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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 351
EARLY ENVIRONMENTAL RISK FACTORS FOR DEPRESSION
Stressful early life experiences can impact brain development, leading to long-
term functional changes that may contribute to lifelong vulnerability for develop-
ing depression. Early environmental risk factors include in utero exposure to
infection, lack of nutrients, and maternal stress. In childhood and adolescence,
risk factors include malnourishment, maltreatment, and abuse. Stressful early
experiences can also aect adaptive mechanisms required to deal with challenges
in adulthood.
ENVIRONMENTAL FACTORS IN THE DEVELOPMENT OF
DEPRESSION
In adolescence and adulthood, depression can be triggered by traumatic physical
or emotional events or illness. For some people, an upsetting or stressful life
event, such as bereavement, divorce, illness, traumatic accident, physical or sex-
ual abuse, job loss, or family or money worries can be the cause. Dierent causes
can often combine to trigger depression. A shared eect produced by these events
is chronic stress.
Stress involves activation of the HPA axis:
»
The hypothalamus (H) receives inputs from sensory, emotional, and memory
brain regions.
»
In response to a traumatic physical, emotional, or stressful event, the
hypothalamus activates the pituitary (P) to release a hormone called ACTH
(adrenocorticotropic hormone).
»
ACTH travels in the blood to the adrenal (A) gland where it stimulates the
release of the stress hormone cortisol into the blood. Cortisol aects many
organs, including the brain.
Small acute increases in cortisol are good to increase energy and lower fatigue in
emergency situations. But chronic stress and elevated cortisol can lead to changes
in neurons and glia. In neurons, cortisol binds to glucocorticoid receptors that
control gene expression. Cortisol also increases brain inammation, and inam-
matory mediators can aect microglia, astrocytes, and neurons.
The neuroplasticity hypothesis
Research studies in rodent models show that placing an animal in a stressful
physical or psychological situation over time leads to a chronic stress response
with elevated cortisol. These animals develop depression-like behaviors, reect-
ing symptoms in human depression. These studies support the conclusion that
chronic stress is a signicant causal factor in the development of depression.
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352 PART 3 Understanding Perception and Cognition
In the rodent chronic stress studies, examination of the brain showed signicant
changes. These include a thinning of the gray matter in the neocortex and
decreased volume in the hippocampus, similar to changes seen in humans with
depression. At a microscopic level in neurons, there were decreases in dendritic
spines and synapses and less neurogenesis. In functional studies, chronically
stressed animals showed reduced synaptic plasticity called long-term potentia-
tion (LTP) in the hippocampus.
The eects observed in rodent models, especially on synaptic plasticity, and in
human studies, are consistent with a reduction in the processes that underlie
neuroplasticity. This has led to the hypothesis that chronic stress and depression
involve the dysregulation of neuroplasticity. The recent discovery of rapid antide-
pressant eects of drugs called psychoplastogens that increase or restore neuro-
plasticity support this hypothesis.
Novel pharmacological treatments:
psychoplastogens
Psychoplastogens are a group of small molecule drugs that can produce rapid and
often sustained eects on neuronal structure and function, and rapid therapeutic
benets. Though they act through dierent initial mechanisms, several psycho-
plastogens have been shown in initial small clinical trials to have eective and
rapidly acting antidepressant action. Psychoplastogens have less addiction poten-
tial than originally thought, and many are in more extensive clinical trials for
treatment of a variety of mental disorders.
Here are some psychoplastogens being studied in clinical trials:
»
Ketamine: This drug was initially developed as an anesthetic. Also known as a
recreational drug, ketamine also has rapid antidepressant eects within a day
and is often tested for treatment-resistant depression. A challenge for the use
of ketamine is the limited time of antidepressant eects (about a week).
Ketamine has been shown to be an NMDA glutamate receptor antagonist. It
has also been proposed to increase BDNF levels and enhance BDNF recep-
tor activity.
»
MDNA: One study has shown that in people with a predisposition to depres-
sion, treatment with MDMA, also known as the party drug ecstasy, caused a
signicant reduction in depressive symptoms. Also rapidly acting, MDMA
binds to monoamine reuptake transporters and vesicular storage transport-
ers. MDMA enhances release and/or blocks reuptake of presynaptic sero-
tonin, dopamine, and norepinephrine.
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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 353
»
Hallucinogens: Humans have used hallucinogens ritualistically for millennia.
