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Neuroscience of Mental Health Disorders


Role of Genes in the Brain
Genes do more than just determine the color of eyes or whether people are tall or short.
Genes are at the center of everything that makes people human.
Genes are responsible for producing the proteins that run everything in the body.
Some proteins are visible, such as the ones that compose hair and skin. Others work out of sight, coordinating basic biological functions.
For the most part, every cell in the body contains exactly the same genes, but inside individual cells some genes are active while others are not.
 When genes are active, they are capable of producing proteins. This process is called gene expression.
When genes are inactive, they are silent or inaccessible for protein production.
At least a third of the approximately 20,000 different genes that make up the human genome are active (expressed) primarily in the brain.
This is the highest proportion of genes expressed in any part of the body.
These genes influence the development and function of the brain, and ultimately control how people move, think, feel, and behave. Combined with the effects of the environment, changes in these genes can also determine whether people are at risk for a particular disease and if they are, the course it might follow. 
What is DNA
In order to understand how genes work in the brain, one has to understand how genes make proteins. This begins with DNA (deoxyribonucleic acid).
DNA is a long molecule packaged into structures called chromosomes. Humans have 23 pairs of chromosomes, including a single pair of sex chromosomes (XX in females and XY in males). Within each pair, one chromosome comes from an individual’s mother and the other comes from the father. In other words, people inherit half of their DNA from each of their parents.
DNA consists of two strands wound together to form a double helix. Within each strand, chemicals called nucleotides are used as a code for making proteins.
DNA contains only four nucleotides – adenine (A), thymine (T), cytosine (C), and guanine (G) – but this simple genetic alphabet is the starting point for making all of the proteins in the human body, estimated to be as many as one million.
What is a Gene?
A gene is a stretch of DNA that contains the instructions for making or regulating a specific protein.
Genes that make proteins are called protein-coding genes. In order to make a protein, a molecule closely related to DNA called ribonucleic acid (RNA) first copies the code within DNA. Then, protein-manufacturing machinery within the cell scans the RNA, reading the nucleotides in groups of three.
These triplets encode 20 distinct amino acids, which are the building blocks for proteins. The largest known human protein is a muscle protein called titin, which consists of about 27,000 amino acids.
Some genes encode small bits of RNA that are not used to make proteins, but are instead used to tell proteins what to do and where to go. These are called non-coding or RNA genes. There are many more RNA genes than protein-coding genes.
What is a Protein?
Proteins form the internal machinery within brain cells and the connective tissue between brain cells. They also control the chemical reactions that allow brain cells to communicate with each other.
Some genes make proteins that are important for the early development and growth of the infant brain. For example, the ASPM gene makes a protein that is needed for producing new nerve cells (or neurons) in the developing brain. Alterations in this gene can cause microcephaly, a condition in which the brain fails to grow to its normal size.
Certain genes make proteins that in turn make neurotransmitters, which are chemicals that transmit information from one neuron to the next. Other proteins are important for establishing physical connections that link various neurons together in networks.
Still other genes make proteins that act as housekeepers in the brain, keeping neurons and their networks in good working order.
For example, the SOD1 gene makes a protein that fights DNA damage in neurons. Alterations in this gene are one cause of the disease amyotrophic lateral sclerosis (ALS), in which a progressive loss of muscle-controlling neurons leads to eventual paralysis and death. The SOD1 gene is believed to hold important clues about why neurons die in the common “sporadic” form of ALS, which has no known cause.
How is Gene Expression Regulated?
One can know which protein a gene will make by looking at its code, also called its DNA sequence. What cannot be predicted is the amount of protein that will be made, when it will be made, or what cell will make it.
Each cell turns on only a fraction of its genes, while it silences the rest. For example, genes that are expressed in brain cells may be silenced in liver cells or heart cells. Some genes are only turned on during the early months of human development and then are silenced later.
What determines these unique patterns of gene expression? Like people, cells have a unique lineage, and they tend to inherit traits from their parents. So, a cell’s origins influence the genes it turns on to make proteins. The cell’s environment – its exposure to surrounding cells and to hormones and other signals – also helps determine which proteins the cell makes.
These cues from a cell’s past and from its environment act through many regulatory factors inside the cell
What determines gene expression?

DNA Binding Proteins

About 10 percent of the genes in the human genome encode DNA binding proteins. Some of these proteins recognize and attach to specific bits of DNA to activate gene expression. Another type of DNA binding protein, called a histone, acts as a spool that can keep DNA in tight coils and thus suppress gene expression.

sRNA

Scattered throughout the genome are many types of small RNA (sRNA) that actively regulate gene expression. Because of their short length, they are able to target, match, and deactivate small bits of genetic code.

