The Netter Collection of Medical Illustrations VOLUME 7 PART l

P late 1-25 Brain: PART I

Cerebral cortex Pial surface MZ
Ventricle CP
Neurons
PP Preplate MZ migrate IZ
MZ Marginal zone SP along radial
SP Subplate glial cells
CP Cortical plate Neuron
IP Intermediate zone PP Basal
SVZ Subventricular zone Neuron progenitors
VZ Ventricular zone

SVZ

VZ

Neuroepithelial cells Radial glial cells Ventricle

Development of cerebral cortex over time

â•…

Neurogenesis and Cell and subplate, thus constituting layer 6 of the cortex. some mammals, the rostral migratory stream remains
Migration in the Developing Each successive cortical neuron cohort, generated in place and guides newly generated neurons from a
Neocortex during the last two thirds of gestation in humans, proliferative zone called the anterior subventricular zone,
migrates past earlier-born neighbors to their final posi- or SVZ, to the olfactory bulb, perhaps throughout life.
Most, if not all, cortical neurons are generated in or tions. Thus there is an “inside-out” gradient of cortical The human brain, however, lacks a rostral migratory
near the ventricle and migrate radially to the cortex that neurogenesis: early born neurons are deepest, and those stream after birth, and it is unlikely that new olfactory
forms on top of the neuroepithelial precursors. Cortical born last, except for Cajal-Retzius cells, are superficial. interneurons are generated long into postnatal life. In
neural stem cells, radial glia, maintain cell bodies at the These distinctions are accompanied by differences in the cerebellum, interneurons (glutamatergic rather than
ventricular zone, where they divide symmetrically and which cortical neurons send their axons dendritic dif- GABAergic) are generated from a proliferative layer
slowly. Radial glia also generate rapidly, asymmetrically ferentiation and connectivity. immediately beneath the pia, called the external granule
dividing intermediate progenitors slightly displaced into cell layer. The postmitotic granule cells then migrate
the subventricular zone, where they generate postmitotic Radial migration and the inside-out neurogenesis back into the rudimentary cerebellum, past Purkinje cells
neurons. Radial glia serve a dual function. Their long gradient together produce cortical projection neurons (cerebellar projection neurons, generated locally) using
processes directed toward the pia provide a migratory whose axons extend to other cortical regions or subÂ

Plate 1-26 Normal and Abnormal Development

Neuronal Proliferation and
Migration Disorders

The complexity and duration of cortical neurogenesis Agenesis of the corpus callosum
and migration makes it a particularly vulnerable target
for disruptions that result in broad range of brain dis- Lissencephaly, posterior predominant
orders. These include a variety of epilepsies, intellectual
disability, and potentially, disorders such as autism and Left schizencephaly
attention deficit/hyperactivity disorder (ADHD). Many
of these disorders, and the cell biologic and genetic â•…
analyses that better defined their pathogenesis as dis-
ruptions of cortical neuronal proliferation and migra- Images courtesy of P. Ellen Grant, MD, Associate Professor of Radiology, Harvard Medical School.
tion, took advantage of structural imaging of the cortex
by using magnetic resonance imaging to identify ana- along with deranged lamination of the cortical mantle, hydrocephalus (see Plate 1-5). The diagnosis may be
tomic irregularities in the size, shape, and gyral and is called polymicrogyria (see Plate 1-5). Schizencephaly is suggested by ocular hypertelorism, an antimongoloid
sulcal patterns of the cortical hemispheres. Neverthe- characterized by an abnormal cleft that joins the cortex slant to the eyes, and other midline facial defects.
less, a “normal” magnetic resonance imaging scan does and the ventricles. It is usually bilateral but can be Aicardi syndrome, a sporadically occurring abnormality
not rule out microscopic localized gyral malformations unilateral. Malformed gyri (polymicrogyria) are aligned seen in female infants, is associated with retinal defects
or, most important, significant defects of the cortical radially around the cleft. that suggest chorioretinitis, infantile spasms, hypsar-
layers and heterotopias of neurons that are initially des- rhythmia, and severe psychomotor retardation. Agen-
tined for one cortical layer, but, due to altered migra- Agenesis of the corpus callosum, partial or complete, is esis is one of the most common anomalies diagnosed
tion, are found in an aberrant laminar location. Clearly, often accompanied by disorders stemming from defec- by MRI in “idiopathic” psychomotor retardation (see
such disruptions of cortical neurogenesis and migration tive neuronal migration. This results in developmental Plates 1-5 and 1-6).
must result in altered circuits that lack the capacity to defects, seizures, mental retardation, and occasional
mediate maximally adaptive behaviors.

Defective Proliferation. A decrease in neuronal
number may lead to microcephaly (microencephaly vera),
whereas an increase may result in megalencephaly. Prena-
tal influences, including familial factors, are paramount
in each abnormality. Microcephaly may be caused by a
variety of genetic and environmental etiologies. It may
be isolated or associated with other anomalies. Primary
microcephaly results from a developmental insult giving
rise to a reduced neuronal population. Secondary
microcephaly occurs from an injury or insult to a previ-
ously normal brain.

Megalencephaly is classified as either anatomic or
metabolic. It may be associated with neurofibromatosis,
achondroplasia, or cerebral gigantism. Familial mega-
lencephaly, the most common and benign form, is
usually inherited through the father. Excessive postna-
tal growth also occurs often, suggesting hydrocephalus.
Measurements of the parental head circumference and
MRI scans showing normal ventricles aid in diagnosis.
Approximately 70% of infants with microcephaly and
30% of those with megalencephaly have developmental
defects.

Defective Migration. After proliferation in the sub-
ependymal region, neurons migrate to the cortex. The
neurons appear to follow radial glial cells like raindrops
on telephone wires. Early migrations form the deepest
cortical layers, and later migrations, the more superfi-
cial layers, ultimately forming a six-layer cortex. The
cellular complement is greatest in the outer cortical
layers, leading to an increased surface area, with buck-
ling causing gyri to begin to appear between 26 and 28
weeks, and become increasingly complex in the final
trimester. If the normal complement of neurons is
absent, gyral formation does not take place, and lissen-
cephaly (smooth brain, agyria) results (see Plate 1-5). An
abnormally thick gyral formation is known as pachygy-
ria. In this anomaly, the cortex lacks the six-layer con-
figuration. Cerebral heterotopias appear to result from
defective neuronal migration and subsequent accumu-
lation of aberrant neurons anywhere between the epen-
dyma and cortex (see Plate 1-5). Significant numbers of
such heterotopias occurring in isolation are likely to
result in some degree of intellectual disability. Most of
the disorders of migration discussed previously have
associated heterotopias. The presence of multiple small
gyri having no resemblance to a normal gyral pattern,

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 29

P late 1-27 Brain: PART I

Developmental Dyslexia

Developmental dyslexia, or developmental reading dis- Child reverses letters (writes
order, is defined as a significant impairment in the “d” for “b”) and sequence
development of reading and related skills, such as spell- of letters in words (writes
ing, writing, and reading comprehension, due to prob- “saw” for “was”)
lems with phonologic processing despite adequate
intelligence and conventional instruction. This disorder Verrucose dysplasia, with focal accumulation Foâ•… cal dysplasia, with abnormally large neurons
frequently occurs in association with other specific of neurons in layer 1 of cerebral cortex extending into white matter of brain
learning disabilities, such as disturbances in auditory
comprehension, expressive language, articulation, and have noted a significant clustering of dyslexia, left- Treatment. Early identification and evaluation of
visual discrimination. It is the most commonly identi- handedness, autoimmune disease, and migraine in dyslexia is essential for proper treatment. The optimal
fied learning disorder, now felt to affect the sexes persons related to each other, indicating an association educational approach is multisensory, including phone-
equally and is often present in siblings and other family between these disorders. mic awareness and enhanced phonologic processing,
members. where virtually all respond. However, given that dys-
Currently, it is felt that developmental dyslexia is a lexia is a lifelong disorder, many continue to struggle
Because the primary deficit in developmental dyslexia disorder of network connections as demonstrated by into adulthood when presented with new or less familiar
is in reading and writing, the abnormality is usually not Vandermosten (2012). By using MRI tractography, words or in reading comprehension settings. Treatment
identified until the first few years of grade school, the adults with dyslexia were noted to have a reduction in should be aimed at enabling those to overcome deficits
time when children begin to read. Most parents are the left arcuate fasciculus, which connects the posterior where possible and to learn strategies to circumvent and
not aware of any disorder in their child before this temporal and frontal areas. This may represent an area compensate for difficulties that cannot be overcome.
stage. Because it is common and affects skills recently of decreased myelination.
acquired by man, developmental dyslexia may have had
certain advantages in preliterate societies, because
dyslexic persons often have enhanced visual-spatial and
artistic skills.

Etiologic Theories. Early investigators postulated
that developmental dyslexia was caused by a lesion in
the left angular gyrus, an area of the brain in which a
lesion in adults produces word blindness. Later, Orton
(1925) felt that the disorder was caused by equipotential
visual association areas in the two cerebral hemispheres
actively competing with each other, with one side
seeing a mirror image of the other. Orton was particu-
larly impressed with reversals of letters and letter
sequences in words, the inconsistency of these errors,
and the ability of some dyslexic students to read better
with the aid of a mirror. Emotional problems and
improper instruction were also thought to cause
dyslexia.

Past investigations, including computed tomography,
computed evoked electroencephalographic studies, and
postmortem studies of the brain have all provided
evidence of a structural basis for dyslexia. More
recently, MRI has demonstrated a variety of structural
changes in the corpus callosum, left temporal lobes,
thalamus, caudate, inferior frontal gyrus, and cerebellum
(Pennington, 1999; Eliez, 2000; Brown, 2011; Leonard,
2001; Rae, 2002; Robichon, 2000; Elnakib, 2012).

Historically, Drake (1968) noted abnormally formed
gyri in the parietal regions and ectopic neurons in the
white matter, arrested during their migration to the
cerebral cortex. Examination of a second brain by
Galaburda and Kemper (1979) showed cerebral cortical
abnormalities characterized by focal and verrucose dys-
plasia in the sensory speech area (Wernicke’s area) and
language dominant left cerebral hemisphere. The third
brain examined showed only verrucose dysplasia almost
exclusively confined to the left cerebral hemisphere
(Kemper, 1984). Thus examination of all three brains
has demonstrated minor malformations.

