The Netter Collection of Medical Illustrations VOLUME 7 PART l

Plate 3-13 Brain: PART I
Temporal lobectomy
RESECTIVE SURGERY

Amygdaloid body
Hippocampus
Temporal lobe

Insula

Amygdaloid body remnant
Temporal lobe remnant

Hippocampus

Lateral ventricle

Area of resection Temporal lobe containing seizure focus resected.
Amygdaloid body and distal hippocampus usually
included in resection.

Hemispherectomy Cingulate gyrus
Corpus callosum
3rd ventricle

Treatment of Epilepsy Frontal lobe remnant Basal
Insula and basal ganglia
(Continued) ganglia preserved
Parieto-occipital remnant Area of resection
proportion of fats and small amounts of carbohydrate
and protein. The basis of the therapeutic effectiveness Temporal lobe and central suprasylvian cortex are resected,
of the ketogenic diet is thought to be the ketosis that preserving basal ganglia. All connections of frontal and
develops when the brain is relatively deprived of glucose parieto-occipital remnants to corpus callosum are severed.
as an energy source and must shift to use of ketone
bodies as the primary fuel. â•…

Patients who do not respond to antiepileptic drugs stimulator that sends electric impulses to the left vagus about exactly how vagal nerve stimulation improves
or dietary therapy may benefit from surgery. In patients nerve in the neck via a lead wire implanted under the seizure control, but proposed mechanisms include
with well-localized seizures focus, resection of the epi- skin. The tenth cranial nerve arises from the medulla alteration of norepinephrine release by projections of
leptic tissue may be possible. If the epileptic focus is and carries both afferent and efferent fibers. The affer- solitary tract to the locus coeruleus, elevated levels of
coming from a brain area where resection would result ent vagal fibers connect to the nucleus of the solitary inhibitory GABA related to vagal stimulation, and inhi-
in a significant neurologic deficit, such as weakness, tract, which, in turn, projects connections to other loca- bition of aberrant cortical activity by reticular system
aphasia, or memory impairment, focal surgery is not tions in the central nervous system. Little is understood activation.
recommended. The most common surgery for focal
seizure is a temporal lobe resection. In rare individuals,
with a severely damaged hemisphere, who have unilat-
eral weakness and seizures arising from that hemi-
sphere, a hemispherectomy can be curative. Patients
with severe focal seizures with secondary generalization
may be helped by cutting the corpus callosum (corpus
callosotomy). This reduces the likelihood that a focal
seizure will become generalized.

Vagus nerve stimulation (VNS) is an adjunctive treat-
ment for certain types of intractable epilepsy and
treatment-resistant depression. VNS uses an implanted

78 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

SECTION 4â•…

PSYCHIATRY

P late 4-1 Brain: PART I

Limbic System Anterior nucleus of thalamus Interthalamic adhesion
Interventricular foramen Fornix

The limbic system is the only brain area receiving major Anterior commissure Stria terminalis
hypothalamic input and providing interconnection Precommissural fornix Stria medullaris
with widespread cortical areas. Major limbic structures Septum pellucidum Habenula
include the amygdala, piriform cortex (parahippocam- Cingulate gyrus
pal gyrus, uncus + amygdala), hippocampus, substantia Indusium griseum Calcarine
innominata, and septal area. The limbic system’s diverse Corpus callosum sulcus (fissure)
roles include memory, drive, affect, autonomic tone, Septal nuclei Gyrus fasciolaris
endocrine control, and immunoregulation. Dentate gyrus
Subcallosal area Fimbria of hippocampus
The amygdala is connected extensively to the hypo- Hypothalamus Hippocampus
thalamus and other limbic structures. It receives input Paraterminal gyrus Parahippocampal gyrus
from widespread sensory cortical regions and paralim- Lamina Descending connections to reticular
bic structures (piriform cortex, entorhinal cortex, and terminalis and tegmental nuclei of brainstem
parahippocampal cortex on the temporal lobe medial (dorsal longitudinal fasciculus)
surface and the cingulate cortex just above the corpus Olfactory bulb â•…
callosum). The amygdala is critical for channeling drive tract olfactory region, widespread cortical regions, and the
and affect. In lesion studies of monkeys, visual informa- medial stria amygdala. The hypothalamus and various limbic and
tion from one eye was restricted to an intact amygdala, lateral stria paralimbic structures give rise to the majority of the
while visual information from the other eye was directed inputs to these structures. This cholinergic network is
toward a lesioned amygdala. The monkey’s typical Anterior perforated essential for intact memory function. Patients with ante-
aggressive behavior when visually provoked was intact substance rior communicating artery aneurysms or with septal
only when stimulated through the intact visual pathway. tumors may develop amnestic states. In Alzheimer
When provoked via the lesioned pathway, the monkey Optic chiasm disease, where memory loss is the major clinical feature,
remained passive. there is a profound loss of cholinergic neurons in the
Postcommissural fornix nucleus basalis as well as in widespread cortical regions.
This is observed in the Klüver-Bucy syndrome that Septal lesions may also produce exaggerated emotional
arises when the amygdala is disconnected from cortical Mammillary body and reactions to novel or threatening stimuli, hyperdipsia,
sensory input. The typical features of the Klüver-Bucy mammillothalamic tract hyperphagia, and altered taste preference. There is evi-
syndrome include (1) indiscriminant sexual behavior dence suggesting a role in attaching motivational value
toward objects in the immediate extrapersonal space, Medial forebrain bundle to extrapersonal objects.
(2) absence of fight-flight reaction toward threat, and
(3) inability to visually distinguish edible from inedible Amygdaloid body (nuclei)
objects except by orally inspecting objects.
Interpeduncular nucleus
The amygdala channels appropriate emotional response Uncus
toward sensory targets while having an important role in the
interpretation and display of affective gestures, including Fasciculus retroflexus
vocalization. The right hemisphere is dominant here.
The amygdala also plays an integral role in the experi- parahippocampal areas in infarcts lead to severe amnestic
ence of strong emotions, including fear, rage, and experi- states, even when the amygdala is spared. These struc-
ences of familiarity. The amygdala imparts the affective tures are necessary for the formation of new memories
coloring of personal experience that reflects a person’s (recording experience) rather than storage of memories.
history, present internal state, and characteristics of In addition, they rekindle memories during retrieval.
their present mental experience. Certain disease states The motivational relevance of experience makes it
engender disruptions of this balance. Thus the affective more likely to be memorized and recalled. This is why
color of a particular mental process may be distorted, storage and retrieval are affected with relative preserva-
amplified, or diminished, thereby changing the very tion of memory banks (long-term memory) in diseases
meaning of the entire experience. This is witnessed in affecting these structures.
panic attacks, dissociative states, depression, and schizo-
phreniform conditions. In humans, the amygdala does The septal nuclei and substantia innominata contain the
not appear to play a direct role in memory formation, major cholinergic cells of the brain, located in the
although amnesia resulting from hippocampal damage medial septal nucleus, the vertical and horizontal limb
seems more severe if there is additional involvement of nuclei of Broca’s diagonal band, and the nucleus basalis
the amygdala. This suggests the amygdala may establish of Meynert. These areas project to the hippocampus,
an affective link in memorization. Additional amygdala
roles include regulation of autonomic, endocrine, and
immunologic function.

The piriform cortex is a relay area for cortical and
olfactory information, much the way the thalamus is the
relay area for every other sensory modality. This area
also has numerous connections with hypothalamus and other
limbic regions. Animal studies suggest a role in regula-
tion of the direction of drive within extrapersonal space,
such as attack or sexual behaviors.

The hippocampus receives almost all of its input
from paralimbic areas, which receive their input from
cortical sensory areas. Other inputs include hypo-
thalamus, amygdala, and septal area. Its major role is
memory and learning. Isolated hippocampal damage is
relatively rare, but combined lesions of hippocampal and

80 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 4-2 Psychiatry

Major Depressive Disorder The Face of Depression

Major depressive disorder (MDD) is a mood disorder “Doctor, what’s wrong with me?”
characterized by the occurrence of one or more major
depressive episodes during one’s lifetime. To diagnose 5-HT, NE Depression is a
a major depressive episode, five (or more) of the follow- biochemically mediated
ing nine symptoms must been present every day or
almost every day during the same 2-week period and state most likely based on
represent a change from a previous level of functioning. abnormalities in metabolism
At least one symptom must be either (1) depressed mood of 5-HT and norepinephrine.
or (2) anhedonia (markedly diminished interest or plea-
sure in all, or almost all, activities. The other seven Clinical syndrome characterized by
criteria are (3) a significant decrease or increase in appetite withdrawal, anger, frustration, and
or weight, (4) insomnia or hypersomnia, (5) psychomotor
retardation or agitation, (6) fatigue or loss of energy, (7) loss of pleasure
feelings of worthlessness or excessive or inappropriate guilt,
(8) poor concentration or difficulty making decisions, and Associated Symptoms and Comorbidities Fatigue Withdrawal
(9) recurrent thoughts of death, suicidal ideation, or a suicide
attempt. These symptoms must cause clinically signifi- Depressed mood with feelings
cant distress or impairment in social, occupational, or of worthlessness and guilt
other important areas of functioning and should not be
due to the direct physiologic effects of a substance (e.g., Poor
a drug of abuse, a medication) or a general medical concentration
condition (e.g., hypothyroidism).
Substance abuse is a Weight loss may result Sleep disturbance is Increased suicide risk
Subtypes of depression may be defined by the pres- common comorbidity from poor nutritional habits a common complaint
ence of psychotic features (delusions, hallucinations),
catatonia (motor disturbances, such as immobility or â•…
agitation, stereotyped movements, mutism), melancholy
(weight loss, insomnia, morning worsening) or atypism estimated heritability of approximately 40%. Through monoamine oxidase inhibitors (MAOIs), and others,
(hypersomnia, hyperphagia), or postpartum onset of linkage, association, and genome-wide association including bupropion, nefazodone, trazodone, and mir-
depression. studies, several candidate genes and regions of the tazapine. The choice of an antidepressant is based on
genome are identified that may contribute to MDD; side-effect profile, tolerability, safety, and history of
In epidemiologic studies, the 12-month and lifetime however, these findings are not consistent in variable prior response to treatment.
prevalence of MDD are, respectively, 5% to 7% and studies. Each individual gene probably contributes only
13% to 18%, and the prevalence seems to be largely to a very small proportion of the variance, interacting After an initial phase of pharmacologic treatment
unrelated to ethnicity or geography (region of the with environmental factors. of 2 to 3 months, aimed at achieving full remission
country or urbanicity). In a recent U.S. epidemiologic of symptoms, pharmacotherapy is typically continued
survey, being female; Native American; widowed, sepa- Initial treatment modality choices in MDD are influ- for approximately 4 to 9 months to prevent early
rated, or divorced; being unemployed or disabled or enced by a number of factors, including symptom relapse. Psychotherapy, alone or combined with medi-
having low income was significantly associated with severity, co-occurring psychiatric or medical condi- cations, may also be considered as initial treatment for
higher rates of MDD. The mean age at onset for MDD tions, psychosocial stressors, and the patient’s prefer- patients with mild-to-moderate MDD. Electroconvul-
is in the early 30s. The hazard for childhood onset ence. Antidepressant medications include selective sive therapy (ECT) is a potentially very successful treat-
MDD is relatively low, increases sharply between ages serotonin reuptake inhibitors (SSRIs), usually used ment option for patients who are more severely ill,
12 and 16 years, and continues to increase, albeit more as a first choice, serotonin-norepinephrine reuptake present psychotic features or catatonia, and for those
gradually, up to the early 40s. The diagnosis of MDD inhibitors (SNRIs), tricyclic antidepressants (TCAs), who are acutely suicidal.
is associated with the presence of one or more psychi-
atric disorders during one’s lifetime in nearly 75% of
cases, including anxiety disorders (60%), substance use
disorders (25%), and impulse control disorders (30%).

The neurobiologic basis and pathophysiology of
MDD continue to be enigmatic. This is likely due in
part to the heterogeneity of MDD, which may repre-
sent a group of disorders with several underlying
pathologies, in which both genetic and environmental
factors play a role. Studies have investigated distur-
bances in several neurotransmitters (serotonin [5-HT,
i.e., 5-hydroxytryptamine], norepinephrine [NE], and
dopamine, and more recently glutamate); in neuroen-
docrine and neuroimmune mechanisms, in particular,
the hypothalamic-pituitary-adrenal axis involved in the
response to stress; and in neurotrophic factors regulat-
ing plasticity in the brain. It is important to emphasize
that neurotransmitters and hormones are integrated in
anatomic and functional circuitry interacting at several
levels. Imaging and postmortem studies suggest that
MDD patients have structural and subtle cellular and
molecular alterations within a complex neural network
involving the prefrontal cortex, subgenual cingulate
cortex, hippocampus, and amygdala.

MDD genetics are complex and multifactorial; this
disorder frequently occurs in families, having an

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 81

P late 4-3 Brain: PART I

Postpartum Depression Patient may have prior history of depression or premenstrual
tension, or prior postpartum depression
The postpartum period has clearly been defined as a
time of increased vulnerability to psychiatric illness in Condition begins
women; up to 85% of women experience some type of 2-12 months
mood disturbance after childbirth. Most of these postdelivery and
women experience transient and relatively mild mood may last 3-14 months
symptoms (“the blues”); however, about 10% to 15%
of women experience a more disabling and persistent Depressive Postpartum depression is characterized by
form of mood disturbance, either postpartum depres- mood a disturbance of mood; a loss of sense of
sion (PPD) or postpartum psychosis. Although postpar- control; intense mental, emotional, and
tum psychiatric illness was initially conceptualized as a physical anguish; and a loss of self-esteem
group of disorders specifically related to childbirth, associated with childbirth
more recent evidence suggests that affective illness
emerging during the postpartum period is clinically Feelings of
indistinguishable from affective illness occurring at worthlessness
other times during a woman’s life. In fact, most women or guilt
with postpartum illness will also go on to have mood
episodes that are not related to either pregnancy or
childbirth.

The Diagnostic and Statistical Manual of Mental Disor-
ders (i.e., DSM-IV) does not list postpartum psychiatric
disorders separately but instead uses a specifier, for
example, “with postpartum onset” to describe any depres-
sive, manic, or mixed episode (in major depressive disor-
der, bipolar disorder, or brief psychotic disorder) when
the episode occurs within the first 4 weeks after delivery.
Although risk of postpartum psychiatric illness is the
highest in the first 4 weeks after childbirth, several dif-
ferent studies indicate that women remain at very high
risk for affective illness during the first 3 months after
delivery. In fact, women remain at heightened risk up
to 1 year after childbirth. Thus many experts define
postpartum psychiatric illness as any episode occurring
within the first year after childbirth.

POSTPARTUM BLUES Decreased Psychomotor
During the first week after the birth of a child, many concentration agitation or
women experience a brief period of affective instability, retardation
commonly referred to as postpartum blues or the “baby
blues.” Given the high prevalence of this type of mood Recurrent thoughts
disturbance, it may be more accurate to consider the blues of death
as a normal experience associated with childbirth rather
than a psychiatric disorder. Women with postpartum â•…
blues report a variety of symptoms, including a rapidly
fluctuating mood, tearfulness, irritability, and anxiety. TREATMENT
These symptoms typically peak on the fourth or fifth
day after delivery and may last for a few days, remitting POSTPARTUM PSYCHOSIS Because the blues are typically mild and resolve on their
spontaneously within 2 weeks of delivery. This is the most severe form of postpartum psychiatric own, no specific treatment is required. The treatment
illness. It is a rare event that occurs in approximately of postpartum depression depends on its severity. Milder
POSTPARTUM DEPRESSION 1 to 2 of 1000 women after childbirth. Its presentation cases may respond to psychotherapy, whereas more severe
Ten to 15 percent of women will present with more is often dramatic, with onset of symptoms early, depressive symptoms are best treated with a combina-
significant depressive symptoms or postpartum depres- typically within the first 2 postpartum weeks. Longitu- tion of psychotherapy and medication. In this setting,
sion after childbirth. Unlike the blues, PPD is more dinal studies indicate that most women with postÂ

P late 4-4 Psychiatry

Bipolar Disorder

Bipolar disorder is a mood disorder characterized by “I bought 11 cars last week. â•…
the occurrence of manias or hypomanias, and depres- I’ll sell them all and make a
sions. Manias consist of elevated, irritable, or expansive fortune. I’m going to set up acid, lamotrigine, and carbamazepine, and second-
mood with at least three of the following symptoms if my own hospital and make generation antipsychotic medications. The treatment
the mood is elevated (four if irritable): (1) decreased us both famous.” of bipolar depression remains a particular challenge, with
need for sleep, (2) flight of ideas, (3) hypertalkativeness molecular level has advanced from a focus primarily on relatively few medications demonstrating clear efficacy.
(including pressured or excessive speech), (4) granÂ

P late 4-5 Brain: PART I

Generalized Anxiety
Disorder

Generalized anxiety disorder (GAD) is characterized by Somatic symptoms, such as chest pain or difficulty
excessive, uncontrollable, and often irrational worry, breathing, are the hallmark of panic attacks. Patients
about everyday things that is disproportionate to the often do not recognize that they are anxious and have
actual source of worry. To diagnose GAD, excessive a very real sense of impending doom. It is easy to
worry must be present for at least 6 months, the person understand why they seek emergency care.
finds it difficult to control the worry, and the anxiety
and worry are associated with three (or more) out of six symptoms. Serotonergic, noradrenergic, and gamma- â•…
symptoms. These include (1) restlessness or feeling keyed aminobutyric acid (GABA) inhibitory systems dysfunc-
up or on edge, (2) being easily fatigued, (3) difficulty concen- tion may relate to expression of GAD. The adrenal Benzodiazepines also provide effective therapies for
trating or mind going blank, (4) irritability, (5) muscle system and chronic stress response is also implicated in GAD, having the advantages of a short latency of thera-
tension, and (6) sleep disturbance (difficulty falling or staying GAD pathophysiology, with the amygdala mediating peutic onset and a generally favorable side-effect
asleep, or restless unsatisfying sleep). As with other axis I arousal and fear by activating the hypothalamic- profile. Major drawbacks include sedation, cognitive
diagnoses, the symptoms must cause clinically signifi- pituitary-adrenal (HPA) axis. Other putative neuroen- impairment, and the possibility of long-term adverse
cant distress or impairment in social, occupational, or docrine mechanisms are currently under investigation. effects (i.e., development of tolerance), physical depen-
other important areas of functioning and are not due to dence, and a withdrawal syndrome. Other drugs used
the direct physiologic effects of a substance (e.g., a drug Different classes of antidepressants are efficacious in GAD management include pregabalin and sympa-
of abuse, a medication) or a general medical condition in GAD. Selective serotonin reuptake inhibitors tholytic agents (propranolol, prazosin, clonidine), and
(e.g., hyperthyroidism), and do not occur exclusively (SSRIs) or serotonin-norepinephrine reuptake inhibi- atypical antipsychotics that may have an adjunctive role
during a mood disorder, psychotic disorder, or a perva- tors (SNRIs) are usually used as first choice, with tricy- to antidepressants in cases of treatment resistance. Psy-
sive developmental disorder. clic antidepressants (TCAs), monoamine oxidase chotherapy, in particular cognitive-behavioral therapy,
inhibitors (MAOIs) and others, including buspirone as monotherapy or combined with medications, may
The prevalence of GAD in the National Comorbid- and mirtaÂz

Plate 4-6 Psychiatry

“Doctor, I’m worried,
but I don't know why.

I'm just worried.
I have no reason
to be, but I am.”

Social Anxiety Disorder

Introduction and Clinical Presentation. Social anxiety Brain Regions Associated With Thalamus
disorder (SAD), or social phobia, is characterized by Panic and Anxiety Disorders
persistent fear of social or performance situations in
which an individual will face exposure to unfamiliar Cerebral cortex
people or scrutiny by others. The individual typically
fears behaving in an embarrassing or humiliating Bed nucleus of the
fashion, or revealing symptoms of anxiety. Exposure to stria terminalis
these situations provokes anxiety or panic symptoms,
leading the individual to avoid such situations whenever Hypothalamus
possible. Physical symptoms may include diaphoresis,
tachycardia, trembling, nausea, flushing, and difficulty Amygdala Locus
speaking, for example. ceruleus

DSM-IV criteria stipulate that this condition contrib- Hippocampus
utes to significant functional impairment (for example,
in work or relationships) or distress. Of note, the â•…
individual recognizes that the fear is excessive or
unreasonable. Although the diagnosis has been criti- potential role of neuropeptides involved in social cogni- for example, on tasks requiring processing of emotional
cized for ascribing a medical diagnosis to a normal tion, such as oxytocin and arginine vasopressin, is also faces. fMRI also suggests there may be abnormal con-
population trait, shyness, the persistence and severity of under active investigation. For example, rodent models nectivity evident in the resting state, involving frontal
these symptoms—and in particular their impact on illustrate the capacity of oxytocin to diminish social and occipital structures. Other studies also suggest basal
functioning—argues otherwise. avoidance, which may inform future treatment develop- ganglia dysfunction in SAD; of interest, SAD is seen
ment in SAD. more commonly in individuals with Parkinson disease,
Diagnostic criteria distinguish a generalized form, which may provide convergent evidence for the role of
that is, occurring in most social situations, or a specific Functional magnetic resonance imaging (fMRI) basal ganglia in these symptoms.
form, that is, one which occurs only in particular cir- implicates the amygdala and insula activation in SAD,
cumstances, such as public speaking or public perfor-
mance, or writing or eating in front of others. However,
these are not necessarily distinct subtypes, although the
generalized form may be more disabling overall.

