2. Chapter Outline
Alzheimer’s Disease: Burning Out with
Age?
Frontotemporal Dementia: Like a Cancer
of the Soul
Huntington’s Disease: A Genetic Rarity, in
Two Senses
Tourette Syndrome: A Case of Involuntary
Volition?
2
3. Chapter Outline
Obsessive-Compulsive Disorder:
Neurological or Psychiatric?
Schizophrenia: A Dementia of the Young
Bipolar Disorder
Depression: A Global Burden
3
4. Alzheimer’s Disease: Burning
Out with Age?
Dementias are neurologic disorders
characterized by slow deterioration of
higher cognitive functions.
Such functions include language, memory,
judgement, and emotion.
Alzheimer’s disease or Alzheimer’s
dementia is thought to affect about 24
million people world-wide.
4
6. Alzheimer’s Disease: Burning
Out with Age?
The major deficit of Alzheimer’s is the loss
of episodic memory.
Executive functions decline throughout
Alzheimer’s disease.
Biological markers of Alzheimer’s disease
include amyloid-beta plaques and
neurofibrillary tau tangles.
6
9. Alzheimer’s Disease: Burning
Out with Age?
Most cases of Alzheimer’s disease occur
in individuals over age 60.
The epsilon 4 variant of the apolipoprotein
E (ApoE4) gene seems to increase the
risk of developing the disease.
Genetic forms of Alzheimer’s disease
account for only a small percentage of
cases.
9
11. Alzheimer’s Disease: Burning
Out with Age?
Treatment of Alzheimer’s disease
There are currently no cures for Alzheimer’s
disease.
No medications significantly slow down or
reverse the progression of the disease.
Acetylcholinesterase inhibitors and NMDA
glutamate receptor antagonists sometimes
slow the progression of the disease.
11
12. Alzheimer’s Disease: Burning
Out with Age?
A potential treatment uses the immune
system to remove plaques, but this has
not resulted in any clinical improvement.
Social, mental, and physical activity can
decrease the risk and severity of
Alzheimer’s disease.
12
13. Frontotemporal Dementia: Like a
Cancer of the Soul
This dementia results from progressive
atrophy of the brain.
This is most common in the inferior frontal
lobes and anterior temporal lobe.
The age of onset is typically about 40 – 50
years of age.
Personality and social behaviors change
significantly.
13
15. Frontotemporal Dementia: Like a
Cancer of the Soul
Behavioral variant frontotemporal
dementia (bvFTD) is most common.
This is characterized by progressive
semantic dementia, personality changes
and loss of empathy.
Frontotemporal dementia is sometimes
associated with an increase in creativity.
15
17. Huntington’s Disease: A Genetic
Rarity, in Two Senses
Patients perform restless involuntary
movements of the face, trunk, and limbs.
It commonly also includes psychiatric
symptoms such as depression, apathy,
anxiety, delusions, and hallucinations.
The biological cause is degeneration of
the anterior caudate nucleus of the
striatum.
17
20. Huntington’s Disease: A Genetic
Rarity, in Two Senses
Huntington’s disease is caused by the
mutation of an autosomal dominant gene.
This mutation encodes the inclusion of a
trinucleotide repeat of the sequence CAG
in the final protein.
Most people have fewer than 28 CAG
repeats, and this results in no issues.
Individuals with more than 35 repeats are at
an increased risk of developing the disease.
20
21. Huntington’s Disease: A Genetic
Rarity, in Two Senses
Risk factors for Huntington’s disease
include both genetic and environmental
factors.
Treatment for Huntington’s disease
involves dopamine receptor antagonists.
These relieve some of the motor and
psychiatric symptoms.
21
23. Tourette Syndrome: A Case of
Involuntary Volition?
In Tourette syndrome, the individual
repeats purposeless movements of the
face, head, shoulders, or hands.
There are also verbal tics, which are
purposeless noises like throat-clearing and
snorting or meaningless phrases.
23
24. Tourette Syndrome: A Case of
Involuntary Volition?
Tourette syndrome is typically a disorder
of childhood.