Analysis of human malformations and animal models
indicates that the focal and verrucose dysplasia probably
arise during the later stages of neuronal migration to
the cerebral cortex, and appear to result from the
migration of neurons into focal areas of cortical destruc-
tion. In man, neuronal migration to the cerebral cortex
occurs from the 8th to approximately the 16th week of
gestation. Consistent with this timing is the presence of
ectopic neurons in the white matter in two of the three
brains examined. The nature of this postulated destruc-
tive process is unknown. Geschwind and Behan (1982)

30 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 1-28 Normal and Abnormal Development

Autism Spectrum Disorders

Autism spectrum disorders (ASD), also known as per- Boy sits apart, detached, demonstrates
vasive developmental disorders, are a group of mental ritualistic behavior by spinning wheels
health problems in children and adolescents character- of upside-down truck while other
ized by severe impairments in several areas of develop- children play
ment, including communication, social interaction, and
range of interests and activities. Prevalence rates for Chr 1 Chr 2 Chr 3 Chr 4 Chr 5 Chr 6 Chr 7 Chr 8 Chr 9 Chr 10 Chr 11 Chr X
ASDs are now estimated at about 1 in 110 children in 1.1 3.1 5.1 8.1 9.1 10.1 X.1
the United States. The prevalence of children with
ASD has now surpassed rates of children with well- 7.1
known conditions such as cancer. For educational pur-
poses, this means that most elementary schools with a 2.1 5.2 11.1
population of 500 children will have 4 or 5 children 3.2 1111..23
with ASD. The greatest risk factor for ASD is being 3.3 5.3 7.2 10.2 X.2
male with autism, occurring approximately four times 9.2 12.1
more often in boys than girls. The pathophysiology of 4.1 X.4 X.3
these pervasive developmental disorders is not known, but 4.2 10.3 XX..56
it is believed to be an inherited abnormality in the 6.1 7.4 7.3
structure and function of certain parts of the brain, 4.3 6.2 777...568 7.7 9.3
including those that govern the development of social 3.4 9.5 9.4
relatedness and language.
1.2 2.2 7.10 7.9
CLINICAL PRESENTATION 7.11
The most severe of these disorders, autistic disorder, is
characterized by markedly abnormal development in 2.4 2.33.5 4.4
communication and social interaction and a markedly 3.6
restricted range of activity and interests. There may be
a complete lack of language, or, if language is present, 1.3 2.5 16.1 15.1 15.2 13.1 12.2
it does not serve to initiate or sustain conversation with 15.3 14.1
others. There is severe impairment in the ability to 21.1 20.1 19.1 17.1 17.2 16.3
form social relationships and to understand others’ feel- 20.2 17.3 16.2
ings. The child may not babble, point, smile, or make 17.5 15.4
meaningful gestures; he or she may have poor eye 17.4
contact, may appear to be hearing impaired, and may 22.1 21.2 16.4
not know how to play with toys or engage in make- 22.2
believe play. The child often has very restricted patterns
of interest and may show little interest in the environ- Chr 22 Chr 21 Chr 20 Chr 19 Chr 18 Chr 17 Chr 16 Chr 15 Chr 14 Chr 13 Chr 12 ChrY
ment. There may be inflexible routines that serve no
function and repetitive behaviors such as hand-flapping A schematic summary of association and linkage studies of ASD, organized by chromosome. Purple bands indicate a
or body-twisting. To meet the diagnosis, the disorder chromosomal region that shows a linkage with ASD. Red and yellow bars (parallel to the chromosome) correspond to
must have been present before age 3 years. Autistic losses/gains in copy number, respectively, that are observed in people with ASD when compared with matched controls.
disorder is accompanied by intellectual disability in up Green bars correspond to genes that are observed to modulate the risk for ASD (either through a rare syndrome or
to 60% of cases, and seizures are often also present in genetic association): light green and dark green bars represent locations of candidate genes. Reprinted with permission
the children who have intellectual disability.
from Macmillan Publishers Ltd. Abrahams BS, Geschwind, DH: Nat Rev Genet 2008; 9:3â4•… 1-355.
A less severe type of these disorders, Asperger disorder,
is characterized by all of the above problems, without complex, and requires input from multiple people who intervention has been identified as very important for
language impairment and intellectual disability. Chil- know the child well. A diagnosis of ASD is based on these children, and most individuals with ASD respond
dren with Asperger disorder who have stronger verbal descriptions of behavior from interviews, question- well to highly structured, specialized programs.
skills are sometimes referred to as sounding like little naires, and a direct behavioral examination. Genetic
adults and struggle to pick up on the normal “give and testing is recommended because single-gene disorders If the child exhibits behaviors that are aggressive,
take of a conversation.” They often have very highly or genetic variations associated with autism are seen destructive, or self-injurious, medications (such as
developed interest in and knowledge about a narrow in ≈10%. atypical antipsychotics) may be helpful. Sometimes
topic. To meet the diagnosis, there must be impairment stimulant medication may be helpful in reducing hyper-
in the youth’s function at home, at school, or with peers. TREATMENT activity and impulsivity, and antidepressants may be
The treatment of autism spectrum disorders is aimed at helpful in reducing compulsive behaviors.
If some of the above behaviors are present, but not enhancing the communication, social, and intellectual
enough to meet the diagnoses, the disorder is called development of the child through language and social COURSE
pervasive developmental disorder, not otherwise specified. skills therapies and educational tutoring. The majority The autism spectrum disorders tend to be lifelong
of these treatments are designed to take place in the problems. Children with these disorders who are iden-
DIAGNOSIS home or at school. There is no single best treatment tified early, who have relatively intact language and
Ideally, the evaluation should be conducted by a multi- package for all children with ASD; however, early intellectual abilities, and receive intensive treatment
disciplinary team of expert clinicians, including a child have the best outcomes.
psychologist, speech pathologist, and a medical proÂ

Plate 1-29 Brain: PART I

Rett Syndrome Dystonic foot

Rett syndrome (RTT; Online Mendelian Inheritance Walking on toes
in Man [OMIM]: phenotype #312750; gene/locus
#300005) is a neurodevelopmental disorder first noted Wringing hands
about 1960 by the Austrian developmental pediatrician Spine dysgenesis
Andreas Rett and the Swedish child neurologist Bengt
Hagberg. RTT is the leading genetic cause of severe Normal Rett syndrome
intellectual disability in females. Its incidence is approx-
imately 1:10,000 female births. inadequately evaluated. Feet and hands are generally â•… Scoliosis
small, unusually cold, and discolored.
After a normal pregnancy and delivery, early develop- neural centers. For example, knockout of GABAergic
ment is apparently normal through age 6 months; Unexplained sudden death occurs, possibly related to function in the forebrain, sparing the brainstem, results
however, retrospectively, subtle deviant patterns occur, unwitnessed seizures, respiratory failure, or prolonged in an absence of periodic breathing abnormalities.
including deceleration of acquired head growth. Devel- QT syndrome; average survival is 50+ years. With
opmental progress stalls between 6 and 18 months, increasing appreciation of the underlying medical In general, RTT is a sporadic condition with recur-
followed by frank regression of fine motor skills and issues, general well-being has improved remarkably. rence in the family being <<0.1%. In 75% or more, new
communication function, including loss of acquired mutations derive from paternal germ lines. In the small
language with poor visual and aural interactions sug- PATHOPHYSIOLOGY number of familial cases, the mother carries the gene
gesting autism. At present, 95% or more of those with features consis- but is normal or shows mild cognitive impairment
tent with RTT have a mutation in the MECP2 gene or a learning disability due to favorable skewing of
Concomitantly, stereotyped hand movements appear (coding for methyl-CpG-binding protein 2), located at X-chromosome inactivation. The differential diagnosis
during wakefulness: hand-wringing, hand-mouthing, Xq28. MECP2, a member of a family of methyl-binding includes autism, Angelman syndrome, and the neuronal
hand-clapping or patting, or unusual finger move- proteins, is an epigenetic regulator of a large and ceroid lipofuscinoses.
ments. Each girl develops her own repertoire, generally increasing number of genes, including BDNF (brain-
evolving over time. Subtle stereotypies occur in the feet derived neurotrophic factor) and CRH (corticotrophin- Males with mutations in MECP2 have a progressive
and circumorally. Although gait is acquired in about releasing hormone). Reduced growth of dendrites and disorder, the abnormal gene being expressed in all cells.
80%, approximately 20% of Rett children require assis- their spines are present throughout the cerebral Duplication of MECP2 produces another distinctive
tance. It is subsequently lost in about 25% to 35%, hemispheres (an explanation for deceleration of head disorder that is modified by the involvement of other
becoming considerably dyspraxic in the remainder, with growth) and brainstem. All neurotransmitter func- genes. These males are quite abnormal, whereas their
broad-based, semipurposeful patterns, toe-walking, or tion is impaired, with an imbalance between excit- mothers, 70% (or more) of whom carry the same dupli-
retropulsion. Overall, about 70% are able to walk, 20% atory (principally glutamatergic) and inhibitory (chiefly cation, appear normal yet have significant obsessive-
of whom require assistance. GABAergic) expression. Conditional knockout mouse compulsive behaviors.
models indicate the diverse functional impact in specific
After the early period of autistic-like behaviors, an At present, substantial research is being conducted in
increasingly interactive phase emerges, typically by age mouse models of RTT/MECP2 mutants, and a number
3 to 5 years. Here the child becomes very responsive to of clinical trials are ongoing or in planning stages.
external stimuli, with intensive eye gaze and markedly Despite this, specific treatment designed to provide a
improved receptive communication skills. However, cure remains elusive.
expressive language remains poor. Their inability to
speak or engage in volitional fine motor functions
makes intellectual assessment difficult. Improved com-
munication is possible through picture boards and
advanced computer-based technologies. Although cog-
nitive function remains stable, gradual slowing of motor
skills occurs in adulthood, with increasing rigidity and
dystonic posturing of ankles and feet.

There are common associated medical problems.
Periodic breathing consists of breath-holding, hyperven-
tilation, or a combination. This is prominent between
ages 5 and 15 years, being exacerbated by unfamiliar
or stressful circumstances, including large crowds or
new surroundings. Gastrointestinal dysfunction includes
disordered chewing and swallowing, gastroesophageal
reflux, delayed stomach emptying, constipation, gall-
bladder dysfunction, and impaired growth, all related
to the neurologic underpinnings of Rett syndrome.
Epilepsy and scoliosis are increasingly common
throughout childhood and adolescence, ultimately
occurring in 80%.

Seizures are infrequent before age 2 years, may be
generalized or partial and usually easily managed. Many
girls have unusual behaviors (“vacant spells”) that are
difficult to distinguish from epilepsy, thus requiring
video electroencephalographic monitoring. Scoliosis
becomes evident by age 4 years, with greater severity in
hypotonic children lacking ability to maintain indepen-
dent upright posture. Surgery is required in 12% to
14%, often improving quality of life. Bracing is
employed with greater frequency; its effectiveness is

32 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

SECTION 2â•…

CEREBRAL CORTEX
AND NEUROCOGNITIVE

DISORDERS

P late 2-1 Brain: PART I

SUPEROLATERAL SURFACE OF BRAIN

Central sulcus Superior (superomedial) margin of cerebrum
Precentral gyrus Postcentral gyrus
Precentral sulcus Postcentral sulcus
Frontal (F), frontoparietal (FP) Supramarginal gyrus
and temporal (T) opercula Superior parietal lobule
Superior frontal gyrus Intraparietal sulcus
Inferior parietal
Superior frontal lobule
sulcus Angular gyrus

Middle frontal Parieto-
gyrus occipital
sulcus

Inferior
frontal
sulcus

Surfaces of Cerebrum Inferior FP Occipital
frontal F pole
The cerebrum is divided into right and left hemispheres gyrus Calcarine
by a longitudinal fissure. Each hemisphere has three Frontal T fissure
surfaces—superolateral, medial, and inferior—all of pole Lunate sulcus
which have irregular fissures, or sulci, demarcating Lateral Anterior ramus (inconstant)
convolutions, or gyri. Although there are variations in (sylvian) Ascending ramus Transverse
arrangement between the two hemispheres in the same fissure Posterior ramus occipital sulcus
brain and in those from different persons, a basic simi- Preoccipital notch
larity in the pattern allows the parts of the brain to be Temporal pole Superior temporal gyrus Inferior (inferolateral)
mapped and named. Superior temporal sulcus margin of cerebrum
SUPEROLATERAL SURFACE Middle temporal gyrus Inferior temporal gyrus
On the superolateral surface, two sulci, the lateral and Inferior temporal sulcus
the central, can be easily identified. The lateral (sylvian)
sulcus has a short stem between the orbital surface of Parietal
the frontal lobe and the temporal pole; in life, the lesser lobe
wing of the sphenoid bone projects into it. At its outer
end, the stem divides into anterior, ascending, and pos- Frontal Occipital
terior branches. The anterior and ascending rami are lobe lobe
each about 2.5╯cm long; the former runs horizontally
into the inferior frontal gyrus, and the latter, vertically. Temporal Central
The posterior ramus is about 7.5╯cm long and inclines lobe sulcus
upward as it extends backward to end in the supramar- of insula
ginal gyrus, which is part of the inferior parietal lobule.
These rami separate triangular areas of cortex called Circular
opercula, which cover a buried lobe of cortex, the sulcus
insula. of insula

The central (rolandic) sulcus proceeds obliquely down- Insula Short gyri
ward and forward from a point on the superior border Limen
almost halfway between the frontal and occipital poles. Long gyrus
It is sinuous and ends above the middle of the posterior
ramus of the lateral sulcus. Its upper end usually runs â•…
onto the medial surface of the cerebrum and terminates
in the paracentral lobule. The occipital lobe lies behind this same imaginary line. the great cortical somatomotor area. The superior and
The temporal lobe lies below the stem and posterior inferior frontal sulci curve across the remaining part of
The parietooccipital sulcus is situated mainly on the ramus of the lateral sulcus, and is bounded behind by the surface, dividing it into superior, middle, and infe-
medial surface of the cerebrum, but it cuts the superior the lower part of the aforementioned imaginary line. rior frontal gyri.
margin and appears for a short distance on the supero-
lateral surface about 5╯cm in front of the occipital pole. Frontal Lobe. The superolateral surface of the frontal Parietal Lobe. The parietal lobe has two main sulci,
At about the same distance from the occipital pole on lobe is traversed by three main sulci and thus divided which divide it into three gyri. The postcentral sulcus lies
the inferior margin, there is a shallow indentation, the into four gyri. The precentral sulcus runs parallel to the parallel to the central sulcus, separated from it by the
preoccipital notch, produced by a small ridge on the upper central sulcus, separated from it by the precentral gyrus, postcentral gyrus, the great somatic sensory cortical area.
surface of the tentorium cerebelli.

