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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 341
outcome— a functional brain without any brain dysfunction. An atypical DNA
sequence paired with typical experience or a typical DNA sequence paired with
atypical experience may lead to brain dysfunction.
Having the outcome of brain development depend on environmental factors and
experience in a hostile and uncertain world may not seem like the best develop-
mental strategy from an evolutionary standpoint. However, this strategy exists
because it’s possible to build a more complicated and competent organism for a
particular environment. If the entire development is hard wired in the genome, as
may be the case with invertebrates, the organism isn’t adaptable. The environ-
ment can aect organisms dierently in the embryonic period, childhood, and
adulthood.
Developing while growing
During embryonic and fetal growth, the brain increases in size and lays down its
major structures and axon tracts. This process is highly susceptible to intrinsic
genetic abnormalities, environmental drugs and toxins, and nutritional decien-
cies. These issues may cause entire brain regions to be missing, malformed, or
improperly connected. Toxins, nutritional deciencies, and drugs that have no
serious long-term ill eects in adults can have devastating eects on brain devel-
opment in utero.
Early childhood is another vulnerable period. During childhood, the processes of
sculpting synapses and myelinating axon tracts in the brain are ongoing. Experi-
ence from sensory inputs and the outcome of behavior aect these processes.
Engaging in a behavior to accomplish goals, like trying to walk, produces its own
sensory input in a feedback loop that helps wire the brain to allow sensory control
of behavior. During early childhood, the brain is highly malleable. Skills like lan-
guage and swimming are easily learned by children but much harder for adults.
Other behaviors including social engagement and communication develop during
childhood. Individuals with autism spectrum disorder who, because of dierences
in sensory systems and/or processing of facial expressions, may develop atypical
social and/or communication skills.
Turning thoughts into synapses
For millennia through the rst half of 20th century, people believed that after
development, the adult brain was entirely xed and unable to generate new neu-
rons or modify synapses and circuits. In the latter half of the century, scientists
discovered that some synapses, such as those in the hippocampus, could be
tweaked by experience and activity for encoding memory. And others observed
that sensory deprivation could aect the neural organization in sensory areas.
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342 PART 3 Understanding Perception and Cognition
However, this was thought to involve only a few neuronal populations and that
producing new neurons or neural connections wasn’t possible in most of the
brain.
New neurons can arise from neural progenitors in some parts of the adult brain,
like the hippocampus. New synapses can be formed in many parts of the brain.
And functional and structural changes in synapses (that aect synaptic transmis-
sion) may dynamically recongure the brain’s functional architecture in many
brain regions. Together these are called neuroplasticity.
The idea of “use it or lose it” may apply to many cognitive functions. Because
many cognitive capabilities enable others, a small positive or negative change in
cognitive function can have far-reaching eects on the brain’s operation that can
change its structure for better or worse. Thoughts, inspirations, trauma, near-
death experiences, and other strong emotional experiences can rewire the brain.
And so can learning and practice.
Exploring Genetic Causes
Several genetic abnormalities can cause brain dysfunction. A few well-studied
syndromes have a genetic basis that is understood in some detail. Some syn-
dromes are caused by mutations at a single DNA nucleotide, which changes the
protein coded by one amino acid. Genetic mutations can occur by dierent mecha-
nisms, such as ionizing radiation, or errors in replication or transcription. Other
genetic syndromes involve larger changes in the gene or chromosomal DNA and
include insertions, deletions, or duplications.
Although there are currently no cures for development disorders caused by identi-
ed genetic abnormalities, early childhood intervention, through physical, occu-
pational, and behavioral therapies can help children with activities of daily living,
social interactions, and learning.
Mutations in DNA nucleotides in a gene can change the amino acids within
the protein coded by that gene. This can change the way the protein folds, its
functional activity, its location, or stability, or all of these. A misfolded protein
may not only fail to perform a necessary function in the brain, but it may itself
be toxic. Here we describe how gene disruptions can aect neural cells and the
four most common developmental disorders caused by identied genetic
abnormalities.