Studies suggest there is a genetic basis to
Tourette syndrome, but no gene has been
isolated.
24
25. Tourette Syndrome: A Case of
Involuntary Volition?
Pediatric Autoimmune Neuropsychiatric
Disorder Associated with group A
Streptococcal infection (PANDAS)
This is characterized by the tics of Tourette
syndrome or the intrusive thoughts and
behaviors of obsessive compulsive disorder.
Sometimes occurs in patients shortly after
they have had a throat infection caused by the
bacteria Group A streptococcus.
25
26. Tourette Syndrome: A Case of
Involuntary Volition?
Patients have a decrease in gray matter in
the caudate nucleus and lateral motor and
premotor cortex.
Gray matter is thinner in medial motor
areas.
26
28. Tourette Syndrome: A Case of
Involuntary Volition?
Therapy for Tourette syndrome includes
education and acceptance.
Neurolepic medications are prescribed for
the most severe cases, where the tics
interfere significantly with daily life.
28
29. Obsessive-Compulsive Disorder:
Neurological of Psychiatric?
“Neurological” disorders and “psychiatric”
disorders are grouped based on the nature
of the condition.
Conditions with an observable brain
abnormality were considered neurological.
29
30. Obsessive-Compulsive Disorder:
Neurological of Psychiatric?
A more modern criteria based on the
symptoms.
Psychiatric conditions impact emotion,
motivation, social behaviors, personality, or
reality testing.
Neurological conditions impact strength,
movement, sensory perception, memory,
attention, or level of consciousness.
30
32. Obsessive-Compulsive Disorder:
Neurological of Psychiatric?
Obsessive-compulsive disorder is a
psychiatric disorder that affects about 2 –
3% of the population.
Symptoms include obsessions (intrusive,
disturbing thoughts) and compulsions
(stereotyped, ritualized behaviors).
32
33. Obsessive-Compulsive Disorder:
Neurological of Psychiatric?
Obsessions include contamination, fear of
committing inappropriate acts, symmetry
and number, and hoarding.
The most common age of onset for
symptoms of obsessive-compulsive
disorder is either about age 11 or 23.
33
35. Obsessive-Compulsive Disorder:
Neurological of Psychiatric?
There is increased activity in the circuits
connecting the basal ganglia to the
orbitofrontal, anterior cingulate, and
dorsomedial prefrontal cortex.
The pattern of activity differs depending on
the types of obsession.
35
37. Obsessive-Compulsive Disorder:
Neurological of Psychiatric?
Cognitive behavioral therapy addresses
cognitive distortions and decreases
anxiety.
Medications than increase serotonin
reduce the obsessions, compulsions, and
anxiety.
Neuroleptics are sometime prescribed for
severe cases.
37
38. Schizophrenia: A Dementia of
the Young
Schizophrenia is characterized by loss of
contact with reality.
The age of onset is typically around early
adulthood.
Schizophrenia affects about 1% of the
world’s population.
38
39. Schizophrenia: A Dementia of
the Young
Positive symptoms include hallucinations
and delusions.
Delusions include paranoid delusions,
delusions of reference, delusions of passivity,
and somatic delusions.
Negative symptoms include poverty of
speech, apathy, social withdrawal, and
loss of emotion.
39
41. Schizophrenia: A Dementia of
the Young
Antipsychotic medications treat the
positive symptoms, but do not treat the
negative symptoms.
Such medications often cause unwanted
side effects.
Second-generation antipsychotic
medications are no better at treating the
negative symptoms.
41
42. Schizophrenia: A Dementia of
the Young
There is a genetic basis to schizophrenia,
but no specific genes have been identified.
Environmental factors during fetal
development or early life seem important
in the incidence of schizophrenia.
42
44. Schizophrenia: A Dementia of
the Young
Neurodevelopmental factors
Abnormal pruning of neurons
Smaller cell bodies of neurons
Decreased functioning of inhibitory GABA
interneurons in the cortex
44
47. Schizophrenia: A Dementia of
the Young
Dopamine hypothesis
There is too much dopamine signaling or the
dopamine receptors are oversensitive.