Epidemiology. The lifetime prevalence of SAD is
≈12%, with 12-month prevalence of ≈7%. SAD often
has early onset, with about half of cases presenting by
age 11 years; on the other hand, later onset in many
patients provides further support for SAD being some-
thing other than the trait of shyness. As with major
depressive disorder, SAD is seen more commonly in
females. As with other psychiatric disorders, rates of
comorbidity are high, having overlap with major
depression and substance use disorder, for example.

Treatment of SAD relies on either cognitive-
behavioral therapy, delivered individually or in a group
setting, or pharmacotherapy. Standard medication
treatments use selective serotonin reuptake inhibitors,
although other antidepressants, including monoamine-
oxidase inhibitors and serotonin-norepinephrine
reuptake inhibitors have also demonstrated efficacy.
Anxiolytic medications, such as benzodiazepines, are
sometimes used as well. Scales such as the Liebowitz
Social Anxiety Scale may be used to quantify severity
over time.

Pathophysiology. SAD has been noted to be familial,
and often coaggregates with major depression, panic
disorder, and agoraphobia. Twin studies suggest that
about 40% of liability is inherited. Although candidate
gene studies have implicated multiple genes, no single
association has been convincingly demonstrated, and
genome-wide studies have not been reported. The

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 85

Plate 4-7 Brain: PART I

Panic Disorder

Patients complaining of panic often describe a dramatic Symptoms result from abnormalities
presentation, including the sudden, unexpected onset of in brain neurotransmitter metabolism
extreme fearfulness or alarm, quickly rising to a cre-
scendo within minutes of commencement, and accom- Serotonin,
panied by a spectrum of physical, behavioral, and norepinephrine, GABA
cognitive symptoms. These may include the bodily sen-
sations of choking, chest pain, trembling, flushing, and Panic disorder is characterized by
rapid heart rate, which mimic a sympathetic, “fight or the presence of panic attacks with
flight” response. The urge to escape, to find shelter, or at least four of the following
to seek help can be overwhelming. Panic victims may symptoms: palpitation, dyspnea,
believe they are dying, losing control, or going crazy nausea, dizziness, sweating,
and will often seek urgent medical care. The indelible, paresthesia, and gastrointestinal
negative impression left by a panic attack often results discomfort
in persistent fear of having another attack or in marked
behavioral changes. Although isolated panic attacks are â•…
relatively common, it is these persistent sequelae that
define the diagnosis of panic disorder. By DSM-IV supportive psychotherapy. Once phobic avoidance or proving effective whether delivered in individual or
criteria, this disorder may also be accompanied by ago- recurrent attacks begin, the aims of treatment are both group therapy settings. CBT conceptualizes panic as the
raphobia, characterized by the phobic avoidance of situ- to prevent further panic attacks, and to eliminate the acquired fear of the bodily sensations associated with
ations that may be difficult or embarrassing to escape, associated avoidance and anticipatory anxiety. Pharma- autonomic arousal, and agoraphobia as the behavioral
should a panic attack recur. cologic treatment for panic includes antidepressants; response to the anticipation of such sensations. Thera-
placebo-controlled trials support the efficacy of SSRIs, pists teach cognitive and somatic coping skills that are
Panic disorder is common, with a lifetime prevalence the SNRI venlafaxine, and the tricyclic antidepressant then used to manage anxiety during exposure to feared
in the United States of up to 5%. The disorder occurs imipramine. Benzodiazepines provide rapid symptom- situations and bodily sensations. Multiple studies and
nearly twice as often in women and tends to manifest atic relief, and may be prescribed alone or together with meta-analyses show that the combination of both medi-
in early adulthood. Comorbid substance use disorders antidepressants. Cognitive-behavioral therapy (CBT) cation and psychotherapy is more effective in treating
and psychiatric illness are very common; major depres- for panic disorder is validated and studied widely, panic than either therapy alone.
sive disorder occurs in nearly two thirds of patients with
panic disorder. These comorbid conditions, if left
untreated, may exacerbate the symptoms of panic or
make treatment more difficult. Of particular concern,
panic disorder is associated with higher risk for suicide.
Of interest, the onset of panic disorder is often related
to a stressful life event. Although most patients experi-
ence some remission of symptoms over time, the
course of panic disorder is chronic for the majority of
affected individuals. Complications can include persis-
tent anxiety symptoms, mood disorders, phobic avoid-
ance, drug and alcohol use disorders, and significant
impairments in functioning and quality of life.

The differential diagnosis of panic disorder includes
a broad list of cardiac, respiratory, endocrine, meta-
bolic, and drug-related causes, as well as other psyÂ

P late 4-8 Psychiatry

Posttraumatic Stress Individuals with PTSD may relive traumatic events in their thoughts during the day and
Disorder in nightmares when they sleep

Posttraumatic stress disorder (PTSD) is a mental dis- â•…
order that develops in response to a traumatic event,
such as a sexual assault, military combat, natural disas- Although a majority of adults will experience at least primarily trauma-focused cognitive-behavioral therapy
ter, or a serious accident. PTSD is characterized by one traumatic event in their lifetime, only a minority and possibly pharmacotherapy. Two types of cognitive-
three clusters of symptoms: (1) reexperiencing symptoms develop PTSD; the lifetime prevalence of PTSD in the behavioral therapy, prolonged exposure and cognitive
wherein the patient relives the trauma in his or her United States is estimated at 6.7%. The disorder is twice processing therapy, were specifically developed for the
thoughts and dreams and cannot get it out of his or her as common in women as in men. Although many indi- treatment of PTSD. Both techniques are based, to
mind; (2) avoidance and numbing symptoms wherein the viduals will experience some PTSD symptoms in the some degree, on a conceptualization of PTSD as a
patient avoids people, places, and anything that reminds immediate days and weeks following a trauma, only a disorder of failure to recover from the traumatic event
her or him of the trauma and shuts off his or her minority of individuals show the persistent symptoms due to avoidance of the traumatic event, per se, includ-
emotional responses; and (3) hyperarousal symptoms required for the PTSD diagnosis. Uncontrollable and ing thoughts, feelings, places, and people associated
that involve difficulty concentrating, constantly feeling threatening events, such as rape, childhood abuse, and with the memory. Prolonged exposure therapy targets
on-guard and in danger, difficulty sleeping, and irrita- military combat, are consistently associated with the avoidance through having the patient reexperience the
bility. To be diagnosed with PTSD, the patient must highest risk for developing PTSD after an event. The memory of the traumatic event and engaging with,
report that the traumatic event was accompanied by risk of developing PTSD is less than 50% even for severe rather than avoiding, reminders of the trauma both
feelings of helplessness and horror, these symptoms events such as a forcible rape. This contrast between in and outsÂ

Plate 4-9 Brain: PART I

Obsessive-Compulsive “I am embarassed that my hands are so chapped.
Disorder I never told you before about my fear of germs
and constant washing because I was afraid you
Introduction. Obsessive-compulsive disorder (OCD) is would think I was crazy.”
diagnosed on the basis of recurrent and intrusive
thoughts, referred to as obsessions, and/or compulsive â•…
behaviors or rituals. The obsessions or compulsions are
recognized by the patient, at least at some point, as particularly focused attention on caudate, orbitofrontal glutamatergic neurotransmission is receiving increasing
excessive and unreasonable, leading to marked distress cortex, and anterior cingulate cortex. In one model, focus based on animal studies and genetic data.
or functional impairment; they may be extremely time- intrusive thoughts are associated with increased activity
consuming. These symptoms are experienced as intru- in orbitofrontal cortex, whereas the sense of anxiety is In rare cases, OCD symptoms may emerge in chil-
sive and inappropriate and are not simply excessive associated with activation of anterior cingulate cortex. dren after streptococcal infection, a phenomenon
worries about real-world concerns. Investigation of OCD is facilitated by the availability of referred to as pediatric autoimmune neuropsychiatric
mouse models with OCD-like symptoms, particularly disorders associated with streptococcal infections
Multiple subtypes of OCD are identified primarily excessive grooming behavior. Despite the efficacy of (PANDAS). This syndrome has focused attention
based on factor analysis. Typical obsessions may include serotonergic antidepressants in this disorder, the role of on the role of basal ganglia and immune mechanisms
fears of contamination, sexual/religious or other moral in OCD.
transgression, harming others, or unrecognized illness.
Compulsions may include hoarding, checking, clean-
ing, and ordering. Of these, the most common symptom
is checking behavior, seen in nearly 80% of cases, fol-
lowed by hoarding behavior. Patients may, for example,
check repeatedly that the stove is turned off, re-read
paragraphs for typographic errors, or contact family
members to confirm that they are healthy. Of impor-
tance, such behavior does not occur once, but may
persist for hours at a time. Hoarding often involves
newspapers, receipts, or other documents, to the point
that patients’ homes may become cluttered and even
unsafe. Of note, compulsions may be mental rituals as
well: needing to count or recite a prayer to prevent a
catastrophic event, for example. OCD is highly comor-
bid with other psychiatric disorders, particularly anxiety
disorders, mood disorders (particularly bipolar disor-
der), and substance use or impulse control disorders.
OCD is sometimes observed in individuals with
Tourette syndrome).

Epidemiologic studies indicate a lifetime prevalence
of ≈2% among the general population, with 1% report-
ing symptoms in the past 12 months. Subthreshold
symptoms may be far more common, with up to one
quarter of respondents reporting some lifetime obses-
sions or compulsions. Mean onset age is between 19
and 20 years, but up to one quarter of males may have
onset before age 10 years; female incidence increases in
adolescence. New cases are rarely observed after age
35 years. Twin and family studies suggest that OCD
is a heritable disorder, particularly childhood-onset
OCD, with between 45% and 65% of liability due to
inherited risk.

Clinical Presentation. OCD symptoms are generally
chronic and contribute to substantial functional and
social impairment, although their severity may fluctuate
over time. Treatment for OCD typically relies on either
cognitive-behavioral therapy, medication treatment, or
both; the individual treatments have similar effect sizes.
Most commonly selective serotonin reuptake inhibitors
or the tricyclic antidepressant clomipramine are pre-
scribed; these medications may require greater dosages
and longer treatment durations (i.e., 12 weeks or more)
to achieve response, compared with the treatment
of other psychiatric disorders. A variety of next-step
pharmacotherapies are under active investigation. An
emerging treatment for refractory OCD is deep-brain
stimulation in regions such as the subthalamic nucleus.

Pathophysiology. Imaging and other studies implicate
corticostriatal-thalamic circuits in the pathophysiology
of OCD symptoms, but recent investigation suggests a
somewhat broader network. Functional imaging has

88 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 4-10 Psychiatry

Somatization Facial expression may be flat, Vibration may be felt
inappropriately unconcerned, or only on one side.
Somatization is one of six major somatoform disorders depressed rather than typically
identified by the American Psychiatric Association’s pained. Patient complains of
Diagnostic and Statistical Manual (DSM). Other somato- Complete hemianesthesia or glove-and- severe back pain, which
form disorders include undifferentiated somatoform stocking anesthesia may be present in may radiate “all over.”
disorder, conversion disorder, hypochondriasis, pain conversion disorder or
disorder associated with psychologic factors, pain dis- hypochondriasis/somatization.
order associated with both psychologic factors and a
general medical condition. Fundamentally, somatization No muscle atrophy despite
is a constellation of physical symptoms lacking medical prolonged disability
explanation. The DSM-IV-TR designates eight symptom
requirements for diagnosis, including four bodily pain History may In some disorders,
symptoms, two gastrointestinal (GI) symptoms, one reveal family or gait and posture
neurologic symptom, and one sexual symptom, result- work problems, may be dramatic,
ing in impairment in function. However, these symp- symptoms of with exaggerated
toms appear to exist along a spectrum, and the current anxiety or de- pain behavior,
diagnostic categorization may not accurately reflect the pression, which implying patient’s
clinical presentation. Therefore the status and charac- patient identifies need to prove
terization of somatoform disorders are being reexam- as secondary he is really sick.
ined for the soon-to-be-published DSM-V, to reclassify to physical
them under the general heading of bodily distress syn- Straight leg raising problems but
drome to encompass both psychiatric and nonpsychiatric to 90° while patient which may be
functional disorders. seated, but primary.

Patients currently classified as having somatization Sciatic nerve
disorder present with multiple physical symptoms that stretched
range from mild and self-limited to severely disabling.
In addition, they express excessive health concerns that are patient cannot Normal response to raising one leg is
demonstrated emotionally (depression, anxiety), cogni- tolerate same test to press down with other leg. Reverse
tively (rumination on symptoms, poor attention), and when recumbent. response may occur in patients who
behaviorally (treatment seeking, “doctor shopping”). As are consciously or unconsciously
a result, they suffer from impairments in functioning, manipulating examination.
and their help-seeking behaviors make them large
consumers of health care, most often presenting to The “green poultice”:
primary care and medical specialty clinics. They often Secondary gain,
mistakenly are diagnosed with fibromyalgia, chronic while often present,
fatigue syndrome, noncardiac chest pain, and irritable is seldom primary cause
bowel syndrome. of pain and disability.

Epidemiologic data suggest somatoform disorder by internal and external stressors may lead to sensitiza- â•…
prevalence estimates of 2% to 6% in the general popu- tion of the central nervous system (CNS) and afferent
lation and 5% to 20% in primary care patients. Rates peripheral nerves and cause altered bodily perceptions. Despite the serious magnitude of effects somatization
are greater in the primary care setting because they are and somatoform disorders have on patients, families,
actively seeking health care compared with the general Some back pain patients have primary or exacerbat- and the health-care system at large, these disorders are
population. Most patients with somatoform disorders ing psychologic factors requiring consideration when seriously understudied. Currently, limited evidence-
are women. Despite these high prevalence rates, the examination demonstrates inappropriate, nonanatomic, based treatment and very limited specialized care exists
somatoform diagnoses rarely are assigned to patients by clinically incongruous findings. Some individuals are for patients with somatization somatoform disorders.
clinicians. Studies show diagnostic rates of less than polysymptomatic, with multiple work-domestic issues Purely medical approaches to evaluation and treat-
0.01%. It is postulated that reluctance of clinicians to often engraved on a complex history of other non– ment by “ruling out” general medical disorders leads
“label” patients, lack of generalizability of the diagnoses organic-defined disorders. Examination demonstrates to serial negative tests, ineffective interventions, and
to the clinical presentations, and lack of physician over-reaction, inexplicable inconsistent straight-leg mutual physician and patient frustration. Of interest,
familiarity with the complex criteria for diagnosis result raising difficulty, nondermatomal sensory loss, poorly most treatments targeting specific symptoms appear
in the underuse of the somatoform diagnoses. Deficien- sustained effort on muscle testing, with inconsistencies nonessential, although probiotics in the use of irritable
cies in treatment, poor reassurance by medical practi- between findings on muscle testing and “unobserved” bowel syndrome and other GI-focused somatic com-
tioners, and avoidance of the proper diagnosis leads to spontaneous activity (i.e., ability to get off the examina- plaints are sometimes beneficial. The most beneficial
excessive testing, high health-care utilization, and spe- tion couch despite apparently “severe extremity weak- treatment uses a combination of pharmacology to target
cialty referrals, all leading to high health-care costs and ness”). The most common mistake while evaluating the central nervous system, such as antidepressants,
poor quality of life. such patients is inadequate attention to the differential exercise, and cognitive-behavioral therapy. In addition,
diagnosis. Outright malingering for material gain is physicians suspecting a somatoform disorder diagnosis
The pathophysiology of somatization and somato- usually fairly apparent and should simply be confronted. should schedule frequent, time-limited visits to address
form disorders currently is not well understood. The patient concerns and to provide reassurance.
observed clinical presentations may be due to aberrant
functioning in neural pathways via the autonomic
nervous system and hypothalamic-pituitary-adrenal
axis, in addition to alterations in central processing of
sensory input. Other data suggest proinflammatory
cytokines, such as interleukin-6 (IL-6) and tumor necro-
sis factor-alpha (TNF-alpha), can lead to a constellation
of behaviors, including exaggerated pain sensitivity
(hyperalgesia), sleep disturbances, and fatigue referred
to as “sickness behavior.” This constellation is observed
in patients having either depression and/or somatoform
disorders. Activation of the proinflammatory cytokines

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 89

Plate 4-11 Brain: PART I

Conversion Disorder Tests for Paralysis of Upper Extremity A. Response in organic paralysis
1. Patient lies supine; examiner raises
Conversion disorder, previously referred to as hysteria, paralyzed arm to postion over patient’s Arm falls directly
is defined by the DSM-IV-TR as a type of somatoform face downward into the
disorder with a loss or distortion of a neurologic func- 2. Arm is suddenly released; examiner face because patient
tion that is (1) not explained by an organic neurologic notes manner in which it falls is unable to support
lesion or medical disease, (2) arising in relation to some the flaccid, paralyzed
psychologic stress or conflict, and (3) not consciously (Test may also be used for extremity
produced or intentionally feigned. Despite being hysterical unconsciousness) B. Response in hysterical paralysis
thought of as a psychiatric disorder, neurologists pre- Arm does not hit the face but follows,
dominantly manage and diagnose conversion disorder. a slow or circuitous course downward,
landing safely to the side of the head
Diagnosis requires appropriate neurologic assess-
ment and testing that finds the physical symptoms to Tests for Weakness in Lower Extremity Hoover test
be incompatible with neurologic pathophysiology and/ Thigh adduction test 1. Patient is instructed to elevate “good” leg
or internally inconsistent to fulfill the first criteria. Cri- 1. Patient is instructed to adduct “good” against resistance by examiner
teria two and three are considered more difficult to leg against resistance by examiner
demonstrate and will be de-emphasized in the diagnos-
tic criteria for conversion disorder in the DSM-V. Adduction 2. Examiner’s other hand is placed
2. Examiner’s other hand is placed beneath heel of “paralyzed” leg to
Examples of conversion disorder include functional against “paralyzed” thigh to detect contraction detect reciprocal downward thrust
limb weakness and paralysis, tremors, anesthesia that used by patient for leverage
does not follow nerve distributions or dermatomes,
vision deficits that are incongruent with anatomically A. Response in B. Response in A. Response in B. Response in
possible visual field deficits, nonepileptic seizures (pseu- organic paralysis hysterical paralysis organic paralysis hysterical paralysis
doseizures) having a normal electroencephalogram Patient is able to elevate Elevation of “good”
(EEG) during events, deafness, amnesia, and abnormal Patient can accomplish In adduction of good leg without leg is accompanied by
movements. Focused physical examination can elicit adduction with no “good” leg, patient concomitant downward downward thrust of
findings that highly suggest diagnosis of conversion contralateral adduction involuntarily adducts thrust of paralyzed leg “paralyzed” leg
disorder. Functional leg weakness is demonstrated with palpable in paralyzed leg “paralyzed” leg
Hoover’s sign (as in this plate), where weakness of hip â•…
extension resolves during contralateral hip flexion
against resistance. Patients with astasia-abasia exhibit revealed decreases in activity of frontal and subcortical than motor symptoms, acuteness of presentation, asso-
an unusual and dramatic gait disturbance, lurching circuits involved in motor control in hysterical paraly- ciation with a stressful event, good premorbid health,
wildly in various directions, and falling only when a sis, decreases in somatosensory cortices during hysteri- good socioeconomic status, and absence of comorbidi-
nearby physician, family member, or soft object will cal anesthesia, and decreases in visual cortex during ties (psychiatric or medical) are associated with a favor-
catch them. Functional tremors may be suspected when hysterical blindness. In addition, activation has been able prognosis. The presence of concurrent depression
the tremor resolves or develops the same frequency shown in limbic regions such as the cingulate and orbi- and/or personality disorders is associated with more
during voluntary rhythmic movement of the unaffected tofrontal cortices. These findings suggest that conver- chronic handicap.
arm (entrainment). An overall pattern is that symptoms sion disorder may involve modulation of sensorimotor
typically become worse with attention and can lessen or representations by primary affective or stress-related Conversion disorder raises interesting questions
disappear with distraction. factors. about the relationships between the body and the mind,
but additional studies and research are needed to
Conversion disorders represent 1% to 4% of all diag- The majority (50% to 60%) of conversion symptoms further understand the underlying cause and potential
noses in general hospitals throughout Western coun- spontaneously remit within 2 years of onset, and only treatments and may improve understanding of normal
tries. It is estimated that 30% to 60% of outpatients in 3% of younger patients (<27 years old) have symptoms attention and volition. For now, emphasis should be
neurologic clinics in the United Kingdom have medi- for more than 1 month. Cognitive-behavioral therapy placed on confirming the diagnosis clinically by pres-
cally unexplained symptoms. Similar to other somato- leads to rapid remission and is considered more effec- ence of positive symptoms, placing less emphasis on
form disorders, patients with conversion disorder have tive than pharmacologic approaches, although antide- psychologic factors and whether or not the patient is
symptoms that cause significant impairment and high pressants may have a role. Young age, sensory rather feigning the illness.
use of health care, leading to elevated costs and poor
quality of life. In addition, some treating physicians
tend to have a negative bias toward these patients
because of difficulty distinguishing conversion disorder
from malingering and other factitious disorders.
Coupled with a deficiency in medical training in how
to approach and appropriately manage patients with
conversion disorder because of health-care providers’
discomfort, patients tend to feel dissatisfied with care
and seek multiple providers without resolution, leading
to inefficiency in the system.

The term “conversion” implies a mechanism whereby
psychologic stress is converted into bodily symptoms
unconsciously. However, the mechanism is largely
unknown and poorly understood. Hypotheses histori-
cally have focused around anosognosia, the distortion
between performance and awareness of performance
that is believed to stem from an altered state of self-
consciousness or altered awareness of a bodily state.

