Control and Prevention, regular exercise may lower your risk of various cancers. Studies have found that working out can reduce risk of recurrence or death by as much as 50% in people with colorectal cancer. Physical activity may also decrease the risk of recurrence for breast cancer patients, by regulating hormone levels. Exercise also has the ability to reduce side effects of cancer treatments such as nausea and fatigue.

Heart Disease

Frequent physical activity lowers blood pressure, helps maintain a healthy body weight, and reduces cholesterol levels which all lower the chance of getting heart disease.

Sleep Apnea

Sleep apnea is a blockage in the upper airway of the throat that prevents proper breathing. Normally, the brain would immediately wake you up to continue normal breathing patterns. People identified as obese have a higher chance of contracting this disease, exercise can help to prevent this disease by lowering weight before problems arise.

Obesity

Obesity is a complex health condition where a person is excessively overweight. People who exercise regularly and eat a healthy diet are much less likely to become obese and experience the health complications it can bring. Any physical activity that you can enjoy week after week will assist in losing weight along with a change in diet.

Dementia

Several studies have shown that aerobic exercise in middle-aged and older adults have reported improvements in thinking and memory, reduced chances of dementia. A study done on 2,000 men in Wales over 35 years were examined on five behaviors (regular exercise, not smoking, moderate alcohol intake, healthy body weight, and healthy diet), exercise had the greatest effect in lowering the risk of dementia(Alzheimer's Society). In another study of 716 people with an average age of 82 years old, people who were in the bottom 10 percent were more than twice as likely to develop Alzheimer's disease than those in the top 10 percent. Aerobic exercise has also been proven to affect the brains of older people. For example, in a modest-size trial, one year of aerobic exercise resulted in a small increase in the size of the hippocampus, which was equal to reversing one to two years of age-related shrinkage (Alzheimer's Society).

Exercise recommendations

According to Exercise and Sport Science Australia, a minimum amount of 210 minutes of moderate intensity exercise or 125 minutes of vigorous intensity exercise should be performed per week. Exercise should include both aerobic and resistance training. For greater health benefits, exercise should be performed regularly with no more than a two-day gap between training sessions.

Elderly

Research has found that having a well planned exercise routine can greatly benefit the elderly. It an reduce the risks of coronary heart disease, diabetes mellitus and insulin resilience, hypertension and obesity as well as vast improvements in bone density and muscle mass.

Exercise program development

Exercise prescription is designed to modulate acute exercise programming variables to create the adaptations desired by the individual or sport. With aerobic exercise prescription, the type of exercise, duration of exercise, frequency, and duration is adjusted. For resistance exercise prescription, the type of exercise, total session volume, rest period, frequency, and intensity are determined. Prescription of stretching and other activities is also commonly seen. Exercise prescription can be divided into 5 components:

• Type of exercise or activity (eg, walking, swimming, cycling)
• Specific workloads (eg, watts, walking speed)
• Duration and frequency of the activity or exercise session
• Intensity guidelines – Target heart rate (THR) range and estimated rate of perceived exertion (RPE)
• Precautions regarding certain orthopedic (or other) concerns or related comments

Steps to a Healthier You

1. Before beginning any exercise program it is best to assess your fitness level. This can be done by:

• Checking your pulse rate before and immediately after walking 1 mile
• Seeing how long it takes to walk a mile
• Count how many half situps, standard pushups, and modified pushups you can do at a time
• Measuring your waist circumference
• Measuring body mass index

2. After assessing your fitness level then create a fitness program.

• Think about what your fitness goals are: ensure clear fitness goals are declared so that you stay motivated and can determine progress
• Design a balanced routine: According to the Department of Health and Human Services, "it is recommended that you get at least 150 minutes of moderate aerobic activity or 75 minutes of vigorous aerobic activity a week, or a combination of moderate and vigorous".
• Begin slowly and progress slowly: if your just starting to exercise then start slowly and gingerly. If you have any pre-existing health conditions or injuries then meet with a doctor before beginning to exercise.
• Incorporate activity into daily routine: Schedule time to workout like any appointment and have it written down on a calendar or a planner.
• Incorporate different types of activities: Participating in the same activity over and over again again can get boring. To prevent boredom, try different types of activities such as walking, biking, swimming, and strength training.
• Have adequate amount of recovery time: Set time in between workout sessions that allow the body to rest and recuperate.
• Write goals and plans on paper: having plans written may help people stick to their goals

3. Get started

• Start slowly and progress gradually: Give enough time to warm up and cool down. Try to start working out for at least 30 minutes then build up to 60 minutes.
• Break a session up: If you don't have time for a full 30 minute or 60 minute session then break it up throughout the day. You can do one 15 minute session in the morning and one 15 minute session in the night.
• Creativity: Include fun activities that also add to your workout regimen such as scuba diving with friends or going for a hike with family.
• Listen to your body: If you're feeling any kind of pain, dizziness, or nausea then take a break and don't over do it. If you're not feeling well and have the flu then take a few days off and give your body the proper time to rest.

Overcoming Psychological Barriers

Low Self Motivation

If it is hard to motivate yourself to go to the gym or to just workout period, then it may be best to find a workout buddy or buddies. Joining fitness groups or classes would be beneficial as well to help motivate you and push you to your highest potential. Working out with a group or a friend can also make it a more enjoyable experience.

Fear of injury

If you have been injured in the past and are afraid of being re-injured then participate in a low-impact activity such as using the elliptical. The fear of re-injury is not a good enough reason to stop exercising which will prolong and benefit your life in the long run.

Poor Self Image

Millions of people have low self-esteem and poor self image. Going to the gym for the first time may be intimidating for some because they are surrounded by people who they feel are fitness experts and that are looking down on them and criticizing them. However, they were all beginners too and there's a high chance that they are not watching you and are focusing on their own workout. Going with a friend for the first time may help or meeting with a therapist may help as well.