The first-generation antipsychotic drugs were
dopamine D2 receptor antagonists.
Drugs that increase dopamine, such as
amphetamines and cocaine, can mimic the
positive symptoms of schizophrenia.
47
49. Schizophrenia: A Dementia of
the Young
Glutamate hypothesis
Schizophrenia is caused by too little
glutamate neurotransmission.
NMDA receptor antagonists, like ketamine,
can mimic both the positive and negative
symptoms of schizophrenia.
Many of the genes associated with
schizophrenia affect NMDA glutamate
receptors.
49
51. Bipolar Disorder
Normal mood alternates with periods of
depression and mania.
This affects 1% of the population and a
milder form may affect as much as 4-5%
of the population.
The age of onset is about 20 years of age.
There is a genetic basis to the condition,
but no specific genes have been identified.
51
53. Bipolar Disorder
Individuals with bipolar disorder show
thinner gray matter in the
Bilateral ventrolateral frontal cortex
Bilateral anterior insula
Dorsomedial prefrontal cortex
Subgenual cingulate cortex
Some of these regions are also affected in
unipolar depression.
53
57. Depression: A Global Burden
Impact of Depression
Causes of Depression
Neurochemical Effects of Depression on
Brain
Functional Effect of Depression on the
Brain
Treatment of Depression
57
58. Impact of Depression
Depression is characterized by a low
mood that makes it difficult to carry out the
functions necessary for daily life.
Individuals with depression do not take
pleasure in typical activities, lack
motivation and energy, and have altered
sleep patterns and appetite.
58
60. Impact of Depression
The worldwide incidence of depression is
5% at any one time.
In the United States, the incidence is 5%
for men and 10% for women.
Lifetime incidence is roughly double the
one-time incidence rates.
The cost of depression is estimated to be
about $80 billion per year in the U.S.
60
62. Causes of Depression
Mood disorders run in families, suggesting
a genetic basis.
Depression may be an evolutionary
adaptation to suffering a trauma or defeat
Depression causes the individual to stay
away from opponents and predators while
waiting for better times.
62
64. Neurochemical Effects of
Depression on Brain
Monoamine hypothesis of depression
There is a shortage of the monoamine
neurotransmitters.
By inhibiting the enzyme monoamine oxidase,
which breaks down these transmitters, mood
will be improved.
64
65. Neurochemical Effects of
Depression on Brain
Serotonin hypothesis
More specific than the monoamine
hypothesis.
There is, specifically, a shortage of serotonin.
Selective serotonin reuptake inhibitors
specifically affect serotonin levels.
65
66. Neurochemical Effects of
Depression on Brain
Other biological theories
There are abnormalities with glutamate
neurotransmission.
There are low levels of the neuronal growth
factor brain-derived neurotrophic factor
(BDNF).
66
68. Functional Effect of Depression
on the Brain
Networks of brain areas are under- and
over-activated in individuals with
depression.
The subgenual cingulate cortex is consistently
hyperactive.
This hyperactivity returns to normal following
successful treatment of depression.
The dorsolateral and dorsomedial prefrontal
cortex tend to be less active.
68
70. Functional Effect of Depression
on the Brain
The pattern of hyper- and hypo-active
brain regions differs across individuals.
Current research is examining the
interactions between different brain
regions.
70
71. Treatment of Depression
Three major treatments are used for
individuals with depression
Psychotherapy
Pharmacotherapy
Somatic therapy
71
72. Treatment of Depression
In psychotherapy, the patient interacts with
a clinician to work through the causes of
their depression.
Cognitive therapy is about as effective as
pharmacotherapy
The effects seem to persist for a longer
time than the medication does.
72
74. Treatment of Depression
Anti-depressant medications include
Monoamine oxidase inhibitors (MAOIs)
Tricyclic antidepressants (TCAs)
Selective serotonin reuptake inhibitors
(SSRIs)
All of these are about equally effective.
Different medications are more or less
effective for different individuals.
74
76. Treatment of Depression
Somatic therapies are more invasive.