The above features divide the cerebrum into frontal,
parietal, occipital, and temporal lobes. The frontal lobe
lies in front of the central sulcus and anterosuperior
to the lateral sulcus. The parietal lobe lies behind the
central sulcus, above the posterior ramus of the lateral
sulcus and in front of an imaginary line drawn between
the parieto-occipital sulcus and the preoccipital notch.

34 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 2-2 Cerebral Cortex and Neurocognitive Disorders
MEDIAL SURFACE OF BRAIN

Precentral sulcus

Cingulate gyrus Central (rolandic) sulcus
Fornix Paracentral lobule
Corpus callosum
Septum pellucidum
Cingulate sulcus Interventricular foramen (of Monro)
Choroid plexus of 3rd ventricle

Sulcus of corpus callosum Interthalamic adhesion
Medial frontal gyrus Stria medullaris of thalamus
Precuneus

Superior sagittal sinus

Thalamus Parietoccipital sulcus

Surfaces of Cerebrum Hypothalamic sulcus AP Habenular commissure
Anterior commissure Cuneus
(Continued) Subcallosal Calcarine cortex
(parolfactory) area (upper bank)
The remaining, larger part of the superolateral parietal Paraterminal gyrus Calcarine sulcus
surface is subdivided into superior and inferior parietal Lingual gyrus
lobules (gyri) by the intraparietal sulcus, which runs Gyrus rectus Calcarine cortex
backward from near the midpoint of the postcentral (lower bank)
sulcus and usually extends into the occipital lobe, where
it ends by joining the transverse occipital sulcus. Lamina terminalis Straight sinus
Optic recess (in tentorium cerebelli)
Occipital Lobe. The outer surface of the occipital Pineal gland
lobe is less extensive than that of the other lobes and
has a short transverse occipital sulcus and a lunate sulcus; Optic chiasm Great cerebral vein (of Galen)
the latter demarcates the visuosensory and visuopsychic Tuber cinereum Posterior (epithalamic)
areas of the cortex. The calcarine sulcus notches the commissure
occipital pole.
Pituitary gland (anterior and posterior) Superior and inferior colliculi
Temporal Lobe. The temporal lobe is divided by supe- Cerebellum
rior and inferior temporal sulci into superior, middle, and
inferior temporal gyri. The sulci run backward and Mammillary body Superior medullary velum
slightly upward, in the same general direction as the
posterior ramus of the lateral sulcus, which lies above Pons 4th ventricle and choroid plexus
them. The superior sulcus ends in the lower part of the Midbrain Inferior medullary velum
inferior parietal lobule, and the superjacent cortex is
called the angular gyrus. The superior temporal gyrus Medulla oblongata Cerebral aqueduct (of Sylvius)
contains the auditosensory and auditopsychic areas.
Cingulate gyrus Genu of corpus
Insula. The insula is a sunken lobe of cortex, overlaid Rostrum callosum
by opercula and buried by the exuberant growth of Mammillothalamic
adjoining cortical areas. It is ovoid in shape and is sur- fasciculus Body
rounded by a groove, the circular sulcus of the insula. Mammillary body Splenium
The apex is inferior, near the anterior (rostral) perfo-
rated substance, and is termed the limen of the insula. Uncus Cuneus
The insular surface is divided into larger and smaller Optic (III) nerve
posterior parts by the central sulcus of the insula, which Calcarine sulcus
is roughly parallel to the central sulcus of the cerebrum. Olfactory tract Lingual gyrus
Each part is further subdivided by minor sulci into short Rhinal sulcus
and long insular gyri. The claustrum and lentiform Collateral sulcus Body of fornix
nucleus lie deep to the insula. Crus
Medial occipitotemporal gyrus Column
MEDIAL SURFACE OF CEREBRAL Lateral occipitotemporal gyrus
HEMISPHERES Occipitotemporal sulcus Fimbria of hippocampus
The medial surfaces of the cerebral hemispheres are
flat, and, although separated for most of their extent by â•… Dentate gyrus
the longitudinal fissure and falx cerebri, they are con-
nected in parts by the cerebral commissures and by the Parahippocampal gyrus
structures bounding the third ventricle.
splenium, overlies the midbrain and adjacent part of the the fornix) that meet to form the body of the fornix and
Corpus Callosum. The corpus callosum is the largest cerebellum. The corpus callosum is about 10╯cm long separate again to become the columns of the fornix,
of the cerebral commissures, and forms most of the roof and 2.5╯cm wide between the points where it sinks into curving downward to the mammillary bodies. The body
of the lateral ventricle. In a median sagittal section, it the opposing hemispheres in the depths of the corpus of the fornix lies in the roof of the third ventricle, and
appears as a flattened bridge of white fibers, and its callosal sulcus. Its fibers diverge to all parts of the cere- the tela choroidea is subjacent; the lateral fringed
central part, or trunk, is convex upward. The anterior bral cortex. margins of this double fold of pia mater are the choroid
end is recurved to form the genu, which tapers rapidly plexuses of the central parts of the lateral ventricles,
into the rostrum. The expanded posterior end, or Fornix. Below the splenium and trunk of the corpus while an extension from the underside of the fold in
callosum are the symmetric arching bundles (crura of

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 35

P late 2-3 Brain: PART I

INFERIOR SURFACE OF BRAIN

Frontal pole

Surfaces of Cerebrum Straight gyrus Cerebral longitudinal fissure
Olfactory sulcus Genu of corpus callosum
(Continued) Orbital gyri Olfactory bulb
Orbital sulcus Olfactory tract
the midline forms the choroid plexus of the third Rhinal sulcus Lamina terminalis
ventricle. Lateral Optic chiasm
(sylvian) Optic (III) nerve
Cingulate Sulcus. The cingulate sulcus is easily iden- fissure Pituitary gland
tified on the medial surface, lying parallel to the corpus Inferior Temporal pole
callosum. It begins below the genu of the corpus cal- temporal Optic tract
losum and ends above the posterior part of the trunk sulcus Anterior (rostal)
by turning upward to cut the superior margin of the Inferior perforated
hemisphere. Opposite the middle of the trunk is another temporal substance
vertical branch sulcus, and the area of cortex between gyrus
these ascending sulci is the paracentral lobule, which
contains parts of the motor and sensory cortical areas. Tuber
The cingulate sulcus separates the medial frontal and cinereum
cingulate gyri, and below the genu and rostrum of the
corpus callosum are small parolfactory sulci separating Mammillary
the subcallosal (parolfactory) areas and paraterminal gyrus. body

Posterior Medial Surface. The posterior part of the Posterior
medial surface has two deep sulci. The upper parietooc- perforated
cipital sulcus inclines backward and upward to cut the substance
superior border. The lower calcarine sulcus extends
forward from the occipital pole to end beneath the Cerebral
splenium of the corpus callosum, and the isthmus of peduncles
cortex between them connects the cingulate and para- (crus
hippocampal gyri. The wedge-shaped region between cerebri)
the parietooccipital and calcarine sulci is the cuneus,
while the area between the parietooccipital sulcus and Lateral
the paracentral lobule is the precuneus. The main visuo- geniculate
sensory area is located in the walls of the calcarine body
sulcus and in the adjacent cortex.
Substantia
INFERIOR SURFACE OF CEREBRAL nigra
HEMISPHERE
The inferior surface is divided by the stem of the Lateral Medial
lateral sulcus into smaller, orbital and larger, tentorial occipito- geniculate
surfaces. temporal body
gyrus Pulvinar
The orbital surface rests on the roofs of the orbit and Red nucleus
nose and is marked by an H-shaped orbital sulcus, as well Occipito- Medial occipito- Superior (cranial) colliculus
as by a straight groove on the medial side, the olfactory temporal temporal gyrus Cerebral aqueduct (of Sylvius)
sulcus, which lodges the olfactory bulb and tract. The sulcus Splenium of corpus callosum
orbital sulcus demarcates the orbital gyri; the small con- Collateral sulcus Apex of cuneus
volution medial to the olfactory sulcus is the straight Occipital pole
gyrus. Parahippocampal gyrus Cerebral longitudinal fissure
â•…
The tentorial surface lies partly on the floor of the Lingual gyrus
middle cranial fossa and partly on the tentorium cere-
belli. It has two anteroposterior grooves, the collateral Uncus
and occipitotemporal sulci. Both run almost directly
forward from the occipital pole to the temporal pole; Calcarine sulcus
like other sulci, they may be subdivided, and the
Cingulate gyrus

anterior end of the collateral sulcus is called the rhinal which is partly occupied by the cortical olfactory area.
sulcus. The parahippocampal and lingual gyri lie medial to The medial occipitotemporal gyrus is fusiform in shape,
the collateral sulcus. The dentate gyrus, a narrow fringe and lies between the collateral and occipitotemporal
of cortex with transverse markings, occupies the groove sulci. The lateral occipitotemporal gyrus lies lateral to the
between the parahippocampal gyrus and the fimbria of occipitotemporal sulcus and is continuous with the infe-
the hippocampus. The anterior end of the parahippo- rior temporal gyrus around the inferior margin of the
campal gyrus becomes recurved to form the uncus, hemisphere.