Hallucinogens are psychoactive, meaning they change a person’s awareness of
their surroundings and alter thoughts and feelings. They can cause mystical
experiences and hallucinations, the perception that images or sounds are real
when they aren’t actually present. Here are types of hallucinogens:
•
LSD: This drug was the rst hallucinogenic synthesized in the 1950s.
•
Psylocibin: A naturally occurring hallucinogen, it’s produced by many
species of mushrooms. Psilocybin-assisted therapy can produce a rapid
and signicant improvement in depressive symptoms, lasting for at least
six months. DMT can be extracted from several plant species. Ayahuascais
a combination of DMT and a plant extract containing monoamine oxidase
inhibitors.
These drugs have a common mechanism acting as serotonin receptor
agonists, specically at 5HT2A serotonin receptors.
Identifying nonpharmacological therapies
Antidepressant drugs are the most commonly used and widely prescribed rst line
treatments for depression. Because some individuals have treatment-resistant
depression, nonpharmacological therapies for depression have been developed
over the past few decades. Here is a description of some current therapies.
COGNITIVE BEHAVIORAL THERAPY (CBT)
CBT is an evidence-based psychological intervention for the treatment of mental
disorders, including depression. CBT is a problem-focused and action-oriented
form of talk therapy. One goal of CBT treatment is to challenge and change think-
ing patterns and their associated behaviors. In depression, negative feelings or
emotions can create negative memories that when recalled lead to a feedback loop
of negative thoughts.
Two strategies of CBT include the following:
»
Break this feedback cycle by identifying the distortions in thinking that are
creating problems and reevaluating them.
»
Get a better understanding of the behavior and motivation of others.
These can lead to improved emotional regulation and development of coping
strategies and problem solving. If CBT can restore neuroplasticity in depression,
it is amazing that a person’s conversations and thoughts can change their brain.
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ELECTRICAL BRAIN STIMULATION
Here are treatments for brain electrical stimulation:
»
Transcranial magnetic stimulation (TMS): It involves creating a millisecond,
high-eld magnetic pulse over a particular brain area via an external coil that
produces currents inside the brain underneath the coil. Some clinical success
has been achieved in treating depression with TMS.
»
Deep brain stimulation: It involves placing electrodes in brain regions.
Current pulses of certain frequencies have been shown to reduce depression
symptoms in patients with treatment-resistant depression.
»
Electroconvulsive therapy (ECT): ECT involves passing electric currents
through the brain via scalp electrodes to induce transient seizure activity. ECT
has been shown to be eective in some individuals for the relief of treatment-
resistant depression.
EXERCISE
People who exercise regularly report have better mental health and emotional
wellbeing and lower rates of mental disorders. Exercise may reduce the risk of
developing mental disorders. Exercise can also help in treating depression. Regu-
lar exercise may help improve mood by increasing the body’s feel-good chemi-
cals, including endocannabinoids and endogenous opioids (refer to Chapters 6
and15).
Exercise can also impact depression by enhancing neuroplasticity. Exercise leads
to the release of myokines from muscle. One myokine called irisin can act on
many tissues, including the brain. Irisin increases the levels of BDNF in the brain
and is suggested to enhance neuroplasticity.
Schizophrenia
Schizophrenia is a mental disorder characterized by disordered thought, paranoia,
and delusional beliefs. It occurs in about 1 percent of the population worldwide
and is associated with signicant social dysfunction and disability. People with
severe cases of schizophrenia are often hospitalized. Here we delve deeper into
what you need to know about schizophrenia.
People often confuse the two, but schizophrenia is not the same as dissociative
identity disorder.
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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 355
Recognizing symptoms
Symptoms of schizophrenia typically appear in young adulthood, and they fall
into two general categories:
»
Positive symptoms: These are active processes that include hallucinations or
delusions such as hearing voices, seeing images or feeling, smelling, or tasting
things that don’t exist outside the mind. They can aect behavior or thoughts.
Brain scans of individuals with schizophrenia show activity in their auditory
cortex during auditory hallucinations. This suggests that an internal source in
the brain is generating activity in areas that the individual can’t distinguish
from something actually sensed.
»
Negative symptoms: Mostly these symptoms are withdrawal and an inability
to engage in social interactions, characterized by at aect and emotion,
anhedonia, loss of motivation, social withdrawal, and lack of attention to
hygiene and routine activities of life. Although positive symptoms are harder
to manage when patients act out delusional ideas, negative symptoms tend to
contribute more to poor quality of life.
Examining the genetic basis
The typical age of onset of schizophrenia is young adulthood, when myelination
in the frontal lobe is being completed. This is the last major stage of axonal mye-
lination during development. Schizophrenia appears to be dysfunction of the
frontal lobe that has strong heritability.