These include
Repetitive transcranial magnetic stimulation
Electroconvulsive therapy
Deep brain stimulation
76
Editor's Notes
Figure 16.2 Subtypes of dementia. Alzheimer’s disease is the most common form of dementia worldwide.
Figure 16.4 The plaques and tangles associated with Alzheimer’s disease. (a) A microscopic view of both the plaques and the tangles in the brain of a patient with Alzheimer’s disease. (b) Plaques and tangles spread over the brain as the disease worsens.
Figure 16.5 The formation of beta- amyloid plaques and tau tangles in Alzheimer’s disease. (a) Beta-amyloid plaques form from extracellular accumulations of beta-amyloid peptides, which are generated during the normal metabolic activity of neurons. (b) Hyperphosphorylation of the tau proteins leads them to detach from microtubules and clump into neurofibrillary tangles.
Figure 16.7 Comparison of maps of functional connectivity and amyloid plaque deposits in patients with Alzheimer’s Disease. (a) A map showing areas of the brain that serve as the busiest “hubs” of brain activity. (b) The density of beta-amyloid plaques in patients with Alzheimer’s disease. note the overlap in brain regions apparent when comparing these two maps.
Figure 16.8 In patients with frontotemporal dementia, the frontal lobes and temporal pole degenerate, leaving smaller gyri and larger sulci.
Figure 16.9 Patients with semantic dementia lose the ability to recall the concepts of things, not just their names. Here, a patient with semantic dementia was asked to draw a swan from memory. The patient drew the swan as an animal with four legs, rather than the two legs of a bird.
Figure 16.11 Brain degeneration in Huntington’s disease. The atrophy is especially pronounced in the anterior caudate nucleus, as can be seen in these two coronal slices through the brain.
Figure 16.12 A simplified view of the corticostriatal loop that is important for motor control and is affected in Huntington’s disease. In healthy control subjects, the excitatory direct pathway and the inhibitory indirect pathway are balanced, allowing for control of voluntary movement. In Huntington’s disease, the medium spiny neurons of the indirect pathway degenerate, leaving the excitatory direct pathway as the main driver of behavior.
Figure 16.13 Gene–environment interactions play a role in many diseases. Most disorders are not caused by a single gene. Instead, many different genes may interact with one another, with some combinations having protective and others having harmful effects. These effects also interact with environmental factors, which may also be protective or harmful in different combinations. This complex interaction of genetic and environmental effects determines the presence and severity of many diseases.
Figure 16.15 Neuroanatomical abnormalities in Tourette syndrome. (a) Areas of shared cortical thinning in siblings who both have Tourette Syndrome. The affected areas include the anterior cingulate cortex and dorsomedial prefrontal cortex, as well as the lateral premotor cortex. (b) Areas activated during motor tics of the fingers. note the activation in the anterior cingulate cortex, within the area affected by the disorder.
Figure 16.17 Some brain disorders are traditionally considered neurological, while others are traditionally considered psychiatric. The distinction is somewhat arbitrary, since both categories of disorders involve abnormal functioning of the neural pathways of the brain. This survey of scientific articles published in the peer reviewed journals Neurology and American Journal of Psychiatry from 1990 to 2011 shows whether the conditions named were more commonly considered neurological or psychiatric.
Figure 16.18 Two corticostriatal loops are consistently identified as important in studies of patients with OCD. One of the loops goes from the anterior caudate nucleus to the dorsomedial prefrontal cortex and nearby anterior cingulate cortex. The other loop goes from the ventral striatum to the lateral orbitofrontal cortex. These loop circuits tend to show excessive activity in OCD compared to healthy controls.
Figure 16.20 Symptom-specific brain abnormalities in OCD. Patients diagnosed with different types of OCD viewed images designed to provoke their specific symptoms, such as compulsive hand-washing, mistake-checking, or hoarding. The patients displayed different patterns of brain activity, depending on which type of symptoms they had.