Epigenetic Factors

The word epigenetics comes from the Greek word epi, meaning above or beside. In a broad sense, epigenetics refers to long-lasting changes in gene expression without any changes to the genetic code. Epigenetic factors include chemical marks or tags on DNA or on histones that can affect gene expression
Variation in Genetic Codes?
A genetic variation is a permanent change in the DNA sequence that makes up a gene.
Most variations are harmless or have no effect at all.
However, other variations can have harmful effects leading to disease.
Still others can be beneficial in the long run, helping a species adapt to change. 
Single Nucleotide Polymorphism (SNP)
SNPs are variations that involve a change in just one nucleotide.
It is estimated that the human genome contains more than 10 million different SNPs.
Because SNPs are such small changes within DNA, most of them have no effect upon gene expression.
Some SNPs, however, are responsible for giving people unique traits, such as hair and eye color.
Other SNPs may have subtle effects on people’s risk of developing common diseases, such as heart disease, diabetes, or stroke.
Copy Number Variation (CNV)
At least 10 percent of the human genome is made up of CNVs, which are large chunks of DNA that are deleted, copied, flipped or otherwise rearranged in combinations that can be unique for each individual. These chunks of DNA often involve protein coding genes. This means that CNVs are likely to change how a gene makes its protein.
Since genes usually occur in two copies, one inherited from each parent, a CNV that involves a single missing gene could lower the production of a protein below the amount needed.
Having too many copies of a gene can be harmful, too. Although most cases of Parkinson’s disease are sporadic (without a known cause), some cases have been linked to having two or more copies of the SNCA gene, which encodes a protein called alpha-synuclein. The excess alpha-synuclein accumulates in clumps inside brain cells, and appears to jam the cells’ machinery. For reasons that are not clear, similar clumps are associated with sporadic Parkinson’s disease. 
Single Gene Mutation
Some genetic variations are small and affect only a single gene. These single gene mutations can have large consequences, however, because they affect a gene’s instructions for making a protein. Single gene mutations are responsible for many rare inherited neurological diseases.
For example, Huntington’s disease is the result of what is called an expanded “triplet repeat” in the huntingtin gene. Normal genes often have triplet repeats, in which the same triplet amino acid code occurs multiple times like a stutter. These repeats are usually harmless.
In the huntingtin gene, triplet repeats of 20 to 30 times are normal. But in people with Huntington’s disease, the number of repeats reaches 40 or more. The mutation creates an abnormally shaped protein that is toxic to neurons. As cells start to die, the symptoms of Huntington’s disease appear uncontrollable writhing movements of the legs and arms, a loss of muscle coordination, and changes in personality and thinking.
The Role of Genes in Neurological Disease
Most of the single gene mutations that cause rare neurological disorders such as Huntington’s disease have been identified.
In contrast, there is still much to learn about the role of genetic variations in common neurological disorders and conditions, like Alzheimer's disease and stroke. A few things are clear:
First, for most people, a complex interplay between genes and environment influences the risk of developing these diseases.
Second, where specific gene variations such as SNPs are known to affect disease risk, the impact of any single variation is usually very small. In other words, most people affected by stroke or Alzheimer's disease have experienced an unfortunate combination of many "hits" in the genome and in the environment.
Finally, beyond changes in the DNA sequence, changes in gene regulation -for example, by sRNAs and epigenetic factors - can play a key role in the disease.
What kinds of Studies Research Gene Disease Relatedness?

Scientists search for connections between genes and disease risk by performing two kinds of studies:

1.Genome-wide association (GWA) study, scientists search for SNPs or other changes in DNA sequence, comparing the genomes of the subjects (people, laboratory animals or cells) that have a disease and subjects that do not have the disease.

2.Gene expression profiling, scientists look for changes in gene expression and regulation that are associated with a disease.

Both kinds of studies often use a device called a DNA microarray, which is a small chip, sometimes called a gene chip, coated with row upon row of DNA fragments. The fragments act as probes for DNA (in a GWA study) or RNA (in gene expression profiling) isolated from a sample of blood or tissue.
Increasingly, scientists are conducting these studies by direct sequencing, which involves reading DNA or RNA sequences nucleotide by nucleotide. Sequencing was once a time-consuming and expensive procedure, but a new set of techniques called next-generation sequencing has emerged as an efficient, cost-effective way to get a detailed readout of the genome.
Genes at Work for Better Cures
Doctors can prescribe DNA-based tests to look for mutations that cause single gene mutation disorders such as Duchenne muscular dystrophy, neurofibromatosis type 1, and Huntington's disease. Genetic tests are often used to confirm the diagnosis of disease in people who already have symptoms, they can also be used to establish the presence of a mutation in individuals who are at risk for the disease but who have not yet developed any symptoms.
In the laboratory, GWA studies and gene expression profiling studies are leading to insights into new possibilities for disease prevention, diagnosis and treatment. When scientists identify a gene or gene regulatory pathway associated with a disease, they uncover potential new targets for therapy. Understanding the relationships between genes and complex diseases also is expected to play an important part in personalized medicine. One day, microarray-based genome scanning could become a routine way to estimate a person’s genetic risk of developing diseases like stroke, Alzheimer’s disease, Parkinson’s disease and certain brain cancers. Researchers hope to develop customized drug “cocktails” that are matched to a person’s unique genetic profile. Researchers believe that these customized drugs will be much less likely than current medicines to cause side effects. 
What is the Brain Iniative?
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is part of a new Presidential focus aimed at revolutionizing our understanding of the human brain.
By accelerating the development and application of innovative technologies, researchers will be able to produce a revolutionary new dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space.
Long desired by researchers seeking new ways to treat, cure, and even prevent brain disorders, this picture will fill major gaps in our current knowledge and provide unprecedented opportunities for exploring exactly how the brain enables the human body to record, process, utilize, store, and retrieve vast quantities of information, all at the speed of thought.
Review of Functions of Components of Brain
Brain Mapping Expands Understanding of Mental Health Disorders

Just one example of use of PET scans: Using the brain mapping technique called positron emission tomography (PET scan) 

  • People who are willing to work hard for rewards had a higher release of dopamine in areas of the brain known to play a role in reward and motivation, the striatum and ventromedial prefrontal cortex.
  • On the other hand, those who were less willing to work hard for a reward had high dopamine levels in another area of the brain that plays a role in emotion and risk perception, the anterior insula.
Comparing fMRI, PET, ERP & MEG
  • fMRI has best spatial resolution and localization
  • ERP and MED have best temporal resolution ( PET has worst temporal resolution)
  • PET use of radioactive compounds is both a disadvantage (For obvious reasons) and an advantage (can radioactively label many different compounds)
  • Cost and availability: ERP is least expensive, the fMRI and MEG and than PET
  • BUT fMRI has become the method of choice
Alzheimer’s and the Brain
Alzheimer's disease leads to nerve cell death and tissue loss throughout the brain.
As the disease progresses, brain tissue shrinks and the ventricles (chambers within the brain that contain cerebrospinal fluid) become larger.
The damage disrupts communication between brain cells, crippling memory, speech, and comprehension.
Alzheimer's disease takes a different path in every patient.
In some people the symptoms worsen quickly, leading to severe memory loss and confusion within a few years.
In others, the changes may be more gradual with the disease taking 20 years to run its course.
The average length of survival after a diagnosis of Alzheimer's is three to nine years.

Early Stage Alzheimer’s Symptoms
  • Short-term memory loss is the most common early symptom of Alzheimer’s disease.
  • Difficulty performing familiar tasks.
  • Disorientation.
  • Increasing problems with planning and managing.
  • Trouble with language
  • Rapid, unpredictable mood swings.
  • Lack of motivation.
  • Changes in sleep

Middle Stage Symptoms

Once a person enters the middle stage, Alzheimer’s disease symptoms begin to demand constant attention and care.