Lack of Confidence

For many beginners, the gym equipment may seem daunting but there are fitness coaches available at the gym that can assist with any confusions. Along with fitness coaches, there are online fitness resources as well that will explain all the different fitness techniques to be successful in the gym and on your new fitness journey.

Self-Management Skills

To overcome this obstacle of not being able to manage yourself then you should set specific goals for your self.

• Set reachable goals
• Be specific
• Have mini goals
• Write down all goals and when you want to meet them by
• Identify what your motives are for working out
• Reward yourself after achieving each goal

Some people love working out while others completely despise it. If your are someone that finds it hard to enjoy exercise then try more creative activities such as rock climbing or playing a game of basketball or soccer. Another fun way of getting your cardio in is dancing instead of just running on the treadmill.

4 Types of Exercise

Endurance

Endurance/aerobic activities enhance breathing and heart rate. They keep your heart, lungs, and circulatory system healthy. Endurance exercises include:

• Jogging
• Working in the yard
• Dancing

Strength

Strength exercises make muscles stronger, protect bone and muscle mass, keeps extra weight off, develop better body mechanisms, and more calories burned. These exercises can help you to become stronger and make doing everyday activities easier. Strength exercises include:

• Weight lifting
• Working out with a resistance band
• Exercising using your own body weight

Balance

Balance exercises aid in preventing falls which is common among older adults. Balance exercises include:

• Standing on one foot
• Heel-to-toe walk
• Tai Chi

Flexibility

Flexibility exercises stretch your muscles and helps the body to stay agile.You experience less pain, fewer injuries, and improved posture and balance. Being more limber gives more freedom of movement for other types of activities and everyday activities. Flexibility exercises include:

• Yoga
• Calf stretch
• Shoulder and upper arm stretch

Amphibian 'apocalypse' caused by most destructive pathogen ever

The first-ever global tally of the disease's toll reveals that it caused declines in at least 501 frog and salamander species.

PUBLISHED March 28, 2019 by Michael Greshko

Original link:  https://www.nationalgeographic.com/animals/2019/03/amphibian-apocalypse-frogs-salamanders-worst-chytrid-fungus/?cmpid=org=ngp::mc=social::src=facebook::cmp=editorial::add=fb20190328animals-chytridfungus::rid=&sf210088124=1&fbclid=IwAR2ND4sCQ0wgA_57M3IbjqfQL1JYN799tCdmiY72XoA26HKBbYwu4XVZZ70

For decades, a silent killer has slaughtered frogs and salamanders around the world by eating their skins alive. Now, a global team of 41 scientists has announced that the pathogen—which humans unwittingly spread around the world—has damaged global biodiversity more than any other disease ever recorded.

The new study, published in Science on Thursday, is the first comprehensive tally of the damage done by the chytrid fungi Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal). In all, the fungi have driven the declines of at least 501 amphibian species, or about one out of every 16 known to science.

Of the chytrid-stricken species, 90 have gone extinct or are presumed extinct in the wild. Another 124 species have declined in number by more than 90 percent. All but one of the 501 declines was caused by Bd.

“We’ve known that's chytrid's really bad, but we didn't know how bad it was, and it's much worse than the previous early estimates,” says study leader Ben Scheele, an ecologist at Australian National University. “Our new results put it on the same scale, in terms of damage to biodiversity, as rats, cats, and [other] invasive species.”

Scheele has seen the fungus's carnage firsthand. At one of his field sites in Australia, an extended El Niño fueled mass frog breeding and dispersal—letting Bd spread as never before. Before the fungus, populations of the alpine tree frog were so abundant there, he had to watch his step when he went out at night. Now, the species is nearly impossible to find.

Saddened and shocked, Scheele resolved to put numbers to the decline. Four years—and innumerable email conversations—later, Scheele's team has finally combined all known reports of chytrid declines into a single consistent database, revealing Bd and Bsal's record-breaking toll.

“Chytrid fungus is the most destructive pathogen ever described by science—that's a pretty shocking realization,” adds Wendy Palen, a biologist at Simon Fraser University in British Columbia who wrote about the study for Science. 

The bulk of amphibian die-offs occurred in the 1980s—when the disease began to circulate around the globe—with a second uptick in mortality in South America in the mid-2000s. Many the affected frogs live in Central and South America, though outbreaks also occur across Europe, North America, Australia, and Africa. There are no known declines from Asia, where the fungus has co-existed for millions of years.

What's more, the study's counts are conservative. Earlier die-offs from the 1950s and 1960s in Europe and North America aren't included for lack of evidence. And the 501 species tallied are just the ones that scientists know about. Researchers keep identifying new species of frogs—even after they've been nearly wiped out in the wild.

The study's authors hope that the new research will act as a call to arms against the pandemic.

“I can totally understand why some people might see this issue as too little, too late, but I strongly disagree with that, because saying that does not truly take into consideration how much worse it can still get,” says study co-author Jonathan Kolby, a National Geographic Explorer and policy specialist at the U.S. Fish and Wildlife Service.

That's why researchers are urging governments around the world to buy amphibians time by curbing the trade of wild amphibians, protecting amphibian habitats, combating invasive species that threaten amphibians, and supporting captive-breeding programs.

Origins of a killer

There are hundreds of species of chytrid fungi, and most of them are unobtrusive decomposers. But Bd is an oddball: It has a fanatical taste for the proteins in amphibian skin. In the early 20th century, human activity—such as trade and war—accidentally spread the fungus around the world.

Along the way, it evolved, spawning a highly virulent strain that's primarily responsible for the pandemic.

Some amphibians can tolerate Bd, but in many others, it degrades the animals' permeable skin, which they use to breathe and regulate their water levels. Runaway infections trigger a death spiral that ends in cardiac arrest.

Not only is Bd lethal, it's also devastatingly effective at spreading. While most pathogens target specific hosts, Bd can infect at least 695 species to varying degrees. It also doesn't kill its victims quickly, which increases the odds that the fungus will spread. Species it doesn't kill, such as the American bullfrog, can act as reservoirs.