Imaging techniques provide a means to study poten-
tial neurologic mechanisms involved in conversion
disorder. However, these studies are limited by
small patient numbers and difficulty controlling for
confounding variables. Functional neuroimaging has

90 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 4-12 Schizophrenia Psychiatry
Neural Pathways Involved in Schizophrenia
Schizophrenia

Schizophrenia is the prototype of a psychotic disorder, Substantia nigra Prefrontal
with the core symptoms of delusions and hallucinations Striatum cortex
as well as disorganized speech. Some patients also
display prominent psychomotor disturbances, including Nucleus
catatonia. Together, these florid and often dramatic accumbens
symptoms are referred to as positive symptoms and Tegmentum
contrasted with negative and cognitive symptoms, the
latter being responsible for much of the disability 5-HT receptor blockers
that characterizes schizophrenia. Negative symptoms
are categorized into a reduced emotional expressivity (e.g., risperidone) increase
cluster (restricted or flat affect) and an avolition/apathy/
anhedonia cluster. Many schizophrenia patients strug- release of DA to alleviate
gle with cognitive impairment in the realms of workÂ

P late 4-13 Brain: PART I

Alcohol Use Disorders Criteria: Three distinct episodes in one year are indicative of alcohol abuse

Alcohol use is associated with 1.8 million deaths annu- Continued use of alcohol
ally; global alcohol use is increasing. Yet many who despite interpersonal problems
drink alcohol do not experience negative health or Recurrent use of alcohol
social consequences, and some health-care studies in hazardous
suggest health benefits may be associated with alcohol situations
consumption. How can we distinguish between risky
drinking and safe drinking? The National Institute on Failure to fulfill major obligations Recurrent legal problems Fri Sat Sun
Alcohol Abuse and Alcoholism (NIAAA), dedicated to at work, school, or home related to alcohol use
providing scientific leadership in the assessment of Sun Mon Tues Wed Thur
alcohol use and its health and social consequences, has Other problem patterns of drinking
established gender-specific guidelines based on current Mon Tues Wed Thur Fri Sat
evidence for “low-risk” drinking. To normalize these
guidelines, a “standard drink” is defined as an ethanol Hazardous behavior
alcohol content of 14 grams (equivalent to 12 ounces of
beer, 5 ounces of table wine, or 1.5 ounces of liquor). Cirrhosis, alcoholic Neurologic
It is considered “low-risk” for healthy adult men under hepatitis
age 65 years to consume no more than 14 standard
drinks per week, with up to 4 drinks per day, and for Belligerence
healthy adult nonpregnant women under age 65 years
and healthy men and women age 65 years and older, no Pancreatitis Spouse abuse
more than 7 standard drinks per week and up to 3 Cardiovascular
standard drinks per day. Intermittent abuse of alcohol at levels
Daily alcohol use at levels likely that result in dangerous and
The following risk factors may increase the potential to cause end organ damage â•… destructive behavior
negative health consequences of drinking even with Intermediate Family (19%). This group of middle-
“low-risk” patterns of consumption: (1) first-degree account for the severity of alcohol dependence at a aged individuals, half of whom have a lifetime history
relative with alcohol or drug dependence (i.e., heritable young age. Co-occurring mental illnesses are common of depression and strong family histories of alcohol
risk for developing an alcohol use disorder), (2) history (depression, anxiety, and personality disorders). One dependence, has high rates of co-occurring mental
or family history of mental illness, (3) history or family third actively seeks treatment. This group is of partiÂ

P late 4-14 Psychiatry

Treatment for Alcohol
Use Disorders

In the United States, alcohol use disorders had Brief counseling assists patients Alcohol use disorders are common and
12-month prevalence rates of 4.65% alcohol abuse and with alcohol use disorders to create treatable. All patients should be routinely
3.81% alcohol dependence from 2001 to 2002. Self- and maintain effective treatment screened with evidence-based assessments,
reported drinking (2010) among those age 12 years and plans to reduce or quit drinking. such as the 3-item AUDIT-C and offered
older indicates that 23% binge drink (more than five Lifestyle changes and reducing medical assistance for positive screening.
drinks per drinking day), and nearly 7% are heavy social drinking risks are
drinkers (binge drink on five or more days per month); recommended to prevent relapse. Patients with alcohol
yet fewer than 2% of the population needing substance in an extended-release monthly intramuscular formula- dependence are encouraged
use treatment receives treatment. tion that improves adherence. It poses hepatotoxicity to use medication therapies
risk and is contraindicated in those with hepatic disease to assist efforts to stop
Screening for alcohol use disorders identifies indi- and those requiring narcotic analgesia. Naltrexone is drinking; these include
viduals at risk for developing alcohol-related problems currently the only evidence-based medication for geriatric naltrexone, acamprosate,
and those already meeting criteria for an alcohol use alcohol dependence. and disulfiram.
disorder. Evidence-based screening, brief intervention, Acamprosate (N-Acetylhomotaurine). A glutamate Patients who actively use mutual support
referral to treatment (SBIRT) is recommended for all neuromodulator, acamprosate is an abstinence-promoting groups (Alcoholics Anonymous or SMART
patients and results in earlier intervention for at-risk medication appropriate for patients who have achieved Recovery) in addition to professional help
drinkers and reduced drinking among those with an early abstinence. It increases time to first drinking improve their chances of achieving and
alcohol use disorder. recurrence. It is metabolized within the kidney, provid- sustaining recovery from alcohol use
ing a good choice for those with hepatic disease. disorders.
Treatment for at-risk drinkers generally involves However, it has poor bioavailability, and the required
education about risk factors for developing alcohol use TID dosing may pose adherence risks. â•…
disorders and alcohol-related problems, a review of the Disulfiram. This aldehyde dehydrogenase inhibitor pre-
National Institute on Alcohol Abuse and Alcoholism vents the final metabolic conversion of ethanol to most effective at reducing anticipated rewards of alcohol
(NIAAA) guidelines to “low-risk” drinking, and a brief water; usage results in accumulation of toxic acetalde- and thus reducing drinking days. Adherence is prob-
intervention consisting of clear advice to reduce or hyde metabolites, leading to flushing, headache, hyper- lematic, and there is a 1 in 50,000 risk of idiopathic
abstain from drinking and referral to self-help tools, tension, sweating, and nausea/vomiting. Disulfiram is fulminant hepatotoxicity; thus careful hepatic monitor-
such as keeping a drinking calendar, writing down ing is required. It is contraindicated in those with auto-
reasons to reduce or stop, setting weekly reduction nomic instability (e.g., diabetes). It is a preferred
goals that are reviewed with a clinician or supportive treatment for impaired professionals and parents at risk
peer, reducing stress, cultivating healthy leisure activi- of losing child custody.
ties and sober social supports, and considering mutual-
help groups, such as Alcoholics Anonymous (AA) or Topiramate. Topiramate is a non–FDA-approved but
SMART Recovery. evidence-based medication that reduces drinking in
treatment-seeking alcohol-dependent patients.
Treatment for alcohol use disorders begins with an
assessment of whether medical detoxification is required This GABAergic potentiator can be administered to
for physiologic dependence at risk for dangerous treatment-seeking patients with alcohol dependence
alcohol withdrawal syndromes; this is especially impor- who are actively drinking but want to reduce and
tant for patients with co-occurring hypertension, are willing to commit to drinking reduction goals
diabetes mellitus, seizure disorder, and history of sui- and medication adherence. Topiramate reduces heavy
cidality. Detoxification may be monitored on an outpa- drinking days and promotes abstinence. Because of its
tient basis, but many patients will require inpatient renal metabolism, it is contraindicated with renal calculi
detoxification to prevent relapse to drinking. Medically or glaucoma.
stabilized patients with alcohol use disorders are
referred to professional counseling for drinking reduc-
tion and relapse prevention and to mutual-help groups
(participation in AA doubles the efficacy of professional
counseling). For alcohol-dependent individuals, absti-
nence from alcohol is most effective at maintaining
recovery gains.

Primary care physicians have a prominent role in
treating alcohol dependence using medical manage-
ment (MM) models of care. MM consists of (1) frequent
visits to assess progress and health, (2) education about
alcohol use disorders, (3) prescribing and monitoring
tolerance and adherence to an alcohol treatment medica-
tion, (4) facilitating weekly drinking goals and recovery
behaviors, (5) encouraging participation in mutual-help
or specialty counseling if indicated, and (6) screening
and treating disorders that commonly co-occur with alcohol
use disorders (e.g., medical, mental illness, domestic
violence). There are three FDA-approved and one
non–FDA approved medications to treat alcohol depen-
dence. Medications are reviewed briefly below.

Naltrexone. An antagonist at central mu-opioid recep-
tors, naltrexone attenuates opioid-mediated reward of
drinking and clinically reduces alcohol cravings, relapse, and
drinking days, and it increases the probability of contain-
ing recurrent drinking to a brief episode rather than full
relapse. Naltrexone is available in daily oral dosage and

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 93

Plate 4-15 Brain: PART I

Alcohol Withdrawal Blood alcohol Headache
concentration (BAC)

An alcohol withdrawal syndrome (AWS) occurs when an Decrease in BAC Visual, tactile,
individual who has alcohol dependence with physio- results in reflex and auditory
logic dependence experiences a period of reduced autonomic hallucinations
dosage or abstinence from drinking. AWS is life- hyperexcitability.
threatening as it poses a risk for seizures, hypertensive Vomiting
crisis, and autonomic instability (especially in patients Blood Sweating
with comorbid hypertension or diabetes) as well as pressure Heart
delirium tremens, leading to death if not rapidly rate
treated. AWS must be medically managed with close Tremor Nausea
monitoring in either an outpatient or inpatient setting,
depending on the patient risk profile. Expression and severity of symptoms vary Anxiety and
with duration and degree of dependence confusion may
Pathophysiology. Alcohol tolerance occurs with and with recognition and treatment of early progress to
neuroadaptations to chronic alcohol exposure. Alcohol withdrawal. disorientation
is a sedative; chronic exposure leads to compensatory Flushing and and delirium.
changes with reduced neurotransmission at inhibitory temperature elevation
type A gamma-aminobutyric acid (GABA) receptors Generalized seizures occur in
and enhanced neurotransmission at excitatory N-methyl- 8% of cases. Focal or multiple
d-aspartate (NMDA) glutamatergic receptors. During seizures suggest other cause.
abrupt abstinence episodes, the unopposed activity of
these compensatory changes results in central hyperex- Stages of alcohol withdrawal
citability responsible for objective and subjective AWS
symptoms. Stage 1 Stage 2 Stage 3

Presentation. AWS onset typically peaks within 48 to Hours after alcohol 24 36 48 (48-72) (72-105)
72 hours of the last ethyl alcohol intake. Clinical signs consumption (peak) Aggravated forms of Acute organic psycho-
of AWS include diaphoresis, tachycardia, hypertension, Symptoms stage 1 symptoms with sis (delirium), con-
fever, vomiting, insomnia, anxiety, tremor, hyperÂ

Plate 4-16 Psychiatry

Opioid Use Disorders PRESCRIPTION DRUG ABUSE
Current alcohol or drug disorder

Opioid misuse, abuse, and dependence (opioid use Alcohol Alcohol-related
disorders) refer to the pathologic self-administration abuse complaints (anxiety,
of substances that activate central mu-opiate receptors, for insomnia)
the purpose of experiencing an altered mental state Alcohol abuse with
(euphoria or relaxation), or in the opioid-dependent complaints not
individual for the purpose of avoiding opioid with- related to alcohol
drawal. Naturally-occurring opiates (morphine, codeine)
are found in Papaver somniferum poppy pods as a Medication Concurrent use Brain
latex sap, opium; heroin is a semisynthetic opioid derived sought to of alcohol and reward high
from opium. Prescription analgesics include semisyn- relieve legitimate
thetic (e.g., hydrocodone, oxycodone) and synthetic medical complaints medication Medication
(e.g., methadone, fentanyl) opioids. Both heroin and
opioid analgesics may be insufflated or injected to get Medications with abuse potential must be carefully sought to
“high”; other routes include smoking heroin and prescribed and monitored in patients with current maintain
swallowing/chewing opioid analgesics. Routine toxicol- or past alcohol or drug abuse. reward high
ogy detects only opiates (heroin metabolites), and
special gas chromatograph/mass spectrometry (GC/ Self-escalation of dosage
MS) detection is required for semisynthetic and syn-
thetic opioid analgesics. Month 1 Month 2 Month 3

According to the 2010 National Survey on Drug Use Increased prescription requests suggest potential prescription drug abuse
and Health, 200,000╯U.S. residents age 12 years and
older endorse past-month heroin use, and 5.1 million Dosing interval Dosing interval
residents endorse past-month prescription opioid
misuse. Prescription opioid misuse has increased three- Effective Reward Therapeutic Effective Reward Therapeutic
fold in the past decade in conjunction with similar range effect effect range effect effect
increases in opioid prescribing and unintentional opioid
overdose deaths. Family and friends are the most fre- Withdrawal Mini-withdrawals Withdrawal Tolerance
quently reported source of illicit opioid analgesics, con- range range
tributing to increased youth exposure, high rates (6%
past-month prevalence) of opioid analgesic misuse If dosing interval is too long, patient may experience With opioids and benzodiazepines, patients develop
among 18- to 25-year-olds, and an alarming number of mini-withdrawals and increase dosing frequency tolerance to reward effect but not to therapeutic
accidental pediatric ingestions and deaths. to maintain therapeutic effect. effect. Dosing increased to maintain reward high.

Opioid intoxication may be recognized by miosis, â•…
dysarthria, altered mental state and sedation, constipa-
tion, impaired judgment and slowed reaction time. youth and adults. Social and legal consequences include clinics. Patients needing close medical monitoring and
Recurrent opioid use results in tolerance to the central loss of employment, domestic violence, and arrest for more intensive social service supports may benefit more
effects and progression to physiologic dependence on drug-related criminal behaviors. from the structure of methadone clinics.
opioid-taking to avoid opioid withdrawal. Physiologic
dependence alone is not an opioid use disorder; however, it FDA-approved medication maintenance for opioid use Safe opioid prescribing will prevent diversion of
is when the individual also experiences preoccupation with disorders includes the mu-opiate receptor antagonist nal- opioid analgesics. Physicians must screen patients for
obtaining, using, and recovering from opioid use such trexone, the mu-opiate receptor partial agonist buprenor- vulnerability to opioid misuse and discuss these risks
that normal social and occupational functioning is phine, or the mu-opiate receptor full agonist methadone. with patients. Prevention strategies include limiting
reduced or impaired. Symptoms of opioid withdrawal Behavioral therapies without medication maintenance quantity, using state prescription monitoring services,
include mydriasis, diaphoresis and fever, increased heart have high failure rates (relapse to opioid use) in both designated pharmacies and treatment contracts, toxi-
rate, abdominal cramps, nausea/vomiting and diarrhea, youth and adults. Optimal treatment combines medica- cology, pill counts, and monitoring aberrant behaviors
lacrimation, rhinorrhea, piloerection, leg cramping, tion management with behavioral therapy and participa- (e.g., “doctor-shopping,” running out early, “lost” or
yawning, insomnia, and anxiety. Although physiologic tion in self-help programs. Naltrexone therapy has stolen prescriptions). Functional improvement with
dependence alone is not sufficient to define an opioid use been limited by poor patient adherence to oral naltrex- opioid analgesics must be monitored closely to prevent
disorder, it poses a risk for developing an opioid use disorder, one; the recent development of an extended-release unnecessary chronic opioid treatment. Patient educa-
particularly in vulnerable populations, such as those injection formulation that endures 4 weeks may have tion on safe storage (lockbox use), safe dosing, and
with a history of substance abuse, mental illness, or superior outcomes. Buprenorphine has a favorable safety safe disposal are essential and may be remembered
genetic loading for addiction disorders. and tolerability profile compared with methadone and using the mnemonic “STOP & DUMP:” secure medi-
also offers office-based access for patients, as opposed cation, take only as prescribed, & discard unused medi-
Medical consequences of opioid misuse are many, and to daily monitored dosing at methadone maintenance cations and pills.
risk is proportionate to the quantity of opioid self-
administration, the route of administration (with injection
use carrying the highest probability of overdose death
as well as high rates of blood-borne infectious disease
transmission, especially hepatitis C virus [HCV] and
human immunodeficiency virus [HIV]), and the dura-
tion of use (women being more rapidly susceptible to
both medical and social consequences, often referred
to as a “telescoping course”). Overdose mortality is
associated with high-dose opioid use, co-occurring use
of alcohol and other sedatives, and injection use. Injec-
tion use is commonly associated with cellulitis and
staphylococcal infection, phlebitis, and endocarditis.
Pain is frequently comorbid among opioid-dependent

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 95

P late 4-17 Brain: PART I

SIGNS AND SYMPTOMS OF OPIOID WITHDRAWAL

Opioid Withdrawal Sweating Nausea
Dilated pupils and
An opioid withdrawal syndrome (OWS) occurs when Lacrimation vomiting
an individual, physiologically dependent on opioids
(either due to chronic opioid analgesic treatment or Rhinorrhea
opioid use disorder), experiences a period of reduced
dosage or abstinence from opioid-taking. OWS is both Yawning
physically aversive and powerfully anxiogenic; thus
individuals with moderate-to-severe OWS are highly Diarrhea
motivated to seek opioid sources for immediate relief.
Locus ceruleus Noradrenergic effects
Pathophysiology. Opioid tolerance and withdrawal may be blocked by
occur as neuroadaptations to chronic opioid exposure. alpha-2 agonists
This neurobiology is complex, involving adaptations at
all levels of opioid-sensitive brain signaling, including X
(1) mu-opiate receptor desensitization, (2) opioid-sensitive
neuron cellular tolerance due to up-regulation of adenylyl Noradrenergic effects of
cyclase activity and changes to cyclic adenosine mono- withdrawal (mediated via
phosphate (cAMP) response element-binding (CREB) locus ceruleus) increase
signaling, (3) system feedback adaptations of neuronal and heart rate and blood
glial networks interacting with opioid-sensitive neurons, pressure.
(4) opioid-sensitive neural circuit changes in synaptic plas-
ticity. Clinically, opioid signaling is inhibitory in function Insomnia and muscle aches are Blood pressure
(e.g., suppression of pain, respiratory drive, arousal, and mediated via mu receptors and Heart rate
anxiety); in contrast OWS symptoms are mediated by relieved by mu agonists.
rebound hyperactivity due to reduction or removal of
chronic opioid agonism. Days since last dose 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Presentation. OWS onset, duration, and severity Onset and Long-acting opioid
vary according to type of opioid exposure (short-acting severity of (methadone)
vs. long-acting, full agonist vs. partial agonist), exposure withdrawal
duration, dosing of exposure, and periodicity of with- symptoms
drawal episodes. OWS is more severe with high-dose,
full-agonist opioid exposure; more frequent OWS Short-acting opioids
episodes worsen future withdrawal episodes. Individu- (morphine, hydromorphone)
als using short-acting opioids (heroin, oxycodone,
or hydrocodone) experience mild-to-moderate OWS Severity of opioid withdrawal varies with dose and duration of opioid use. Onset and duration of
within 8 to 12 hours of last dosing, whereas persons symptoms after last drug dose depend on half-life of particular drug.
using long-acting opioids (sustained-release oxycodone
or methadone) experience mild-to-moderate OWS â•…
within 24 to 36 hours of last dosing. The duration of
OWS is briefer (days) with shorter-acting opioids and pregnancy (deleterious cardiovascular effects on the sublingual buprenorphine every 4 hours PRN, not
may persist for weeks with longer-acting opioids. In fetus and third trimester premature labor risk), cardio- exceeding 16╯mg over 24 hours. Dosing in pregnancy
both instances, protracted withdrawal may persist for vascular disease, disorders involving autonomic is generally similar, although requirements may be
weeks to months characterized by residual dysphoria instability, and vulnerability to dehydration. OptiÂ

Plate 4-18 Psychiatry

Borderline Personality Psychodynamic theorists trace the origins of
Disorder borderline personality disorder to dis-
turbances in the parent-child relationship
in the second and third years.