Symptoms linked to the middle stages of Alzheimer’s disease include:

  • Difficulty completing everyday tasks, such as getting dressed, going to bathroom, or preparing meals
  • Hallucinations
  • Strong feelings of paranoia and anger
  • Wandering

Later Stage Symptoms

In the later stages, a person with Alzheimer’s disease is unable to care for himself or herself at all.

Late-stage Alzheimer's disease symptoms:

  • Inability to communicate with or recognize other people
  • Inability to walk
  • Difficulty swallowing
  • Inability to smile

Is Alzheimer's Disease Hereditary?
  • Genetic research has turned up evidence of a link between Alzheimer's disease and genes on four chromosomes, labeled numerically as 1, 14, 19, and 21.
  • The APOE gene on chromosome 19 has been linked to late-onset Alzheimer's disease, which is the most common form of the disease. Dozens of studies around the world have confirmed that inheritance of one particular variant of the APOE gene, termed APOE4, increases the lifetime risk of developing Alzheimer's disease.
  • One of the puzzles surrounding APOE is why some people with the APOE4 variant do not develop Alzheimer's disease and why, conversely, many people develop the disease even though they have not inherited APOE4 . APOE, in other words, although clearly influencing the risk of developing Alzheimer's, is not a consistent genetic marker for the disease.

What Is the Role of Genetics in Familial Alzheimer's Disease?
  • Alzheimer's disease strikes early and fairly often in certain families, often enough to be singled out as a separate form of the disease and given a label: early-onset familial Alzheimer's disease, or FAD. Combing through the DNA of these families, researchers have found an abnormality in one gene on chromosome 21 that is common to a few of the families. And they have linked a much larger proportion of early-onset families to recently identified and related genes on chromosomes 1 and 14.
  • The chromosome 21 gene also intrigues Alzheimer's researchers because of its role in Down syndrome. People with Down syndrome have an extra copy of chromosome 21 and, as they grow older, usually develop abnormalities in the brain like those found in Alzheimer's disease, though often at a younger age.
  • Few researchers think that the search for Alzheimer's genes is over. Most investigators are convinced that there are many more genes involved in Alzheimer's disease and, moreover, that other conditions must also be present for the disease to develop. One of these conditions may be a problem with the way in which nerves turn sugar, or glucose, into energy, a process known as glucose metabolism.
Autism Spectrum Disorder

What is Autism Spectrum Disorder?
Autism spectrum disorder includes conditions previously called autism, pervasive developmental disorder, and Asperger's syndrome.
Autism spectrum disorder is a brain disorder that often makes it hard to communicate with and relate to others.
With autism spectrum disorder, the different areas of the brain fail to work together.
The causes are not known.

Symptoms of Autism Spectrum Disorder
  • A delay in learning to talk, or not talking at all. A child may seem to be deaf, even though hearing tests are normal.
  • Repeated and overused types of behavior, interests, and play. Examples include repeated body rocking, unusual attachments to objects, and getting very upset when routines change.

Autism may also include other problems:

  • Many children with autism have below-normal intelligence.
  • Teenagers with autism often become depressed and have a lot of anxiety, especially if they have average or above-average intelligence.
  • Some children get a seizure disorder such as epilepsy by their teen years.

Social Interactions and relationships Symptoms may include:
  • Significant problems developing nonverbal communication skills, such as eye-to-eye gazing, facial expressions, and body posture.
  • Failure to establish friendships with children the same age.
  • Lack of interest in sharing enjoyment, interests, or achievements with other people.
  • Lack of empathy. People with autism may have difficulty understanding another person's feelings, such as pain or sorrow.

Verbal and Nonverbal Communication Symptoms may include:
  • Delay in, or lack of, learning to talk. As many as 40% of people with autism never speak.
  • Problems taking steps to start a conversation. Also, people with autism have difficulties continuing a conversation after it has begun.
  • Stereotyped and repetitive use of language. People with autism often repeat over and over a phrase they have heard previously (echolalia).
  • Difficulty understanding their listener's perspective. For example, a person with autism may not understand that someone is using humor. They may interpret the communication word for word and fail to catch the implied meaning.

Limited Interests in Activities or Play Symptoms may include:
  • An unusual focus on pieces. Younger children with autism often focus on parts of toys, such as the wheels on a car, rather than playing with the entire toy.
  • Preoccupation with certain topics. For example, older children and adults may be fascinated by video games, trading cards, or license plates.
  • A need for sameness and routines. For example, a child with autism may always need to eat bread before salad and insist on driving the same route every day to school.
  • Stereotyped behaviors. These may include body rocking and hand flapping.

Physical assessments and laboratory tests for Autism Spectrum Disorder

Tests may be used to determine whether a physical problem may be causing symptoms. These tests include:

Physical exam, including head circumference, weight, and height measurements, to determine whether the child has a normal growth pattern.
Hearing tests, to determine whether hearing problems may be causing developmental delays, especially those related to social skills and language use.
Testing for lead poisoning, especially if a condition called pica (in which a person craves substances that are not food, such as dirt or flecks of old paint) is present. Children with developmental delays usually continue putting items in their mouth after this stage has passed in normally developing children. This practice can result in lead poisoning, which should be identified and treated as soon as possible.

Other lab tests may be done under specific circumstances

These tests include:

Chromosomal analysis, which may be done if intellectual disability is present or there is a family history of intellectual disability. For example, fragile X syndrome, which causes a range of below-normal intelligence problems as well as autistic-like behaviors, can be identified with a chromosomal analysis.

Electroencephalograph (EEG), which is done if there are symptoms of seizures, such as a history of staring spells or if a person reverts to less mature behavior (developmental regression).
MRI, which may be done if there are signs of differences in the structure of the brain.

How Does Autism Spectrum Affect the Brain?
  • Autism Spectrum Disorder (ASD) affects parts of the brain that control emotions, communication, and body movements.
  • By the toddler years, some children with ASD have unusually large heads and brains – which may be because of problems with brain growth.
  • Abnormal genes, passed down through a family, have been linked to poor functions in some parts of the brain. 
  • Researchers hope to find a way to diagnose Autism Spectrum Disorder through brain scans.