In addition, the fungus can spread by touch or by water; Bd spores can swim a short distance. And if conditions are right, the fungus can live outside of its host for weeks to months—maybe even years—at a time. “In some respects, it’s the perfect pandemic recipe,” says biologist Dan Greenberg, a Ph.D. student at Simon Fraser University. “If it were a human pathogen, it'd be in a zombie film.”

As National Geographic has previously reported, Bd snuck up on researchers much like a fictional zombie plague. Scientists first started noticing frog die-offs in the 1970s, but researchers didn't realize these “enigmatic declines” were a global phenomenon until the 1990s. Researchers described Bd in 1997; within a decade, it was the top suspect in the killings.

Study co-author Karen Lips, an ecologist at the University of Maryland, watched as the fungus spread through sites she had been monitoring for more than 15 years. From 2004 to 2008, one of her sites in Panama lost more than two fifths of its amphibian species to Bd. “You get to know this system, and it’s all completely wiped out,” she says. “It’s just horrible to see that degree of change.”

Similar scenes played out in the French Pyrenees, where midwife toads keel over by the hundreds on mountain lake shores. “Early in the outbreak, midwife toads would be calling at full volume—it’s a beautiful chorus. Once the disease has swept through, you don't hear any calling,” adds study co-author Mat Fisher, an epidemiologist at Imperial College London. “The world becomes very quiet.”

Holding the line

Researchers say that we can't reverse the damage that Bd has already done. The fungus is already worldwide, and purging it from the environment is impossible. While topical fungicides can heal Bd-stricken amphibians in the wild, they can't be applied on a global scale.

In the face of this reality, the study's authors say our best bet is to greatly curtail the global trade of wild amphibians, or at the very least improve screening procedures. The pet and meat trades probably play a major role in continuing the pathogen's spread. A 2018 study confirmed that all major strains of Bd, including the one most responsible for the global pandemic, are present in pet-shop animals.

Despite its impact, the fungus hasn't attracted the same attention as wildlife diseases such as white-nose syndrome, a fungal disease that infects bats.

“If you look at the number of species impacted, [white-nose syndrome] is so incredibly dwarfed by the number of amphibians—and then you look at the levels of effort and funding and attention,” says Kolby. “Why aren’t we giving that much attention to the frogs?”

U.S. officials are monitoring the situation, but because Bd is already widespread in the United States, there's only so much they can do. But researchers have pointed out that Bd consists of many different lineages. One 2011 study suggested that BdGPL, the deadliest strain of all, emerged when separate Bd strains hybridized.

“If we stop trying to emphasize the importance of biosecurity, disease control, and disease surveillance at the government level, it's hard to think that we're not going to have another hybrid event,” says Kolby. “That would start everything all over again: a new strain, with new virulence. That's what I find scary.”

The U.S. has room to take a more proactive approach to Bsal, which has ravaged salamanders in Europe but hasn't yet been detected in the U.S., a global haven for salamander biodiversity. In 2015, U.S. government agencies formed a task force expressly focused on Bsal. In 2016, U.S. officials moved to ban the import of 201 salamander species.

The U.S. is hardly alone in the fight against Bd; officials around the world are working to curb the fungus. Scientists have set up regional networks to track the fungi's spread, and the World Organization for Animal Health (OIE)—the non-human equivalent of the World Health Organization—has issued recommendations for how to trade amphibian products while minimizing the risk of spreading Bd. In 2015, the OIE and CITES, the treaty that oversees the global wildlife trade, signed an agreement to work more closely together.

Even now, some species stand a chance of evolving resistance to Bd and Bsal. Of the 292 chytrid-stricken species that have survived, 60 show some signs of recovery.

To buy critical time, Scheele says, the world needs to lessen the other threats amphibians face, from habitat loss to invasive species. In addition, captive-breeding efforts such as the Amphibian Ark could act as genetic lifeboats.

But Palen notes that the basic remedies have been known for decades: “It's pretty sobering that we haven’t been able to do those sorts of obvious things,” she says. “Maybe this is a real wake-up call.”

Neurobiological effects of physical exercise

From Wikipedia, the free encyclopedia

Neurobiological effects of physical exercise
Exercise therapy – medical intervention
A woman engaging in aerobic exercise
ICD-9-CM	93.19
MeSH	D005081
LOINC	73986-2
eMedicine	324583

The neurobiological effects of physical exercise are numerous and involve a wide range of interrelated effects on brain structure, brain function, and cognition. A large body of research in humans has demonstrated that consistent aerobic exercise (e.g., 30 minutes every day) induces persistent improvements in certain cognitive functions, healthy alterations in gene expression in the brain, and beneficial forms of neuroplasticity and behavioral plasticity; some of these long-term effects include: increased neuron growth, increased neurological activity (e.g., c-Fos and BDNF signaling), improved stress coping, enhanced cognitive control of behavior, improved declarative, spatial, and working memory, and structural and functional improvements in brain structures and pathways associated with cognitive control and memory. The effects of exercise on cognition have important implications for improving academic performance in children and college students, improving adult productivity, preserving cognitive function in old age, preventing or treating certain neurological disorders, and improving overall quality of life.

In healthy adults, aerobic exercise has been shown to induce transient effects on cognition after a single exercise session and persistent effects on cognition following regular exercise over the course of several months. People who regularly perform aerobic exercise (e.g., running, jogging, brisk walking, swimming, and cycling) have greater scores on neuropsychological function and performance tests that measure certain cognitive functions, such as attentional control, inhibitory control, cognitive flexibility, working memory updating and capacity, declarative memory, spatial memory, and information processing speed. The transient effects of exercise on cognition include improvements in most executive functions (e.g., attention, working memory, cognitive flexibility, inhibitory control, problem solving, and decision making) and information processing speed for a period of up to 2 hours after exercising.