The genetic basis of schizophrenia is apparent in the fact that if one identical twin
has schizophrenia, the other twin has a 40 percent chance of developing the dis-
order, even if the other twin was raised separately. Moreover, known subclinical
traits in schizophrenia, like a particular kind of abnormal eye tracking, occur fre-
quently in close relatives of people with schizophrenia.
Identifying treatment options
Pharmacological treatments for alleviating positive symptoms of schizophrenia
have improved in the last decades. Negative symptoms still don’t respond well to
most current medications. Researchers are unclear why some drugs work better in
some patients with schizophrenia than others for positive symptoms and why
none of them alleviates negative symptoms well.
Most individuals with schizophrenia are treated with typical or atypical antipsy-
chotic medications. Many of these drugs preferentially aect the dopaminergic
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356 PART 3 Understanding Perception and Cognition
system to decrease positive symptoms. Unfortunately these drugs can have seri-
ous side eects. Some antipsychotics may also increase acetylcholine levels or
enhance serotonin function with less eect on dopamine.
Nicotine, as from cigarettes, is a nicotinic receptor agonist, and cigarette smok-
ing, as a form of self-medication, is prevalent among people with schizophrenia.
Research suggests a specic mutation in the alpha-7 nicotinic acetylcholine
receptor acts as a major molecular genetic susceptibility for schizophrenia.
Recent evidence suggests that abnormally low numbers of NMDA glutamate
receptors are involved in schizophrenia. Postmortem analysis of the brains of
patients with schizophrenia show reduced receptor numbers compared to normal.
NMDA receptor–blocking drugs such as phencyclidine and ketamine mimic
schizophrenia symptoms, and the hallucinogen LSD has similar eects to
ketamine.
Obsessive compulsive disorders
Obsessive compulsive disorder (OCD) is an anxiety disorder characterized by intru-
sive thoughts that generate repetitive behaviors to alleviate the anxiety related to
the intrusive thoughts. Obsessive-compulsive personality disorder (OCPD) is marked
by an intense focus on perfection, order, and control. About 2 percent of the popu-
lation have OCD or OCPD symptoms.
Typical symptoms of OCD include washing excessively (particularly hand wash-
ing), repeatedly checking for something undone or missing, and performing ever-
yday activities— such as dining or washing— in a ritualistic way. OCD is also
associated with traits such as hoarding, preoccupation with sexual or religious
thoughts, and irrational aversions, such as extreme fear of germs. Extreme cases
of OCD are associated with paranoia and psychosis.
Unlike schizophrenia (see our discussion in the previous section), however, people
with OCD are typically aware of their obsessions and usually nd them distress-
ing, although they’re unable to stop.
Some OCD has been linked to an abnormal serotonin neurotransmission, some-
times successfully treated with SSRIs. Mutations in genes linked to serotonin have
been identied in some individuals with OCD, but a strong genetic basis for its
occurrence hasn’t been identied. The genetic basis may be a susceptibility that
environmental factors act on to produce the disorder.
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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 357
Posttraumatic stress disorder
Posttraumatic stress disorder (PTSD) is a severe anxiety disorder that develops after
psychological trauma— such as experiencing a war or sexual abuse— that over-
whelms the person’s coping ability. Traumatic psychological events cause an
overactive adrenaline response that persists after the event, making a person
hyperresponsive to future fearful situations.
PTSD is associated with low basal cortisol levels and high catecholamine secre-
tion, characteristic of the classic ght-or-ight response. It may have a genetic
susceptibility associated with dierences in GABA receptors and is associated with
having a smaller than normal hippocampus.
People prone to PTSD are also statistically more likely to have generalized anxiety
disorders; a tendency toward alcohol, nicotine, and drug misuse; and a history of
abuse as children.
Desensitization therapies, which involve paring systematic re-exposure with relax-
ation techniques in a carefully controlled environment, can sometimes mitigate
some of its eects. Preliminary studies have shown eectiveness of the psycho-
plastogens ketamine and MDMA in the treatment of PTSD.
Epilepsy
Epilepsy is when seizures occur in the brain. Seizures are incidents of hypersyn-
chronous neural activity during which normal brain function is severely compro-
mised. The underlying cause of epilepsy is usually a dysfunctional brain area
where the seizures originate and then spread to the rest of the brain. These
seizure-originating areas are called epileptic foci. They occur commonly in the
temporal lobe but can exist anywhere in the brain.