The term borderline was initially assigned to those The borderline child is unable
patients who were neither neurotic, nor psychotic, but to integrate disparate experiences
proved to be clinically troubling cases. Today, a diagno- of parental love and hostility.
sis of borderline personality disorder (BPD) refers to
patients characterized by emotional turmoil and chronic Borderline patients have unstable mood and self-image,
suicidality. According to the Diagnostic and Statistical are often inappropriately angry, and overreact to minor
Manual of Mental Disorders (DSM-IV-TR), BPD patients slights and disappointments.
must show a “pervasive pattern of instability of inter-
personal relationships, self-image, and affects, with behavior therapy (DBT) is the most heavily researched â•…
marked impulsivity beginning by early adulthood and psychosocial treatment. Rooted in cognitive-behavioral
present in a variety of contexts.” Specifically, patients therapy, DBT uses individual and group therapy to pathology was significantly impacted by the antipsy-
must present with at least five symptoms out of a pos- address impulsivity and affective instability by teaching chotic aripiprazole. Anticonvulsants, including topira-
sible nine that can be organized into four categories: mindfulness, emotion regulation, and distress tolerance mate, valproate, and lamotrigine, are preferred first-line
affective, impulsive, interpersonal, and cognitive. skills. This has reduced suicide attempts, hospitaliza- agents for affective dysregulation, whereas second-
tions and emergency room visits, and treatment drop- generation antipsychotics (SGA) and haloperidol also
Affective symptoms include extreme reactivity of out. Cognitive-behavioral therapy systems training for showed positive results. Selective serotonin reuptake
mood, feelings of chronic emptiness, and inappropriate emotional predictability and problem solving, and even inhibitors (SSRI) treatment is only recommended for
or intense anger. Impulsive symptoms include recurrent psychodynamic treatments (i.e., mentalization-based patients experiencing a comorbid axis I condition (i.e.,
suicidal behavior, including ideation, threats, and therapy and transference-focused therapy) demonstrate a major depressive episode) that requires antiÂd

Plate 4-19 Brain: PART I
Physicians must not disregard the medical needs of patients with
Antisocial Personality personality disorders
Disorder

Antisocial personality disorder (ASPD) is defined by the Patients with personality disorders often provoke intense and hostile feelings in their caregivers
Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV-TR) as “a pervasive pattern of disregard for, â•…
and violation of, the rights of others” beginning in early
childhood or adolescence and continuing into adult- ASPD, and presently there are no guidelines put forth deception and manipulation. The most promising
hood. To meet criteria for a diagnosis of ASPD, indi- by the American Psychiatric Association for the treat- treatment modality for ASPD is homogeneous group-
viduals must have a history of conduct disorder before the ment of ASPD. ASPD patients are characterized as based cognitive and behavioral interventions that focus
age of 15 years, characterized by aggression toward having poor insight and minimal motivation to change on reducing offending behavior. It is suggested that
people and animals, destruction of property, deceitful- behavior. When they do present for treatment, it may perhaps a more productive target may be early inter-
ness or theft, or serious violation of rules or social be due to legal mandate or because of the presence of vention and prevention programs to reduce the likeli-
norms. As adults, these persons may continue to ignore a comorbid condition. Individual psychotherapy is not hood that conduct disorder in childhood will become
social rules, be manipulative and dishonest, be impul- recommended for ASPD. Beyond the difficulty of ASPD in adulthood. Other studies suggest antisocial
sive without considering the consequences, be irritable establishing a therapeutic alliance with ASPD patients, behaviors tend to decrease with age; time alone may be
and aggressive, disregard their own or other’s safety, therapy itself provides yet another opportunity for the best treatment for these patients.
behave irresponsibly, lack remorse for the consequences
of their actions, and may be involved in criminal activ-
ity. Antisocial behavior has a negative impact on
academic and professional achievement, material-life
success, physical health, social relationships, psycho-
logic well-being, and is linked to negative outcomes,
such as legal problems, incarceration, and increased
mortality due to reckless behavior. Although not all
persons with ASPD are violent, ASPD is also more
strongly associated with violence toward others com-
pared with other psychiatric disorders.

The prevalence of ASPD is estimated to be 1% to
4% of the adult general population (3% of males and
1% of females) (APA, 2000). One potential explanation
for the gender discrepancy is that women are more
likely to be diagnosed with other personality disorders,
such as borderline. Rates of ASPD are 10 times greater
among prisoners compared with the general popula-
tion. This disorder is equally represented across all
races, ethnicities, and cultures. Comorbid psychiatric
disorders are common among individuals with ASPD.
Specifically, ASPD is highly associated with substance
use disorders, other personality disorders, and anxiety
disorders, in particular social phobia and PTSD. Symp-
toms of ASPD appear to decline with age.

The exact etiology of ASPD is unknown, although
several possible biologic and psychosocial factors are
identified. Adoption studies suggest a genetic link, with
higher rates of ASPD present in the offspring of antiÂ

P late 4-20 Psychiatry

Intimate Partner Abuse ABUSE: PHYSICAL AND SEXUAL

Intimate partner abuse refers to physical, sexual or psy- Common injury sites in abuse
chologic maltreatment by a current or prior partner or Head and neck
spouse. It can take place in the context of heterosexual
or same-sex couples and can consist of a single incident Causes of abuse are multifactorial
or recurrent, severe violence lasting many years. but alcohol, drugs, and domestic
discord are common factors
There are four major categories of intimate partner
abuse: (1) physical abuse, whereby physical force is used Defensive injuries common
to kill, disable, injure, or otherwise hurt a partner; on upper extremities
(2) sexual abuse, which involves coercing a partner Chest and
to engage in a sex act without consent; 3) threats breasts
of violence, in which verbal statements, gestures, or Abdomen
weapons convey a desire to kill, disable, injure, or
otherwise hurt a partner; and 4) psychologic or emotional Initial event with Sexual abuse may involve children
abuse, including insults, controlling behavior, deliberate (minor) as well as adults
damage to self-esteem, stalking, and preventing a E. Hatton
partner from accessing family, friends, information, Provocation
money, or other resources. Abuse Cycle (inconsequential)
Provocation
In the United States, there are 4.8 million physical
assaults and rapes of women and 2.9 million physical Tension Tension
assaults of men annually due to intimate partner abuse. building building
In 2007, there were 2,340 deaths in the United States
due to intimate partner violence, of which 70% were Battering Battering
women and 30% were men.
Contrition Contrition
Clinical Presentation and Diagnosis. Risk factors
for intimate partner abuse include poor self-esteem, Severity of Severity of
poverty, substance use disorders, minimal social sup- inciting incident violence
ports, belief in strict gender roles, social isolation, past
experience of physical or psychologic abuse, borderline Cycle of abuse is characterized by progressively smaller incidents, inciting progressively greater violence
personality disorder (Plate 4-18), antisocial personality interspersed with periods of remorse â•…
disorder (Plate 4-19), relationship instability, financial
stressors, and community tolerance of intimate partner honeymoon phase, which consists of statements of sequelae can include depression, anxiety disorders,
violence. apology, displays of affection, or attempts to overlook eating disorders, substance use disorders, high-risk
the preceding abuse, followed by a “calm phase.” sexual behaviors, suicidality, low self-esteem, dissocia-
Victims of intimate partner abuse can present with tive disorders, and posttraumatic stress disorder.
physical injuries, such as scratches, cuts, bruises, welts, In addition to an increased risk of bodily injury
broken bones, internal bleeding, and head trauma. The and even murder, intimate partner abuse can nega- Of note, more than 3 million children in the United
psychologic trauma from intimate partner violence can tively impact a victim’s physical health in the form States witness intimate partner violence each year.
manifest as depression, suicidal ideation and attempts, of headaches, fibromyalgia, irritable bowel syndrome, Observing intimate partner abuse in the home can have
flashbacks, panic attacks, and difficulty sleeping. cardiovascular disorders, gastrointestinal disorders, an adverse effect on the emotional, social, behavioral,
gynecologic disorders, neurologic disorders, sexually and cognitive development of a child, as well as increas-
The pneumonic SAFE (Sebastian, 1996) is often used transmitted illnesses, and obstetric complications, such ing the likelihood that the child will engage in intimate
to facilitate the discussion of intimate partner abuse by as poor neonatal health and perinatal death. Psychologic partner abuse later in life.
asking about (1) Stress and Safety in the relationship,
(2) being Afraid of or Abused by one’s partner, (3)
having Friends or Family who can serve as social sup-
ports, and (4) having an Emergency plan if in danger.

Management. Physicians must provide victims of
intimate partner abuse with an environment where they
feel safe. A thorough history and physical examination
are required, with detailed documentation in the
medical record of all findings and interventions. Inti-
mate partner abuse must be acknowledged to the
patient, who needs to be told that there is no excuse for
abuse and that he or she is not at fault.

The patient must receive medical and surgical treat-
ment as needed for sequelae of abuse, as well as evalu-
ation for signs and symptoms of psychologic trauma.
Victims need to be warned that violence often becomes
more severe with time. A risk assessment should evalu-
ate the safety of victims and their children. Intimate
partner abuse must be reported to legal authorities if
appropriate. Physicians need to formulate a safety plan
with the patient and offer referrals for shelter, legal
assistance, and mental health services.

Course. Lenore Walker published a theory in 1979
that describes the cyclic pattern of abusive relation-
ships: (1) the tension-building phase occurs before an
abusive incident and involves mounting tension in the
setting of ineffective communication and passive-
aggressive behavior; (2) the acting-out phase involves
violent or otherwise abusive acts; (3) the reconciliation/

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 99

P late 4-21 Brain: PART I

Physical Abuse

Elder Abuse

Elder abuse refers to the maltreatment and neglect of Physical abuse demonstrated through assaults, rough handling, burns, and sexual abuse
adults 60 years of age or older, usually by a caregiver or Physical Neglect
other person upon whom the elder is dependent. It
includes physical abuse (injury, physical threats or inap- Physical neglect demonstrated through poor hygiene, malnutrition, soiled clothing, giving wrong
propriate restraints), sexual abuse (sex acts or sexual medicines, not getting medical care when needed, or complete abandonment without supervision
contact without the elder’s consent), psychologic or emo- or care
tional abuse, neglect (failure to meet the elder’s physical,
emotional, and social needs or to provide protection), â•…
abandonment, or financial abuse (inappropriate use of the
elder’s resources for personal gain, including forgery, elder’s assets can decrease the risk of financial abuse. home if he or she has decision-making capacity and
theft, manipulation of the elder to transfer money or Finally, caregivers should never hesitate to seek mental declines treatment interventions. A multidisciplinary
belongings, and exploitation of guardianship or power health counseling for themselves, should they develop team approach to elder abuse interventions is optimal
of attorney). feelings of depression or a substance use disorder. and should include physicians, nurses, social workers,
visiting nurses, and caseworkers from adult protective
According to the National Elder Abuse Incidence At elder care facilities, regular monitoring for abuse, services.
Study, in 1996 there were 551,000 documented victims clear policies and protocols outlining proper elder
of elder abuse, neglect, or self-neglect in domestic set- treatment, thorough employee training, and regular Course. Victims of elder abuse are at increased risk
tings in the United States. Only 115,000 (21%) of those visits to the facility by community members may all of adverse health consequences that can differ from
victims, however, were fully verified by adult protective decrease the risk of elder abuse. the health impact of normal aging, including physical
services. Thus most cases of elder abuse were either injuries, malnutrition, dehydration, poor sleep, elevated
never reported to adult protective services or were ulti- Suspected elder abuse should be reported to adult risk of sexually transmitted illnesses, exacerbation of
mately never confirmed by the agencies involved. protective services. The patient may require hospital preexisting medical conditions, and premature death.
Victims of elder abuse are often reluctant to report admission to ensure safety and provide medical or sur- Psychologic sequelae include increased rates of depres-
abuse due to fear of losing their caregivers or social gical treatment in the aftermath of abuse. Attempts sion, anxiety disorders, symptoms of posttraumatic
supports. should be made to help place the patient in a safe home, stress disorder, and other forms of distress.
or alternatively, the patient should be allowed to return
Clinical Presentation and Diagnosis. Risk factors for
perpetrating elder abuse include active mental illness,
alcohol abuse, insufficient training for caregiving, per-
sonal history of physical or emotional abuse, significant
emotional or financial dependence upon the elder, inad-
equate social support, lack of elder support services,
negative cultural beliefs about elders and aging, and
institutional settings with poor working conditions for
staff and/or insufficient administrative monitoring of
elder treatment.

The abused elder individual must be listened to
because he or she often reports the maltreatment, per
se, or there may be abrupt changes in his or her behav-
ior; sometimes rather unusual behaviors develop. The
caregiver may refuse to permit visitors from seeing the
elder alone. However, when observational opportunity
presents, signs and symptoms of elder abuse include bruises,
welts, cuts, lacerations, rope marks or other signs of
being restrained, broken bones, or internal bleeding. In
addition, the abused elder patient may evidence injury
to the breasts or genitals, unexplained sexually trans-
mitted illnesses, dehydration, malnutrition, bed sores,
poor hygiene, and unauthorized or unexplained banking
transactions. Laboratory results often indicate medica-
tion overdose or inadequate dosing.

Prevention and Management. Caregivers can use a
variety of strategies to reduce stress and decrease their
own likelihood of perpetrating elder abuse. First,
obtaining adequate training before assuming elder care
responsibilities can markedly reduce feelings of inade-
quacy and frustration during caregiving. Caregivers
should also enlist the help of other members of the
community, including family, friends, and local services
that have additional resources to assist in caregiving.

Respite for caregivers between long shifts can signifi-
cantly decrease stress and is made feasible by volunteer
programs that offer temporary relief from caregiving
tasks and related errands. Adult daycare programs can
be highly beneficial. Moreover, involving independent
financial planning services in the management of an

100 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 4-22 Stage I Personality changes, Psychiatry
vacant stare
Delirium and Acute Stage II Lethargy, flapping tremor, muscle twitching
Personality Changes

Delirium is an acute confusional state commonly seen Stage III Noisy, abusive, violent
in patients with medical illness, especially among the Alcohol dependence and
geriatric population. Delirium encompasses four key Wernicke syndrome should
clinical features, including (1) a disturbance of con- always be considered
sciousness with impaired attention and concentration,
(2) the disturbance develops over a short period of time Electroencephalogram
(hours to days) and often fluctuates in severity. (3) a per- changes
ceptual disturbance that is not related to a pre-existing
condition such as dementia, and (4) an underlying Knee clonus Fetor hepaticus
medical condition, intoxication, or medication side effect is Stage IV Coma
evident. Approximately 30% of older patients experi- Ankle clonus
ence delirium in the course of hospitalization, with
higher rates among more frail patients and those under- ϩ Babinski sign
going complex surgery. In the intensive care unit (ICU),
the prevalence of delirium is about 70% as measured cohesive train of thought or action. Patients are typically â•…
by standardized screening and diagnostic tools. disoriented to time. In more advanced cases, patients may
become more obviously drowsy and lethargic, even Delirium is often misattributed to psychiatric diagnoses—
There are multiple pathophysiologic mechanisms obtunded. However, the opposite may occur in some usually depression and catatonic schizophrenia in
that may cause delirium; there is no final common forms of delirium, where the patient becomes hypervigi- hypoactive deliriums, and personality disorders and
pathway allowing a simple approach to diagnosis or lant, irritable, and agitated, as seen in alcohol withdrawal. psychosis in hyperactive deliriums. A patient with a
treatment. The neurobiologic basis of delirium is, Hallucinations may occur. Cognitive deficits, including first-episode psychosis or mania should be of typical
therefore, poorly understood, and diagnosis relies on a amnesia, aphasia, agnosia, and apraxia may also appear. age, that is, a young adult, and should appear generally
comprehensive clinical assessment with judicious use of Other clinical manifestations may include emotional well, not diaphoretic, flushed, befuddled, jaundiced, or
ancillary studies. In general, areas of the brain that lability, disturbance of sleep cycle, motor restlessness, and clumsy. Psychiatric illness usually does NOT account
govern arousal, attention, insight, and judgment are sometimes motor signs, such as asterixis, myoclonus, or for disorientation, and does NOT cause motor symp-
affected. These include the subcortical ascending retic- action tremor. In the elder patient, the most common toms or fevers. Fluctuations in degree of alertness, vari-
ular activating system (ARAS) and integrated cortical presentation is of a withdrawn, quiet state that may be able motor signs, and uneven cognitive performance are
regions. The ARAS predominantly serves arousal easily mistaken for depression. expected in delirium and do not signify a manipulative
mechanisms, whereas integrated cortical function is personality. Use of antipsychotic medication may
necessary for proper orientation to person, place, and enable care, shorten duration of delirium, and improve
time, as well as higher cognitive functions.

Of the neurochemical pathogenic mechanisms of
delirium, the best understood is the cholinergic system.
Anticholinergic drugs are commonly associated with
delirium in healthy patients but much more so in the
elderly. Conditions that may predispose to delirium
secondary to acetylcholine depletion include hypoxia,
hypoglycemia, thiamine deficiency, and Alzheimer
disease. In addition, many commonly used drugs may
precipitate delirium due to secondary anticholinergic
effects. Additional neurotransmitter systems that may
precipitate delirium include GABA, endorphins, neuro-
peptides, serotonin, and norepinephrine. Other neuro-
chemical precipitants of delirium include endogenous
chemicals, such as proinflammatory cytokines and
tumor necrosis factor-alpha, which may explain delir-
ium occurring in the context of infection/sepsis, surgery,
and hip fractures. The blood-brain barrier is weakened by
sepsis, even in pediatric cases. Other than advanced age,
pre-existing CNS disease, such as Alzheimer disease,
Parkinson disease, stroke, etc., accounts for a significant
increase in risk for delirium. Indeed, a new delirium in
an elder patient may be a heralding sign of previously
unrecognized or impending dementia.

The presentation of delirium is typically acute, over
hours or days, and may persist for days to months.
There may be a prodromal phase, especially in elder
patients, including fatigue and lethargy, sleep distur-
bance, anxiety and/or depression, or restlessness. The
acuity of onset differentiates delirium from dementia in most
cases, although delirium in a demented patient may be
difficult to detect, especially early in the course. More-
over, the severity of confusion may fluctuate through-
out the day, becoming particularly more prominent
toward night-time. Initially, there may be a subtle
change in mental clarity, inattention, and disorientation
before more obvious behavior changes take place. The
patient is often very distractible, unable to maintain a

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 101

P late 4-23 Brain: PART I

Delirium and Acute Herpes zoster Analgesic
Personality Changes lesions medication

(Continued)

mortality, even when the underlying cause is not Use of analgesics and sedatives can precipitate
psychiatric. delirium in patients with limited cognitive reserve,
especially the elderly and the demented.
Psychiatric illness is a diagnosis of exclusion for
delirium and should be confirmed with a psychiatric Delirium is a
consultant when suspected. Similarly, if a delirious medical emergency.
patient is under psychiatric care, neurologic consulta-
tion should be obtained. Frontal brain tumors, multiple The mental state of delirious patients
sclerosis, epilepsy, encephalitis, and dementia can all often changes from hour to hour.
have delusions, hallucinations, mania, and aggression as
manifesting signs. Repeating sequences of odd behav- “Sundowning.” Delirious patients
ior, indifferent attitude, amnesia, atypical age, absence are often more confused and agitated
of prior or family history of mental illness, and presence at night.
of primitive reflexes indicate more screening for neuro-
logic disease. drug syndromes exist as well. When no mechanism is â•…
identified for the acute personality change, particularly
Substance abuse very frequently leads to various con- in young women, abdominal/pelvic imaging studies as clonus. Lithium, along with other narrow-window ther-
fusional presentations. The use of illicit substances and well as anti-NMDAR autoantibodies must be evaluated apeutic drugs, such as digitalis, can cause delirium even
overuse of alcohol are usually denied in medical set- in serum or cerebrospinal fluid to exclude anti-NMDAR with levels in the recommended therapeutic range.
tings; however, ingestion of toxins and drug overdose, encephalitis. Lithium toxicity usually manifests with vomiting or
either recreational or suicidal, should be consÂ

P late 4-24 Psychiatry

Insomnia

Most people experience occasional insomnia sometime Reading in bed can assist those with insomnia relax,
in their lives. However, a diagnosis of insomnia disÂ

Plate 4-25 Brain: PART I

Pediatrics: Depressive Symptoms of depressive disorder include
Disorders at least 2 weeks of marked change in
mood and/or loss of interest and pleasure,
The depressive disorders are a group of mental health and significant changes in patterns of
problems in children and adolescents characterized by appetite, weight, sleep, activity,
a sad or irritable mood. In simple terms, these disorders concentration, energy level, or motivation.
are caused by a difference in the structure and function
of the part of the brain that controls the intensity of sad â•…
and irritable moods. Vulnerability to the development
of depressive disorders can be genetically determined. activities that are soothing and comforting, how to dis- Antidepressant medication may help the youth feel
Concomitantly, there is often something in the youth’s cover and appreciate good things about themselves, and more motivated to work on coping skills in therapy.
environment that triggers the sad or irritable feelings, how to build hope for the future. If environmental
such as poor relationship(s) with peers or with a parent circumstances are triggering the sad feelings, it is Course. The depressive disorders respond well to the
or loss of loved ones. It is estimated that 4 to 5 of 100 important to change these circumstances, if at all pos- above treatments when delivered by qualified mental
youths have depressive disorders. sible, to increase the chance of a successful treatment. health professionals. If left untreated, the depressive
disorders can lead to death through suicide. This very
The most severe of these disorders, major depressive If the depressive disorder is severe, for example, if the serious illness also can cause failure in school and
disorder, is characterized by a distinct period of at least youth is thinking about wanting to die or has lost most involvement in risky behaviors and subsequent difficul-
2 weeks during which the child/adolescent experiences ability to function, then antidepressant medication may ties with maintaining or establishing relationships and
a depressed or irritable mood that is present most of be used as a treatment in addition to psychotherapy. jobs in adulthood.
the day nearly every day and/or is associated with loss
of interest or pleasure in nearly all activities. There are
often severe problems with eating, sleeping, energy,
concentration, feelings of worthlessness or extreme
guilt, and loss of the desire to live. These symptoms
may manifest as the youth being cranky, having loss of
interest in hanging out with friends, refusal to get out
of bed for school in the morning, or preoccupation with
song lyrics that suggest life is meaningless. To meet the
diagnosis, the problems must cause distress and/or
impair the youth’s function at home, at school, or with
peers. After puberty, major depressive disorder is more
common in girls than boys.

The less severe but longer lasting of these disorders,
dysthymic disorder, is characterized by a depressed or
irritable mood for most of the day, more days than not,
for at least 1 year. There also are problems with eating,
sleeping, energy, and concentration, feelings of hope-
lessness, and low self-esteem. To meet the diagnosis, the
problems must cause distress and/or impair the youth’s
function at home, at school, or with peers. Dysthymic
disorder occurs equally in boys and girls, and children
with this disorder are more likely to develop major
depressive disorder in their teenage or early adult years.