Aerobic exercise induces short- and long-term effects on mood and emotional states by promoting positive affect, inhibiting negative affect, and decreasing the biological response to acute psychological stress. Over the short-term, aerobic exercise functions as both an antidepressant and euphoriant, whereas consistent exercise produces general improvements in mood and self-esteem.

Regular aerobic exercise improves symptoms associated with a variety of central nervous system disorders and may be used as an adjunct therapy for these disorders. There is clear evidence of exercise treatment efficacy for major depressive disorder and attention deficit hyperactivity disorder. The American Academy of Neurology's clinical practice guideline for mild cognitive impairment indicates that clinicians should recommend regular exercise (two times per week) to individuals who have been diagnosed with this condition. Reviews of clinical evidence also support the use of exercise as an adjunct therapy for certain neurodegenerative disorders, particularly Alzheimer’s disease and Parkinson's disease. Regular exercise is also associated with a lower risk of developing neurodegenerative disorders. A large body of preclinical evidence and emerging clinical evidence supports the use of exercise therapy for treating and preventing the development of drug addictions. Regular exercise has also been proposed as an adjunct therapy for brain cancers.

Long-term effects

Neuroplasticity

Neuroplasticity is the process by which neurons adapt to a disturbance over time, and most often occurs in response to repeated exposure to stimuli. Aerobic exercise increases the production of neurotrophic factors (e.g., BDNF, IGF-1, VEGF) which mediate improvements in cognitive functions and various forms of memory by promoting blood vessel formation in the brain, adult neurogenesis, and other forms of neuroplasticity. Consistent aerobic exercise over a period of several months induces clinically significant improvements in executive functions and increased gray matter volume in nearly all regions of the brain, with the most marked increases occurring in brain regions that give rise to executive functions. The brain structures that show the greatest improvements in gray matter volume in response to aerobic exercise are the prefrontal cortex, caudate nucleus, and hippocampus; less significant increases in gray matter volume occur in the anterior cingulate cortex, parietal cortex, cerebellum, and nucleus accumbens. The prefrontal cortex, caudate nucleus, and anterior cingulate cortex are among the most significant brain structures in the dopamine and norepinephrine systems that give rise to cognitive control. Exercise-induced neurogenesis (i.e., the increases in gray matter volume) in the hippocampus is associated with measurable improvements in spatial memory. Higher physical fitness scores, as measured by VO₂ max, are associated with better executive function, faster information processing speed, and greater gray matter volume of the hippocampus, caudate nucleus, and nucleus accumbens. Long-term aerobic exercise is also associated with persistent beneficial epigenetic changes that result in improved stress coping, improved cognitive function, and increased neuronal activity (c-Fos and BDNF signaling).

Structural growth

Reviews of neuroimaging studies indicate that consistent aerobic exercise increases gray matter volume in nearly all regions of the brain, with more pronounced increases occurring in brain regions associated with memory processing, cognitive control, motor function, and reward; the most prominent gains in gray matter volume are seen in the prefrontal cortex, caudate nucleus, and hippocampus, which support cognitive control and memory processing, among other cognitive functions. Moreover, the left and right halves of the prefrontal cortex, the hippocampus, and the cingulate cortex appear to become more functionally interconnected in response to consistent aerobic exercise. Three reviews indicate that marked improvements in prefrontal and hippocampal gray matter volume occur in healthy adults that regularly engage in medium intensity exercise for several months. Other regions of the brain that demonstrate moderate or less significant gains in gray matter volume during neuroimaging include the anterior cingulate cortex, parietal cortex, cerebellum, and nucleus accumbens.

Regular exercise has been shown to counter the shrinking of the hippocampus and memory impairment that naturally occurs in late adulthood. Sedentary adults over age 55 show a 1–2% decline in hippocampal volume annually. A neuroimaging study with a sample of 120 adults revealed that participating in regular aerobic exercise increased the volume of the left hippocampus by 2.12% and the right hippocampus by 1.97% over a one-year period. Subjects in the low intensity stretching group who had higher fitness levels at baseline showed less hippocampal volume loss, providing evidence for exercise being protective against age-related cognitive decline. In general, individuals that exercise more over a given period have greater hippocampal volumes and better memory function. Aerobic exercise has also been shown to induce growth in the white matter tracts in the anterior corpus callosum, which normally shrink with age.

The various functions of the brain structures that show exercise-induced increases in gray matter volume include:

• Prefrontal and anterior cingulate cortices – required for the cognitive control of behavior, particularly: working memory, attentional control, decision-making, cognitive flexibility, social cognition, and inhibitory control of behavior; implicated in attention deficit hyperactivity disorder (ADHD) and addiction
• Nucleus accumbens – responsible for incentive salience ("wanting" or desire, the form of motivation associated with reward) and positive reinforcement; implicated in addiction
• Hippocampus – responsible for storage and consolidation of declarative memory and spatial memory; implicated in depression
• Cerebellum – responsible for motor coordination and motor learning
• Caudate nucleus – responsible for stimulus-response learning and inhibitory control; implicated in Parkinson's disease and ADHD
• Parietal cortex – responsible for sensory perception, working memory, and attention

Persistent effects on cognition

Concordant with the functional roles of the brain structures that exhibit increased gray matter volumes, regular exercise over a period of several months has been shown to persistently improve numerous executive functions and several forms of memory. In particular, consistent aerobic exercise has been shown to improve attentional control, information processing speed, cognitive flexibility (e.g., task switching), inhibitory control, working memory updating and capacity, declarative memory, and spatial memory. In healthy young and middle-aged adults, the effect sizes of improvements in cognitive function are largest for indices of executive functions and small to moderate for aspects of memory and information processing speed. It may be that in older adults, individuals benefit cognitively by taking part in both aerobic and resistance type exercise of at least moderate intensity. Individuals who have a sedentary lifestyle tend to have impaired executive functions relative to other more physically active non-exercisers. A reciprocal relationship between exercise and executive functions has also been noted: improvements in executive control processes, such as attentional control and inhibitory control, increase an individual's tendency to exercise.