Medication for Autism Spectrum Disorder
There's no medical treatment for autism itself, but medicine may help with some symptoms.
Anti-psychotic medicines may be given for serious behavior problems. One drug in this category, Risperdal, has FDA approval to help with aggression, self-injury, and tantrums in autistic children.
If seizures are an issue, an anti-convulsant drug may help.
Drugs that treat depression are sometimes prescribed.
A child’s response to medications should be closely monitored.
ADHD

Neurobiological View of ADHD

Amen, a child, adolescent, and adult psychiatrist who serves as medical director of the Amen Clinics in California, Washington, and Virginia, has used a combination of symptoms and brain scans to come up with his own types of ADHD.

Amen considers these to be the hallmark symptoms of ADHD:

  • Short attention span
  • Distractibility
  • Disorganization
  • Procrastination
  • Poor judgment and ability to plan ahead
  • Difficulty with impulse control

Use of SPECT to Diagnose ADHD
Single photon emission computed tomography (SPECT) brain scans are used on people with psychological problems.
SPECT uses a radioactive dye to create a three-dimensional image of the blood flow and activity in the brain.
It is typically used to diagnose medical conditions such as Alzheimer's disease, Parkinson's disease, and head injury.
Amen used the symptoms of ADHD he had identified and used brain scans to measure blood flow (SPECT), to highlight activity in the parts of the brain related to attention, short-term memory, and forethought, and he came up with 6 types of ADHD

Amen’s Six Types of ADHD

Type 1: Classic ADHD. Symptoms of ADHD, plus hyperactivity and impulsivity; responds well to stimulant medications

Type 2: Inattentive ADHD. Features of ADHD, but instead of hyperactivity, there is low energy; responds well to stimulant medications

Type 3: Overfocused ADHD. Symptoms of ADHD and negative thoughts and behaviors, such as opposition and arguing; tends to respond better to an antidepressant (such as Prozac) combined with a stimulant

Type 4: Temporal Lobe ADHD. The hallmark features of ADHD, plus irritability, aggressiveness, and memory and learning problems; responds better to antiseizure medications (like Neurontin) than to stimulants

Type 5: Limbic ADHD. Combines ADHD with depression and low energy and decreased motivation; responds better to stimulating antidepressants than to stimulants

Type 6: The Ring of Fire. Cross between ADHD and bipolar disorder; characterized by moodiness, aggressiveness, and anger. Anticonvulsants or newer antipsychotic medications tend to work better than stimulants.


Causes of ADHD

Children with ADHD have less activity in areas of the brain that control attention. They may also have imbalances in brain chemicals called neurotransmitters which are less active in areas of the brain that control attention.  It's unclear what causes these irregularities, but ADHD runs in families, so many experts believe genetics play a role


ADHD an Evolutionary Advantage?

One genetic variation that causes ADHD-like traits is more common in the world's nomadic peoples. Researchers think that traits such as impulsive behavior, novelty-seeking, and unpredictability might help nomads track down food and other resources. So the same qualities that make it challenging to excel at a desk job may have been an advantage to nomadic ancestors.


Medication Treatment for ADHD

The most common medicines for ADHD are stimulants. It may seem ironic that people who are restless or hyperactive get help from stimulants. These drugs may sharpen concentration and curb distractibility by fine-tuning brain circuits that affect attention.

Stimulant medications can help increase a child's attention span while controlling hyperactivity and impulsive behavior. Studies suggest these drugs work in 70% to 80% of patients, although they may have some troubling side effects. Non-stimulant medications are also options for some children.

If stimulants don't help enough, a doctor may prescribe an antidepressant to stabilize mood or a selective norepinephrine reuptake inhibitor, such as atomoxetine, which can help control impulsive behaviors.


ADHD Diets?

The jury is still out on whether diet may improve ADHD symptoms. While studies on ADHD diets have produced mixed results, some health experts believe foods that are good for the brain could reduce symptoms of ADHD.

High-protein foods, including eggs, meat, beans, and nuts, may improve concentration. It might also be helpful to replace simple carbs, like candy and white bread, with complex carbs, like pears and whole-grain bread. Parents need to talk to their pediatrician before making any dramatic changes to their child's diet.

While many kids bounce off the walls after eating junk food, there is no evidence that sugar is a cause of ADHD. The role of food additives is less certain. Some parents believe preservatives and food colorings worsen the symptoms of ADHD, and the American Academy of Pediatrics says it's reasonable to avoid these substances. 


Preventing ADHD?

There is no surefire way to prevent ADHD in children, but there are steps one can take to reduce the risk.

One can increase one’s chance of one’s child not having ADHD by staying healthy during pregnancy. Start by avoiding alcohol, drugs, and tobacco during pregnancy. Children whose mothers smoked during pregnancy are twice as likely to develop ADHD.

Schizophrenia

Brain Chemistry of Schizophrenia
Scientists think that an imbalance in the complex, interrelated chemical reactions of the brain involving the neurotransmitters dopamine and glutamate, and possibly others, plays a role in schizophrenia.
Neurotransmitters are substances that allow brain cells to communicate with each other.
Scientists are learning more about brain chemistry and its link to schizophrenia.

Brain Scans Difference due to Schizophrenia
In small ways the brains of people with schizophrenia look different than those of healthy people.
For example, fluid-filled cavities at the center of the brain, called ventricles, are larger in some people with schizophrenia.
The brains of people with the illness also tend to have less gray matter, and some areas of the brain may have less or more activity.

Early Development of Schizophrenia
Studies of brain tissue after death also have revealed differences in the brains of people with schizophrenia.
Scientists found small changes in the distribution or characteristics of brain cells that likely occurred before birth.
Some experts think problems during brain development before birth may lead to faulty connections.
The problem may not show up in a person until puberty.
The brain undergoes major changes during puberty, and these changes could trigger psychotic symptoms.
Scientists have learned a lot about schizophrenia, but more research is needed to help explain how it develops.

Risk Factors for Schizophrenia

You could be at risk for schizophrenia if:

  • Your mother, father, brother, or sister has schizophrenia.
  • Your mother had certain problems while she was pregnant with you. For example, if your mother didn't get enough to eat (malnutrition), had a viral infection, or took certain medicines for high blood pressure, you may be at increased risk.
  • You or a family member have another disorder that is like schizophrenia. An example of this is a delusional disorder, which means you believe things that you know are false.
  • You have a problem with alcohol or drugs. Experts don't know whether substance abuse triggers schizophrenia or whether schizophrenia makes a person more likely to have this problem.
Bipolar Disorder

The Brain and Bipolar Disorder
Experts believe bipolar disorder is partly caused by an underlying problem with specific brain circuits and the balance of brain chemicals called neurotransmitters.