Diagnosis. Qualified health professionals experi-
enced with children, including child and adolescent
psychiatrists, pediatricians, child psychologists, child-
trained social workers, counselors, and clinical nurse
specialists are best trained and have the most experience
to accurately diagnose these depressive disorders. The
evaluation typically requires input from multiple people
who know the child, and the diagnosis is based upon
the findings from interviews of parents/caregivers as
well as interviews with the child and a mental status
examination. There are no imaging studies, blood tests,
or other specific medical testing modalities to diagnose
these disorders.

Treatment. Psychotherapy is an effective treatment
for these disorders, especially because it particularly
helps the youth understand and learn how to cope with
sad feelings. These coping strategies include learning
how to identify and talk about feelings, how to stop
thinking automatic negative thoughts, how to find

104 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 4-26 Psychiatry

Pediatrics: Anxiety Disorders

The anxiety disorders (AD) are mental health problems Social anxiety disorder Generalized anxiety
found in children and adolescents, characterized by dis- (afraid of social interactions) disorder (many worries
abling scared or worried feelings. These disorders are and children tend to report their anxiety symptoms and fears)
common, with 10 to 15 of 100 youths estimated to have more accurately than their parents who may not even
one of these disorders. These occur more commonly in be aware of the child’s symptoms. There are no imaging â•…
girls. ADs are caused by a difference in the structure or studies, blood tests, or other medical tests to diagnose
function of the brain that controls worries and fears. these disorders. body. When a child’s anxiety disorder does not respond
Vulnerability to the development of anxiety disorders to traditional therapy, then antianxiety medication may
can be genetically transmitted. Parents who are over- Treatment. Psychotherapy to help the youth to learn be considered. Antianxiety medication may help the
protective or overcontrolling appear more likely to how to cope with worry and fear is the best treatment. youth feel more relaxed when working on coping skills
have anxious children, and children also can learn to be These coping strategies include learning how to iden- in therapy.
anxious from parents who are anxious. Sometimes envi- tify and talk about feelings, how to stop thinking auto-
ronmental events can trigger an anxiety disorder. For matic negative thoughts, and how to relax the mind and Course. The anxiety disorders respond well to the
example, separation anxiety disorder can be caused above treatments when delivered by qualified mental
by exposure to frightening events, such as domestic health professionals. If left untreated, the anxiety disor-
violence. ders can cause long-standing distress and problems with
social relationships and school performance.
Generalized Anxiety Disorder. Generalized anxiety
disorder is characterized by excessive worry/angst
occurring on more days than not about a variety of
areas, such as schoolwork, friendships, family, health/
safety, and world events. The worry is accompanied by
feeling tired, tense, restless or irritable; having difficulty
focusing; and having trouble falling or staying asleep.
Sometimes these youngsters have associated physical
symptoms, including muscle aches, stomach cramps, or
nausea. The youth finds it difficult to control the worry.
To meet the diagnosis, the problems must be present for
at least 6 months, and must cause distress and/or impair
the youth’s function at home, at school, or with peers.

Separation Anxiety Disorder. Separation anxiety dis-
order is characterized by excessive worry about being
separated from the home or from parents. The child
may feel very upset about leaving home to go to school,
about being separated from the parent, about sleeping
alone in his or her own bedroom, about something bad
happening to the parent, or something bad happening
to the child that will separate him or her from the
parent. These children may refuse to go to school or
may develop physical problems (headaches, nausea)
before going to school or when at school. Some young-
sters may experience bad dreams about being separated
from the parent. To meet the diagnostic criteria, these
problems must be at least a 1-month duration, causing
distress and/or impairing the youth’s function at home,
at school, or with peers.

Social Anxiety Disorder. Social anxiety disorder is
characterized by excessive worry about social or perfor-
mance situations where embarrassment may occur.
This angst can arise when meeting new people or per-
forming in front of others (i.e., speaking up in the
classroom or performing musically or athletically).
When this becomes so severe that it causes panic, a
pattern develops, leading to the youth avoiding social
or performance situations. To meet the diagnosis, the
problems must have been present for at least 6 months,
causing distress and/or impairing the youth’s function
at home, at school, or with peers.

Diagnosis. Qualified mental health professionals
experienced with children (child and adolescent psy-
chiatrists, child psychologists, child-trained social
workers, counselors, and clinical nurse specialists) are
best trained to accurately diagnose the various anxiety
disorders. The evaluation for these diagnoses typically
takes several hours and requires input from multiple
people who know the child very well. The diagnosis is
based upon the findings from parent and child inter-
views, questionnaires, and a mental status examination.
In contrast to disruptive disorders, anxiety disorders
often cause more distress in the child than the parents,

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 105

Plate 4-27 Brain: PART I
Conduct disorder
Pediatrics: Disruptive (bullying and aggression to others)
Behavior Disorders

The disruptive behavior disorders (DBDs) are mental strategies include developing a warm, loving relation- Disruptive behavior disorder
health problems occurring in children and adolescents, ship between parent and child; providing a predictable,
more commonly in boys, characterized by out-of- structured environment; setting clear and simple house- Oppositional defiant disorder
control behavior. Prevalence rates vary from 1% to hold rules; consistently praising and rewarding positive (defiant and disobedient )
16%. A cluster of factors, including the child’s charac- behaviors (such as completing chores or homework); â•…
teristics, parental interactions, and environmental consistently ignoring annoying behaviors (such as extensive, sometimes involving other child-serving
factors contribute to their development. whining or arguing), followed by praise when the agencies (i.e., juvenile justice and child welfare). Treat-
annoying behavior ceases; and consistently outlining ment is likely to be effective when administered early
Ineffective parenting strategies often underlie these potential consequences (such as loss of privileges) for in the course of the disorder before maladaptive behav-
disorders. Parents may have insufficient time and emo- dangerous or destructive behaviors. Social-emotional iors become more entrenched. If physically aggressive
tional energy for the child or may use inconsistent skills training for the child, helps them develop skills to behavior is prominent in conduct disorder, medications
methods of disciplining and limit setting. These identify and manage feelings, get along with others, and (including atypical antipsychotics) can be helpful.
ineffective strategies include authoritarian parenting, make good decisions based on thinking rather than
wherein the parent demonstrates too much anger or is feeling. Course. Oppositional defiant disorder, and to a lesser
too harsh, and permissive parenting, with the parent extent, conduct disorder respond well to the above
giving in to the child’s excessive demands. Authoritative Because conduct disorder is an extremely serious treatments when delivered by qualified mental health
parenting is defined as having high levels of both condition, treatment must be more intensive and professionals. Although some children grow out of the
warmth and firmness and is the most effective parenting DBDs, if untreated, these disorders can go on to cause
strategy. significant problems, including difficult relationships
with parents and other adults, failure at school and
The DBD child may be strong-willed because of delinquency, and in adulthood, antisocial or criminal
genetically inherited personality characteristics, certain behavior.
intrauterine exposures (such as cigarette smoking),
lack of positive parental attachment, because of stress,
or a lack of predictable structure in the home or com-
munity environment. Disruptive behavior disorders are
more common in families with serious marital discord,
families of low socioeconomic status and in neighbor-
hoods characterized by high crime rates and social
disorganization.

Oppositional Defiant Disorder. Oppositional defiant
disorder is the less severe. It is characterized by a recur-
rent pattern of negativistic, defiant, disobedient, and
hostile behavior, such as deliberately annoying others,
frequent arguments, and angry outbursts directed
toward authority figures, that is, parents and teachers.
To confirm the diagnosis, these behaviors must be more
frequent and more severe than normal children exhibit,
present at least 6 months and impair the youth’s func-
tion at home, at school, or with peers.

The more serious DBD—conduct disorder—is charac-
terized by a persistent pattern of serious rule-violating
behavior, including instances that harm or have the
potential to harm others. Physical aggression to people
and animals, destruction of property, lying or stealing,
running away from home, and truancy are typical exam-
ples. Boys are more likely to have conduct disorder
compared with oppositional defiant disorder. Rather
than physical aggression, girls are more prone to use
verbal attacks, ostracism, or character defamation. To
confirm this diagnosis, DBDs must be present at least
1 year, impairing the youth’s home, school, and/or peer
function.

Diagnosis. DBDs are most accurately diagnosed by
child and adolescent psychiatrists, child psychologists,
child-trained social workers, and clinical nurse special-
ists. The evaluation requires input from multiple indi-
viduals who know the child. The diagnosis is based
upon findings from interviews and a mental status
examination. There are no specific diagnostic imaging
studies, blood tests, or other medical tests that are
diagnostic.

Treatment. The best therapy for oppositional defiant
disorder is helping the parent learn effective parenting
strategies. Treatment goals include helping the young-
ster become more cooperative and less argumentative
or destructive. It is very useful to ascertain the child’s
and family’s strengths and build on them in addition to
focusing on their problems. Behavior modification

106 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 4-28 Psychiatry

Pediatrics: Attention-
Deficit/Hyperactivity
Disorders

The attention-deficit hyperactivity disorders (ADHD) Attention-deficit/hyperactivity disorder is a highly treatable
are a group of childhood, adolescent mental health neuropsychiatric disorder, common in school-age children,
problems characterized by difficulty controlling atten- especially boys. Affected children are at increased risk for
tion, motivation, and behavioral impulses. These are academic failure.
common childhood psychiatric conditions, affecting
5% to 12% of children worldwide. More common in Hyperactivity improves or resolves spontaneously in adulthood, but 50% of patients
boys, there is increasing evidence that the principal maintain their cognitive disabilities. Substance abuse and antisocial personality
cause of ADHD is genetically based. A greater Ameri- disorder are commonly associated with ADHD.
can prevalence may result from varied diagnostic prac-
tices and cultural expectations. ADHD is related to â•…
differences in prefrontal cerebral cortex structure and
function. These are important for controlling organiza- At school, accommodations for inattention can be third of ADHD youths demonstrate learning and/or
tion, planning, attention, and impulses. Maternal drink- requested. These include frequent reminders to stay on language disabilities. These are identified through
ing or smoking during pregnancy, low birth weight, task, reducing distractions, rewarding persistence, pro- psycho-educational testing, and remediated with tutor-
chemical injuries to the brain (e.g., lead poisoning), and viding reminders to complete assignments (e.g., turning ing and/or speech therapy. Testing (and remediation if
severe child neglect are associated with ADHD. in homework), and giving extra time to complete work. needed) should be requested from the school.
Other school accommodations can be requested, such
Clinical Presentation. Four types of ADHD are rec- as providing opportunities for physical activity or Course. ADHD responds well to the above treat-
ognized. ADHD, as the predominantly inattentive type, “boredom breaks” during the day, providing a variety ments. About one third of children grow out of ADHD
is characterized by a persistent pattern of poor attention of interesting approaches to learning, giving rewards in the teen or early adult years. The remaining two
and lack of motivation, particularly when sustained for control of behavioral impulses, and giving conse- thirds of children may continue to need support as
mental effort is required (such as for schoolwork or quences for failing to control behavioral impulses. they grow into adulthood, including ongoing use of
homework). These children are often described as medication as well as accommodations and supports at
“daydreamers” or “spacey.” ADHD, as the predomi- Other useful strategies include providing a predict- school, at work, and at home. If untreated, ADHD can
nantly hyperactive/impulsive type, is characterized by a able, structured environment at home and a supportive go on to cause significant problems, including failure at
persistent pattern of overactive behavior (such as being environment for homework, such as a quiet place to school, injuries and accidents, substance abuse, other
fidgety, restless, walking around without permission in work, breaking tasks into small portions, while offering risky behaviors, difficult relationships with parents and
class, or talking excessively when it is important to small rewards for completing each item. About one peers, and poor self-esteem.
behave quietly), as well as impulsive behavior (such
as difficulty waiting, not stopping to think before
acting or blurting out answers). ADHD, as the com-
bined type is characterized by both inattention and
hyperactivity/impulsivity. To meet such diagnoses,
these problems must be more frequent and severe than
children normally exhibit, start before age 7 years, be
present for at least 6 months, be noted in two or more
settings, and impair the youth’s function at home, at
school, or with peers. A child with ADHD observed in
a highly structured environment or engaged in a stimu-
lating activity (i.e., playing video games), may not
exhibit any symptoms. Unstructured, boring, and mini-
mally supervised environments tend to enhance typical
ADHD symptoms.

If some of the above problems are present, but
not enough to meet the diagnoses, the disorder is
called attention-deficit/hyperactivity disorder, not otherwise
specified.

Diagnosis. Child and adolescent psychiatrists,
pediatricians, child psychologists, child-trained social
workers, counselors, and clinical nurse specialists are
best trained to accurately diagnose ADHD. The evalu-
ation typically takes several hours, requiring input in
the form of interviews and/or questionnaires from
parents/caregivers and teachers as well as a careful
mental status examination of the child. There are no
specific blood tests, imaging studies, or other medical
tests to diagnose these disorders.

Treatment. The cornerstones of treatment are edu-
cation about the disorder, appropriate school class
placement, and medication. Medications are the most
effective treatment for ADHD, with stimulant medica-
tions the first line of treatment. Stimulant medication
is effective because it works by “stimulating” the brain,
presumably the prefrontal cortex that controls atten-
tion, motivation, and behavioral impulses.

Tutoring the child in effective study skills (such as
setting goals, planning ahead, self-rewarding) is helpful.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 107

P late 4-29 Brain: PART I

Pediatrics: Eating Disorders Refusal to maintain weight at or
above a minimally normal weight or
Eating disorders occur in adolescents who have intense failure to gain weight during a period
preoccupation with body weight and shape and impaired of expected growth; intense fear of
eating habits. Patients have distorted thoughts and gaining weight;
emotions concerning their appearance as well as abnor- disturbance in body
mal eating behaviors; these lead to alterations in body image; and the
composition and functioning occur. The etiology of absence of at least
eating disorders is multifactorial and includes a genetic 3 spontaneous
component, sociocultural pressures to be thin, and the menstrual cycles
promotion of dieting. Performers and athletes, particu- in postmen-
larly those participating in activities that reward a lean archeal females
body (e.g., gymnastics, running, wrestling, dance, or are symp-
modeling) are at particular risk. Girls who feel most toms/signs of an
negatively about their bodies at puberty are at highest eating disorder.
risk for the development of eating difficulties. The
prevalence of eating disorders is variably reported, “No matter what anyone says, I am too fat!”
0.8% to 14%. Their epidemiology has gradually
changed concomitantly in the United States and world- Two Forms Restrictive anorexia nervosa
wide, with an increasing prevalence in males, younger Bulimia nervosa; binge eating
age groups, minority populations in the United States,
and now countries where eating disorders uncommonly Common Findings Body image distortion at ages 14-18; women Ͼ men
occurred. Acculturation to Western values is a risk Amenorrhea at least 3 months, and often precedes
factor for eating disorders in U.S. immigrants. Weight loss Ͼ15% of ideal body weight
Preserved secondary sex characteristics
Clinical Presentation. There are two primary eating
disorders: anorexia nervosa (AN) and bulimia nervosa Psychiatric Associated Disorders Affective
(BN). A third category, eating disorder not otherwise Anxiety
specified (ED NOS), represents those disorders not Obsessive-compulsive disorder
meeting criteria for AN or BN. ED NOS includes more Personality
patients than the other two primary diagnoses. Substance abuse

Anorexia nervosa is characterized by fear of gaining Differential Diagnosis Adrenal insufficiency
weight, low body mass index, denial of current low Inflammatory bowel and other GI disease
weight and its impact on health, and amenorrhea. Prev- Diabetes mellitus recent onset
alence is highest in teenage girls; up to 0.7% may be CNS posterior fossa lesions
affected. Behaviors used to reduce weight include Primary depression
restricting meals and calories, hyperexercising, self-
induced vomiting (purging), and use of diet pills or Endocrine Findings Serum cortisol and growth hormone increased
laxatives. Psychiatric and personality disorders, such as Serum LH and FSH low
depression, anxiety disorders, obsessive-compulsive dis- Insulin-like growth factor-(IGF-I) low
order, and perfectionism, are common.
initial therapeutic goal for AN patients is the restora- â•…
Bulimia nervosa patients have regular episodes of tion of physical health. Family therapy provides the
uncontrolled overeating (binge eating) associated with most promising results in adolescent AN and BN. there are high rates of residual psychiatric illness, pre-
extreme measures to counteract the feared effects of the Cognitive-behavioral therapeutic strategies are helpful dominantly depression and anxiety. The potential for
overeating, such as occur with AN. Approximately 90% in BN for behavioral changes, for example, for binge- significant growth retardation, pubertal delay or inter-
of BN patients are women who become symptomatic purge reduction. No medications are approved by the ruption, and peak bone mass reduction are significant
in late adolescence; their binge eating typically begins FDA for AN treatment. Although pharmacotherapy medical problems for adolescents in contrast to adults.
in the context of dieting. As BN patients may have is sometimes prescribed, it is typically targeted at Young anorectic women have an increased risk of frac-
normal weight or be overweight, this diagnosis is more comorbid depression and anxiety. Selective serotonin tures later in life. Eating disorders in adolescents are
difficult to entertain. Although BN patients experience reuptake inhibitor antidepressants may reduce binge identified as the psychiatric condition with the highest
weight variations, they rarely approach the low AN eating episodes and purging. mortality rate; however, these are lower than those
weights. Higher obesity rates, mood disorder, sexual historically reported. In a recent meta-analysis, the
and physical abuse, parental obesity, and substance Course. Although most eating disorder individuals mortality rate among AN adolescents was 1.8% com-
misuse exist in BN patients. recover completely or partially, about 5% die and 20% pared with 5.9% when adults and adolescents were
develop a chronic eating disorder. Even after recovery, considered together. Mortality is most often attribut-
Short-term medical complications include electro- able to the complications of starvation or to suicide.
lyte disturbances, esophageal tears, gastric disturbances,
dehydration, orthostatic blood hypotension, and cardiac
dysfunction and sometimes require hospitalization.
Long-term medical complications typically resulting
from chronic malnutrition include growth hormone
changes, hypothalamic hypogonadism, bone marrow
hypoplasia, and brain structural abnormalities.

Diagnosis. Pediatricians, child and adolescent psy-
chiatrists, child psychologists, child-trained social
workers, counselors, and clinical nurse specialists are
best trained to accurately diagnose eating disorders.
Because these can affect every organ system, and the
medical complications can be serious to life-threatening,
a comprehensive history and physical examination is
required.

Treatment. This requires that individual, family,
medical, and nutritional aspects be addressed. The

108 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 4-30 Psychiatry

FRACTURES IN ABUSED CHILDREN

Radiograph shows fracture of proximal
right femur for which patient was brought
to the hospital. Healing fracture of growth
plate of distal femur noted, arousing
suspicion of child abuse. Abused child characteristically sad
or withdrawn. Signs such as poor
skin and hair care or malnutrition
should increase suspicion.

Twisting of Further examination may reveal
extremity bruises, welts, or cigarette burns
in various stages of healing on
other parts of body.

Child Abuse

Child abuse is defined by the Child Abuse Prevention and Spiral fractures in young children
Treatment Act (CAPTA) as “Any recent act or failure to may occur accidentally but often
act on the part of a parent or caretaker that results in due to abuse
death, serious physical or emotional harm, sexual abuse
or exploitation; or an act or failure to act that presents Sudden jerk on extremity
an imminent risk of harm.” There are four major types avulses metaphyseal tips
of maltreatment: neglect, physical abuse, psychologic mal-
treatment, and sexual abuse. Most states set up their own Avulsion fracture of metaphysis
guidelines indicating the level of evidence to make the
distinguishing finding or disposition for the abuse. Spiral fracture in infant
â•…
The National Child Abuse and Neglect System
(NCANDS) of the Administration of Children, Youth, Physical abuse most often manifests with signs of posttraumatic disorder (PTSD), but not schizophrenia or
and Families (ACYF) Annual Report 2009 indicates abuse, including bruising and/or skeletal injury. In addi- somatoform disorders.
that there were 9.3 unique abuse victims confirmed per tion, physical abuse is often associated with psychologic
1,000 children in the United States. Children 1 year impacts, including increased anger, aggression, poor academic With psychologic abuse, it is more difficult to quantify
and younger had the highest rate of victimization; there performance, sleep problems, drug abuse, and suicidality. and identify consistent patterns of presentation. Chil-
was an almost equal distribution of boys and girls; some Sexually abused children often present to physicians for dren of psychologic abuse present with increased levels of
children experienced multiple abuses. Neglect was most evaluation of genital injury. The sequelae includes depression, academic difficulties, aggression, and behavior
frequent (78.3%), followed by physical abuse (17.8%). impaired mental health with increase in rates of depression, problems. Often, children are exposed to more than one
Sexual and psychologic maltreatment each occurred in anxiety disorders, sleep disorders, suicide attempts, and type of abuse, and so the impact of abuse can be
10% of abused children overall. The 2009 national complex. In addition, physical, sexual, and psychologic
fatality rate was 2.34 per 100,000 and has been increas-
ing over the past 5 years. Health and mental health-care
professionals should maintain the possibility of abuse
on their differential every time they see a child.