36 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 2-4 Cerebral Cortex and Neurocognitive Disorders

CEREBRAL CORTEX: LOCALIZATION OF FUNCTION AND ASSOCIATION PATHWAYS

Cerebral Cortex: Function Motor-sensory Ms I Sm I
and Association Pathways Ms II Sm II
Sensory-motor
In humans, the cerebral cortex is highly developed, and
the complexity of the interhemispheric and intrahemi- Premotor; orientation; (to Ms II) Sensory analysis
spheric connections parallels this degree of develop- eye and head movements
ment. The cerebral cortex has definite areas related to
specific neurologic functions, either for primary sensory Prefrontal; inhibitory Visual III
reception or for complex integrated activity. control of behavior; Visual II
higher intelligence Visual I
Association Pathways. When one cortical area is
activated by a stimulus, other areas also respond. This Motor control of speech Language; reading; speech
is due to the rapid activity along a large number of Auditory I
precisely organized, reciprocally acting association Auditory II
pathways. The pathways may be very short, linking
neighboring areas and running only within the gray Motor-sensory Ms I Sm I Sensory-motor
matter, or they may be longer (arcuate) bundles, Ms II Sm II
passing through the white matter to connect gyrus to Temporocingulate and
gyrus or lobe to lobe within a cerebral hemisphere– Premotor parietocingulate pathway
intrahemispheric connection. Other commissural bundles
conduct interhemispheric activity: the most prominent Prefrontal; inhibitory Visual III
are the corpus callosum, a large band of fibers, which lies control of behavior; Visual II
immediately beneath the cingulum; the anterior commis- higher intelligence Visual I
sure, which connects both temporal lobes; and the hip-
pocampal commissure (commissure of the fornix), which Fronto- Olfactory Corpus callosum
connects the right and left hippocampus. cingulate
pathway â•… Hippocampal commissure
The reciprocal activity of the connections in the Anterior commissure
cerebral cortex ensures the coordination of sensory Cingulate gyrus
input and motor activity, as well as the regulation of (emotional behavior)
higher function. For example, for the appreciation and and cingulum
integration of visual information, the primary visual
sensory area of the occipital cortex is linked to the visual Temporal Lobe. The posterior part of the temporal lobe psychomotor seizures or, if they occur in the region of
association areas. These visual centers are connected by is concerned with the reception and interpretation of the uncus, by uncinate “fits” characterized by alteration
intrahemispheric fibers to the ipsilateral parietal cortex, auditory information, and with some aspects of pattern of consciousness and hallucinations of taste and odor.
as well as to other areas, such as the temporal lobe, for recognition and higher visual coordination; the intercon-
further integrated activity. The right and left parietal nections of the auditory and visual segments of the Lesions. In general, lesions of primary receptive areas
and posterior temporal areas, in turn, are connected by occipital, temporal, and parietal lobes make this a highly produce identifiable deficits. A lesion in a specific area
the corpus callosum. integrated function. The anterior part of the temporal lobe of the cerebral cortex may produce a deficit far beyond
is concerned with visceral motor activity and certain the functional identity of that particular area because
Prefrontal Cortex. The prefrontal cortex, (which aspects of behavior. Lesions here may be manifested by the complex interconnections beneath that cortical
includes the three frontal gyri, the orbital gyri, most of region may be damaged.
the medial frontal gyrus, and approximately half of the
cingulate gyrus) is concerned with higher mental func-
tions, and is involved with many behavioral aspects of
man. This area receives numerous connections from
the temporal and parietal lobes via pathways in the
cingulum, a bundle of long association fibers lying
within the cingulate gyrus. Bilateral lesions of the pre-
frontal area produce a loss of concentration, a decreased
intellectual ability, and memory and judgment deficits.

Motor and Sensory Cortices. The somatosensory cortex,
which occupies contiguous parts of the frontal and pari-
etal lobes, and the premotor cortex of the frontal lobe are
concerned with the initiation, activation and perfor-
mance of motor activity, and the reception of primary
sensation of the body. Lesions of the somatosensory
cortex result in contralateral paralysis and loss of
somatosensory reception or perception.

Parietal Lobe. The parietal lobe is primarily con-
cerned with the interpretation and integration of infor-
mation from sensory areas, that is, the visual areas and
the somatosensory cortex. Lesions in the parietal lobe
result in sensory ataxia, a loss of general awareness,
defective recognition of sensory impulses, and a lack of
interpretation of spatial relationships.

Occipital Lobe. Lesions of the striate cortex (the
primary visual area) on one side result in a contralateral
hemianopsia, while lesions of the secondary regions of
the visual cortex cause a lack of ability to interpret visual
impulses.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 37

Plate 2-5 Brain: PART I

Superior occipitofrontal fasciculus
Superior longitudinal fasciculus

Inferior occipito-
frontal fasciculus

Uncinate fasciculus

Superior occipito- Cingulum
frontal fasciculus

Major Cortical Association Superior Lateral
Bundles longitudinal fissure
fasciculus

Association fibers are predominantly located in the Caudate Claustrum
cerebral white matter and connect intrahemispheric nucleus
cortical regions. There are two main types of associa-
tion fibers, and they are differentiated by size and func- Putamen Thalamus Internal capsule
tion. Short association fibers known as arcuate fibers
or “U fibers” connect adjacent gyri, thus allowing for Globus
communication between neighboring cortical regions. pallidus
Long association fibers provide the architectural basis
for large-scale neurocognitive networks. These net- Hypothalamus
works connect more widespread cortical regions and
are visualized as “bundles of fibers” that allow com- Inferior occipito- Uncinate fasciculus
munication between primary and association cortical frontal fasciculus
regions. For instance, the superior longitudinal fasciculus
(SLF) (which has three major bundles, I, II, and III) â•…
allows communication between the parietal and frontal
lobes. In particular, the SLF I allows information from The cingulum bundle enables monoamines (dopamine, right anterior frontal cortex (e.g., from a stroke) will
the superior parietal lobe, or motor cortex, to be relayed norepinephrine, and serotonin), along with cholinergic have a “disconnection” between the temporal and
to the supplementary motor cortex. SLF II connects the projections, to travel to widespread cortical targets. frontal lobes. This individual may develop amnesia for
caudal parietal region with the prefrontal lobes, thus experiences predating the stroke, along with impair-
allowing an individual to have a visual perception of Lesions to cortical association bundles can provide ment of self-awareness of personal experiences across
space. SLF III connects rostral parietal areas with the clinical relevance to fiber pathway tracts and cortical time (this clinical finding is also known as a disruption
frontal opercular region (the region that controls facial origins and destinations. For instance, a patient who of autonoetic consciousness).
movements), thus enabling an individual to imitate an develops acute damage to the uncinate fasciculus and
action. Other long association fibers include the fronto-
occipital fasciculus, which links the posterior and medial
parietal and occipital areas; the uncinate fasciculus (or the
anterior limbic fiber bundle), which connects the tem-
poral lobe and frontal lobes; the inferior longitudinal
fasciculus, which connects the temporal lobe to the
occipital and parietal regions, and the cingulum bundle
(or the posterior limbic fiber bundle), which stretches
from the frontal lobe to the parahippocampal gyrus.

38 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 2-6 Cerebral Cortex and Neurocognitive Disorders

Corticocortical projections Subcorticocortical projections
Nucleus basalis
Frontal Primary motor cortex of Meynert
association Primary somato- (acetylcholine)
cortex sensory cortex

Primary
visual cortex

Primary auditory cortex Locus ceruleus
Temporal association cortex (norepi-
nephrine)
Corticocortical projection neurons
connect with adjacent cortical Cortical activity
areas and interconnect primary is modulated via
motor and sensory cortices excitatory and
with association areas. inhibitory sub-
corticocortical
projections in
subcortical areas.

Raphe nuclei (serotonin)
Selective loss of corticocortical and subcorticocortical projections

Normal Alzheimer disease
Corticocortical Loss of corticocortical
projection neuron projection neuron
Neurofibrillary
tangle

Corticocortical and
Subcorticocortical
Projection Circuits

The cerebral white matter consists of myelinated Corticocortical Subcortico- Loss of cortico- Preservation
axons that link cortical areas with both cortical and projections cortical cortical projection of some
subcortical regions. There exist three main categories projections intracortical
of efferent fibers from a cortical area: association fibers, Nucleus basalis neurons
striatal fibers, and commissural/subcortical fibers. Cor- (acetylcholine)
ticocortical projections allow both adjacent and distant
cortical regions to communicate, whereas corticosub- Locus ceruleus Loss of
cortical projections allow reciprocal communication (norepinephrine) subcortical
between cortical regions and subcortical structures. neurons
These subcorticocortical projections connect the cortex Raphe nuclei projecting
to the thalamus, the pontocerebellar system, brainstem, (serotonin) to cortex
and spinal cord. Noncortical projections Preservation of noncortical
projection neurons
Corticocortical Circuits. Local short association Corticocortical projection neurons project Alzheimer-related loss of subcorticocortical
fibers, or U fibers, connect adjacent cortical gyri and lie to neurons in distant areas of cortex. They projection-neurons results in loss of those
beneath the sixth cortical layer. Neighborhood associa- receive subcorticocortical projections circuits and cognitive dysfunction.
tion fibers traverse longer distances than U fibers, but from neurons in subcortical nuclei.
still connect nearby cortical regions. Long association
fibers travel within the same hemisphere and connect â•…
more distant cortical regions. These include the supe-
rior, middle, and inferior longitudinal fasciculi, arcuate Cortical activity is modulated via excitatory and inhibi- of adjacent cortex and cortical association areas. The
fasciculus, extreme capsule, fronto-occipital fasciculus, tory projections in subcortical areas. For instance, disconnection of subcorticocortical circuits is evident
uncinate fasciculus, and cingulum bundle (see Plate 2-5, diffuse cortical cholinergic projections to the cortex rise in the reduction of cholinergic projections throughout
Major Cortical Association Bundles). from the nucleus basalis of Meynert, and norepineph- the cortex, resulting in reduced acetylcholine levels
rine projections from the locus ceruleus. in the cortex. This observation led to the development
Subcorticocortical Circuits. Striatal fibers describe of the first effective therapies for Alzheimer disease,
fiber groups that connect cortical regions to the stria- In the case of Alzheimer disease, a loss of corticocor- acetylcholinesterase inhibitors, which boost acetylcho-
tum (the caudate and putamen). For instance, these tical projection neurons is associated with neurofibril- line levels in the brain.
fibers allow cortical motor control. The commissural lary tangle formation. This indicates a “disconnection”
bundle is a collection of fibers that travel from a cortical
region to the opposite hemisphere via the corpus cal-
losum or anterior commissure. Subcortical fibers travel
via the internal capsule to diencephalic structures (e.g.,
thalamus) and brainstem (e.g., pons). The origins of the
subcorticocortical cell bodies are laminae V and VI.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 39

Plate 2-7 Brain: PART I

Frontal forceps (forceps minor)

Commissural fibers

Indusium griseum

Medial longitudinal stria

Lateral longitudinal stria

Occipital forceps (forceps major)
Schematic view of the lateral extent of major components

Forceps minor

Corpus Callosum

The corpus callosum is the major commissure of the Color imaging of the corpus callosum, by diffusion Genu
forebrain, connecting homologous cortical regions of tensor imaging (DTI), axial view. From Felten DL, Body
the two cerebral hemispheres. The corpus callosum is Shetty AN. Netter’s Atlas of Neuroscience, 2nd ed. Lateral fibers of corpus callosum
divided into anterior and posterior parts, known as the Philadelphia: Elsevier, 2010. Splenium
genu and splenium, respectively. The genu includes Forceps major
fibers of the frontal forceps (forceps minor) intercon-
necting frontal areas. Posteriorly, the splenium includes â•…
the occipital forceps (forceps major), interconnecting
the parietal, occipital, and temporal lobes. A corpus
callosotomy, a surgical lesioning of the corpus callosum,
has been performed in patients with medication-
refractory epilepsy. The goal of this surgery is to
prevent seizure spread from one hemisphere to another.