Three neurotransmitter (brain chemicals) identified with Bipolar Disorder are:

  • Noradrenaline (norepinephrine)
  • Serotonin
  • Dopamine
Serotonin is connected to many body functions such as sleep, wakefulness, eating, sexual activity, impulsivity, learning, and memory. Researchers believe that abnormal functioning of brain circuits that involve serotonin as a chemical messenger contribute to mood disorders (depression and bipolar disorder).
Dopamine is commonly linked with the pleasure system of the brain. Disruption to the dopamine system is connected to psychosis and schizophrenia, a severe mental disorder characterized by distortions in reality and illogical thought patterns and behaviors, thus the reason for confusion in gaining an accurate diagnosis of an individual with Bipolar who is also psychotic and/or delusional
Depression

Neurobiology of Depression – Depression Is In the Brain
  • The neurobiology (biology of the brain) of major depression research areas include:
  • Psychosocial stress and stress hormones
  • Neurotransmitters such as serotonin, norepinephrine, dopamine, glutamate and gamma-aminobutyric acid (GABA)
  • Neurocircuitry (neuroimaging)
  • Neurotrophic factors
  • Circadian rhythms

Areas of Brain Impacted by Depression (See graphics on Part 3 PDF)
Limbic System
  • Amygdala
  • Hippocampus
  • Thalmus
  • Cerebral Cortex
  • Cingulate Gyrus
  • Nucleus Accumbens
Neurons and Neurotransmitters: the chemical messengers within the brain that facilitate communication between nerve cells. 
  • Serontonin

Neurotransmitters and Depression
A reduction of norepinephrine and serotonin have been found in those with depression
Drugs that alleviate mania reduce norepinephrine
Diminished Serotonin Activity  
Results in overactive deep limbic system resulting in:
  • Depression
  • Negativity
  • Moodiness
  • Irritability
  • Social isolation
  • Hopelessness
  • Excessive guilt
  • Becoming easily offended

The Social Cognitive Approach to Depression
The social cognitive approach to depression suggests that depression arises partly from self-defeating beliefs and negative explanatory styles
Brain Circuits and Symptoms in Depression
  • Monoamine pathways hypothetically relate to all symptosm of Major Depressive Disorder (MDD)
  • Separate branches of monoamine pathways may independently modulate various malfunctioning brain areas that create a unique portfolio of symptoms
  • Modulating separate branches of monoamine pathways with treatment may casue some but not all symptoms to be resolved.
Depression and Anxiety are ultimately about how the Brain responds to the Environment

Stressors: Psychological, nutritional, hormonal, medication, drug/alcohol all function as stimuli for either an anxious or depressed mood response

Parts of the Brain involved in this response cycle are:
Genes: Have multiple suceptibility alleles each of small effect
  • Promoters: bind RNA polymerase
  • Suppressors: block phenotypic expression BDNF (which promotes the growth and survival of brain cells) and Bcl-2 (which exerts pro- and anti-apostosis via mitochondria membrane)
Epigenetics: Gene and protein expression, e.g. BDNF levels reduced during depression, mania
Cells: Gilial and neuronal abnormalities; mitochondrial dysfunction
Systems: Abnormal function and information processing in multiple, interacting cirucuits

RESULTING IN: Depression and/or Anxiety
Behavior: Complex interaction affecting emotinal, psychomotor, cognitive and viceromotor function

3-D Active SPECT of Brain with Anxiety and/or Depression
Show increased anterior cingulate and deep limbic activity
Anxiety Disorders

Variety of Faces of Anxiety Disorders

Common of anxiety disorders include:

  • Panic disorder: In addition to anxiety, common symptoms of panic disorders are palpitations (feeling your heart beat), dizziness, and shortness of breath. These same symptoms also can be caused by coffee (caffeine), amphetamines ("speed" is the street slang for amphetamines when they are not prescribed by a doctor), an overactive thyroid, abnormal heart rhythms, and other heart abnormalities (such as mitral valve prolapse).
  • Generalized anxiety disorder
  • Phobic disorders
  • Stress disorders

Causes of Anxiety

Anxiety may be caused by a mental condition, a physical condition, the effects of drugs, or a combination of these and the initial task is to see if the anxiety is caused by a medical condition.

Other causes are:

  • Stress at work
  • Stress from school
  • Stress in a personal relationship such as marriage
  • Financial stress
  • Stress from an emotional trauma such as the death of a loved one
  • Stress from a serious medical illness
  • Side effect of medication
  • Use of an illicit drug, such as cocaine
  • Symptom of a medical illness (such as heart atack, heat stroke, hypoglycemia)
  • Lack of oxygen in circumstances as diverse as high altitude sickness, emphysema or pulmonary embolism (a blood clot in the vessels of the lung)

What Causes Panic Disorder?

Although the exact cause of panic disorder is not fully understood, studies have shown that a combination of factors, including biological and environmental, may be involved. These factors include.

  • Family history. Panic disorder has been shown to run in families. It may be passed on to some people by one or both parent(s) much like hair or eye color can.
  • Abnormalities in the brain. Panic disorder may be caused by problems in parts of the brain.
  • Substance abuse. Abuse of drugs and alcohol can contribute to panic disorder.
  • Major life stress. Stressful events and major life transitions, such as the death of a loved one, can trigger panic disorder.

Always rule out Medical Condition with Panic Disorder
Doctors have the often-difficult task of determining which symptoms come from which causes.
For example, in a study of people with chest pain - a sign of heart disease - 43% were found to have a panic disorder, not a heart-related condition.
Doctors may do blood or urine tests to rule out other conditions, such as thyroid problems that can cause similar symptoms.

Brain Chemistry of Generalize Anxiety Disorder

GAD has been associated with abnormal levels of certain neurotransmitters in the brain.

Neurotransmitters are special chemical messengers that help move information from nerve cell to nerve cell.

If the neurotransmitters are out of balance, messages cannot get through the brain properly.

This can alter the way the brain reacts in certain situations, leading to anxiety.