Clinical Presentation. Presentations vary greatly
depending on the type(s) of abuse as well as social and
emotional developmental stage. Children with develÂ

Plate 4-31 Brain: PART I

Staging of injuries
Bruises

Purple (1-5 days) Green (5-7 days)

Acute bruise Yellow (7-10 days) Brown (Ͼ10 days)
with marked
swelling (1-3 days)
Subdural hematomas

Organizing
membranes

Acute Fluid Organized clot
hemorrhage mistaken for
Fresh subdural atrophic brain
hematoma (acute) tissue on CT
Child abuse injury patterns scan

Organized subdural Organized subdural
hematoma (weeks) hematoma (months)

Child Abuse (Continued)

abuse are associated with poor self-esteem, personality Typical bruise left by gag Blistering and edema in
disorders, and impaired interpersonal relationships. Pigment changes in acute binding injury
chronic binding injury
Diagnosis. Evaluations must be carried out by quali- Typical slap pattern
fied pediatric health-care professionals, such as child 3 cm Loop or cord marks on buttocks
and adolescent psychiatrists, pediatricians, child psy- â•…
chologists, child-trained social workers, pediatric coun- Bite pattern. 3 cm or greater distance exaggerated startle responses. Longitudinal studies
selors, and clinical nurse specialists, depending on the between canines indicates adult bite indicate that adults continue to suffer from low self-
type of abuse—physical and/or psychologic. If there is interactions), and developmental victimology (describes esteem, maladaptive sexual behavior, and impaired
a concern about physical abuse, physical and diagnostic the processes involved in the onset and maintenance of interpersonal relationships (e.g., parenting, romantic/
examinations should be performed as soon as abuse is abusive behavior). intimate). Despite these findings, not every child who
suspected. With concern about sexual abuse, pregnancy experiences abuse develops these symptoms, indicating
tests and/or sexually transmitted infections must be Course. Child abuse is hypothesized to mediate a role for protective factors, such as cognitive factors,
evaluated. In all instances, information should be gath- response biases, resulting in impaired emotional and meaningful relationships, and the impact of treatment
ered from multiple people within the child’s psychoso- cognitive regulation. Adult victims of prior childhood interventions.
cial sphere (e.g., parents/caregivers, family members, abuse are found to have higher rates of sleep disorders,
teachers, counselors). abdominal disorders, obesity, chronic pain (e.g., head-
ache, back ache, premenstrual syndrome), fatigue, and
Treatment. The first step after identification of sus-
pected abuse is reporting to a child protective service
(CPS) agency. The CPS will carry out a thorough inves-
tigation of the suspected person(s) abusing the child and
their living situation. The CPS will engage a treatment
team to support the child and his or her family. In
instances where the child’s safety has been compro-
mised and/or future abuse is suspected without inter-
vention, then the child may be placed in a safe
environment until the investigation is complete or
sufficient supports are put in place for the child to
return home. The primary treatment for child abuse
includes psychotherapy, which can include components
of cognitive-behavioral therapy (change behavior by
addressing distorted cognitions), behavioral and learn-
ing therapy (modifying habitual responses to situations/
stimuli), family therapy (explore patterns of family

110 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

SECTION 5â•…

HYPOTHALAMUS,
PITUITARY, SLEEP,
AND THALAMUS

Plate 5-1 Brain: PART I

ANATOMY AND RELATIONS OF THE HYPOTHALAMUS AND PITUITARY GLAND

Optic nerves

Temporal pole of brain
Optic chiasm

Right optic tract

Pituitary gland

Oculomotor nerve (III)

Tuber cinereum

Mammillary bodies

Trochlear nerve (IV)

Trigeminal nerve (V) Fornix

Abducens nerve (VI) Interven- Choroid plexus
tricular of 3rd ventricle
Pons foramen Thalamus

Anatomic Relationships Hypothalamic sulcus Corpus callosum Pineal
of the Hypothalamus gland

The hypothalamus is a small area, weighing about Anterior commissure
4╯g of the total 1,400╯g of adult brain weight, but it
is the only 4╯g of brain without which life itself is Lamina terminalis
impossible. The hypothalamus is so critical for life
because it contains the integrative circuitry that coor- Tuber cinereum
dinates autonomic, endocrine, and behavioral responses
that are necessary for basic life functions, such as Mammillary body
thermoregulation, control of electrolyte and fluid
balance, feeding and metabolism, responses to stress, Chiasmatic cistern
and reproduction.
Optic chiasm
Perhaps for this reason, the hypothalamus is particu-
larly well protected. It lies at the base of the skull, just Diaphragma sellae
above the pituitary gland, to which it is attached by the
infundibulum, or pituitary stalk. As a result, trauma that Pituitary gland
affects the hypothalamus would almost always be lethal.
It receives its blood supply directly from the circle of Sphenoidal sinus
Willis (see Plate 5-3), so it is rarely compromised by
stroke, and it is bilaterally reduplicated, with survival of Nasal septum
either side being sufficient to sustain normal life.
Interpeduncular cistern
On the other hand, the hypothalamus may be
involved by a number of pathologic processes that arise Nasopharynx
from structures that surround it, and the signs and
symptoms that first attract attention in those disorders Pontine cistern
are often due to the involvement of those neighboring
structures. Examination of the ventral surface of the Optic chiasm
brain shows that the hypothalamus is framed by fiber Internal carotid artery
tracts. The optic chiasm marks the rostral extent of the
hypothalamus, and the optic tracts and cerebral pedÂ

Plate 5-2 Hypothalamus, Pituitary, Sleep, and Thalamus

CYTOGENETIC DISEASE: PRADER-WILLI SYNDROME

p 1 23
1
{Deleted 1
2 3
segment
15q11-15q13 4
15

q1

2 2
3
4
5
6
Interstitial
deletion

Interstitial deletion in long arm of
one chromosome 15

Development and
Developmental Disorders
of the Hypothalamus

The hypothalamus in mammals arises as a part of the Skin lesions caused Small genitalia and
ventral diencephalon and the adjacent telencephalon, by scratching cryptochidism
and its embryologic origins are intimately related to
those of the optic chiasm and tracts and to the pituitary Blood sugar (mg/dL) Obesity, small hands, and feet Dental caries
gland. Thus disorders that affect the hypothalamus fre- 250
quently manifest with signs and symptoms resulting 200 â•…
from dysfunction of neighboring, developmentally
related structures. The developing neural tube is 150 The relationship of the hypothalamus and pituitary
divided into three primary regions: forebrain, midbrain, 100 gland has its embryologic origins as an anatomic juxta-
and hindbrain. The forebrain is further subdivided into position between the anterior diencephalon and the
the telencephalon, which gives rise to the cerebral 50 ectodermally derived Rathke’s pouch, from which por-
cortex and basal ganglia, and the diencephalon, from tions of the ventral pituitary are derived. Thus both the
which the thalamus and hypothalamus are derived. The 01 Hours 23 hypothalamus and pituitary are patterned by similar
hypothalamus develops from the anterior portion of the signaling pathways, and dysfunction in these systems
diencephalon in a series of steps that involve the activa- Abnormal glucose tolerance test may disrupt the development and function of both
tion of suites of transcription factors, which determine structures. Craniopharyngiomas are the most common
the fates of the developing cell populations. rise to the regional complexity of the hypothalamus. non-neural intracranial tumors in childhood and derive
Although still poorly understood, rare genetic muta- from the remnants of Rathke’s pouch. Clinical presen-
First, the prechordal mesoderm that underlies the tions have been identified in humans and tested in tation includes optic, pituitary, and/or hypothalamic
developing neural tube secretes sonic hedgehog (Shh) animal models that demonstrate that dysfunction of symptoms, including obesity, hypopituitarism, and
that induces the normal patterning of the anterior specific genes results in loss of specific hypothalamic sleep and circadian rhythm dysfunction.
midline of the brain, including the formation of the neurons and corresponding phenotypes. For example,
hypothalamus and the separation of the optic system. the Prader-Willi syndrome, which manifests as morbid
Abnormal mesodermal induction occurs with mutations obesity, hypersomnolence, hypogonadism, and intellec-
that affect Shh signaling and can result in one of the tual disability, is caused by a deletion of the paternally
most common human brain malformations, holopros- inherited chromosome 15q11. This genomic region
encephaly, which manifests with a spectrum of failed contains several genes implicated in the normal devel-
division of the midline structures of the brain. In its opment of the paraventricular nucleus, a cell group with
most severe form, holoprosencephaly results in cyclopia critical integrative functions in feeding and responses
and complete or partial loss of the hypothalamus, which to stress (see later).
is not compatible with life. In its more mild forms,
holoprosencephaly can manifest with endocrine abnor-
malities because of defective development of the
hypothalamic-pituitary system. After initial patterning
by Shh-mediated induction, hypothalamic precursor
cells proliferate before exiting the cell cycle and undergo
terminal differentiation into the many cells types that
comprise the hypothalamus’ compact, yet complex
structure. Finally, the developing neurons express
unique combinations of transcription factors, such as
Nkx and Lhx family members, and Sim1, and Six3.
Deletions of individual transcription factors have pro-
found effects upon development of specific hypotha-
lamic nuclei.

Terminal differentiation of the hypothalamic nuclei
requires the combined action of “codes” of transcrip-
tion factors that, when expressed with anatomically
restricted and developmentally timed precision, give

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 113

Plate 5-3 Brain: PART I

Blood Supply of the
Hypothalamus and
Pituitary Gland

The hypothalamus is what the circle of Willis encircles. Hypothalamic vessels
The internal carotid artery runs through the cavernous
sinus, which is just below the hypothalamus, and the Primary plexus of Anterior branch Superior hypophyseal
site of its venous drainage. As the internal carotid artery hypophyseal portal system Posterior branch artery (from internal
emerges from the cavernous sinus, it ends in the middle carotid artery or posterior
cerebral artery laterally, the posterior communicating Long hypophyseal communicating artery)
artery caudally, and the anterior cerebral artery ros- portal veins
trally. The anterior cerebral artery runs above the optic Artery of trabecula
nerve, crosses the olfactory tract, and meets the anterior Short hypophyseal
communicating artery in the midline before turning portal veins Trabecula
upward and back. The posterior communicating artery
runs back to meet the posterior cerebral artery shortly Capillary plexus of
after it emerges from the basilar artery. As a result, the infundibular process
hypothalamus is fed by small penetrating arteries that
originate directly from the tributaries of the circle Posterior lobe
of Willis.
Efferent vein to cavernous sinus
The anterior part of the hypothalamus, above the
optic chiasm, is supplied by arterial feeding vessels from Anterior lobe
the anterior cerebral artery. These vessels densely pen- Secondary plexus of hypophyseal
etrate the basal forebrain just in front of the optic portal system
chiasm, giving it the name the “anterior perforated sub-
stance.” The tuberal, or midlevel of the hypothalamus, Efferent vein to Efferent vein to
is fed mainly by small branches directly from the inter- cavernous sinus cavernous sinus
nal carotid artery and the posterior communicating
artery. Posteriorly, small penetrating vessels from the Lateral branch Stalk
posterior cerebral arteries running through the inter- and
peduncular fossa give it the name “posterior perforated Medial branch Anterior lobe
substance.” Many of these small blood vessels supply of Posterior lobe
the posterior part of the thalamus, but some also Inferior hypophyseal artery
provide blood to the posterior hypothalamus. The cell (from the internal carotid artery)
groups within the hypothalamus are not uniformly sup-
plied with blood vessels. The paraventricular and supra- Cavernous sinus Inferior aspect
optic nuclei, which contain neurons that make the Internal carotid artery
vasoactive hormones oxytocin and vasopressin, have Posterior communicating artery
particularly rich capillary networks. Superior hypophyseal artery

The superior hypophyseal artery is one of the Portal veins
branches derived from the internal carotid artery. It Lateral hypophyseal veins
supplies the pituitary stalk, where it breaks up into a Inferior hypophyseal artery
series of looplike capillaries in the median eminence
and pituitary stalk. The hypothalamic neurons that Posterior lobe veins
make pituitary releasing (and release-inhibiting) hor-
mones send axons that terminate on these loops, which, â•…
unlike most brain capillaries, have fenestrations to
permit easy penetration by these small peptide hor- also permit blood-borne substances to enter the brain. involved in thirst and water balance, and perhaps some
mones (see Plate 5-6). These capillaries drain into the The hormone leptin, which is made by white adipose cytokines that may play a role in the fever response.
hypophyseal portal veins, which along with some tissue during times of plenty, is believed to enter the These regions are called circumventricular organs
branches of the inferior hypophyseal artery, provide brain via the median eminence to signal satiety to cell because they are around the edges of the ventricles.
blood flow to the adenohypophysis or anterior pituitary groups in the basal medial hypothalamus. There is Another circumventricular organ, the area postrema, is
gland. The posterior pituitary gland is supplied almost another area of fenestrated capillaries along the anterior found at the outflow of the fourth ventricle in the
entirely by the inferior hypophyseal artery. Because wall of the third ventricle, called the organum vasculo- medulla and is probably involved in emetic reflexes
most of the blood flow to the anterior pituitary gland sum of the lamina terminalis, which may allow entry of based on blood-borne toxins or hormones, such as
is from the portal system, it is possible, on occasions, other hormones, such as angiotensin, which may be glucagon-like protein 1.
for the gland to outgrow its blood supply. This occurs
mainly during pregnancy or can occur when a pituitary
adenoma, an otherwise benign tumor, becomes larger
than can be accommodated by the blood supply. At this
point, there is infarction of the pituitary, often with
bleeding, which may become life threatening (pituitary
apoplexy). The typical presentation is sudden onset of
dysfunction of cranial nerve II, III, IV, or VI, with a
severe headache that is generally localized between the
eyes, and often impaired consciousness.

Finally, the fenestrated capillary loops in the median
eminence not only allow egress of hypothalamic-
releasing hormones to the anterior pituitary gland, but

114 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-4 Hypothalamus, Pituitary, Sleep, and Thalamus
GENERAL TOPOGRAPHY OF THE HYPOTHALAMUS

17 19
16 15

13 14

Overview of Hypothalamic 26
Cell Groups 1 79

The hypothalamus consists of a complex assemblage 3
of cell groups. The borders of these cell groups often 4 8 5 10
are not quite as distinct as those shown in the drawings, 12 20 20 18
but the different cell groups are also distinguished
based upon their neurotransmitters, functions, and 11
connections. 21 22

In general, the hypothalamus can be divided into 23 24
three tiers of nuclei. Most medially, along the wall of
the third ventricle, is the periventricular nucleus, shown 1 Preoptic nuclei 18 Interpenduncular fossa
here in green. Along the base of the periventricular 2 Paraventricular nucleus 19 Thalamus
nucleus is an expansion laterally along the edge of the 3 Anterior hypothalamic area 20 Tuber cinereum
median eminence, known as the arcuate or infundibular 4 Supraoptic nucleus 21 Optic nerve
nucleus. The periventricular stratum contains many 5 Lateral hypothalamic area 22 Infundibulum
neurons that make releasing or release-inhibiting hor- 6 Dorsal hypothalamic area 23 Anterior lobe of pituitary
mones (see Plate 5-6) and whose axons end on the 7 Dorsomedial nucleus 24 Posterior lobe of pituitary
capillary loops of the hypophysial portal vessels in the 8 Ventromedial nucleus
median eminence. Many axons from the brainstem run 9 Posterior hypothalamic area â•…
through the periventricular gray matter, in the poste- 10 Mammillary body
rior longitudinal fasciculus, and into the periventricular 11 Optic chiasm
region of the hypothalamus. 12 Lamina terminalis
13 Anterior commissure
The next tier of nuclei is sometimes called the medial 14 Hypothalamic sulcus
tier. These nuclei are generally involved in intrinsic 15 Interthalamic adhesion
connections within the hypothalamus that allow inte- 16 Fornix
gration of various functions. The most rostral of the 17 Septum pellucidum
medial nuclei is the medial preoptic region (orange),
which sits along the wall of the third ventricle as it are controlled by means of outputs to the portion of the gland, where they release their hormones into the
opens. Along the anterior wall of the third ventricle is anterior hypothalamic area between the suprachias- circulation. The paraventricular nucleus also contains
the median preoptic nucleus (not shown here). These matic nucleus and the paraventricular nucleus (blue), neurons that make releasing hormones (especially
two cell groups are involved in integrating control of called the subparaventricular zone. corticotrophic-releasing hormone) and project to the
body temperature with fluid and electrolyte balance, median eminence. A third population of neurons in the
wake-sleep cycles, and reproductive function. The supraoptic and paraventricular nuclei are also at paraventricular nucleus sends axons through the medial
this anterior level in the medial tier. Both nuclei contain forebrain bundle in the lateral hypothalamus to the
The next most caudal region is called the anterior large numbers of oxytocin and vasopressin neurons, brainstem and spinal cord, to control both the sympa-
hypothalamic area (purple). At the base of the anterior whose axons travel through the pituitary stalk in the thetic and parasympathetic nervous systems. Many of
hypothalamic area, just above the optic chiasm, is tuberohypophysial tract, to the posterior pituitary
the suprachiasmatic nucleus (see Plate 5-5). These
structures are involved in regulating circadian rhythms.
The suprachiasmatic nucleus is the body’s main biologic
clock, and it sets the timing of rhythms of sleep, feeding,
body temperature, and reproduction. These functions

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 115

Plate 5-5 Brain: PART I

OVERVIEW OF HYPOTHALAMIC NUCLEI

Septum Corpus callosum
pellucidum
Lateral Fornix
ventricle

Thalamus From hippo-
campal formation

Lateral hypo- Interthalamic
thalamic area adhesion

Paraventricular
nucleus

Medial Anterior Anterior hypothalamic area
forebrain commissure
Dorsal hypothalamic area
bundle
Dorsomedial nucleus

Mammillothalamic tract

Overview of Hypothalamic Lateral Posterior area
Cell Groups (Continued) preoptic
Medial Periventricular
these neurons use either oxytocin or vasopressin as a area preoptic nucleus
central neurotransmitter in this autonomic pathway,
but they are an entirely separate set of neurons from area Tuberomammillary nucleus
those that send axons to the posterior pituitary gland.
Suprachiasmatic
Just caudal to the anterior hypothalamic area, in the nucleus
tuberal level of the hypothalamus, the medial tier con-
tains three cell groups. The ventromedial nucleus (tan) Fornix Red
sits just above the median eminence and is mainly nucleus
involved in feeding, aggression, and sexual behavior.
The dorsomedial nucleus (yellow), which is just dorsal Optic (II) Olfactory Ventromedial Mammillary
to it, has extensive outputs to much of the rest of the nerve tract nucleus complex
hypothalamus. The subparaventricular zone sends cir-
cadian outputs to both the dorsomedial and ventrome- Optic chiasm Oculomotor (III) nerve
dial nuclei, and the dorsomedial nucleus uses this input Cerebral peduncle
to organize circadian cycles of wake-sleep, corticoste-
roid secretion, feeding, and other behaviors. The dorsal Tuberohypophyseal tract
hypothalamic area, just above the dorsomedial nucleus,
contains neurons that are involved in regulating body Supraoptic nucleus Dorsal
temperature. longitudinal
fasciculus
At the most posterior end of the hypothalamus, the
mammillary bodies form a prominent pair of protuber- Descending
ances along the base of the brain. Despite having very hypothalamic tract
clear-cut, heavily myelinated connections, the function
of the mammillary nuclei remains mysterious. They Posterior lobe of pituitary Pons
receive a major brainstem input from the mammillary
peduncle and a large bundle of efferents from the Supraopticohypophyseal tract
hippocampal formation through the fornix. The large
fiber bundle that emerges from the mammillary body Anterior lobe of pituitary â•…
splits into a mammillotegmental tract to the brainstem
and a mammillothalamic tract to the anterior thalamic lateral hypothalamic area project through the medial At the posterior hypothalamic level, there is also a
nucleus. Neurons in the mammillary body appear to be forebrain bundle, either to the basal forebrain or cere- cluster of histaminergic neurons, called the tuberoÂ

Plate 5-6 Hypothalamus, Pituitary, Sleep, and Thalamus

HYPOTHALAMIC CONTROL OF THE ANTERIOR AND POSTERIOR PITUITARY GLAND

Emotional and exteroceptive VP, OXY Paraventricular
influences via afferent nerves nucleus
to hypothalamus
Hypothalamic Control of Parvicellular neurons
the Pituitary Gland Arcuate, periventricular, for releasing and
and paraventacular nuclei release-inhibiting
The hypothalamus contains two sets of neuroendocrine hormones
neurons, the magnocellular neurons, which send axons Supraoptic
to the posterior pituitary gland, and the parvicellular nucleus
neurons, which secrete releasing or release-inhibiting
hormones into the pituitary portal circulation. Supraoptic nucleus

The magnocellular neurons consist of two clusters: Hypothalamic Neurosecretion of releasing factors
the supraoptic and paraventricular nuclei. Each cell artery and inhibitory factors from hypo-
group contains both oxytocin (OXY) and vasopressin thalamus into primary plexus of
(VP) neurons. These cells secrete the hormones from Blood-borne Superior hypo- hypophyseal portal circulation
their terminals in the posterior pituitary gland into the feedback on physeal artery Hypophyseal portal veins carry
general circulation. Vasopressin controls urinary water hypothalamus neurosecretions to anterior lobe
and sodium excretion, as well as having direct vasocon- and pituitary
strictor effects on blood vessels. Oxytocin has some Posterior Specific secretory cells
vasoconstrictor properties and causes uterine contrac- lobe (neuro- of anterior lobe (adeno-
tions but also is involved in the milk let-down reflex hypophysis) hypophysis) influenced
during suckling. Cutting the pituitary stalk causes loss by neurosecretions
of secretion of both hormones, but the predominant from hypothalamus
symptom is diabetes insipidus, due to lack of vasopres- Blood levels—regulatory influence
sin. Such individuals have excess loss of water in the Muscleα-MSH
urine, requiring the ingestion of up to 20 liters of water
per day to maintain blood osmolality in the normal TSH FSH Skin (melanocytes)
range, unless the hormone is replaced. ACTH LH GH