Agenesis of the corpus callosum (ACC) is a congeni-
tal birth defect characterized by an absence of a corpus
callosum. This condition can occur in isolation (with
little to no impact on cognitive performance) or can
occur as part of abnormalities such as Dandy-Walker
syndrome, Arnold-Chiari malformation, schizenÂ

P late 2-8 Cerebral Cortex and Neurocognitive Disorders

Rhinencephalon and Anterior nucleus of thalamus Fornix Stria terminalis
Limbic System Interventricular foramen Interthalamic adhesion
Anterior commissure Stria medullaris
The rhinencephalon is a term that describes quite liter- Habenula
ally the “nose” or “smell” regions of the brain. The Cingulate gyrus
limbic system refers to the structures and tracts involved Indusium griseum Calcarine
with emotion, including memory formation, as well Corpus callosum sulcus
as autonomic and endocrine response to emotional Septum pellucidum Gyrus fasciolaris
stimuli. The terms rhinencephalon and limbic system Septal nuclei Dentate gyrus
are sometimes used synonymously, but the rhinenceph- Subcallosal area Fimbria of hippocampus
alon refers to olfactory structures and related pathways. Paraterminal gyrus Hippocampus
Located in the medial and inferior surface of the fore- Lamina terminalis Parahippocampal gyrus
brain, these parts include the olfactory bulb, tract and Descending connections to reticular
striae, the anterior perforated substance, the uncus, the bulb and tegmental nuclei of brainstem
hippocampus, the dentate gyrus, the gyrus fasciolaris, Olfactory tract
the indusium griseum, the habenular trigone, the sub-
callosal area, the paraterminal gyrus, the fornix, and the medial stria
amygdaloid body as direct olfactory afferents project to lateral stria
the amygdala. The olfactory pathway is described and
illustrated in Plate 5-8. Anterior perforated substance
Optic chiasm
The limbic forebrain refers to the areas that are
functionally and anatomically connected structures that Mamillary body and mamillothalamic tract
relate to emotion, motivation, and self-preservation. Medial forebrain bundle
The limbic system is thought to be a major substrate Amygdaloid body
for regulation of emotional responsiveness and behav- Interpeduncular nucleus
ior, for individualized reactivity to sensory stimuli and Uncus
internal stimuli, and for integrated memory tasks. The Fasciculus retroflexus
main regions of the limbic forebrain include the hypo-
thalamus, amygdala, hippocampus, and limbic cortex Corpus callosum and indusium griseum
(prefrontal cortex and orbital frontal cortex). The hip- Cerebral longitudinal fissure
pocampal formation and amygdala send axonal projec- Genu of corpus callosum
tions through the forebrain, via the fornix and stria Indusium griseum (on upper
terminalis, respectively, to the hypothalamus and septal surface of corpus callosum)
region. The amygdala also has a more direct pathway Medial longitudinal striae
to the hypothalamus via the anterior amygdalofugal Lateral longitudinal striae
pathway. The septal nuclei lie rostral to the hypothala- Trunk of corpus callosum
mus, and send axons to the habenular nuclei via the stria Splenium of corpus callosum
medullaris thalami.
â•…
Piriform Area. The anterior (rostral) perforated
substance, the uncus, the anterior end of the dentate perception of smell. The anterior perforated substance is Anteriorly, it curves around the genu and rostrum to
gyrus, and the anterior part of the parahippocampal continuous with the paraterminal gyrus and separated merge with the paraterminal gyri; laterally, it becomes
gyrus medial to the rhinal sulcus are often referred to from the anterior part of the globus pallidus of the continuous with the cortex of the cingulate gyrus; and
as the piriform area. These regions function to give lentiform nucleus by the anterior (rostral) commissure, posteriorly, it passes over the splenium to blend with
ansa lenticularis, and ansa peduncularis; posteromedi- the dentate and parahippocampal gyri through the
ally, it blends into the tuber cinereum. narrow gyrus fasciolaris. Two slender strands of white
fibers, the medial and lateral longitudinal striae, are
The indusium griseum is a thin layer of gray matter embedded in the indusium griseum.
spread over the upper surface of the corpus callosum.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 41

P late 2-9 MAJOR AFFERENT AND EFFERENT CONNECTIONS OF THE HIPPOCAMPAL FORMATION Brain: PART I

Afferent connections Cingulate cortex Fornix Mammillothalamic
Efferent connections tract
Postcommissural fornix Mammillotegmental
Precommissural fornix tract
Calcarine fissure
Corpus Inputs to hippocampus
callosum and dentate gyrus:
Raphe nuclei (5HT)
Association areas Thalamus Locus coeruleus (NE)
of frontal lobe Hypo-
Septal nuclei thalamus

Nucleus accumbens (ventral striatum) Fimbria
Mammillary body Inputs to entorhinal cortex:
Sensory association cortices
Amygdala Polysensory association cortex
Prefrontal cortex
Efferents of subiculum to amygdala, Dentate gyrus Subiculum Entorhinal cortex Insular cortex
association areas of temporal lobe Perforant pathway Amygdala
Olfactory bulb
CA regions of hippocampus Inputs to subiculum:
Amygdala

â•…

Hippocampus hippocampus is an important part of the olfactory appa- The dentate gyrus contains granule cells that project
ratus in lower animals; in humans, few or no secondary to the pyramidal cells of the hippocampus and subicu-
Hippocampal Formation. The hippocampus, the pos- olfactory fibers end in it. However, it possesses substan- lum and receive hippocampal input. The afferent con-
terior part of the dentate gyrus and the indusium tial connections with the hypothalamus, which regu- nections to the hippocampal formation include the
griseum are sometimes grouped together as the hip- lates many visceral activities that influence emotional cerebral association cortices, prefrontal cortex, cingu-
pocampal formation. In humans, the attenuated gray behavior and with temporal lobe areas reputedly associ- late cortex, the insular cortex, amygdaloid nuclei, and
and white structures of this formation are produced by ated with memory. olfactory bulb via projections to the entorhinal cortex.
the enormous enlargement of the corpus callosum, Afferent cholinergic axons from septal nuclei traverse
which encroaches upon the parahippocampal and The dentate gyrus (dentate fascia) is a crenated fringe the fornix to provide the dentate gyrus and hippocam-
dentate gyri and the hippocampi, thus expanding them. of cortex occupying the narrow furrow between the pal CA regions.
fimbria of the hippocampus and the parahippocampal
The hippocampus is a part of the marginal cortex gyrus. Anteriorly, this fringe fades away on the There exist several clinical conditions where damage
of the parahippocampal gyrus that has been invagi- surface of the uncus, and posteriorly, it becomes con- unique to the hippocampal formation occurs. CA1
nated, or rolled, into the floor of the inferior horn of tinuous with the indusium griseum through the gyrus neurons are particularly susceptible to ischemic condi-
the lateral ventricle by the exuberant growth of the fasciolaris. tions as seen in cardiorespiratory arrest. Also, patients
nearby temporal cortex. The curved hippocampal emi- with temporal lobe epilepsy can suffer CA1 neuronal
nence is composed mostly of gray matter, and its ante- The hippocampus contains pyramidal cells in regions loss. The most common clinical scenario affecting
rior end is expanded and grooved like a paw, the pes CA1 and CA3 that project via the efferent fornix to the hippocampal formation is Alzheimer disease (AD).
hippocampi. Axons conveying efferent impulses from the the septal nuclei and hypothalamus. The subiculum AD is pathologically associated with neuronal cell loss,
pyramidal cells of the hippocampus form a white layer receives input from the hippocampal pyramidal cells neurofibrillary tangles, neuritic amyloid plaques, and
on its surface, the alveus, and then converge toward and also projects via the fornix to the mammillary granule vacuolar degeneration of the hippocampal
its medial edge to form a white strip, the fimbria. The nuclei and anterior nucleus of the thalamus. It is con- region. AD is discussed in more detail in Plates 2-24
nected reciprocally with the amygdala and sends axons to 2-26.
to cortical association areas of the temporal lobe.

42 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 2-10 Cerebral Cortex and Neurocognitive Disorders

Superior HIPPOCAMPUS AND FORNIX
dissection Genu of corpus callosum (cut)

Septum pellucidum

Head of caudate nucleus

Columns of fornix

Stria terminalis

Body of fornix

Pes hippocampus

Thalami

Crura of fornix

Commissure of fornix

Dentate gyrus

Fimbria of hippocampus

Hippocampus

Splenium of corpus
callosum (cut)

Lateral ventricle

Calcar avis

Fornix Body of fornix Occipital (posterior) horn
of lateral ventricle
The fornix is an almost circular arrangement of white
fibers conveying the great majority of the hippocampal Tail of caudate nucleus
efferents to the hypothalamus and carrying commis- Choroid plexus
sural fibers to the opposite hippocampus and habenular Fimbria of hippocampus
trigone. The fornix rises out of the fimbria of the hip- Optic tract
pocampus, which turns upward beneath the splenium
of the corpus callosum and above the thalamus to form Columns of fornix Commissure of fornix
the crura (posterior columns) of the fornix. Anterior to
the commissure of the fornix, the two crura unite for a Crura of fornix Hippo-
variable distance in the midline and create the triangu- campal
lar body of the fornix. The free lateral edges of the fornix sulcus
help to bind the choroid fissure, through which the pia Dentate
mater of the tela choroidea becomes invaginated into gyrus
the lateral ventricles.
Hippocampus
Above the interventricular foramina, the two halves
of the body of the fornix separate to become the (ante- Mammillary Fimbria of Alveus of hippocampus
rior) columns of the fornix. As each column descends, it bodies hippocampus
sinks into the corresponding lateral wall of the third Hippocampus Temporal (inferior) horn of lateral ventricle
ventricle; the majority of its fibers end in the mammil- Amygdaloid bodies Coronal section: posterior view
lary body, although some also pass to other hypotha- Fornix: schema â•…
lamic nuclei.
demarcating the superior and medial surfaces of the The fresh relay of fibers arising in the habenular nucleus
The fornix is the main efferent pathway from the thalamus. This stria conveys fibers from the anterior passes by way of the fasciculus retroflexus to the inter-
hippocampus to the hypothalamus. Fibers ending in perforated substance, the paraterminal gyrus and sub- peduncular nucleus in the posterior (interpeduncular)
the mammillary body form synapses around its cells. callosal area, and perhaps other fibers detached from perforated substance. Efferent fibers from the interpe-
The axons of these cells pass upward in the mammil- the stria terminalis near the interventricular foramen. duncular nucleus then descend in or near the medial
lothalamic tract to the homolateral anterior thalamic Most of these fibers end in the homolateral habenular longitudinal fasciculus to be distributed to tegmental
nucleus, from which they are relayed to the cingulate nucleus, but some decussate in the small habenular and reticular nuclei in the brainstem. The amygdaloid
gyrus. commissure lying above the stalk of the pineal gland. body is described in Plate 2-11.

Other Structures. The habenular trigone is a small
area found bilaterally between the posterior end of the
thalamus, the superior (cranial) colliculus and the stalk
of the pineal gland. Each trigone overlies a habenular
nucleus, which receives afferent fibers via the stria medul-
laris of the thalamus (stria habenularis), a fine strand

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 43

Plate 2-11 Brain: PART I

HORIZONTAL BRAIN SECTIONS SHOWING THE BASAL GANGLIA

Level of section (amygdala,
anterior limb of internal capsule)

Body of corpus callosum

Cingulate cortex

Septum pellucidum Cingulum

Lateral fissure Body of lateral ventricle
Body of caudate nucleus

Insular cortex Temporal lobe
Columns of fornix Putamen
Genu/anterior limb
of internal capsule

Amygdala Inferior horn of Globus pallidus
lateral ventricle Optic tract
The amygdala is an almond-shaped complex located in
the medial temporal lobe, and contains approximately Amygdala III ventricle
13 nuclei. The three main regions are the corticomedial
nuclei, basolateral nuclei (both receive afferents and Hypothalamus
project axons to target structures), and central nucleus From Felten DL, Shetty AN. Netter’s Atlas of Neuroscience, 2nd ed.
(which provides mainly efferent projections to the Philadelphia: Elsevier, 2010.
brainstem). Afferent connections to the amygdala origi-
nate from cortical and thalamic areas, and hypothalamic Cleft for internal capsule
and brainstem areas. Its function is to provide emo-
tional relevance to external and internal sensory infor- Caudate nucleus Body Thalamus
mation and to provide a behavioral and emotional Head
response, particularly a fearful and aversive response, to
a sensory input. Lentiform nucleus (globus Pulvinar
pallidus medial to putamen) Medial geniculate body
The majority of afferent information arises from
the glutamatergic projections arising from pyramidal Lateral geniculate body
neurons in layer V of the cortex. These projections
largely travel ipsilaterally via the extreme capsule. Amygdaloid body Tail of caudate nucleus
Information from sensory association areas and
memory-related structures, such as the hippocampus, Schematic illustration showing interrelationship of thalamus, lentiform
are relayed via cortical and thalamic inputs. Autonomic nucleus, caudate nucleus, and amygdaloid body (viewed from side)
and behavioral inputs arise from the hypothalamus and
brainstem. â•…