Mechanism of effects

BDNF signaling

One of the most significant effects of exercise on the brain is the increased synthesis and expression of BDNF, a neuropeptide and hormone, in the brain and periphery, resulting in increased signaling through its receptor tyrosine kinase, tropomyosin receptor kinase B (TrkB). Since BDNF is capable of crossing the blood–brain barrier, higher peripheral BDNF synthesis also increases BDNF signaling in the brain. Exercise-induced increases in brain BDNF signaling are associated with beneficial epigenetic changes, improved cognitive function, improved mood, and improved memory. Furthermore, research has provided a great deal of support for the role of BDNF in hippocampal neurogenesis, synaptic plasticity, and neural repair. Engaging in moderate-high intensity aerobic exercise such as running, swimming, and cycling increases BDNF biosynthesis through myokine signaling, resulting in up to a threefold increase in blood plasma and brain BDNF levels; exercise intensity is positively correlated with the magnitude of increased BDNF biosynthesis and expression. A meta-analysis of studies involving the effect of exercise on BDNF levels found that consistent exercise modestly increases resting BDNF levels as well.

IGF-1 signaling

IGF-1 is a peptide and neurotrophic factor that mediates some of the effects of growth hormone; IGF-1 elicits its physiological effects by binding to a specific receptor tyrosine kinase, the IGF-1 receptor, to control tissue growth and remodeling. In the brain, IGF-1 functions as a neurotrophic factor that, like BDNF, plays a significant role in cognition, neurogenesis, and neuronal survival. Physical activity is associated with increased levels of IGF-1 in blood serum, which is known to contribute to neuroplasticity in the brain due to its capacity to cross the blood–brain barrier and blood–cerebrospinal fluid barrier; consequently, one review noted that IGF-1 is a key mediator of exercise-induced adult neurogenesis, while a second review characterized it as a factor which links "body fitness" with "brain fitness". The amount of IGF-1 released into blood plasma during exercise is positively correlated with exercise intensity and duration.

VEGF signaling

VEGF is a neurotrophic and angiogenic (i.e., blood vessel growth-promoting) signaling protein that binds to two receptor tyrosine kinases, VEGFR1 and VEGFR2, which are expressed in neurons and glial cells in the brain. Hypoxia, or inadequate cellular oxygen supply, strongly upregulates VEGF expression and VEGF exerts a neuroprotective effect in hypoxic neurons. Like BDNF and IGF-1, aerobic exercise has been shown to increase VEGF biosynthesis in peripheral tissue which subsequently crosses the blood–brain barrier and promotes neurogenesis and blood vessel formation in the central nervous system. Exercise-induced increases in VEGF signaling have been shown to improve cerebral blood volume and contribute to exercise-induced neurogenesis in the hippocampus.

Short-term effects

Transient effects on cognition

In addition to the persistent effects on cognition that result from several months of daily exercise, acute exercise (i.e., a single bout of exercise) has been shown to transiently improve a number of cognitive functions. Reviews and meta-analyses of research on the effects of acute exercise on cognition in healthy young and middle-aged adults have concluded that information processing speed and a number of executive functions – including attention, working memory, problem solving, cognitive flexibility, verbal fluency, decision making, and inhibitory control – all improve for a period of up to 2 hours post-exercise. A systematic review of studies conducted on children also suggested that some of the exercise-induced improvements in executive function are apparent after single bouts of exercise, while other aspects (e.g., attentional control) only improve following consistent exercise on a regular basis. Other research has suggested performative enhancements during exercise, such as exercise-concurrent improvements in processing speed during visual working memory tasks.

Exercise-induced euphoria

Continuous exercise can produce a transient state of euphoria – a positively-valenced affective state involving the experience of pleasure and feelings of profound contentment, elation, and well-being – which is colloquially known as a "runner's high" in distance running or a "rower's high" in rowing. Current medical reviews indicate that several endogenous euphoriants are responsible for producing exercise-related euphoria, specifically phenethylamine (an endogenous psychostimulant), β-endorphin (an endogenous opioid), and anandamide (an endogenous cannabinoid).

Effects on neurochemistry

β-Phenylethylamine

β-Phenylethylamine, commonly referred to as phenethylamine, is a human trace amine and potent catecholaminergic and glutamatergic neuromodulator that has similar psychostimulant and euphoriant effects and a similar chemical structure to amphetamine. Thirty minutes of moderate to high intensity physical exercise has been shown to induce an enormous increase in urinary β-phenylacetic acid, the primary metabolite of phenethylamine. Two reviews noted a study where the average 24 hour urinary β-phenylacetic acid concentration among participants following just 30 minutes of intense exercise increased by 77% relative to baseline concentrations in resting control subjects; the reviews suggest that phenethylamine synthesis sharply increases while an individual is exercising, during which time it is rapidly metabolized due to its short half-life of roughly 30 seconds. In a resting state, phenethylamine is synthesized in catecholamine neurons from L-phenylalanine by aromatic amino acid decarboxylase (AADC) at approximately the same rate at which dopamine is produced.

In light of this observation, the original paper and both reviews suggest that phenethylamine plays a prominent role in mediating the mood-enhancing euphoric effects of a runner's high, as both phenethylamine and amphetamine are potent euphoriants.

β-Endorphin

β-Endorphin (contracted from "endogenous morphine") is an endogenous opioid neuropeptide that binds to μ-opioid receptors, in turn producing euphoria and pain relief. A meta-analytic review found that exercise significantly increases the secretion of β-endorphin and that this secretion is correlated with improved mood states. Moderate intensity exercise produces the greatest increase in β-endorphin synthesis, while higher and lower intensity forms of exercise are associated with smaller increases in β-endorphin synthesis. A review on β-endorphin and exercise noted that an individual's mood improves for the remainder of the day following physical exercise and that one's mood is positively correlated with overall daily physical activity level.