The parvicellular neurons are located along the Thyroid Adrenal Testis Ovary Prolactin Growth Diabetogenic
wall of the third ventricle in the periventricular, gland cortex factor factor
paraventricular, and arcuate nuclei. Different popula-
tions of parvicellular endocrine neurons, secreting spe- Breast (milk Fat tissue
cific pituitary releasing or release-inhibiting hormones, production) Insulin
have characteristic locations within this region. The
corticotropin-releasing hormone neurons, which cause Adrenocortical Estrogen Bone, muscle, Pancreas
secretion of adrenocorticotrophic hormone (ACTH), organs (growth)
and ultimately adrenal corticosteroids, are mainly
located in the paraventricular nucleus. Many neurons Thyroid hormones Testosterone Progesterone
that secrete thyrotropin-releasing hormone neurons, hormones
which cause secretion of thyroid-stimulating hormone
(TSH), or somatostatin, which inhibits secretion of â•…
growth hormone (GH), are also in the paraventricular
nucleus, but some are found rostral to it in the periven- upon the parvicellular endocrine neurons, providing release-inhibiting hormones. Thus precocious puberty
tricular nucleus. Neurons that secrete gonadotropin- short loop feedback. Prolactin is the only pituitary is sometimes seen with hypothalamic hamartomas that
releasing hormone neurons (which cause secretion hormone that is primarily under inhibitory tone from secrete gonadotropin-secreting factor. On the other
of luteinizing hormone [LH] and follicle-stimulating the hypothalamus. Hence, when the pituitary stalk is hand, amenorrhea may occur from increased secretion
hormone [FSH]) are found in the most rostral part damaged, the secretion of other anterior pituitary hor- of prolactin. Cushing syndrome—the oversecretion of
of the periventricular nucleus and dorsal arcuate mones is diminished, but prolactin increases. adrenal corticosteroids—may result from a steroid-
nucleus. The rostral part of the arcuate nucleus also secreting adrenal tumor, a pituitary tumor (or some-
contains growth hormone–releasing hormone neurons. Endocrine disorders may ensue from either excess times a lung or other tumor) that secretes ACTH, or
Neurons secreting dopamine (a prolactin release– secretion or lack of secretion of either an anterior hypersecretion of corticotropin-releasing hormone.
inhibiting hormone) are found widely distributed pituitary hormone or its hypothalamic-releasing or
along the wall of the third ventricle in the periÂ

P late 5-7 Inputs to autonomic Preganglionic Brain: PART I
preganglionic neurons sympathetic
Hypothalamic Control Postganglionic Preganglionic Forebrain inputs to the autonomic
of the Autonomic sympathetic parasympathetic preganglionic neurons arise from:
Nervous System
Postganglionic Infralimbic cortex
parasympathetic Paraventricular and arcuate nuclei (blue)
Lateral hypothalamic area (red)

Other than a relatively modest projection to the pre- Nucleus of
ganglionic neurons from the infralimbic cortex, the Edinger-Westphal
hypothalamus is the highest level of the neuraxis that
provides substantial input to the autonomic nervous Pupillary constrictor muscle Ciliary ganglion Superior
system. It regulates virtually all autonomic functions salivatory
and coordinates them with each other, and with ongoing Ciliary muscle nucleus
behavioral, metabolic, and emotional activity. The Lacrimal and nasal Inferior
hypothalamus contains several sets of neurons, using mucosa glands Pterygopalatine ganglion Oculomotor (III) nerve salivatory
different neurotransmitters, that provide innervation to nucleus
the sympathetic and parasympathetic preganglionic Cerebral vasculature Facial (VII) nerve Dorsal motor
neurons, as well as brainstem areas that regulate the Submandibular ganglion vagal and
autonomic nervous system. Many of these neurons are ambiguus nuclei
in the paraventricular nucleus of the hypothalamus. Submandibular gland
These form populations of small neurons that are Sublingual gland Thoracic spinal
typically dorsal or ventral to the main endocrine groups, Salivary Glossopharyngeal (IX) nerve cord (T1-L2)
and most of the paraventricular-autonomic neurons glands Otic ganglion
contain messenger ribonucleic acid (mRNA) for either Sacral spinal
oxytocin or vasopressin. The descending pathways also Parotid gland Vagus (X) nerve cord (S2-S4)
stain immunohistochemically for these peptides and are
probably involved in stress responses. Smooth muscle, cardiac Lateral horn (inter-
muscle, secretory glands mediolateral cell column)
A second set of hypothalamic-autonomic neurons is in heart, lung, viscera, GI Intramural
found in the lateral hypothalamic area. These consist tract to descending colon ganglia
mainly of neurons containing orexin or melanin-
concentrating hormone (MCH) neurons, and some- To cardiac and vascular smooth Spinal nerve
times the peptide cocaine- and amphetamine-regulated muscle, sweat glands, and
transcript (CART), which is thought to be involved in arrector pili muscles Ventral
regulation of feeding and metabolism as well as wake- White ramus Gray root
sleep and locomotor activity. A third population of Adrenal communicans ramus
hypothalamic-autonomic cells is found in the arcuate Secretion of medulla Splanchnic communicans
nucleus and adjacent retrochiasmatic area. These epinephrine
neurons contain α-melanocyte–stimulating hormone and norepine- nerve Sympathetic
and CART and may also be involved in feeding and chain ganglia
metabolic regulation. phrine into blood

All three sets of neurons send axons to the brainstem, To smooth muscle and Preventebral Intermediate gray
where they innervate the nucleus of the solitary tract secretory glands of gut, ganglia Ventral root
(which receives visceral afferent input from the glos- metabolic cells (fat, liver),
sopharyngeal and vagus nerves), as well as the regions cells of immune system
that coordinate autonomic and respiratory reflexes in
the ventrolateral medulla. Other axons innervate the Smooth muscle, Intramural Pelvic nerves
parasympathetic preganglionic neurons in the Edinger- secretory glands in ganglia
Westphal nucleus (pupillary constriction), the superior lower GI tract, bladder, â•…
salivatory nucleus (associated with the facial nerve, other pelvic viscera
which supplies the submandibular and sublingual sali-
vary glands as well as the cerebral vasculature), the targets. For example, the main projection from the neurons that innervate the sympathetic preganglionic
inferior salivatory nucleus (associated with the rostral orexin neurons is to the upper thoracic spinal cord, column at multiple levels and regulate populations of
tip of the nucleus of the solitary tract, supplying the which may be important for autonomic functions asso- neurons involved in thermoregulation. This pathway is
parotid gland), the dorsal motor vagal nucleus (which ciated with ingestion. The oxytocin neurons innervate thought to be a major mechanism for regulating body
supplies the abdominal organs), and the nucleus ambig- specific clusters of sympathetic preganglionic neurons temperature.
uus (which is the main source of vagal input to the at multiple spinal cord levels.
thoracic organs, including the esophagus, heart, and Damage to the descending hypothalamic-autonomic
lungs). In addition, there is a major input to the medullary pathway, in the lateral medulla or spinal cord, causes an
raphe nuclei from the preoptic area and dorsomedial ipsilateral central Horner syndrome. Such patients not
Finally, there are descending axons from the hypo- nucleus of the hypothalamus. The medullary raphe only have a small pupil and ptosis on that side but lack
thalamus that innervate the sympathetic preganglionic nuclei contain both serotoninergic and glutamatergic sweating on the affected side of the face and body.
neurons in the thoracic spinal cord. Different popula-
tions of hypothalamospinal neurons contact distinct

118 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-8 Hypothalamus, Pituitary, Sleep, and Thalamus
Distribution of olfactory
epithelium on septum
(schematically shown
in blue).

Distribution of olfactory epithe- BG N BG Structure of olfactory
lium on lateral nasal wall B mucosa (schematic):
(schematically shown in blue). B: Basal cells
O BG: Bowman’s gland
G N: Olfactory nerve filament
G S O: Olfactory bipolar cells
S: Supporting cells

MM Olfactory portion of anterior commissure

Olfactory Inputs to T
the Hypothalamus T

GL

There are about 1,000 olfactory receptor genes, each of N NN
which recognizes a different class of chemical olfactory Structure of olfactory bulb:
stimulus. Each olfactory receptor cell expresses a single G: Granular cell
olfactory receptor type, and each gene is expressed in GI: Glomerulus
several hundred cells, spread across the olfactory M: Mitral cell
mucosa. The axons from olfactory receptor cells then N: Olfactory nerve filaments
run through openings in the cribriform plate, which T: Tufted cell
forms the base of the skull over the olfactory mucosa,
and axons from individual cells, which express a single Hypothalamus
receptor gene, then converge in the olfactory bulb on
one or a few individual olfactory glomeruli. Medial Olfactory
olfactory stria cortex
The glomeruli are on the surface of the olfactory Amygdala Hippocampus
bulb and are spherical areas, each about one third mil- Olfactory epithelium Cribiform Lateral Entorhinal
limeter across. The outside of the glomerulus is lined of ethmoid olfactory cortex
with tiny periglomerular cells, which are interneurons. stria
Just deep to the glomerular layer are mitral and tufted
cells, which send their apical dendrites up into the Schematic representation of the olfactory system
glomeruli, where they receive olfactory sensory infor-
mation. These excite granule cells, which, in turn, â•…
inhibit the other mitral and tufted cells, as well as
receiving centrifugal axons, which allow them to modu- branch provides inputs to the primary olfactory cortex, In many mammals, there is an accessory olfactory
late the perception of the sensory stimulus. Only the which appears to be necessary for processing the con- system. A small pit in the nasal mucosa, called the vom-
mitral and tufted cells send their axons into the brain scious appreciation of odors, as well as the entorhinal eronasal organ, contains olfactory sensory neurons that
via the olfactory tract. In humans, this is a long white cortex, which is a point of convergence of information are important for sensing pheromones. These olfactory
matter bundle that runs the length of the frontal lobe from multiple sensory systems and a major relay into neurons synapse in a specialized region called the acces-
and is sometimes erroneously called the “olfactory the hippocampal formation. There is also input to the sory olfactory bulb and relay information concerned
nerve.” amygdala, which may be important for relaying olfac- with social behaviors into the amygdala and hypothala-
tory signals related to food acquisition and sexual mus. Such a system has never been clearly identified in
The olfactory tract supplies information about smell behavior to the hypothalamus. humans, and its very existence remains controversial.
to a variety of targets in the brain. It bifurcates as it
approaches the temporal lobe into one branch that runs
medially into the basal forebrain and another that runs
laterally to supply olfactory inputs to cortical structures.
The basal forebrain branch provides inputs to the ante-
rior olfactory nucleus, which sends axons through the
anterior commissure to the opposite hemisphere, and
the olfactory tubercle, which is the part of the striatum
that receives olfactory inputs. The lateral olfactory

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 119

Plate 5-9 Brain: PART I

Visual Inputs to the
Hypothalamus

The hypothalamus is largely framed by the optic The axons bound for the suprachiasmatic nucleus have been stained blue, shown at higher magnifications.
chiasm, which underlies its most rostral part (the pre-
optic area) and provides the lateral boundary for its Photographs reprinted with permission from Hattar S, Liao HW, Takao M, et al. Melanopsin-containing retinal ganglion cells:
middle, tuberal part. Despite this close relationship, it
remained a mystery for many years how the hypothala- architechture, projections, and intrinsic photosensitivity. Science 295:1065-1070, 2002.
mus used visual input to synchronize its biologic clock
with the external world. In 1972, two groups of scien- 3rd ventricle
tists demonstrated that some axons leave the optic
chiasm as it passes by the hypothalamus and provide an Suprachiasmic
input that is now called the retinohypothalamic tract. nucleus

The retinohypothalamic tract originates from about Supraoptic
1,000 scattered retinal ganglion cells in each retina. nucleus
In 2001, it was discovered that these retinal ganglion
cells have the peculiar property of making their own Optic chiasm
light-sensing pigment, called melanopsin. So, although Melatonin receptor binding in the hypothalamus with a hotspot at the suprachiasmic nucleus.
other retinal ganglion cells that are concerned with
patterned vision are “blind” and depend upon input Courtesy Dr. David Weaver, University of Massachusetts Medical School.
from rods and cones to signal to them the presence of
light in their receptive fields, the melanopsin-containing â•…
retinal ganglion cells are intrinsically photosensitive.
These neurons act essentially as light level detectors hormone is mainly secreted at the onset of the dark ventrolateral preoptic nucleus, may explain why people
and relay this information both to the hypothalamus as period and in humans may promote sleepiness. One of turn out the lights and close their eyes when falling
well as to the olivary pretectal nucleus, which is a criti- the major targets in the brain for melatonin is the asleep. Other inputs to the lateral hypothalamus may
cal relay in the pupillary light reflex pathway. suprachiasmatic nucleus itself, which stands out when contact neurons involved in regulating arousal and
the brain is stained for melatonin receptors. feeding. In rodents, who might be recognized as poten-
By replacing the melanopsin gene with one for tial prey when they venture into a lighted area, an
β-galactosidase, one can then stain the melanopsin- Other retinal axons to the hypothalamus may be important response to light is immobility. This reduced
containing retinal ganglion cells blue and follow their important in providing visual inputs to neurons con- locomotion in light appears to be regulated by retinal
axons into the brain. The densest site of retinohypotha- cerned with a variety of diverse functions. For example, inputs to the subparaventricular zone.
lamic input is to the suprachiasmatic nucleus, although retinal inputs to a sleep-promoting cell group, the
other axons, in smaller numbers, enter other parts
of the hypothalamus. The suprachiasmatic nucleus is
the brain’s biologic clock; damage to this cell group
causes animals and humans to lose their 24-hour pat-
terns of activity in wake-sleep, feeding, body tempera-
ture, corticosteroid secretion, and other important
physiologic and behavioral functions. Although the
neurons in the suprachiasmatic nucleus maintain an
approximately 24-hour rhythm of activity even when
placed into tissue culture, retinal input is necessary to
reset their clock rhythm to maintain synchrony with the
external world. In the absence of light cues, circadian
rhythms in both people and animals show a free-
running cycle that is generally just a bit different from
24 hours and may vary among individual (humans
average about 24.1 hours). Although this may seem like
a small difference from 24 hours, without a mechanism
for synchronization, someone with a 24.1-hour cycle
would be 3 hours off-cycle from the rest of the world
by the end of 1 month. Some blind individuals, with
total loss of retinal input to the brain, show this type of
shift of their circadian rhythms over time so that they
go through periods every few months where their cycles
go out of phase with the rest of the world. Other blind
people, such as those with rod and cone degeneration,
who retain intrinsically photosensitive melanopsin-
containing retinal ganglion cells, remain in synchrony
with the world that they cannot see.

Melatonin is one of the hormones whose 24-hour
cycle of secretion is driven by the suprachiasmatic
nucleus. Suprachiasmatic axons directly contact neurons
in the paraventricular nucleus, which, in turn, inner-
vates the sympathetic preganglionic neurons in the
upper thoracic spinal cord. The latter project to the
superior cervical ganglion, which sends axons along
the internal carotid artery intracranially to innervate
the pineal gland, causing secretion of melatonin. The

120 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-10 Hypothalamus, Pituitary, Sleep, and Thalamus
CONTROL OF HYPOTHALAMUS BY SENSORY INPUTS

Hippocampus
and amygdala

Spino-hypothalamic tract

PVN

Cingulate and
infralimbic cortex

Releasing and release- Median Parabrachial
inhibiting hormones to eminence nucleus
anterior pituitary gland Oxytocin from posterior
pituitary gland

Delivery of hormones Norepinephrine, ACTH Preganglionic Medullary autonomic
to organs epinephrine vagal efferents pattern generators
Dorsal motor vagal nucleus
Vagal control of heart Cortisol Vagus (X) n. and nucleus ambiguus

Sympathetic Nipple stimulation
control of gut from suckling

Sympathetic Adrenal medulla Adrenal cortex Preganglionic
control of heart Collateral sympathetic sympathetic
Vagal control of ganglion
gut and bladder axon
Sympathetic control
of bladder sphincter
Sympathetic control
of blood vessels

Somatosensory Inputs to Post-operative pain
the Hypothalamus

The somatosensory system provides a major source of Herpes zoster âp•… ain
direct inputs to the hypothalamus. For many years it
was thought that the somatosensory system primarily Somatosensory inputs are also important in sexual milk requires somatosensory stimulation as well. The
fed through the thalamus to the cerebral cortex and that behavior. Neurons in the preoptic area promote erec- infant suckling at the breast causes sensory input that
sensory inputs to the hypothalamus must be relayed tion in males, and nerve cells in the ventromedial reaches the oxytocin neurons in the paraventricular and
from the cortex. However, in 1980, it was discovered nucleus of the hypothalamus can potently drive sexual supraoptic nuclei in the hypothalamus. These neurons
that some axons from the ascending somatosensory behaviors, including mounting postures in males and fire in bursts, which causes them to release oxytocin
pathways directly reach the hypothalamus. These receptive postures in females. The neurons that produce into the circulation from their axon terminals in the
inputs originate from somatosensory neurons in the these responses are, in turn, driven by a range of visual, posterior pituitary gland. The oxytocin, in turn, causes
spinal and trigeminal dorsal horn. Many of these olfactory, and tactile stimuli. In some species, ovulation milk to flow from the breast.
neurons are concerned with painful stimuli. These may is also triggered by sexual somatosensory stimuli (such
be used in orchestrating emotional responses, such as as vaginal stimulation). In each of these examples, autonomic, endocrine, and
anger, fight, or flight in response to a physical injury. behavioral responses must be coordinated, the hallmark
On the other hand, they may be important stimuli for Another hypothalamically mediated response that of a hypothalamically mediated behavior. The integra-
the underlying autonomic and endocrine responses is dependent upon somatosensory input is the milk tion of these responses in each case depends upon
associated with pain, such as elevation of blood pressure let-down reflex during breastfeeding. Breast milk pro- somatosensory input that is delivered directly to the
and heart rate, or secretion of cortisol. duction is stimulated by prolactin, but the release of the hypothalamus.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 121

Plate 5-11 Brain: PART I

Usual pathway
Accessory pathway

Ventroposteromedial parvicellular
nucleus of the thalamus
Insular cortex
Hypothalamus
Amygdala

Taste and Other Visceral Mesencephalic Parabrachial nucleus
Sensory Inputs to nucleus Trigeminal nerve (V)
the Hypothalamus and
Motor nucleus Trigeminal (semilunar) ganglion
A special class of visceral sensory pathway provides taste of trigeminal Ophthalmic nerve (V1)
information to the hypothalamus and other areas of the nerve Maxillary nerve (V2)
brain. Taste receptor cells are found in taste buds, Mandibular nerve (V3)
located in clusters along the surface of the tongue. Dif- Pons
ferent classes of taste receptors respond to different Otic Pterygopalatine
classes of chemicals in food, including acids (sour), Greater petrosal nerve ganglion ganglion
sugars (sweet), sodium (salty), glutamate (an important Geniculate ganglion Nerve (Vidian) of
amino acid component of proteins, whose taste is said Facial nerve (VII) Chorda pterygoid canal
to be “beefy” or “umame” in Japanese), and complex and tympani Lingual nerve
plant alkaloids that often warn of poisonous compounds Intermediate nerve (of Wrisberg) nerve
(bitter). The taste receptor cells are innervated by Nucleus of solitary tract Fungiform
sensory neurons from the facial (VII nerve, to the (rostral part) papillae
anterior two thirds of the tongue), glossopharyngeal Glossopharyngeal nerve (IX)
(IX nerve, to the posterior tongue and tonsillar arches), Foliate
and vagus (X nerve, to the posterior tongue and Medulla papillae
oropharynx) cranial nerves. Much like other somato- oblongata
sensory systems, the gustatory sensory neurons are (lower part) Vallate
located in ganglia (geniculate for the facial nerve, petro- papillae
sal for the glossopharyngeal nerve, and nodose for the Inferior (petrosal) ganglion Epiglottis
vagus nerve) and consist of pseudounipolar cells, with of glossopharyngeal nerve
a single axon that bifurcates in the ganglion into a Larynx
central and a peripheral branch. The central branches Inferior (nodose) ganglion of vagus nerve
terminate in the rostral third of the nucleus of the soli- Vagus nerve (X) Superior laryngeal
tary tract in the medulla. The axons end in a roughly nerve
topographic order with respect to the surface of the a roughly topographic order, with gastrointestinal â•…
tongue (axons from the anterior two thirds of the inputs in the middle part of the nucleus and cardiore-
tongue ending most rostrally). The nucleus of the soli- spiratory in the caudal part. The nucleus of the solitary parabrachial nucleus. Parabrachial neurons then contact
tary tract gives off local connections in the brainstem tract provides local inputs to cell groups in the medulla the visceral sensory thalamus, which, in turn, projects
to reflex pathways for salivation and for regulation of that control gastrointestinal functions, including gastric to the insular cortex, where sensations such as gastric
biting, chewing, and swallowing activity. acid secretion and gut motility as well as cardiovascular fullness or air hunger reach conscious appreciation.
and respiratory reflexes (e.g., the baroreceptor reflex Other parabrachial outputs are joined by smaller
Ascending axons from the nucleus of the solitary tract that stabilizes blood pressure when moving from a lying numbers of axons from the nucleus of the solitary tract
travel through the brainstem, and a large proportion of to a standing position, and the increase in both respira- itself in projecting to the amygdala, where they may be
them synapse in the parabrachial nucleus. From there, tory rate and blood pressure when there is a high level involved in visceral conditioned reflexes. Parabrachial
axons continue on to the thalamus (for conscious appre- of carbon dioxide in the blood). inputs to the hypothalamus may play a role in a wide
ciation of taste), amygdala (for taste associations), and range of functions, from regulation of behaviors such
hypothalamus (presumably for regulation of feeding). Other axons from the posterior two thirds of as feeding and drinking to control of secretion of hor-
The inputs to the hypothalamus and amygdala are aug- the nucleus of the solitary tract terminate in the mones such as vasopressin (during hypovolemia) and
mented by a smaller number of axons that reach these oxytocin (during emesis).
sites directly from the nucleus of the solitary tract. In
primates, there is evidence that some axons from the
taste portion of the nucleus of the solitary tract may
reach the thalamus directly, without requiring a relay
in the parabrachial nucleus. Taste neurons in the thala-
mus are located adjacent to the tongue somatosensory
area, and they innervate the insular cortex, which is the
primary taste cortex.