Afferents to the corticomedial nuclei arrive primarily (hypermetamorphosis), visual agnosia, apathy, and aggressive behavior, and even apathy, can evolve in
from subcortical limbic sources, including the olfactory withdrawal. They linked this behavior to bilateral these patients. Damage to the hypothalamic connecÂ

Plate 2-12 Cerebral Cortex and Neurocognitive Disorders

Cerebral regions associated with hypothalamus

Premotor area Motor area (4)

Gyrus cinguli Somatosensory area
Fornix Corpus callosum
Hippocampus
Thalamus
Mammillary Hippocampal
body gyrus
Prefrontal
area Visual

Olfactory area

bulb

Forebrain Regions Associated Orbital cortex Rhinencephalic
with Hypothalamus Rhinal system 1 and isocortical
Rhinal system 2 regions presumably
The cerebral cortex influences the “autonomic” neuro- concerned in emotional and
visceral outflow and the neurohumoral output of the Amygdaloid complex visceroautonomic functions
endocrine glands, as can be demonstrated experimen- Rhinal system 3
tally by stimulating the orbitofrontal cortex of the
cingulate gyrus to produce respiratory, cardiovascular, Some circuits concerned with emotion,
and digestive responses, as well as certain emotional etc., affecting hypothalamic and
reactions. The responses are less marked than those cortical functions related to
produced by stimulating the hypothalamus but are blood preserve regulation
still striking; some of them, moreover, do not depend
upon the integrity of the hypothalamus, a fact that Frontal Gyrus cinguli Corpus callosum
suggests mediation by corticoreticular fibers to lower cortex (Area 24)
“centers.” In humans, subjective emotional experiences From
are associated with autonomic discharges (e.g., tachy- septal Septum
cardia, increased blood pressure, blushing) and changes subcallosal pellucidum
in endocrine activity (e.g., stress-induced amenorrhea preoptic (septal Ant. Medial Habenula
or anorexia nervosa). fronto- nuclei) Thal. thalamic
temporal Nuc. nucleus Stria
Behavioral changes produced by cortical ablations, areas terminalis
such as prefrontal lobotomy, are well known. Other Mammillo-
such changes, varying from mania and hyperphagia to Prefrontal and tegmental
apathy, aphagia, and somnolence, result from lesions to orbital cortex
certain parts of the hypothalamus. tract
Olfactory bulb Dorsal
Thus hypothalamic circuitry is tied into countless longi-
other circuits—in the cerebral cortex, limbic system, Hypothalamic nucleus Posteromedial tudinal
brainstem reticular formation, and other parts of the Anteromedial bundle
diencephalon. These circuits are poorly understood, Vagus
but rich connections with the frontotemporal and cin- Posterior hypothalamic area Red nucleus nerve
gulate cortex, septal/preoptic areas, amygdala, anterior Hypophysis
mesencephalic tegmentum, and numerous thalamic
nuclei (midline, intralaminar, medial posterior, anterior, Mammillary hypothalamic nuclei
etc.) have been demonstrated.
Hippocampus
Some of these connections are indicated schemati-
cally in the illustration. Connections between the orbital Amygdala
cortex of the frontal lobe and the hypothalamus have
been demonstrated in certain mammals. Indirect con- Interpeduncular nucleus
nections with the prefrontal areas through the medial
posterior thalamic nucleus are well established. The hypo- Reticular formation
thalamus is linked with the cingulate gyrus by way of the Medullary cardiovascular centers
anterior thalamic nuclei and with the hippocampal forma-
tion via the fornix. The amygdala has reciprocal conÂ

P late 2-13 Brain: PART I

Central sulcus

Thalamocortical Radiations

All pathways carrying information from the periphery Internal medullary lamina
or the brainstem to the neocortex relay in the nuclei of
the posterior thalamus. These nuclei can be divided into Intralaminar nuclei
two groups on the basis of their structure, connections, Other medial nuclei
and function.
MD Midline (median) nuclei
Nonspecific Nuclei. The first group includes the Interthalamic adhesion
midline (median) and intralaminar nuclei and the medial
portion of the ventral anterior nucleus. These nuclei Anterior nuclei LD CM Pulvinar
receive ascending input from the mesencephalic reticu- From globus LP VPM
lar formation and from the spinal cord (paleospinotha- pallidus and Medial
lamic tract), and descending input from the cerebral substantia nigra VA geniculate
cortex. They project widely, both to other thalamic Reticular nucleus VL body (MGB)
nuclei and to the cortex, especially to its frontal regions. (pulled away) VI Acoustic
These projections are thought to be essential in regulat- VPL pathway
ing the general excitability of neurons in the thalamus Lateral geniculate body (LGB)
and cortex. From cerebellum Optic tract

Another nucleus included in the first group is the Somesthetic from head (trigeminal nerve)
reticular nucleus, which overlies the lateral surface of
the thalamus. Neurons of this nucleus, which receive Somesthetic from body (spinothalamic tract and medial lemniscus)
input from collaterals of thalamocortical fibers and proÂ

P late 2-14 Cerebral Cortex and Neurocognitive Disorders

Neuronal Structure Structure of a neuron (pyramidal cell of cerebral motor cortex)
and Synapses
Dendrites
NEURONAL STRUCTURE
A typical neuron of the central nervous system consists Dendritic spines (gemmules)
of three parts: dendritic tree, cell body (soma), and axon.
Rough endoplasmic reticulum
The highly branched dendritic tree has a much greater (Nissl substance)
surface area than the remainder of the neuron and is
the receptive part of the cell. Incoming synaptic termi- Ribosomes
nals make contact directly with the dendritic surface or
with the small spines (gemmules) that protrude from it. Mitochondrion
The membrane potential induced in the dendrites
spreads passively onto the cell soma, which allows all Nucleus Axon
inputs acting on the neuron to summate in controlling Nucleolus
the rate of neuronal discharge through the axon.
Axon hillock
The soma contains the various organelles that control
and maintain neuronal structure: nucleus, Golgi appa- Neurotubules
ratus, lysosomes, ribosomes, mitochondria, and smooth Golgi body
and rough endoplasmic reticula. The rough endoplas- Lysosome
mic reticulum, studded with ribosomes, is called the Cell body (soma)
Nissl substance because of its characteristic blue staining Axosomatic synapse
with Nissl stain. The ribosomes are the site of synthesis Glial (astrocyte) process
of neuronal proteins; as in other cells, the ribonucleic Axodendritic synapse
acid (RNA) templates that control protein structure are
transcribed from patterns in the nuclear deoxyribonu- Types of synapses B. Dendritic spine synapse C. Dendritic crest synapse
cleic acid (DNA). The soma membrane is also covered A. Simple axodendritic or
with synaptic endings separated by glial processes.
Because of their proximity to the origin of the axon, axosomatic synapse
these synaptic endings have an especially potent effect
on the rate of discharge of the neuron. Axon Dendrite or Axon Dendritic Axon
Glial cell body spine
In humans, the axon can extend for several feet. Such process Dendrite (gemmule)
lengths pose supply problems because the neuron must D. Simple synapse plus
transport proteins and other synthesized substances as E. Combined axoaxonic F. Varicosities
far as the axon terminals. Certain key substances are axoaxonic synapse and axodendritic synapse (“boutons en passant”)
transported, at a rate as high as 400╯mm/day, by rapid
axonal transport, a process probably associated with the I. Serial synapse
microtubules that originate in the soma and run the
length of the axon. Other soluble and particulate sub- G. Dendrodendritic synapse H. Reciprocal synapse
stances move by slow axonal transport at a rate of 1 to
4╯mm/day, aided partly by the peristalsis-like motion of Den- Dendro- K. Inner plexiform layer of retina
the axon. drite dendritic Ganglion cell
synapse
The axon originates from a conical projection (axon
hillock) on the soma (as shown in Plate 2-14) or on one J. Cerebellar glomerulus Granule cell dendrites
of the proximal dendrites. The axon membrane is spe- Glial capsule Bipolar cell axon
cialized for the transmission of action potential. Because
of its shape and high excitability, the initial segment of Golgi cell axon
the axon is usually the site of action potential genera-
tion. The action potential then spreads down the axon Müller cell (supporting)
and back to the soma and proximal dendrites. Because
of the low excitability of the dendrites, the impulse Golgi cell Mossy cell axon Amacrine cell processes
usually does not spread very far into the dendritic tree. dendrite
At its distal end, the axon divides into numerous â•…
branches, which end in synapses.
of presynaptic inhibition. Axoaxonic synapses are also Other synapses are those formed between the periph-
TYPES OF NEURONAL SYNAPSES seen in the efferent vestibular system and in connection eral axonal processes of sensory neurons and sensory
The most common central nervous system (CNS) syn- with motor neuron dendrites and other terminals receptor cells, as in the inner ear. Here, the axon terminal
apses are those between axon terminals and dendrites ending on those dendrites. forms the postsynaptic element that is depolarized by
(axodendritic) or between axon terminals and somata the presynaptic sensory cell.
(axosomatic). Axodendritic synapses take several forms. The CNS also contains several less common types of
Spine synapses are of particular interest, because they synapses. Dendrodendritic synapses are found in the olfac- There are also specialized axosomatic synapses
may be the site of morphologic changes accompanying tory bulb. In the internal plexiform layer of the retina, formed by efferent motor axons on muscle (motor
learning. Axosomatic synapses are of the simple type synaptic interactions involve synaptic triads of bipolar, end plates) and by autonomic axons on secretory
shown in example A. Synaptic interconnections between amacrine, and ganglion cell processes. cells.
a number of neurons occur within structures of a
complex organization, such as the cerebellar glomeru-
lus, although all synapses within the glomerulus are
axodendritic.

Axons also form axoaxonic synapses with other axon
terminals, and these are responsible for the phenomenon

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 47

P late 2-15 Brain: PART I

Chemical Synaptic Excitatory Inhibitory
Transmission + + Na+ + + +
– – – –– Synaptic ++ + ++
Chemical synaptic transmission proceeds in three steps: vesicles –– – ––
(1) the release of the transmitter substance from the K+ in synaptic
bouton in response to the arrival of an action potential, bouton Cl–
(2) the change in the ionic permeabilities of the post- Presynaptic
synaptic membrane caused by the transmitter, and (3) membrane
the removal of the transmitter from the synaptic cleft. Transmitter
Depending on the type of permeability changes pro- substances
duced in the second step, synaptic activation may have Synaptic cleft
either an excitatory or an inhibitory effect on the post- Postsynaptic
synaptic cell. membrane