Components of Anxiety

  • Emotional: anxious mood, depressed mood
  • Cognitive: Intellectual
  • Somatic: Muscular, sensory, cardiovascular, respiratory, gastrointestinal, genitournary, autonomic
  • Behavioral: Tension, fears, insomnia, interpersonal issues

Use of fMRI in study of lowering anxiety in patients
  • Using functional magnetic resonance imaging (fMRI), Yale researchers displayed the activity of the orbitofrontal cortex, a brain region just above the eyes, to subjects while they lay in a brain scanner.
  • Through a process of trial and error, these subjects were gradually able to learn to control their brain activity. This led both to changes in brain connectivity and to increased control over anxiety. These changes were still present several days after the training.
  • Extreme anxiety associated with worries about dirt and germs is characteristic of many patients with obsessive-compulsive disorder (OCD). Hyperactivity in the orbitofrontal cortex is seen in many of these individuals.
  • fMRI-driven neurofeedback has been used before in a few contexts, but it has never been applied to the treatment of anxiety. The findings raise the possibility that real-time fMRI feedback may provide a novel and effective form of treatment for OCD.
Obsessive Compulsive Disorder

What is OCD?
Obsessive-compulsive disorder (OCD) is a potentially disabling illness that traps people in endless cycles of repetitive thoughts and behaviors.
People with OCD are plagued by recurring and distressing thoughts, fears, or images (obsessions) they cannot control.
The anxiety (nervousness) produced by these thoughts leads to an urgent need to perform certain rituals or routines (compulsions).
The compulsive rituals are performed in an attempt to prevent the obsessive thoughts or make them go away.
Although the ritual may temporarily alleviate anxiety, the person must perform the ritual again when the obsessive thoughts return.
This OCD cycle can progress to the point of taking up hours of the person's day and significantly interfering with normal activities.
People with OCD may be aware that their obsessions and compulsions are senseless or unrealistic, but they cannot stop them.

What Are the Symptoms of OCD?

The symptoms of OCD, which are the obsessions and compulsions, may vary. Common obsessions include:

  • Fear of dirt or contamination by germs
  • Fear of causing harm to another
  • Fear of making a mistake
  • Fear of being embarrassed or behaving in a socially unacceptable manner
  • Fear of thinking evil or sinful thoughts
  • Need for order, symmetry, or exactness
  • Excessive doubt and the need for constant reassurance

Common OCD Compulsions
Repeatedly bathing, showering, or washing hands
Refusing to shake hands or touch doorknobs
Repeatedly checking things, such as locks or stoves
Constant counting, mentally or aloud, while performing routine tasks
Constantly arranging things in a certain way
Eating foods in a specific order
Being stuck on words, images or thoughts, usually disturbing, that won't go away and can interfere with sleep
Repeating specific words, phrases, or prayers
Needing to perform tasks a certain number of times
Collecting or hoarding items with no apparent value

What Causes OCD? Biological Factors
  • Although the exact cause of OCD is not fully understood, studies have shown that a combination of biological and environmental factors may be involved.
  • At one time, it was thought that low levels of the neurotransmitter serotonin was responsible for the development of OCD. 
  • Now, however, scientists think that OCD is a disturbance of brain  circuitry between the frontal lobe and subcortical areas. This results in problems in the pathways of the brain that link areas dealing with judgment and planning with another area that filters messages involving body movements.
  • In addition, there is evidence that OCD symptoms can sometimes get passed on from parents to children. This means the biological vulnerability to develop OCD may sometimes be inherited.
  • Studies also have found a link between a certain type of infection caused by the Streptococcus bacteria and OCD. This infection, if recurrent and untreated, may lead to the development of OCD and other disorders in children.

What Causes OCD? Environmental Factors

There are environmental stressors that can trigger OCD in people with a tendency toward developing the condition. Certain environmental factors may also cause a worsening of symptoms. These factors include:

  • Abuse
  • Changes in living situation
  • Illness
  • Death of a loved one
  • Work- or school-related changes or problems
  • Relationship concerns
PTSD
What is PTSD
  • People respond to a life-threatening event by fighting or fleeing.
  • Potent chemical messengers in the brain warn people of danger and prepare them to defend themselves.
  • If there's too much of this stimulation, or if it goes on for too long, the brain may suffer side effects. Some of these side effects appear to contribute to PTSD.
  • PTSD is associated with changes in brain function and structure.
  • There's also a tendency for key stress hormones to get out of whack.
  • Research has shown that PTSD changes the biology of the brain.
  • MRI (magnetic resonance imaging) and PET (positron emission tomography) scans show changes in the way memories are stored in the brain.
  • PTSD is an environmental shock that changes a person’s brain, and scientists do not know if it is reversible.
  • Risk factors that may contribute to PTSD include a family history of anxiety, early separation from parents, earlier childhood abuse, or prior trauma.

Who gets PTSD?
  • In USA, 60% of men and 50% of women experience a traumatic event during their lifetimes. Of those, 8% of men and 20% of women may develop PTSD.
  • A higher proportion of people who are raped develop PTSD than those who suffer any other traumatic event. Because women are much more likely to be raped (9% versus less than 1% for men), thus higher prevalence of PTSD in women than men.
  • Some 88% of men and 79% of women with PTSD also have another psychiatric disorder. Nearly half suffer from major depression, 16% from other types of anxiety disorders besides PTSD, and 28% from social phobia. They also are more likely to have risky health behaviors such as alcohol abuse, which affects 52% of men with PTSD and 28% of women, while drug abuse is seen in 35% of men and 27% of women with PTSD.\

TBI - Common Comorbidity with PTSD for OIF & OEF Veterans
What is TBI?
A traumatic brain injury (TBI) can range from a mild concussion to a severe head injury.
It is caused by a blow to the head or body, a fall, or another injury that jars or shakes the brain.
This can cause bruising, swelling, or tearing of brain tissue.
With rest, most people fully recover from a mild brain injury.
But some people who have had a severe or repeated brain injury may have long-lasting problems with movement, learning, or speaking.
For Veterans from OIF and OEF there is a strong likelihood that mTBI is comorbid with PTSD

What is a Concussion?
A concussion is caused by a jolt that shakes the brain back and forth inside the skull.
Any hard hit to the head or body --whether it's from a football tackle or a car accident --can lead to a concussion.
Although a concussion is considered a mild brain injury, it can leave lasting damage if the person doesn't rest long enough to let the brain fully heal afterward.
After a fall or hit to the head, the person may be knocked out for a few seconds.
But many people with concussions do not black out.
A few telltale symptoms will show that a person may have a concussion. Dizziness, nausea or vomiting, blurry vision, headache, and trouble thinking clearly are all signs that the person needs to see a doctor to get the head injury checked out.