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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 343
Fragile X syndrome
Fragile X syndrome results from an expansion of a DNA sequence called the CGG
repeat within the FMR1 (fragile X messenger ribonucleoprotein 1-FMRP) gene on
the X chromosome. It’s the most common genetic cause of intellectual disability.
Intellectual disability is a term used when a person has certain limitations in cogni-
tive functioning and skills, including conceptual, social, and practical skills, such
as language, social, and self-care skills. It’s associated clinically with an IQ score
below 70.
Expansion of the CGG repeat part of the gene leads to deciency of the FMRP.FMRP
is an mRNA transport protein required to provide mRNAs for the synthesis of pro-
teins involved in neuronal functions and synaptogenesis. The other behavioral
traits include learning disability, social anxiety, and an aversion to looking at
faces (called gaze aversion). These behavior traits are associated with reduced
function in the prefrontal areas of the brain.
Rett syndrome
Rett syndrome is a developmental disorder characterized by a tendency toward
microcephaly (small brain) and reduced levels of the neurotransmitters norepi-
nephrine and dopamine. It is caused by a mutation of a gene called MECP2 located
on the X chromosome. The MECP2 protein is a transcriptional regulator shown to
repress the expression of many genes; it may also activate expression of other
genes. The syndrome aects females almost exclusively because aected males
typically don’t survive in utero. Behavior traits include intellectual disability, poor
verbal language skills, and repetitive hand wringing.
Williams syndrome
Williams syndrome is a rare developmental disorder that aects many parts of the
body. It’s characterized by mild to moderate intellectual disability, but strong
language skills. It can be caused by a deletion of a number of dierent genes on
chromosome 7, several of which are transcription factors. Individuals with
Williams syndrome tend to be overly sociable and highly verbal. They typically
have diculty with visual-spatial tasks such as drawing and assembling puzzles,
but they tend to do well on tasks that involve spoken language and music.
Down syndrome
Down syndrome (also called trisomy 21) is caused by an extra chromosome 21 (or
part of it). It’s the most common chromosomal abnormality. It occurs in more
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344 PART 3 Understanding Perception and Cognition
than 1in 1,000 births and is more common in children born of older parents due
to the statistically greater chance of this chromosome duplication with aging.
Down syndrome is associated with developmental delays and moderate to severe
intellectual disability. It also produces complications in other organ systems that
reduce life expectancy.
Linking Genetic and Environmental
Factors
The majority of developmental disorders aren’t caused by a single genetic abnor-
mality but rather involve the interaction between genes and the environment. A
genetic mutation is a change in the gene’s nucleotide sequence that leads to the loss
of function or gain of a negative function in the protein it encodes. Genetic muta-
tions are rare in the population and can be dominant or recessive:
»
Dominant mutations lead to disorder or disease even when the good copy
is present.
»
Recessive mutations are tolerated because one good copy of the gene is
present that can perform the function.
Although the DNA of all humans is about 99.9 percent identical, small variations
are present among genes that lead to dierences in individuals, for example in
blood type, eye color, and height. Genetic variants are common in the population
and involve a dierence in the gene’s nucleotide sequence that changes some
aspect of the protein it encodes without having a disruptive eect. Less common
gene variants can persist over many generations if they don’t provide an overall
disadvantage compared to more common variants. The following focuses on the
two most common developmental disorders, identied risk factors, and
treatments.
Attention decit hyperactivity disorder
Attention decit hyperactivity disorder (ADHD) is characterized by diculty in
sustaining attention, as well as hyperactivity and impulsivity. These symptoms
are thought to result from executive dysfunction and emotional dysregulation.
ADHD is the most common developmental disability. It currently aects between
5 to 8 percent of people in the United States. For most individuals, the causes of
ADHD aren’t known, but several genetic and environmental risk factors interact
to cause the disorder.