Synaptic transmitter substances are concentrated in When impulse reaches excitatory synaptic At inhibitory synapse, transmitter substance
synaptic vesicles within the bouton. Although the exact bouton, it causes release of a transmitter released by an impulse increases permeability
mechanism of its release is unknown, it appears that the substance into synaptic cleft. This increases of the postsynaptic membrane to Cl–. K+ moves
transmitter substance is released in packets, or quanta, permeability of postsynaptic membrane to out of postsynaptic cell, but no net flow of Cl–
of 1,000 to 10,000 molecules at a time, and that the Na+ and K+. More Na+ moves into post- occurs at resting membrane potential.
probability of release of these quanta increases with the synaptic cell than K+ moves out, due to
degree of depolarization of the terminal membrane. greater electrochemical gradient.
Thus the intense depolarization caused by an action
potential actuates the nearly simultaneous release of a Synaptic bouton
large number of quanta. A reasonable hypothesis to
account for the quantal nature of transmitter release is Resultant net ionic current flow is in a direction Resultant ionic current flow is in direction that
that the contents of an entire vesicle are discharged at that tends to depolarize postsynaptic cell. If tends to hyperpolarize postsynaptic cell. This
once into the synaptic cleft, perhaps by the process of depolarization reaches firing threshold, an makes depolarization by excitatory synapses
exocytosis. impulse is generated in postsynaptic cell. more difficult—more depolarization is required
to reach threshold.
After their release, transmitter molecules diffuse Current
across the synaptic cleft and combine with specific –65 Potential –70 0 msec 16
receptor molecules in the postsynaptic membrane. This 4 8 12
combination gives rise to a change in the ionic perme-
ability of the postsynaptic membrane and results in a Potential (mV) Potential
flow of ions down their electrochemical potential gra- Potential (mV)
dients. This ionic flow is not synchronous with the –70 0 –75 Current
arrival of the action potential in the terminal but begins
after a synaptic delay of 0.3 to 0.5╯msec, which is the time 4 8 12 16
required for transmitter release and diffusion and for msec
the completion of reactions within the postsynaptic
membrane, which alter membrane permeability. Current flow and potential change Current flow and potential change
â•…
The direction of current flow produced by transmit-
ter action depends upon which ionic permeabilities are potential (IPSP), moves the membrane potential away the synaptic current charges the membrane capacitance,
altered. In an excitatory synapse, the transmitter causes from the threshold for action potential initiation. The which then discharges passively over a period of 10 to
an increase in the permeability of the postsynaptic increased ionic permeability of the postsynaptic mem- 15╯msec. The short duration of the synaptic current is
membrane to sodium ions (Na+) and potassium ions brane also contributes to the inhibitory effect by the consequence of the removal of transmitter from the
(K+). Because of their respective concentration gradi- tending to “short out” any membrane depolarization synaptic cleft. This removal is accomplished in part by
ents across the neuronal membrane (see Plate 2-15), occurring simultaneously. passive diffusion and in part by specific mechanisms
Na+ tends to move into the postsynaptic cell, and K+, that lead to transmitter uptake by surrounding cells or
out of it. The negative potential of the neuronal cyto- The ionic current and the resulting membrane transmitter breakdown by enzymatic degradation.
plasm, however, assists the inward flow of positive ions potential change have different time courses because
and retards their outward flow so that the combined
electrochemical force for Na+ influx greatly exceeds that
for K+ efflux. Thus the predominant ionic movement
across the postsynaptic membrane is an inward flow of
Na+. As shown, the resulting current flow causes a shift
of the postsynaptic cell membrane potential in the
depolarizing direction. This depolarizing potential
change, which is called an excitatory postsynaptic potential
(EPSP), brings the postsynaptic cell closer to its thresh-
old for action potential initiation.

In an inhibitory synapse, transmitter action causes an
increase of the postsynaptic membrane’s permeability
to K+ and chloride ions (Cl−) but not to Na+. Because
Cl− is approximately at electrochemical equilibrium
across the neuronal membrane, the major ionic move-
ment is an outward flow of K+. The resulting current
flow is in the opposite direction to that of the current
flow in an excitatory synapse, and gives rise to a shift
of the postsynaptic cell membrane potential in the
hyperpolarizing direction. This hyperpolarizing poten-
tial change, which is called an inhibitory postsynaptic

48 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 2-16 Cerebral Cortex and Neurocognitive Disorders

Summation of Excitation A. Resting state: motor nerve cell Excitatory fibers mV
and Inhibition shown with synaptic boutons of Inhibitory fibers –70
excitatory and inhibitory nerve
Summation of excitation and inhibition is the vital fibers ending close to it Axon
principle on which the functioning of the CNS is
based. The illustration shows the various intracellular Excitatory fibers mV B. Partial depolarization: impulse
potential changes observed during temporal and spatial –70 from one excitatory fiber has caused
summation of excitation and inhibition, as voltage- partial (below firing threshold)
versus-time tracings similar to those produced by an Axon depolarization of motor neuron
oscilloscope.
Inhibitory fibers mV
The principle of summation relates to the fact that a –70
neuron typically has a large number of synaptic termi- Excitatory fibers
nals (boutons) ending upon it; alone, each bouton is Axon
capable of producing only a small synaptic potential. C. Temporal excitatory summation:
The small excitatory postsynaptic potential (EPSP) a series of impulses in one excitatory Inhibitory fibers
produced by a single excitatory terminal is not sufficient fiber together produce a suprathresh-
to depolarize the motor neuron to its threshold point. old depolarization that triggers an
For suprathreshold depolarization to be produced, action potential
either temporal or spatial summation of excitation must
take place. Excitatory fibers mV D. Spatial excitatory summation:
–70 impulses in two excitatory fibers
Temporal summation occurs when a burst of action cause two synaptic depolarizations
potentials reaches a nerve fiber terminal. If the terminal Axon that together reach firing threshold
is excitatory, the first action potential in the burst pro- triggering an action potential
duces a depolarizing EPSP in the motor neuron that Inhibitory fibers
begins to decay toward the resting potential. Before mV
the decay is complete, another action potential arrives Excitatory fibers –70
in the terminal and evokes a second EPSP. The depo-
larization caused by this EPSP adds to the residual E. Spatial excitatory summation Axon
depolarization remaining from the first EPSP and with inhibition: impulses from two
moves the membrane potential closer to the threshold excitatory fibers reach motor neuron
level. Finally, the EPSP evoked by a third action poten- but impulses from inhibitory fiber
tial adds its depolarization to that produced by the first prevent depolarization from reaching
two to drive the membrane potential past the threshold threshold
level and to trigger an action potential in the motor Inhibitory fibers
neuron. Thus, because of temporal summation, a burst
of action potentials in an excitatory fiber is able to evoke Excitatory fibers mV E. (continued): motor neuron now
the firing of a target neuron, even though the individual Inhibitory fibers –70 receives additional excitatory
EPSPs evoked by single action potentials are too small impulses and reaches firing thresh-
to produce a suprathreshold depolarization. In a similar Axon old despite a simultaneous inhibitory
manner, the inhibitory postsynaptic potentials (IPSPs) impulse; additional inhibitory impulses
produced by a burst of action potentials in an inhibitory â•… might still prevent firing
fiber can summate to produce a large hyperpolarizing
potential. Axon(s) activated in each scenario

Spatial summation involves the activation of two or will discharge action potentials, causing a small twitch excitation to cause them to fire, and muscle stretch may
more terminals at approximately the same time. When of the stretched muscle; the remaining motor neurons, result in a vigorous contraction of that muscle and its
such synchronous activation occurs, the inward and which receive EPSPs too small to evoke firing, consti- synergists. In a similar way, motor neurons that fall
outward currents evoked by excitatory and inhibitory tute the subliminal fringe of the stretch reflex. If the within the subliminal fringe of two different reflexes
terminals summate to produce a net shift in the mem- body is in an active state, central nervous pathways will may be fired when both reflexes occur together. This
brane potential of the target cell. If two excitatory ter- produce a steady excitatory input to the motor neurons kind of reflex interaction by spatial summation helps to
minals are activated, the net membrane potential shift involved in the stretch reflex. Thus many of the neurons adapt reflex patterns to meet the demands of different
will be a depolarization approximately equal to the sum in the subliminal fringe will receive sufficient additional external conditions.
of the EPSPs that would be evoked by each terminal
acting alone; this combined depolarization exceeds the
threshold level and triggers an action potential. If, in
addition to the two excitatory terminals, an inhibitory
terminal is also activated, the net depolarization will be
reduced by an outward flow of current at the inhibitory
synapse. Under these conditions, additional excitation
is required to produce a suprathreshold depolarization.

Spatial summation plays a vital role in the interaction
of patterns of activity originating in various neuronal
pathways. For example, in the case of the effect of
central motor tone on the reflex evoked by muscle
stretch, the stretch produces a volley of action poten-
tials in the group Ia fibers from the stretched muscle.
The synaptic action of the Ia fiber terminals evokes
medium-to-large EPSPs in motor neurons supplying
the stretched muscle and small EPSPs in motor neurons
supplying synergistic muscles. If the body is in a relaxed
state, only the motor neurons receiving large EPSPs

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 49

P late 2-17 Brain: PART I

Ia g
II

c
III

h

IV f d
e

i

Types of Neurons in V
Cerebral Cortex
j

The six layers of the cerebral cortex contain different b
types of neurons, which can be broadly classified as VI
interneurons, association neurons, and efferent (projection)
neurons. White
matter
Interneurons. Interneurons have axons that do not
leave the cortex and may be of several kinds. The most Cortical interneurons Cortical association Efferent
common are stellate (star-shaped), or granule, cells, neurons neurons
which have symmetrically branching dendritic trees and
short axons that end upon nearby neurons. These cells Black—cell bodies and dendrites Key for Abbreviations
are especially prevalent in layer IV, which is accordingly Brown—axons of interneurons and association neurons a Horizontal cell
named the “granule cell layer.” Other interneurons are Red—axon of efferent neurons b Cell of Martinotti
horizontal cells, which are found in layer I; Martinotti’s c Chandelier cell
cells, which are located in deeper layers and send axons â•… d Aspiny granule cell
toward the cortical surface; and the small pyramidal cells e Spiny granule cell
of layers II and III, which send axons to deeper layers. f Stellate (granule) cell
g Small pyramidal cell of layers II, III
Association Neurons. Association neurons are small h Small pyramidal association cell
pyramidal cells found in the deep parts of layer III or i Small pyramidal association
in the superficial parts of layer V; they send axons
through the white matter to other regions of the cortex. and projection cells of layer V
j Large pyramidal projection cell
Efferent Neurons. Efferent neurons leave the cortex
to innervate structures in the brainstem or spinal cord (Betz cell)
and originate from the giant pyramidal (Betz) cells in
layer V or from spindle-shaped cells in layer VI. In to other cortical neurons via intrinsic connections properties. These columns are approximately 0.5 to
addition to their main axons, which leave the cortex, within the cortex. 1.0╯mm wide and extend across all six cortical layers. In
efferent neurons may also have collateral axons, which the sensory cortex, neurons within an individual column
project to nearby cortical neurons for association. Cortical Organization. An important aspect of the all respond to the same stimulus; within the motor
flow of information mediated by cortical neurons is that cortex, the activity of all neurons in one column is
Afferent Fibers. Two major classes of nerve fibers it occurs predominantly in a vertical direction across the related to the activity of a single muscle or muscle
bring information to the cortex. Specific cortical afferent six cortical layers. With the exception of the horizontal group. These columns, as well as the underlying vertical
fibers, which originate in corresponding thalamic relay cells of layer I, there are very few cortical neurons that neural organization, appear to represent one of the
nuclei, project to layer IV to end in a highly branched relay activity laterally over any significant distance. The central features of information processing by the cere-
terminal arborization. Nonspecific cortical afferent fibers, vertical cell axons and dendrites are arranged within bral cortex.
which originate in the thalamus or in other areas of the the cortex in columns of neurons that have similar
cortex and ascend through the entire depth of the corti-
cal gray matter, giving off terminal branches in all
layers. Specific afferent fibers may thus activate granule
cells and efferent neurons of layers III, V, and VI (via
their dendrites in layer IV), whereas nonspecific affer-
ents may influence all classes of cortical neurons.
Neurons activated by incoming fibers relay information

50 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 2-18 Cerebral Cortex and Neurocognitive Disorders