Most initial treatment for epilepsy use drugs called anticonvulsants. Most of the 20
or so anticonvulsants approved by the Food and Drug Administration (FDA) are
aimed at increasing GABA transmission in the brain. About 70 percent of patients
experience a reduction of seizures with one or more of these drugs.
For individuals with epilepsy in which anticonvulsants do not work, or those who
can’t tolerate the negative drug side eects, surgery is an option. In epilepsy sur-
gery, the surgical team tries to locate the focus of the seizure and remove it with-
out damaging important nearby brain areas, particularly those associated with
language.
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Eating and Drinking for Brain Function
The foods you eat and the liquids you drink contain many substances that can
aect brain activity and function. Well-known substances include caeine, alco-
hol, and nicotine. Nutritional supplements and even the balance of fat versus meat
versus vegetables in the diet can aect neurotransmitter balances in the brain
with cognitive and behavioral results as we discuss in these sections.
Considering naturally occurring
psychoactive substances
Nutrition, neuroactive substances, and drugs can have signicant eects on brain
function, for good or bad. These substances can be ingested from plants or pills.
Many drugs and supplements act by mimicking neurotransmitters, while others
modulate cell metabolism or membrane function.
Naturally occurring psychoactive substances have been used in religious rituals
for thousands of years. Notable examples include peyote (mescaline) and psilocy-
bin, which activate serotonin receptors to produce hallucinations and euphoria.
Cannabinoids in marijuana activate receptors called CB1 and CB2 in the brain’s
pain and immune control systems. There are also naturally occurring cholinergic
antagonists from plants, such as the deadly nightshade and mandrake, which are
hallucinogenic.
Feeding the brain properly
Healthy brain activity depends on a healthy body, including its cardiovascular
system. Nutrition and exercise that promote general health tend to promote brain
health.
Some vitamins are thought to enhance brain function or slow its decline with
aging. These include the B vitamins, vitamin D, omega-3 fatty acids, and
isoavones.
Certain agents, sometimes called nootropics, are thought to specically enhance
some brain functions such as cognition, memory, intelligence, motivation, atten-
tion, and concentration. These are variously called smart drugs, memory enhancers,
neuroenhancers, cognitive enhancers, and intelligence enhancers.
Most so-called smart drugs work by mimicking neurotransmitters, altering their
endogenous levels, or antagonizing receptors. Many are derived from drugs used
to treat neurological conditions like Alzheimer’s disease or Parkinson’s disease,
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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 359
such as L-dopa, the precursor to dopamine. Other dopamine agents include
modanil, L-phenylalanine L-tyrosine, biopterin, and pyridoxal-phosphate.
Some psychiatric drugs such as methylphenidate (Ritalin, used for ADHD) are
taken in the belief that they increase productivity without producing euphoria or
psychosis. Some common supplements include resveratrol (an MAO-A inhibitor),
St. John’s wort (an herbal supplement used for mild depression), ginseng, kava,
co-enzyme Q-10 (an antioxidant), creatine (which modulates ATP levels), and
ginkgo biloba and vincamine (which are vasodilators).
Needless to say, mucking around with your brain and nervous system without a
thorough knowledge of the eects of these agents and without being able to mon-
itor neurotransmitter and receptor levels is potentially very dangerous. Many of
the agents we describe here have been used as herbal medication in other coun-
tries for some time, so at least they have a history of use to look at. If you take any
supplement, do so carefully and under the advice of a physician.
Looking at commonly misused drugs
People misuse drugs that aect the brain for many dierent reasons. Often, tak-
ing drugs is a way to self-medicate that is habit forming. Here are some com-
monly misused substances:
»
Stimulants: Some stimulants, such as amphetamines and methamphet-
amines, are initially taken to enhance productivity but end up causing
addiction and psychosis.
»
Nicotine: Taken in from cigarette smoking, vaping, or patches, nicotine can
have short-term positive eects on alertness, attention, memory, and ne
motor control. It seems to reduce some schizophrenic symptoms. However,
cigarettes produce scores of toxic by-products that lead to lung cancer,
emphysema, and vascular system damage.
»
Caeine: Commonly ingested in coee and tea, caeine increases energy
and alertness. It has a marginal paradoxical protective eect against
Parkinson’s disease, for unknown reasons.
»
Other substances: Some drugs are taken only for euphoria, of course. These
include dopaminergic agents such as cocaine, heroin, ecstasy (MDMA), and to
a lesser extent marijuana, a cannabinoid. These drugs and alcohol are
frequently misused although the potential varies among individuals.
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