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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 345
Environmental risk factors for ADHD include traumatic brain injury, exposure to
toxins during pregnancy, and extreme postnatal nutritional deprivation. Because
ADHD tends to run in families with a heritability rate of about 75 percent, genetic
factors also play an important role. Susceptibility genes, which have mutations or
variants, include genes that encode the dopamine receptor, proteins that control
monoamine levels, and synaptic proteins. Nearly half of individuals diagnosed
with ADHD in childhood will go on to have adult ADHD.Treatments for ADHD
include medication, education, skills training, and psychological counseling. The
most common medications include Ritalin (methylphenidate) and Adderall
(amphetamine and dextroamphetamine), which control monoamine uptake and
increase the levels of dopamine and norepinephrine at synapses (refer to
Chapter6).
Autism spectrum disorder
Autism spectrum disorder (ASD) is the second most prevalent developmental dis-
ability aecting about 2 percent of children in the United States. The core symp-
toms of ASD are impaired social communication and restricted and repetitive
patterns of behavior. Common specic symptoms include diculty with social
interactions and verbal and nonverbal communication, eye contact avoidance,
rigid routines, hypersensitivity to sensory stimuli, and repetitive movements. ASD
is called a spectrum disorder because it can manifest very dierently in each indi-
vidual. Symptoms range from mild to severe, and some individuals with ASD have
other disorders, called comorbidities, such as epilepsy, ADHD, or intellectual
disability.
Although the causes of ASD aren’t known, ASD involves interactions among sus-
ceptibility genes and environmental factors. The environmental factors include
parental age, complications during pregnancy or birth, low birth weight, extreme
prematurity, and exposure to viral infections or air pollution. More than a thou-
sand ASD susceptibility genes have been identied, which include gene mutations
and gene variants.
There’s no cure for ASD.Early intervention services including behavioral, speech,
and occupational therapy can help children with ASD gain self-care and social and
language skills. Pharmacological treatments include risperidone and aripiprazole,
which are atypical antipsychotic drugs. The eld of psychiatry traditionally has
classied ASD as a mental disorder. However, many people in the autism rights
movement and ASD researchers view ASD as part of neurodiversity, the natural
diversity in human cognition and experience, with dierences between people
with ASD and neurotypical individuals. Even if a cure for ASD is developed, many
individuals with ASD wouldn’t want it.
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346 PART 3 Understanding Perception and Cognition
Recognizing How the Environment Can
Damage the Developing Brain
Developmental disorders can occur in a genetically typical brain if it suers
organic damage during development. Trauma, stress, toxins, and nutritional de-
ciencies can all generate brain dysfunction. These injuries can be severe and irre-
versible if they happen to the embryo or fetus. Here we discuss two common
injuries.
Substance-related syndromes
Several substances have the potential to compromise the neurological, mental,
and physical health of developing babies if a mother misuses these substances.
The most common is fetal alcohol syndrome, which develops from excessive
alcohol consumption by the mother during pregnancy. Fetal alcohol exposure is a
signicant cause of intellectual disability, occurring in about 1 per 1,000 live
births.
Alcohol readily crosses the placental barrier. In the developing fetus, alcohol can
damage neurons and brain structures and is associated with varying degrees of
cognitive and functional disability, such as attention and memory decits, impul-
sive behavior, and stunted overall growth. Besides alcohol, exposure to prenatal
cocaine and methamphetamine are statistically associated with mental and
behavioral problems. Even excessive caeine and nicotine (from cigarettes) or
poor diets with vitamin or nutrient deciencies may contribute to developmental
disorders.
Maternal stress and infections
Chronic stress can lead to preterm birth or low birthweight, and the child has a
higher risk of developmental disorders such as ADHD or ASD. Maternal stress
changes the mother’s hormone prole through the hypothalamic-pituitary-
adrenal (HPA) axis via the secretion of cortisol, a stress hormone that can aect the
developing nervous system. Some of these eects may be long lasting, such as
eects on hippocampal function.
Maternal viral infections, such as from rubella, can disrupt development of
sensory systems and other circuits leading to hearing loss, visual impairment, or
developmental disorders. Other viral infections such as HIV can be passed to the
fetus. HIV infection can result in the baby being immunocompromised. HIV-
infected babies and children are atgreater risk for infections and cancers and for
developmental delay and disorders.