What are the Symptoms of TBI?
Symptoms of a traumatic brain injury range from mild to severe and can last for hours, days, weeks, or even months.

These symptoms may include:

  • Not thinking clearly, or having trouble remembering new information.
  • Having headaches, vision problems, or dizziness.
  • Feeling sad, nervous, or easily angered.
  • Sleeping more or less than usual.
If a person develops these kinds of symptoms at any time after a head injury—even much later—they need to contact their doctor.
Substance/Alcohol Use Disorders

What is Addiction?

Addiction is a brain disease

Characterized by:

  • Compulsive behavior
  • Continued abuse of drugs despite negative consequences
  • Persistent changes in the brain’s structure and function

Addictive Brain Response

If alcohol or other drugs makes a person feel really good the person is at high risk of addiction

This is because alcohol and drugs:

  • Flood the brain with pleasure chemicals
  • Deprive the brain of warning chemicals
  • Create euphoria
  • Inhibit anxiety and fear even when in real threat
  • Impair judgment and impulse control

Addiction is like any other Disease

It is:

  • Preventable
  • Treatable
  • It changes the biology of the body
  • If untreated it lasts a lifetime
Alcohol Use Disorder

Impact of Alcohol Use Disorder

Signs of Alcohol Use Disorder are:

  • Alcoholic beverages found missing from the home storage cabinet
  • Alcohol or mouthwash (used to cover up alcohol) breath or hangover symptoms (nausea, vomiting, or headache), if recently used

One has an alcohol problem if the person’s use of alcohol interferes with personal health or daily living.

  • People develop alcoholism if they physically or emotionally depend on alcohol to get them through their day.
  • People who drink alcohol are more likely to engage in high-risk sexual behavior, have poor grades or job performance, use tobacco products, and experiment with illegal drugs.
  • Alcohol and drug use may be an unconscious attempt at self-treatment for another problem, such as depression.

Physiological Effects of Alcohol Use Disorder
Although many people have a drink as a "pick me up," alcohol actually depresses the brain.
Alcohol lessens inhibitions, slurs speech, and decreases muscle control and coordination, and may lead to severe alcohol use disorder
Long-term heavy drinking damages the liver, nervous system, heart, and brain -Alcohol is the most common cause of liver failure in the US.
Alcohol can cause heart enlargement and cancer of the esophagus, pancreas, and stomach.
It can lead to high blood pressure, stomach problems, medicine interactions, sexual problems, osteoporosis, and cancer
Withdrawal from alcohol can cause anxiety, irregular heartbeat, tremor, seizures, and hallucinations.
In its severest form, withdrawal combined with malnutrition can lead to a life-threatening condition called delirium tremens (DTs). 

Social Impact of Alcohol Use Disorder
Alcohol use disorder can also lead to violence, accidents, social isolation, jail or prison time, and problems at work and home.
Symptoms of an alcohol problem include personality changes, blackouts, drinking more and more for the same "high," and denial of the problem.
A person with an alcohol problem may gulp or sneak drinks, drink alone or early in the morning, and suffer from the shakes.
He or she may also have family, school, or work problems or get in trouble with the law because of drinking.
The use of alcohol with medicines or illegal drugs may increase the effects of each
Tobacco Use Disorder

Signs and Symptoms of Tobacco Use Disorder

A person who is dependent on tobacco can be identified by:

  • A distinctive smell on the breath and clothing
  • Cigarettes and lighter in his or her possession
  • Cigarette butts outside a bedroom window or in other odd places around the home

Impact of Tobacco Use Disorder
  • People cite many reasons for using tobacco, including pleasure, improved performance and vigilance, relief of depression, curbing hunger, and weight control.
  • The primary addicting substance in cigarettes is nicotine.
  • But cigarette smoke contains thousands of other chemicals that also damage health.
  • Hazards include heart disease, lung cancer and emphysema, peptic ulcer disease, and stroke.
  • Withdrawal symptoms of smoking include anxiety, hunger, sleep disturbances, and depression.
  • Smoking is responsible for nearly a half million deaths each year. Tobacco use costs the nation an estimated $100 billion a year, mainly in direct and indirect health care costs.
Substance Use Disorders

What is Substance Use Disorder?

Substance use disorder includes the use of illegal drugs:

  • Marijuana
  • Methamphetamines
  • Cocaine,
  • Heroin, or other "street drugs“
And use of legal prescription and nonprescription drugs.

Some people use drugs to get a "high" or to relieve stress and emotional problems.

General Signs of substance abuse:

  • Changes in sleeping patterns
  • Changes in appetite or weight loss
  • Changes in dress
  • Loss of interest and motivation
  • Hoarseness, wheezing, or persistent cough

Signs of various Substance Use Disorders

Inhalants

Chemical breath, red eyes, or stains on clothing or face, if recently used
Soaked rags or empty aerosol containers in the trash

Club drugs

Skin rash similar to acne
Small bottles with liquid or powder in his or her possession

Stimulants

Persistent runny nose and nosebleeds, injection marks on arms or other parts of the body, or long periods of time without sleep
Possession of drug paraphernalia, such as syringes, spoons with smoke stains, small pieces of glass, and razor blades

LSD or other hallucinogens

Trance-like appearance with dilated pupils, if recently used
Small squares of blotter paper (sometimes stamped with cartoon characters) or other forms of the drug in his or her possession

Heroin

Very small pupils and a drowsy or relaxed look, if recently used
Possession of injecting supplies, called an outfit or rig, that may consist of a spoon or bottle cap, syringe, tourniquet, cotton, and matches

Anabolic steroids

An unpleasant breath odor
Mood changes, including increased aggression
Changes in physical appearance that can't be attributed to expected patterns of growth and development
Possession of medicines or syringes

Signs of Marijuana Abuse

A person who is abusing marijuana can be identified by:

  • Sweet smell on clothing or bloodshot eyes, if recently used, and frequent use of eyedropsto reduce the redness
  • Drug paraphernalia (pipes) in his or her possession
  • Carelessness in grooming, increased fatigue, and changes in eating and sleeping patterns, if using regularly

Impact of Marijuana Use Disorder

Marijuana is also known as grass, pot, weed, herb.