The posterior two thirds of the nucleus of the solitary
tract receives inputs from other internal organs via the
glossopharyngeal and vagus nerves. These terminate in

122 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 5-12 Hypothalamus, Pituitary, Sleep, and Thalamus

Limbic Cortex and Relationship to Hypothalamus

Supplementary motor (premotor) area Motor area
Somatosensory area
Cingulate gyrus
Fornix Corpus callosum

Thalamus

Prefrontal Visual area
area

Limbic and Cortical Inputs
to the Hypothalamus

In addition to having direct sensory inputs, the hypo- Olfactory bulb
thalamus receives highly processed information from Orbital cortex
the cerebral cortex, which is relayed via the limbic Hypothalamus
system. The limbic lobe of the brain was first defined Amygdala
by Paul Broca, in 1878, as the cortex surrounding the
medial edge of the cerebral hemisphere, as shown in Hippocampal formation
orange in the upper figure. Broca’s limbic lobe includes Parahippocampal gyrus
the cingulate gyrus (the infralimbic, prelimbic, anterior
cingulate, and retrosplenial areas), the hippocampal Deep Limbic Structures and Relationship to Hypothalamus Fornix
formation (including the entorhinal area, subiculum, Stria terminalis
hippocampal CA fields, and dentate gyrus), and the Interventricular foramen Anterior nucleus of thalamus
amygdala. These limbic regions all receive highly pro- Anterior commissure
cessed sensory information from the association regions
of the cerebral cortex, process that information for its Cingulate gyrus Interthalamic
emotional content, and then project back to the associa- Indusium griseum adhesion
tion cortical areas to provide emotional coloring to
cognition. Corpus callosum Stria
Septum pellucidum medullaris
Each of the limbic areas also sends descending inputs
to the hypothalamus. The inputs from the cingulate Precommissural fornix Habenula
gyrus mainly originate in the infralimbic and prelimbic
regions (around and just beneath the splenium of the Septal nuclei Calcarine
corpus callosum). These areas mainly send axons to sulcus
the lateral hypothalamus, as well as to components of Subcallosal area (fissure)
the autonomic system in the brainstem and the spinal Gyrus
cord, and are believed to provide much of the auto- Hypothalamus fasciolaris
nomic component of emotional response.
Paraterminal gyrus Dentate
Neurons in the hippocampal formation, particularly gyrus
the CA1 field and the subiculum, send axons to the Lamina terminalis
hypothalamus through the fornix. This long looping Fimbria of
pathway, shown in yellow in the figure, curves just bulb hippocampus
under the corpus callosum, and then dives into the tract Hippocampus
diencephalon at the foramen of Monro. Many axons Olfactory medial stria Parahippocampal gyrus
leave the fornix in the hypothalamus and provide inputs Ascending and descending
to the ventromedial nucleus. However, a dense column lateral stria connections with brainstem
of fornix axons reach the mammillary body, where they
terminate. These structures are shown in blue in the Anterior perforated substance
upper figure and red in the lower one. Although the
hippocampus appears to be very important in memory Optic chiasm
consolidation, isolated damage to the fornix or mam-
millary bodies has more limited and inconsistent effects Postcommissural fornix
on memory, so the function of this pathway remains
enigmatic. Mammillary body and
mammillothalamic tract
The mammillary nuclei provide another salient
bundle of axons to the anterior nucleus of the thalamus. Medial forebrain bundle
This mammillothalamic tract is heavily myelinated and
easily seen, but its contribution to memory formation Amygdaloid body (nuclei)
is more subtle, like that of the mammillary body itself. Interpeduncular nucleus Uncus
Lesions of the mammillothalamic tract have been
reported to prevent the generalization of limbic sei- Fasciculus retroflexus
zures, however, and this pathway has been suggested as
a target for deep brain stimulation to prevent general- â•…
ization of seizures. The anterior thalamic nucleus
projects to the cingulate gyrus, and, in 1937, James circuit,” completed by a projection from the cingulate the lateral ventricle just below the tail and body of the
Papez hypothesized that perhaps the momentum of cortex back to the hippocampus, to neurons that con- caudate nucleus in the stria terminalis, shown in blue
emotions could be explained by a “reverberating tribute to the fornix. Although there is no credible in the lower figure. Other amygdaloid inputs to the
evidence for this last link in the “circuit” actually exist- hypothalamus take a much more direct anterior route,
ing or for the proposed circuit actually playing a role in running over the optic tract into the lateral hypothala-
emotion, the theory has achieved great attention. mus. Many hypothalamic cell groups receive inputs
from the amygdala, which are thought to be important
The amygdala provides the hypothalamus with inputs for the visceral components of conditioned emotional
via two pathways. Some axons leave the amygdala in responses.
parallel to the fornix, running along the lateral edge of

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 123

Plate 5-13 Brain: PART I

OVERVIEW OF HYPOTHALAMIC AND PITUITARY DISEASE

Hypothalamic lesion

Overview of Hypothalamic Stalk Etiology
Function and Dysfunction lesion Tumor (pituitary adenoma,

The hypothalamus works to integrate autonomic, meningioma,
endocrine, and behavioral functions of the brain that craniopharyngioma,
subserve basic life functions, such as maintaining fluid hamartoma, glial tumor)
and electrolyte balance, feeding and metabolism, body Infection (granuloma,
temperature and energy expenditure, cycles of sleep and lymphocytic hypophysitis)
wakefulness, and a wide range of emergency responses. Vascular (pituitary
As a result, the range of disorders that occur when the apoplexy)
hypothalamus malfunctions is also very great. Demyelination (multiple
sclerosis)
Because the hypothalamus is very small, injuries Developmental (Prader-
often involve multiple systems. Hence, a patient with a Willi syndrome)
pituitary tumor or craniopharyngioma impinging on
the hypothalamus may have disorders extending into Somnolence
many functions. Such patients are often quite somno-
lent because an important branch of the ascending Diabetes insipidus
arousal system runs through the lateral hypothalamic
area. There may also be loss of circadian (24-hour) Obesity Adrenal cortical Hypothyroidism
rhythms of behavior so that the relatively limited or insufficiency
waking time may occur during the night rather than in
the day. Emaciation (rarely) Hypogonadism or Growth deficiency
precocious puberty (dwarfism)
Alfred Froehlich in 1901 described the patients with
such lesions as having an “adiposogenital syndrome” â•…
because they became obese and had failure of sexual
maturation. Research in the last decade has identified hypothalamic lesions, such as multiple sclerosis plaques, Hypothalamic hamartomas can cause gelastic epilepsy,
the reason for this association. Feeding in humans (and have been reported to cause emaciation. Lesions of the in which the child laughs uncontrollably but mirth-
other animals) is controlled in part by the hormone preoptic area can cause loss of thirst and loss of ability lessly, and sometimes precocious puberty (if the
leptin, which is made by white adipose tissue during to increase vasopressin secretion during dehydration. hamartoma includes gonadotropic-releasing hormone
times of plenty. In the absence of leptin or its receptors, On hot days, such patients may have substantial volume neurons). On the other hand, a large hypothalamic
both humans and animals are ravenous and become depletion without becoming thirsty. lesion in an infant is more likely to present with wasting
quite obese. Leptin is now known to act on the hypo- and emaciation than with obesity, but such children
thalamus in the region just above the pituitary stalk, to Hypothalamic lesions in children may also have may be quite happy and playful, rather than somnolent.
decrease activity in circuits that promote eating. When somewhat different clinical presentations than in adults.
tumors in the region of the pituitary gland damage this
part of the hypothalamus, feeding circuits become dis-
inhibited and the patient becomes obese. An adequate
nutritional state is also required for the brain to trigger
the hormonal changes that accompany puberty. These
circuits are also dependent upon leptin to provide a
signal that there are sufficient energy stores to make
reproduction possible. Patients whose pituitary tumors
develop before puberty may fail to go through the tran-
sition. Adults who are severely underweight may have
regression of sexual organs, accompanied by amenor-
rhea in women.

The hypothalamic-releasing hormones, in general,
are required by the anterior pituitary gland to secrete
adequate amounts of growth, thyroid, corticotrophic,
and gonadal hormones. In the presence of a pituitary
tumor that damages the hypophysial portal bed in the
pituitary stalk, secretion of all of these hormones is
diminished. On the other hand, prolactin is mainly
under inhibitory control by the hypothalamus, priÂ

Plate 5-14 Hypothalamus, Pituitary, Sleep, and Thalamus
REGULATION OF OSMOLALITY AND WATER BALANCE
Osmoreceptors
in the preoptic area Water and electrolyte
regulate drinking exchange between
and release of blood and tissues:
vasopressin normal or patho-
(antidiuretic logic (edema)
hormone)
Supraoptic and Fluid intake
paraventricular (oral or parenteral)
axons release
vasopressin in the ACTH Water and electrolyte loss via
posterior pituitary gut (vomiting, diarrhea); via
gland cavities (ascites, effusion); or
externally (sweat, hemorrhage)

Adrenal cortical hormones

Antidiuretic 80% to 85% of filtered Approximately 70 Circulating blood
hormone water passively to 100 liters of fluid
(ADH or reabsorbed in proximal filtered from blood
vasopressin) convoluted tubule due plasma by glomeruli
Antidiuretic to active reabsorption in 24 hours (filtration
hormone makes of salts, leaving 15 to promoted by
distal convoluted 20 liters per day adrenal cortical
tubule permeable hormones)
to water and thus
Regulation of Water permits it to be Naϩ Naϩ
Balance reabsorbed along
with actively O O
The anterior part of the preoptic area, just above the reabsorbed salt
optic chiasm, contains the neurons of the median pre- H H
optic nucleus, which play an important role in sensing
blood osmolality, sodium levels, and fluid volume. The 2 2
individual neurons in this region appear to be sodium
and osmolality sensors, and they also receive sensory Naϩ Naϩ
inputs concerning fluid volume from atrial stretch
receptors (through the vagus nerve and nucleus of the H 2O
solitary tract). There are also mineralocorticoid sensor
neurons in the nucleus of the solitary tract, which O
provide input to the hypothalamus that regulates salt
appetite. H

Fluid and electrolyte balance is maintained by auto- 2
nomic, endocrine, and behavioral means. The renal
blood flow is under autonomic control, as is the juxta- Antidiuretic Naϩ
glomerular apparatus, which releases renin, an enzyme hormone makes
that acts on angiotensinogen to produce a range of collecting tubule H2O Naϩ H2O
angiotensin hormones. After conversion to angiotensin, permeable to
this hormone both increases vasoconstriction (thus sup- water, permitting H2O Naϩ Naϩ Distal limb of Naϩ H 2O
porting blood pressure) and aldosterone secretion, as its reabsorption Henle’s loop Naϩ
well as causing drinking by direct action on the brain. due to high H2O Naϩ Naϩ impermeable to
The drinking behavior appears to be mediated by osmolality of Naϩ Naϩ water; actively Naϩ
angiotensin II leaking across the blood-brain barrier in renal medulla Naϩ reabsorbs salt, Naϩ
the organum vasculosum at the anterior end of the third 14 to 18 liters Naϩ creating high
ventricle, near preoptic neurons expressing angiotensin reabsorbed daily under osmolality of
II receptors. These neurons then project into the hypo- influence of antidiuretic Naϩ renal medulla
thalamus to affect salivary secretion (dry mouth, a signal hormone, resulting in
to drink) and activate general arousal (foraging for 1 to 2 liters of urine â•…
water) and specific motor systems (that increase licking in 24 hours
and swallowing responses) associated with drinking.
resorption of salt and water in the distal limb of to make aldosterone, the major mineralocorticoid.
The endocrine response to dehydration has both the renal tubules and in the collecting ducts. At the Aldosterone secretion is also stimulated by the presence
anterior and posterior pituitary limbs. The release of same time, vasopressin has a direct vasoconstrictor of angiotensin III.
vasopressin by the posterior pituitary causes active effect that supports blood pressure. The anterior pitu-
itary gland releases more ACTH, under control of Individuals with lesions in the preoptic area some-
both corticotropin-releasing hormone and vasopressin times have inability to appreciate thirst. Some of these
secreted into the pituitary portal circulation from the individuals also have deficits in vasopressin secretion
hypothalamus. Cortisol itself has some mineralocorti- in response to dehydration. Such patients must be
coid effects, but ACTH also primes the adrenal cortex reminded to drink, especially on hot days, to avoid
dehydration.

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P late 5-15 Brain: PART I

HYPOTHALAMIC REGULATION OF BODY TEMPERATURE

Preoptic area: Afferent inputs
Thermoreception and from limbic forebrain
fever responses
structures

Paraventricular and dorsomedial nuclei:
Heat production and conservation

Inflammatory cytokines, prostaglandin E2 Motor pattern generator for shivering
Paraventricular and periventricular secretion
Respiratory pattern generator
of thyrotropin-releasing hormone Sympathetic pattern generator for thermogenesis

Pituitary
gland
Thyrotropic
hormone

Shivering Increased thyroid
activity

37° C (98.6° F) Accelerated
respiration, panting
Sweating

Cutaneous Sympathetic
vasoconstriction trunk ganglion

Brown adipose tissue (thermogenesis)

â•…

Temperature Regulation This protein permits mitochondria to burn fat to typically occurs before the onset of motor activity or
produce heat. rest, and so is not due to a simple change in muscle
One of the key roles of the hypothalamus is in main- activity. There are also changes in body temperature
taining an even body temperature. This is necessary The other major way to increase body tempera- during the menstrual cycle, which may reflect the fact
for optimal function of neurons, metabolic enzymes, ture is by heat conservation. Particularly in larger that the preoptic area is also involved in reproductive
and actions of the immune system. The preoptic mammals, such as adult humans, the body makes suf- function.
area contains neurons that are specialized for thermo- ficient heat from its internal metabolism so that body
reception. These are located in close proximity to the temperature can be increased merely by shunting blood In addition to inhibiting the heat production and
neurons that detect osmolality and control fluid and flow away from the skin to deep vascular beds. In conservation systems, warm-sensitive neurons in the
electrolyte balance, and some neurons may have dual animals with fur, piloerection, another sympathetic preoptic area also increase blood flow to the skin as well
roles in both systems. (For example, on a hot day it response, increases the thickness of the fur coat and as sweating, to permit heat loss, and increase vasopres-
is necessary to conserve fluid for use by sweat glands thus conserves heat. Humans also have piloerection sin secretion, which permits conservation of fluids that
to maintain cooling.) Some preoptic neurons them- called gooseflesh, but this is not nearly as effective in are necessary to support increased sweating. Sweating
selves are thermoreceptors, but many also receive heat conservation. The thermogenic (brown adipose) is mediated by two sets of sympathetic nerves, one of
inputs from the skin, which informs them about the and heat-conserving mechanisms are coordinated by which is noradrenergic and the other cholinergic. The
external temperature. Warm-responsive neurons inhibit medullary raphe neurons that activate both pathways. cholinergic sympathetic input appears to be of primary
a series of cell groups that increase body temperature, importance for thermoregulatory sweating, whereas the
including the paraventricular and dorsomedial hypo- A third mechanism for generating heat is by increased noradrenergic axons may be more important for emo-
thalamic nuclei and the raphe nuclei in the medulla. muscle activity or shivering. Less is known about this tional sweating.
These latter cell groups activate the sympathetic pathway, but it is presumed that hypothalamic neurons
nervous system to increase body temperature by two activate motor pattern generators that cause increased Paroxysmal hypothermia is a rare neurologic disor-
major pathways. The first of these is heat generation, muscle activity, which is thermogenic. All three mecha- der, most often seen in individuals who have agenesis
due to activation of brown adipose tissue. Once thought nisms require energy, and so the heat production system of the corpus callosum (due to a failure of the anterior
to be present only in small mammals, including newborn also activates the cardiovascular system to increase wall of the third ventricle to develop properly) or a
humans, recent studies have shown that even adult cardiac output and the respiratory system to maintain congenital tumor or other lesion affecting the preoptic
humans have residual brown adipose tissue. Brown blood oxygenation. area. Such individuals have periods of several days at a
adipose is found in small patches along the back time during which their body temperature drops to
and consists of adipose cells that contain large numbers Anterior pituitary hormones do not seem to play about 30° C, and they lapse into a stuporous state.
of mitochondria and express uncoupling protein I. much of a role in the regulation of body temperature Presumably this represents an unusual hypothalamic
over a period of minutes or even hours, although in response, similar to that seen in hibernation states, but
the absence of thyroid hormone, body temperature there have been too few patients with this syndrome to
falls. Body temperature also rises (during the active study it closely.
cycle) and falls (during the sleep cycle) daily, and this

126 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-16 Hypothalamus, Pituitary, Sleep, and Thalamus
CYTOKINES AND PROSTAGLANDINS CAUSE THE SICKNESS RESPONSE
The Sickness Response
Sickness behavior, pain, anorexia
Cognitive and affective responses
Fever and autonomic responses
Cortisol/endocrine responses

Cerebral vasculature and meninges I
1
2
3

Organum vascularum of the lamina terminalis (OVLT) I

Vasculature to hypothalamus 8
I
I ‫ ؍‬Inflammatory Mediators
Inflammatory cytokines:

Interleukin (IL)-1␤, IL-6, tumor

necrosis factor ␣, and others Sensory Nucleus tractus solitarius
Prostaglandins: ganglion of X

Prostaglandin E2 and others Vagal afferents Dorsal motor (autonomic)
nucleus of X
in viscera Dorsal root
Vagal efferents to ganglion
I4

intramural ganglia

Paraganglion cells Somatic Peripheral Dorsal horn
associated with afferents nerve
vagal afferents

I5 Sympathetic Spinal cord
ganglion
6I

1 Prostaglandins crossing blood-brain barrier (BBB) or released from Target I7
meninges can alter cognitive function.
Cytokine and prostaglandins act on sensory neurons,
2 Cytokines and prostaglandins can enter brain at circumventricular organs, such as OVLT, 5 modulating pain.
that lack BBB.
Cytokine modulation of norepinephrine release from
3 Cytokines act on cerebral blood vessels to release prostaglandin E2, which directly 6 sympathetic nerve terminals.
crosses BBB into brain.
Cytokine modulation of neurotransmitter intracellular
Cytokines and prostaglandins act on vagal afferents and associated paraganglion cells, 7 signaling in target cells.
4 activating visceral sensory pathways from the nucleus of the solitary tract that influence
8 Cytokine modulation of pituitary hormone release.
autonomic, endocrine, and behavioral responses. â•…

Fever: Hypothalamic many microorganisms are less able to defend them- most important for causing sickness responses is pros-
Response to Systemic selves at this temperature. taglandin E2 (PGE2), and it has a series of four differ-
Inflammation ent E-type prostaglandin receptors (EP receptors) that
There are several processes by which invading infec- are found on different classes of cells in the central
During systemic infections, there is a characteristic, tious organisms can set off the sickness response. One nervous system (CNS). For example, EP3 receptors in
hypothalamically mediated “sickness response” that is that they can act locally on white blood cells that then the median preoptic nucleus recognize PGE2 during an
includes an array of adaptive adjustments. Among these produce circulating hormones called cytokines. The inflammatory response and are critical for causing a
are a feeling of malaise, achiness, and sleepiness (which cytokines can have direct actions on certain types of fever response. Activation of corticosteroid secretion
reinforces rest); increased secretion of adrenocortico- neurons, but most of the “sickness response” is due during a sickness response requires EP3 receptors in
steroids (to mobilize adipose energy stores); and to the cytokines (or certain components of invading the preoptic area and the ventrolateral medulla, as well
anorexia (to keep blood sugar low because many micro- bacteria themselves) inducing white blood cells and as EP1 receptors, which may be in the paraventricular
organisms prefer sugars as fuel, while the human body vascular endothelial cells to make prostaglandins. The hypothalamic nucleus or the central nucleus of the
can adapt to using fat stores such as ketone bodies). primary role of prostaglandins in the sickness responses amygdala. Increased sensitivity to pain during fever is
However, the most prominent symptom of the “sick- is demonstrated by the fact that inhibitors of cyclooxy- likely to be due to EP3 receptors, but the exact locus
ness response” is an elevation of body temperature genase, the enzyme that produces prostaglandins, is of those receptors is not yet known.
called a fever. Experimental studies show that white sufficient to prevent most of these responses.
blood cells are more active at 39° C than 37° C, while The fever response during sickness appears to be
Prostaglandins can act on receptors on peripheral due to neurons in the median preoptic nucleus with-
nerves, but they also can cross the blood-brain barrier drawing γ-aminobutyric acid (GABA)ergic inhibition
and act directly on brain neurons that express prosta- of the neurons in the paraventricular and dorsomedial
glandin receptors. The prostaglandin that is probably

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