Anandamide

Anandamide is an endogenous cannabinoid and retrograde neurotransmitter that binds to cannabinoid receptors (primarily CB₁), in turn producing euphoria. It has been shown that aerobic exercise causes an increase in plasma anandamide levels, where the magnitude of this increase is highest at moderate exercise intensity (i.e., exercising at ~⁠70⁠–⁠80⁠% maximum heart rate). Increases in plasma anandamide levels are associated with psychoactive effects because anandamide is able to cross the blood–brain barrier and act within the central nervous system. Thus, because anandamide is a euphoriant and aerobic exercise is associated with euphoric effects, it has been proposed that anandamide partly mediates the short-term mood-lifting effects of exercise (e.g., the euphoria of a runner's high) via exercise-induced increases in its synthesis.

In mice it was demonstrated that certain features of a runner's high depend on cannabinoid receptors. Pharmacological or genetic disruption of cannabinoid signaling via cannabinoid receptors prevents the analgesic and anxiety-reducing effects of running.

Cortisol and the psychological stress response

Diagram of the hypothalamic–pituitary–adrenal axis

The "stress hormone", cortisol, is a glucocorticoid that binds to glucocorticoid receptors. Psychological stress induces the release of cortisol from the adrenal gland by activating the hypothalamic–pituitary–adrenal axis (HPA axis). Short-term increases in cortisol levels are associated with adaptive cognitive improvements, such as enhanced inhibitory control; however, excessively high exposure or prolonged exposure to high levels of cortisol causes impairments in cognitive control and has neurotoxic effects in the human brain. For example, chronic psychological stress decreases BDNF expression which has detrimental effects on hippocampal volume and can lead to depression.

As a physical stressor, aerobic exercise stimulates cortisol secretion in an intensity-dependent manner; however, it does not result in long-term increases in cortisol production since this exercise-induced effect on cortisol is a response to transient negative energy balance. Individuals who have recently exercised exhibit improvements in stress coping behaviors. Aerobic exercise increases physical fitness and lowers neuroendocrine (i.e., HPA axis) reactivity and therefore reduces the biological response to psychological stress in humans (e.g., reduced cortisol release and attenuated heart rate response). Exercise also reverses stress-induced decreases in BDNF expression and signaling in the brain, thereby acting as a buffer against stress-related diseases like depression.

Glutamate and GABA

Glutamate, one of the most common neurochemicals in the brain, is an excitatory neurotransmitter involved in many aspects of brain function, including learning and memory. Based upon animal models, exercise appears to normalize the excessive levels of glutamate neurotransmission into the nucleus accumbens that occurs in drug addiction. A review of the effects of exercise on neurocardiac function in preclinical models noted that exercise-induced neuroplasticity of the rostral ventrolateral medulla (RVLM) has an inhibitory effect on glutamatergic neurotransmission in this region, in turn reducing sympathetic activity; the review hypothesized that this neuroplasticity in the RVLM is a mechanism by which regular exercise prevents inactivity-related cardiovascular disease.

Effects in children

Sibley and Etnier (2003) performed a meta-analysis that looked at the relationship between physical activity and cognitive performance in children. They reported a beneficial relationship in the categories of perceptual skills, intelligence quotient, achievement, verbal tests, mathematic tests, developmental level/academic readiness and other, with the exception of memory, that was found to be unrelated to physical activity. The correlation was strongest for the age ranges of 4–7 and 11–13 years. On the other hand, Chaddock and colleagues (2011) found results that contrasted Sibley and Etnier's meta-analysis. In their study, the hypothesis was that lower-fit children would perform poorly in executive control of memory and have smaller hippocampal volumes compared to higher-fit children. Instead of physical activity being unrelated to memory in children between 4 and 18 years of age, it may be that preadolescents of higher fitness have larger hippocampal volumes, than preadolescents of lower fitness. According to a previous study done by Chaddock and colleagues (Chaddock et al. 2010), a larger hippocampal volume would result in better executive control of memory. They concluded that hippocampal volume was positively associated with performance on relational memory tasks. Their findings are the first to indicate that aerobic fitness may relate to the structure and function of the preadolescent human brain. In Best’s (2010) meta-analysis of the effect of activity on children’s executive function, there are two distinct experimental designs used to assess aerobic exercise on cognition. The first is chronic exercise, in which children are randomly assigned to a schedule of aerobic exercise over several weeks and later assessed at the end. The second is acute exercise, which examines the immediate changes in cognitive functioning after each session. The results of both suggest that aerobic exercise may briefly aid children’s executive function and also influence more lasting improvements to executive function. Other studies have suggested that exercise is unrelated to academic performance, perhaps due to the parameters used to determine exactly what academic achievement is. This area of study has been a focus for education boards that make decisions on whether physical education should be implemented in the school curriculum, how much time should be dedicated to physical education, and its impact on other academic subjects.

Another study found that sixth-graders who participated in vigorous physical activity at least three times a week had the highest scores compared to those who participated in moderate or no physical activity at all. The kids who participated in vigorous physical activity scored three points higher, on average, on their academic test, which consisted of math, science, English, and world studies.

Animal studies have also shown that exercise can impact brain development early on in life. Mice that had access to running wheels and other such exercise equipment had better neuronal growth in the neural systems involved in learning and memory. Neuroimaging of the human brain has yielded similar results, where exercise leads to changes in brain structure and function. Some investigations have linked low levels of aerobic fitness in children with impaired executive function in older adults, but there is mounting evidence it may also be associated with a lack of selective attention, response inhibition, and interference control.