Marijuana comes from the plant Cannabis sativa and is the most commonly used illegal drug in the United States. The plant produces delta-9-tetrahydrocannabinol (THC), the active ingredient associated with intoxication.
Marijuana resin, called hashish, contains an even higher concentration of THC.
The drug is usually smoked, but it can also be eaten. Its smoke irritates lungs more and contains more cancer-causing chemicals than tobacco smoke.
Common effects of marijuana use include pleasure, relaxation, and impaired coordination and memory.
Often, the first illegal drug people use, marijuana is associated with increased risk of progressing to more powerful and dangerous drugs such as cocaine and heroin. The risk for progressing to cocaine is 104 times higher if you have smoked marijuana at least once than if you never smoked marijuana.
Impact of Methamphetamine Use Disorder
Methamphetamines is also known as meth, crank, ice, speed, crystal.
Methamphetamine is a powerful stimulant that increases alertness, decreases appetite, and gives a sensation of pleasure.
The drug can be injected, snorted, smoked, or eaten.
It shares many of the same toxic effects as cocaine-heart attacks, dangerously high blood pressure, and stroke.
Withdrawal often causes depression, abdominal cramps, and increased appetite.
Other long-term effects include paranoia, hallucinations, weight loss, destruction of teeth, and heart damage.

Meth and the Brain
Methamphetamine enter the brin throug the blood stream
Meth stimulates a region of the brain that releases dopamine
Dopamine, a neurotransmitter, carries messages from one brain cell, or neuron, to another
In a normal brain, neurons release dopamine in response to thing that bring pleasure. 

Impact of Cocaine Use Disorder

Cocaine is also known as crack, coke, snow, rock.

  • Cocaine use has gone down in the last few years; from 2007 to 2012, the number of current users in the U.S. ages 12 or older dropped from 2.1 million to 1.7 million.
  • Derived from the coca plant of South America, cocaine can be smoked, injected, snorted, or swallowed. The intensity and duration of the drug’s effects depend on how you take it. Desired effects include pleasure and increased alertness.
  • Short-term effects also include paranoia, constriction of blood vessels leading to heart damage or stroke, irregular heartbeat, and death. Severe depression and reduced energy often accompany withdrawal.
  • Both short- and long-term use of cocaine has been associated with damage to the heart, the brain, the lung, and the kidneys.
Commonly Abused Prescription  & Over the Counter Drugs

Amphetamines
  • When prescribed, stimulants like the amphetamines Adderall and Dexedrine can help people with ADHD.
  • But some people use amphetamines to get high, to increase energy and alertness, or to keep their weight down.
  • One can get addicted to stimulants.
  • High doses can cause a dangerous rise in body temperature, irregular heartbeat, and even cardiac arrest.
  • Nicknames for amphetamines include "bennies," "black beauties," and "speed."

Methylphenidate
  • Methylphenidate is a stimulant in ADHD drugs like Concerta, Metadate, Methylin, and Ritalin.
  • Its nicknames include "MPH," "R-ball," "Skippy," "the smart drug," and "vitamin R."
  • If one take stimulants, combining them with common decongestants can cause dangerously high blood pressure or an irregular heartbeat

Barbiturates
  • Barbiturates (sedatives): phenobarbital, Mebaral, Nembutal & Seconal
  • They help with anxiety, sleep problems, and some seizures. But if taken more than prescribed, one can get addicted.
  • High doses can cause trouble breathing, especially if one uses them when drinking alcohol.
  • If a person can’t function without barbiturates, they must get help.
  • Going into withdrawal can be dangerous.

Benzodiazepines
  • Valium and Xanax are two examples of benzodiazepines which are sedatives that can help with anxiety, panic attacks, and sleep problems.
  • Benzodiazepines work well and they're safer than barbiturates.
  • But overused, they can also lead to physical dependence and addiction.
  • Prescription drugs shouldn't be shared.
  • They are only for the person with the prescription

Sleep Medications
  • For people who have trouble sleeping, drugs like Ambien, Lunesta, and Sonata can help them get the rest they need.
  • But if used longer than one’s doctor suggests, a person may start to believe in the need for them in order to sleep.
  • Although they are not as addictive as some sleeping pills, doctors are concerned about abuse if they are not taken as prescribed.

Codeine and Morphine
  • Some of the most commonly abused prescription meds are painkillers specifically, opioids.
  • These drugs dull pain, but in large doses they can also cause a euphoric high and dangerous side effects.
  • Doctors usually prescribe morphine for severe pain and codeine for milder pain or coughing.
  • Brands of morphine include Avinza, Kadian, MS Contin, Oramorph, and Roxanol.

Oxycodone: OxyContin and Percocet
  • Oxycodone is an opioid painkiller. It's in drugs like OxyContin, Percocet, Percodan, and Roxicodone.
  • People who abuse oxycodone sometimes crush it and snort it or inject it which greatly increases the risk of overdose.
  • Street names include "oxy," "O.C.," and "oxycotton" for OxyContin and "percs" for Percocet or Percodan

Hydrocodone: Vicodin, Lortab, Lorcet
  • Lorcet, Lortab, and Vicodin contain the opioid hydrocodone plus acetaminophen.
  • Opioids cause drowsiness and constipation.
  • High doses can cause dangerous breathing problems.
  • Vicodin's street names include "vike" and "Watson-387."

Dextromethorphan (DXM)
  • Dextromethorphan (DXM) is a common ingredient in over-the-counter cold and cough medicines
  • It helps clear out mucus.
  • But large doses can get a person high and cause hallucinations.
  • It's popular among teens, since cough syrup is so easy to find in medicine cabinets.
  • High doses also cause vomiting, rapid heart rate, and rarely brain damage.

Pseudoephedrine
  • Pseudoephedrine is a decongestant in lots of non-prescription cold medicines.
  • While it helps clear up a stuffy nose, it's also an ingredient in illegal methamphetamine ("meth").
  • To curb meth abuse, U.S. laws now control how one buys pseudoephedrine products.
  • That's why some cold medicines are located behind the counter and why one may have to sign for some.