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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 347
Combining Genes with Environment
in Mental Disorders
The ve most common and well-studied mental disorders are depression, schizo-
phrenia, obsessive compulsive disorder (OCD), post-traumatic stress disorder
(PTSD), and epilepsy. These disorders have multiple causes, and the severity of
symptoms varies greatly. They’re caused by complex interactions between genetic
and environmental factors. Signicant progress has been made in the 21st century
using brain imaging, genetics, and systems neuroscience to understand what
occurs in various kinds of mental disorders.
Depression
Depression includes several types of mood disorders. Clinically they’re called
depressive disorders. The symptoms involve a depressed mood and loss of pleasure
or interest in activities for long periods of time, and it can aect many aspects of
daily life.
Approximately 10 to 15 percent of the U.S. general population is estimated to
experience depression during their lifetime. It’s by far the most common mental
disorder worldwide in terms of disability and total expense, costing more than an
estimated $50 billion annually in the United States alone. People who have lived
through severe loss, abuse, or other stressful events are more likely to develop
depression. Worldwide, women are nearly twice as likely as men to be diagnosed
with depression.
Here are some of the more common types of depressive disorders listed in the
Diagnostic and Statistical Manuel of Mental Disorders (DSM-5):
»
Major depressive disorder (single and recurrent episodes)
»
Persistent depressive disorder
»
Premenstrual dysphoric disorder
»
Major depressive disorder with seasonal pattern
»
Major depressive disorder with peripartum onset
The common feature of depressive disorders is the presence of sad, empty, or
irritable mood, along with changes, such as those in cognitive functions that
aect a person’s capacity to function. What diers among these are duration,
timing, contributing factors, and etiology.
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348 PART 3 Understanding Perception and Cognition
Depression involves a combination of genetic susceptibility and environmental
factors. In this context, environmental factors refer to the physical, medical and
emotional events, incidents and situations experienced over a lifetime.
Some types of depression have a strong genetic basis. A high incidence of depres-
sion can run in families and can be highly heritable without any known environ-
mental triggers. Depression can also occur in individuals from a single incident in
people who hadn’t previously tend to be depressed. For example, someone may
live into adulthood without any signicant depression until a single traumatic
experience occurs, such as the death of a loved one. Depression can also result
from chronic lower-level stress. When depression is caused by environmental
factors in what was before a nondepressed brain, clearly those factors produce
changes in brain function in some way.
Since the 1950s, clinicians and researchers have proposed many ideas about what
may happen in the brain to lead to depression. Here we discuss several of these
ideas.
Early hypotheses about the etiology of depression
Initial hypotheses about depression were based on eects of drugs that aect
monoamine neurotransmitters. These hypotheses were updated as more data
became available about changes in the brain that occur in depression.
MONOAMINE HYPOTHESIS
In the late 1950s, two drugs were discovered by serendipity that improved the
mood of patients with depression. The drugs had a common eect of acutely
increasing monoamine levels. This led to the hypothesis that the basis of depres-
sion is depletion in the monoamines: serotonin, norepinephrine, and/or dopa-
mine in the brain. Monoamines are neurotransmitters. Their receptors are
neuromodulators that work through second messenger signaling pathways lead-
ing to long-term changes in neurons.
This hypothesis was strengthened after the development in the 1980s of mono-
amine reuptake inhibitors to treat depression. Prozac is a selective serotonin
reuptake inhibitor, or SSRI.Other reuptake inhibitors can elevate the levels of
norepinephrine and dopamine. The monoamine hypothesis also argued that spe-
cic monoamine decits cause particular features of depression. Norepinephrine
deciency reduces alertness and energy; serotonin deciency produces anxiety,
obsessions, and compulsions; and low dopamine levels lead to lowered attention,
motivation, and anhedonia (reduced feelings of pleasure).