Effects on central nervous system disorders

Addiction

Clinical and preclinical evidence indicate that consistent aerobic exercise, especially endurance exercise (e.g., marathon running), actually prevents the development of certain drug addictions and is an effective adjunct treatment for drug addiction, and psychostimulant addiction in particular. Consistent aerobic exercise magnitude-dependently (i.e., by duration and intensity) reduces drug addiction risk, which appears to occur through the reversal of drug-induced, addiction-related neuroplasticity. One review noted that exercise may prevent the development of drug addiction by altering ΔFosB or c-Fos immunoreactivity in the striatum or other parts of the reward system. Moreover, aerobic exercise decreases psychostimulant self-administration, reduces the reinstatement (i.e., relapse) of drug-seeking, and induces opposite effects on striatal dopamine receptor D₂ (DRD2) signaling (increased DRD2 density) to those induced by pathological stimulant use (decreased DRD2 density). Consequently, consistent aerobic exercise may lead to better treatment outcomes when used as an adjunct treatment for drug addiction. As of 2016, more clinical research is still needed to understand the mechanisms and confirm the efficacy of exercise in drug addiction treatment and prevention.

Attention deficit hyperactivity disorder

Regular physical exercise, particularly aerobic exercise, is an effective add-on treatment for ADHD in children and adults, particularly when combined with stimulant medication (i.e., amphetamine or methylphenidate), although the best intensity and type of aerobic exercise for improving symptoms are not currently known. In particular, the long-term effects of regular aerobic exercise in ADHD individuals include better behavior and motor abilities, improved executive functions (including attention, inhibitory control, and planning, among other cognitive domains), faster information processing speed, and better memory. Parent-teacher ratings of behavioral and socio-emotional outcomes in response to regular aerobic exercise include: better overall function, reduced ADHD symptoms, better self-esteem, reduced levels of anxiety and depression, fewer somatic complaints, better academic and classroom behavior, and improved social behavior. Exercising while on stimulant medication augments the effect of stimulant medication on executive function. It is believed that these short-term effects of exercise are mediated by an increased abundance of synaptic dopamine and norepinephrine in the brain.

Major depressive disorder

A number of medical reviews have indicated that exercise has a marked and persistent antidepressant effect in humans, an effect believed to be mediated through enhanced BDNF signaling in the brain. Several systematic reviews have analyzed the potential for physical exercise in the treatment of depressive disorders. The 2013 Cochrane Collaboration review on physical exercise for depression noted that, based upon limited evidence, it is more effective than a control intervention and comparable to psychological or antidepressant drug therapies. Three subsequent 2014 systematic reviews that included the Cochrane review in their analysis concluded with similar findings: one indicated that physical exercise is effective as an adjunct treatment (i.e., treatments that are used together) with antidepressant medication; the other two indicated that physical exercise has marked antidepressant effects and recommended the inclusion of physical activity as an adjunct treatment for mild–moderate depression and mental illness in general. One systematic review noted that yoga may be effective in alleviating symptoms of prenatal depression. Another review asserted that evidence from clinical trials supports the efficacy of physical exercise as a treatment for depression over a 2–4 month period.

A 2015 review of clinical evidence which included a medical guideline for the treatment of depression with exercise noted that the available evidence on the effectiveness of exercise therapy for depression suffers from some limitations; nonetheless, it stated that there is clear evidence of efficacy for reducing symptoms of depression. The review also noted that patient characteristics, the type of depressive disorder, and the nature of the exercise program all affect the antidepressant properties of exercise therapy. A meta-analysis from July 2016 concluded that physical exercise improves overall quality of life in individuals with depression relative to controls.

Mild cognitive impairment

The American Academy of Neurology's January 2018 update of their clinical practice guideline for mild cognitive impairment states that clinicians should recommend regular exercise (two times per week) to individuals who have been diagnosed with this condition. This guidance is based upon a moderate amount of high-quality evidence which supports the efficacy of regular physical exercise (twice weekly over a 6-month period) for improving cognitive symptoms in individuals with mild cognitive impairment.

Neurodegenerative disorders

Alzheimer's disease

Alzheimer's Disease is a cortical neurodegenerative disorder and the most prevalent form of dementia, representing approximately 65% of all cases of dementia; it is characterized by impaired cognitive function, behavioral abnormalities, and a reduced capacity to perform basic activities of daily life. Two meta-analytic systematic reviews of randomized controlled trials with durations of 3–12 months have examined the effects of physical exercise on the aforementioned characteristics of Alzheimer's disease. The reviews found beneficial effects of physical exercise on cognitive function, the rate of cognitive decline, and the ability to perform activities of daily living in individuals with Alzheimer's disease. One review suggested that, based upon transgenic mouse models, the cognitive effects of exercise on Alzheimer's disease may result from a reduction in the quantity of amyloid plaque.

The Caerphilly Prospective study followed 2,375 male subjects over 30 years and examined the association between healthy lifestyles and dementia, among other factors. Analyses of the Caerphilly study data have found that exercise is associated with a lower incidence of dementia and a reduction in cognitive impairment. A subsequent systematic review of longitudinal studies also found higher levels of physical activity to be associated with a reduction in the risk of dementia and cognitive decline; this review further asserted that increased physical activity appears to be causally related with these reduced risks.

Parkinson's disease

Parkinson's disease (PD) is a movement disorder that produces symptoms such as bradykinesia, rigidity, shaking, and impaired gait.

A review by Kramer and colleagues (2006) found that some neurotransmitter systems are affected by exercise in a positive way. A few studies reported seeing an improvement in brain health and cognitive function due to exercise. One particular study by Kramer and colleagues (1999) found that aerobic training improved executive control processes supported by frontal and prefrontal regions of the brain. These regions are responsible for the cognitive deficits in PD patients, however there was speculation that the difference in the neurochemical environment in the frontal lobes of PD patients may inhibit the benefit of aerobic exercise. Nocera and colleagues (2010) performed a case study based on this literature where they gave participants with early-to mid-staged PD, and the control group cognitive/language assessments with exercise regimens. Individuals performed 20 minutes of aerobic exercise three times a week for 8 weeks on a stationary exercise cycle. It was found that aerobic exercise improved several measures of cognitive function, providing evidence that such exercise regimens may be beneficial to patients with PD.