Figure 16.22 A family pedigree of the DISC1 gene. This pedigree shows five generations of a family known to carry the DISC1 mutation. Individuals with the mutation are marked with a dot, and individuals with a known diagnosis are indicated by a color code. note that the same genetic mutation leads to different types of mental illness in different individuals, and that not everyone who carries the mutation has an illness; this illustrates the importance of gene–gene and gene–environment interactions.
Figure 16.23 Compared with healthy control subjects, individuals with schizophrenia show a decrease in gray matter over time. The abnormal loss of gray matter usually begins in adolescence, well before the symptoms of psychosis become prominent in early adulthood.
Figure 16.24 The hypothesis of abnormal neuron migration in schizophrenia. If neurons fail to migrate to the correct layers of the cortex during development, they may not connect or communicate properly. In some studies of the layers of cortex in individuals with schizophrenia, the gABAergic interneurons fail to migrate to the correct location. This disrupts the circuitry of the cortex at a microscopic level.
Figure 16.25 Antipsychotic medications are D2 receptor antagonists. (a) All known antipsychotic medications act by blocking the D2 dopamine receptor. The medication must block about 65–80% of the receptors in the ventral striatum in order to achieve its desired effect. (b) The effective dose of antipsychotic medications correlates closely with how tightly they bind to D2 receptors. Medications with higher affinity for D2 receptors are effective at lower daily doses.
Figure 16.26 The loops connecting the prefrontal cortex to the striatum and thalamus use a variety of neurotransmitters, including dopamine, glutamate, and GABA. The interaction of dopamine and glutamate in these loops means that the glutamate and dopamine hypotheses of schizophrenia are not mutually exclusive—both neurotransmitters likely play a role in the illness, as does GABA.
Figure 16.27 Individuals with bipolar disorder cycle from a depressed state to a manic state and back again. These cycles can vary in length, with a single phase of the cycle lasting from days to months, depending on the individual.
Figure 16.28 Brain regions with gray matter loss in bipolar disorder. Compared to healthy controls, patients with bipolar disorder have a reduction in gray matter in certain areas, including the anterior insula, ventrolateral prefrontal cortex, and ventromedial prefrontal cortex. (lines at lower right indicate the positions of these axial slices within the brain.
Figure 16.29 Mood stabilizers for bipolar disorder. Several different classes of medications are used as mood stabilizers in bipolar disorder. These include the element lithium, antipsychotic medications (of which haloperidol or risperidone are two examples among dozens available), and certain antiepilepsy medications such as valproic acid, carbamazepine, and lamotrigine.
Figure 16.31 Depression is one of the leading causes of years of life lost to disability, worldwide. Darker colors indicate countries with a higher burden of years lost to disability from depression.
Figure 16.33 Depression over the adult lifespan. Hospitalizations for major depression peak at ages from the late 30s to early 50s, and again in late life. The rates of illness and hospitalization are nearly twice as high in women as in men.
Figure 16.34 Interacting effects of genetic background and environmental events in depression. In one influential study (Caspi et al., 2003), having two copies of the short form of the 5HTTlPR serotonin transporter gene, as well as a more stressful life, significantly increased the individual’s chance of developing depression.
Figure 16.35 Selective serotonin reuptake inhibitors (SSRIs) work by blocking the reuptake of serotonin into the presynaptic terminal, thus increasing the concentration of serotonin in the synaptic cleft.
Figure 16.36 The subgenual cingulate cortex plays a key role in regulating the amygdala and other core limbic structures, and it is overactive in major depression. It is part of a larger network of cortical and subcortical regions involved in emotion regulation. In patients who recover from depression, the activity of the subgenual cingulate cortex returns to normal—a consistent finding across many different types of treatment for depression, including medications, therapy, and brain stimulation.
Figure 16.38 Response to antidepressant medication versus cognitive behavioral therapy in depression. After 16 weeks of treatment, the percent of subjects responding to treatment is similar for both antidepressant medication and for cognitive behavioral therapy.
Figure 16.37 Successfully alleviating the symptoms of depression is associated with a decrease in activity in the subgenual cingulate cortex. This proved to be true not just for patients treated with an SSRI medication, but even for patients who improved while taking a placebo.