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CHAPTER 18 Brain Dysfunction in Developmental and Mental Disorders 349
BEYOND THE MONOAMINE HYPOTHESIS
Although monoamines systems are clearly aected in depression, scientic evi-
dence over the past three decades shows that the monoamine hypothesis is too
simplistic and needs a serious overhaul.
Here’s some of the evidence: Depressed people don’t have abnormally low sero-
tonin levels. Drugs that deplete monoamine levels don’t cause depression in
healthy people, nor do they worsen depressive symptoms in depressed people.
People with genetic variants of serotonin transporters that increase transport
have a reduced incidence of depression whereas people with variants that decrease
transport have increased incidence of depression.
There’s a delayed onset of therapeutic eects of conventional antidepressants
(two to six weeks) even though monoamine levels are rapidly restored. Following
long-term antidepressant treatment, when therapeutic eects occur, mono-
amines return to pre-drug levels. Reuptake inhibitors are fully eective in less
than half of patients. Several drugs with antidepressant eects don’t act directly
through monoamine systems. And nondrug therapies including behavioral cogni-
tive therapy, exercise, transcranial magnetic stimulation, and transcranial direct
current stimulation have antidepressant eects.
Brain dysfunction theories of depression
Numerous structural and functional changes in brain regions and brain networks
correlate with depression. This suggests that more global changes in synaptic
transmission and neuronal circuit activity could be involved in depression. Here
we explore these theories in greater detail.
BRAIN REGIONS AFFECTED IN DEPRESSION
Human functional imaging (fMRI) studies and analysis of postmortem human
brain have shown changes in specic regions of the brain that correlated with
depression. Here are some brain regions aected:
»
Cerebral cortex and hippocampus: Human fMRI studies have shown
anomalies and/or thinning in the orbitofrontal cortex, middle prefrontal
cortex, dorsolateral prefrontal cortex, and anterior cingulate cortex in
individuals with depression. In some people, increased activity in the amyg-
dala and posterior parietal cortex were observed. Postmortem studies show a
decrease in volume (most likely because of decreased dendrites, synapses,
and glia) in the prefrontal cortex, cingulate cortex, and hippocampus of
depressed subjects. In some subjects an increase in volume in the amygdala
was observed.
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350 PART 3 Understanding Perception and Cognition
»
Raphe nuclei: Located in the upper brainstem, raphe nuclei are the primary
location of serotonin neuron cell bodies that project axons throughout the
brain. Depression is often associated with abnormally low activity in the dorsal
raphe nuclei.
»
Ventral tegmental area: Located in the midbrain, this area is a major part of
the brain’s reward system. Dopaminergic neurons in this area project to the
nucleus accumbens and frontal lobe. Long-term stress decreases dopamine
release in the nucleus accumbens.
»
Subgenual cingulate: This area appears to be overactive in some types of
depression. It may keep the suerer stuck in a feedback loop in which
negative, self-focused thoughts reinforce themselves. Deep brain stimulation
(which we discuss in the section “Electrical brain stimulation” later this
chapter) in this area has had success in alleviating depression.
NETWORK HYPOTHESIS
The brain areas in the previous section communicate through important networks
to generate attention, perception, emotion, cognition, and behavior. Another the-
ory is that changes in connectivity among brain regions and dysfunction at the
network level is the basis of depression.
The network hypothesis predicts that a number brain regions involving several
neurotransmitter systems are involved in depression. Functional imaging studies
have identied seven large-scale brain networks based on connectivity and mutual
activity. Three of the best studied networks are the default mode network, salience
network, and central executive network.
Researchers are using fMRI to examine if these networks are aected in individu-
als with neurological or mental disorders. Dierences in activity in all three net-
works have been observed in subjects with depression compared with nondepressed
controls. Default mode network activity has been linked to the tendency of indi-
viduals with depression to ruminate (engage in self-focused negative thinking).
Genes and environment in depression
Depression involves an interaction between genes and environmental factors.
Many genetic variants contribute to depression susceptibility, including genes
involved in monoamine systems and synaptic structure and function. What are
the environmental factors that contribute to the development of depression? And
what can these reveal about underlying causes of depression?
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