Neurotoxicity

From Wikipedia, the free encyclopedia

Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to substance – specifically, a neurotoxin – alters the normal activity of the nervous system in such a way as to cause permanent or reversible damage to nervous tissue. This can eventually disrupt or even kill neurons, which are cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from organ transplants, radiation treatment, certain drug therapies (e.g., substances used in chemotherapy), recreational drug use, and exposure to heavy metals, pesticides, certain industrial cleaning solvents, and certain naturally occurring substances. Symptoms may appear immediately after exposure or be delayed. They may include limb weakness or numbness, loss of memory, vision, and/or intellect, uncontrollable obsessive and/or compulsive behaviors, delusions, headache, cognitive and behavioral problems and sexual dysfunction.

The term neurotoxicity implies the involvement of a neurotoxin; however, the term neurotoxic may be used more loosely to describe states that are known to cause physical brain damage, but where no specific neurotoxin has been identified.

The presence of neurocognitive deficits alone is not usually considered sufficient evidence of neurotoxicity, as many substances may impair neurocognitive performance without resulting in the death of neurons. This may be due to the direct action of the substance, with the impairment and neurocognitive deficits being temporary, and resolving when the substance is eliminated from the body. In some cases the level or exposure-time may be critical, with some substances only becoming neurotoxic in certain doses or time periods. Some of the most common naturally occurring brain toxins that lead to neurotoxicity as a result of excessive drug use are beta amyloid (Aβ), glutamate, dopamine, and oxygen radicals. When present in high concentrations, they can lead to neurotoxicity and death (apoptosis). Some of the symptoms that result from cell death include loss of motor control, cognitive deterioration and autonomic nervous system dysfunction. Additionally, neurotoxicity has been found to be a major cause of neurodegenerative diseases such as Alzheimer's disease (AD).

Neurotoxic agents

Beta amyloid

Aβ was found to cause neurotoxicity and cell death in the brain when present in high concentrations. Aβ results from a mutation that occurs when protein chains are cut at the wrong locations, resulting in chains of different lengths that are unusable. Thus they are left in the brain until they are broken down, but if enough accumulate, they form plaques which are toxic to neurons. Aβ uses several routes in the central nervous system to cause cell death. An example is through the nicotinic acetylcholine receptor (nAchRs), which is a receptor commonly found along the surfaces of the cells that respond to nicotine stimulation, turning them on or off. Aβ was found manipulating the level of nicotine in the brain along with the MAP kinase, another signaling receptor, to cause cell death. Another chemical in the brain that Aβ regulates is JNK; this chemical halts the extracellular signal-regulated kinases (ERK) pathway, which normally functions as memory control in the brain. As a result, this memory favoring pathway is stopped, and the brain loses essential memory function. The loss of memory is a symptom of neurodegenerative disease, including AD. Another way Aβ causes cell death is through the phosphorylation of AKT; this occurs as the element phosphate is bound to several sites on the protein. This phosphorylation allows AKT to interact with BAD, a protein known to cause cell death. Thus an increase in Aβ results in an increase of the AKT/BAD complex, in turn stopping the action of the anti-apoptotic protein Bcl-2, which normally functions to stop cell death, causing accelerated neuron breakdown and the progression of AD.

Glutamate

Glutamate is a chemical found in the brain that poses a toxic threat to neurons when found in high concentrations. This concentration equilibrium is extremely delicate and is usually found in millimolar amounts extracellularly. When disturbed, an accumulation of glutamate occurs as a result of a mutation in the glutamate transporters, which act like pumps to drain glutamate from the brain. This causes glutamate concentration to be several times higher in the blood than in the brain; in turn, the body must act to maintain equilibrium between the two concentrations by pumping the glutamate out of the bloodstream and into the neurons of the brain. In the event of a mutation, the glutamate transporters are unable to pump the glutamate back into the cells; thus a higher concentration accumulates at the glutamate receptors. This opens the ion channels, allowing calcium to enter the cell causing excitotoxicity. Glutamate results in cell death by turning on the N-methyl-D-aspartic acid receptors (NMDA); these receptors cause an increased release of calcium ions (Ca²⁺) into the cells. As a result, the increased concentration of Ca²⁺ directly increases the stress on mitochondria, resulting in excessive oxidative phosphorylation and production of reactive oxygen species (ROS) via the activation of nitric oxide synthase, ultimately leading to cell death. Aβ was also found aiding this route to neurotoxicity by enhancing neuron vulnerability to glutamate.

Oxygen radicals

The formation of oxygen radicals in the brain is achieved through the nitric oxide synthase (NOS) pathway. This reaction occurs as a response to an increase in the Ca²⁺ concentration inside a brain cell. This interaction between the Ca²⁺ and NOS results in the formation of the cofactor tetrahydrobiopterin (BH4), which then moves from the plasma membrane into the cytoplasm. As a final step, NOS is dephosphorylated yielding nitric oxide (NO), which accumulates in the brain, increasing its oxidative stress. There are several ROS, including superoxide, hydrogen peroxide and hydroxyl, all of which lead to neurotoxicity. Naturally, the body utilizes a defensive mechanism to diminish the fatal effects of the reactive species by employing certain enzymes to break down the ROS into small, benign molecules of simple oxygen and water. However, this breakdown of the ROS is not completely efficient; some reactive residues are left in the brain to accumulate, contributing to neurotoxicity and cell death. The brain is more vulnerable to oxidative stress than other organs, due to its low oxidative capacity. Because neurons are characterized as postmitotic cells, meaning that they live with accumulated damage over the years, accumulation of ROS is fatal. Thus, increased levels of ROS age neurons, which leads to accelerated neurodegenerative processes and ultimately the advancement of AD.

Prognosis

The prognosis depends upon the length and degree of exposure and the severity of neurological injury. In some instances, exposure to neurotoxins can be fatal. In others, patients may survive but not fully recover. In other situations, many individuals recover completely after treatment.

Etymology and pronunciation

The word neurotoxicity (/ˌnʊəroʊtɒkˈsɪsɪti/) uses combining forms of neuro- + tox- + -icity, yielding "nervous tissue poisoning".