NEURONS AND GLIAL CELLS

Ventricle

Ependyma Microglial
cell
Tanycyte

Neuron Oligodendrocyte
Dendrite
Synapse

Astrocyte Axon
Astrocyte foot process

Pia mater Capillary Perivascular
pericyte

â•…

Astrocytes CNS for immune surveillance for a period of approxi- in the process, also generates lactate. Astrocyte-
mately 24 hours. generated lactate is then exported to the recently acti-
Astrocytes provide structural isolation of neurons and vated synapse neurons to help meet its increased energy
their synapses and provide ionic (K+) sequestration, Recent years have witnessed a growing apprecia- needs. This relationship defines what is called the
trophic support, and support for growth and signaling tion for functional roles astrocytes play within the “astrocyte-neuron lactate shuttle hypothesis,” and sug-
functions to neurons. Oligodendroglia provide myelin- CNS. It increasingly appears to be the case that astro- gests the classic bipartite synapse of a presynaptic
ation of axons in the CNS. Microglia are scavenger cytes are integral to brain energy utilization. For and postsynaptic neuron might more accurately be
cells that participate in phagocytosis, inflammatory example, at glutamate synapses astrocytes take up the thought of as a tripartite synapse consisting of a pre-
responses, cytokine and growth factor secretion, and glutamate that is released into the synaptic space by synaptic neuron, postsynaptic neuron, and associated
some immune reactivity in the CNS. Perivascular cells the presynaptic neuron. The glutamate is co-imported astrocyte. It is also important to note that glutamate
participate in similar activities at sites near the blood into the astrocyte along with a sodium cation. The absorbed by the synaptic astrocyte is recycled back
vessels. Schwann cells provide myelination, ensheath- sodium cation, in turn, is removed from the astrocyte to the presynaptic neuron. This is accomplished by
ment, trophic support, and actions that contribute to by the action of the plasma membrane adenosine tri- converting it to glutamine before releasing it into the
the growth and repair of peripheral neurons. Activated phosphate (ATP)-dependent Na+-K+ pump. This con- extracellular space. The presynaptic neuron is able
T lymphocytes normally can enter and traverse the sumes ATP, which activates astrocyte glycolysis, and, to take up the glutamine, and once it is back inside
in turn, this stimulates glucose uptake from neighbor- the neuron, the glutamine is converted back to
ing capillaries. By consuming more glucose through glutamate.
glycolysis, the astrocyte restores its energy supply but,

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 51

Plate 2-19 Brain: PART I
Belligerent
A. Appearance and interpersonal behavior
Pleasant, neatly dressed, good spirits Depressed, sloppily dressed, careless

B. Language Good Defective
Doctor: “Write me a brief

paragraph about
your work.”

Testing for Defects of C. Memory 5 minutes later:
Higher Cortical Function Doctor: “Here are three objects: a pipe, a Patient: “I’m sorry,
pen, and a picture of Abraham Lincoln. I can’t remember.
It is useful to test functions that can be localized to I want you to remember them, and in 5 Did you show
individual brain regions because abnormalities on these minutes, I will ask you what they me something?”
tests can help localize a neuroanatomic defect and were.”
thereby suggest a specific etiology. Screening for disor-
ders of higher cortical function can be completed D. Constructional praxis and visual-spatial function “Draw a clock face for me.”
within the context of an office visit, whereas extensive Doctor: “Draw me a simple
examinations can take up to several hours. picture of a house.”

Test Language Function. Judge the fluency of the Good Abnormal Good Abnormal
patient’s language. Note whether language is effortful E. Reverse counting
or not, and if there are mistakenly spoken phonemes
or mistakes in grammar. Evaluate comprehension by Doctor: “Count backward Doctor: “Spell the word world
testing the patient’s ability to follow simple or complex from 20 by 3’s.” backward for me.”
commands. Determine whether the patient can repeat,
read, write, and name. Some people may express them- Patient: “17...15...16, Patient: “W..L..R..D.”
selves well and understand what is said, yet still have ...17...18...” â•…
a language problem. More sensitive approaches that
could prove useful in this setting include counting how Test Ability to Concentrate. Ask the patient to recite Test Executive Function. Determine whether the
many animals the patient can name in 1 minute (a test in reverse a series of numbers or to subtract 7s serially patient can shift from one set to another, perform
of semantic fluency). In most language is a relatively from 100. Also observe the patient’s degree of alertness actions in a sequence, think abstractly, and calculate.
left brain–mediated cognitive domain, so inability to and orientation, manner of dress, and grooming, and For example, asking the patient how much money is
perform any of these tasks indicates dysfunction of the note whether the patient is happy, sad, or indifferent “two quarters, two dimes, and two nickels” screens
perisylvian region of the dominant, usually left, cerebral and how he relates to others. Such objective observa- several of these skills. Executive dysfunction suggests a
hemisphere. tions are an important part of a complete neurologic lesion of the posterolateral prefrontal cortex, or a dis-
examination. connection between this area and other brain regions.
Test Memory. Memory is often thought of as long
versus short term, but these are potentially misleading
terms. What is referred to as short-term memory is
really memory stored in “buffer” storage, particularly
the posterolateral prefrontal cortices. Long-term
memory is information stored in the brain “hard
drive,” which requires function of the medial temporal
structures such as the hippocampus. These different
problems can be distinguished by giving the patient
information to encode, ensuring that information has
entered the buffer memory, and then distracting the
patient. Later on, determine if the information is still
available to the patient. Good preservation and easy
accessing of the information suggests intact memory
“retention,” whereas good preservation that requires
cueing implies a deficit of “retrieval.”

Test Visual-Spatial Functions. Have the patient
draw a clock, house, daisy, or bicycle, and check for
organization, angulation, and asymmetry. Also ask the
patient to copy a simple design. If the drawings indicate
abnormal visual-spatial orientation, the patient may
have a lesion in the right cerebral hemisphere.

52 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 2-20 Cerebral Cortex and Neurocognitive Disorders

Memory Circuits Afferent and efferent cortical connections of entorhinal cortex

Direct connections Orbitofrontal Perirhinal cortex Indirect connections
cortex

Olfactory bulb Area 9
Area 23
Insula Areas 11–13
Area 46
Superior Area 8
temporal Area 22
gyrus
Area 21
Entorhinal
cortex Area 20

Cingulate Area 7
gyrus Area 19

Entorhinal cortex

Entorhinal cortex is a major source of projections to hippocampus (major processing center for recent memory).
Polysensory association cortices project directly to entorhinal cortex or indirectly via perirhinal cortex or
parahippocampal gyrus. Association cortices receive reciprocal projections from entorhinal cortex. Area numbers
refer to Brodmann classifications.

Possible processing circuit for recent memory

Primary sensory cortices Unisensory Polysensory Specific sensory input successively
association association processed through primary sensory,
Primary somato- cortices cortices unisensory, and polysensory association
sensory cortex cortices. These cortices project directly
or indirectly to entorhinal cortex, which
Primary projects to hippocampus. All sensory
visual cortex information indexed in hippocampus
and projected back to entorhinal cortex,
Primary from which it is diffusely projected to
auditory neocortex for storage as memory.
cortex

Long-term memory is a term that encapsulates the Corticocortical CA1 Entorhinal-
brain’s ability to store information. It is subdivided into projections hippocampal
two main types: explicit memory (also known as declar- CA3 circuit
ative memory) and implicit memory (also known as Neuronal loss or dysfunction in entorhinal hippo-
nondeclarative memory). Explicit memory refers to the campal circuit, as in Alzheimer disease, may dis- Dentate
acquisition of information about objects, stimuli, and connect this memory processing area from input gyrus
information that is consciously noted and recallable. of new sensory information and from retrieval of Subiculum
The mesial temporal lobe, which includes the hippocam- memory stored in neocortex. Loss of corticocortical
pal formation (CA1, CA3, and dentate gyrus) and ento- projections interferes with memory processing and Perforant
rhinal cortex, is the region responsible for this process. may contribute to memory deficits in Alzheimer pathway
While the hippocampal formation stores memories, the disease.
entorhinal cortex mediates learning and memory via its Olfactory
interaction with the hippocampus and neocortex. For undergo selective neuronal degeneration in AD. The bulb
instance, neocortical information from a visual stimulus loss of connections between the hippocampal formation
is translated via the entorhinal cortex to higher-order and entorhinal cortical neurons, which project to the Amygdala
complex memory representations such that an emotion hippocampus via the perforant pathway, account for the
can trigger a visual memory. Layer II of the entorhinal clinical presentation of explicit memory problems in Entorhinal cortex (Primary olfactory
cortex is the first region affected in Alzheimer disease AD patients. Implicit memory, on the other hand, is cortex may project
(AD). The memory circuit that integrates the mesial “unconscious,” can sometimes be linked to an emotion, â•… directly to entorhinal
temporal lobe and hippocampal formation includes and can be procedural (for instance, remembering how cortex)
several pathways: the perforant pathway (input to the to drive a car).
hippocampus from the entorhinal cortex), Mossy fiber The study of one particular patient, H.M., provided
pathway (dentate gyrus to CA3 region), Schaffer significant insights into the formation of memory and
collateral/associational commissural pathway (from CA3 the role of the mesial temporal structures in memory.
to CA1 region), and CA1-subiculum-entorhinal cortex H. M. underwent a bilateral resection of the medial
pathway (the principal output of the hippocampus). temporal regions as part of an experimental treatment
for medically refractory seizures. Subsequently, he
There are two main types of explicit memory: epi- developed profound loss of personal memories but had
sodic and semantic memory. Episodic memory is preserved language, attention, procedural memory, and
likened to autobiographic memory, as an episode of general intellectual ability.
one’s life is recalled (remembering a certain vacation to
the beach). Semantic memory refers to memory about
facts, and general knowledge that is unrelated to a spe-
cific experience (for instance, I know that a zebra has
stripes). Not surprisingly, CA1 and the subiculum

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 53

Plate 2-21 Brain: PART I
Transient global amnesia.
Sudden loss of memory; e.g., workman asks
“Where am I? What am I doing?” Differentiate
from psychogenic amnesia, in which personal
identity is often confused.

Amnesia

The term “amnesia” is used generally to describe Amnesic stroke. Bilateral infarction of
impairment or loss of memory. It is often subclassified hippocampus and medial temporal lobes
as being either retrograde or anterograde. With retro-
grade amnesia, memories that had previously been Korsakoff syndrome. Small hemorrhages
stored are no longer available. With anterograde around enlarged 3rd ventricle and shrunken
amnesia, information occurring in real time does not mamillary bodies (arrows). Clinical features
enter long-term storage. Memory is a complex process include memory loss, confabulation, con-
comprising three different functions: (1) registration of fusion, peripheral neuritis, nystagmus
information, (2) storage by reinforcement, and (3) and opthalmoplegia.
retrieval.
A BC
Registration of Information. If information is not
registered initially, it will not be remembered later. Herpes simplex encephalitis. May also cause memory loss. Microglial nodules (A), perivascular
Failure to register is the explanation for absentminded- lymphocyte cupping (B) and intranuclear inclusion bodies (C) in brain.
ness, probably the most common abnormality of
memory. â•…

Storage by Reinforcement. Repetition of information classified by the degree of retrograde amnesia that results; moments later. The patient cannot form new memories
to be remembered or relating such information to other the longer the period of retrograde amnesia, the worse and is often unable to recall events of the past days,
factors or events enhances later recall. the injury. Head injury victims may also experience a months, and even years. Speech, reading, writing, cal-
period of anterograde amnesia. culations, drawing, and copying are normal, as are the
Retrieval. To recall the information, a person must results of the rest of the neurologic examination. Behav-
search the “memory bank,” where it has been stored. Transient Global Amnesia. Total global amnesia is a ior and memory usually return to normal within 24
Inability to recall information on request could result particularly common memory disorder. In this benign hours, but the patient is never able to recall events
from a defect in any of the three aspects of memory syndrome, the patient seems bewildered and asks repet- during the period of amnesia. Such attacks may recur,
function. itive questions about the environment and activities, but the cause of the syndrome remains obscure.
and, despite appropriate replies, asks the same questions
The key anatomic regions for registration and storage
of memory traces are in an area often referred to as the
Papez circuit, in which the fornix connects the hippo-
campus to the mammillary bodies, which, in turn, are
connected to the anterior nuclei of the thalamus by the
mammillothalamic tract. The anterior thalamic nuclei
project to the cingulate gyri, which then connect with
the hippocampus, completing the circuit. The memory
system is primarily cholinergic. The left medial tempo-
ral lobe is most concerned with verbal memory and the
right temporal lobe with visual recall.

The prototype of amnestic disorders is Korsakoff syn-
drome, seen in chronic alcoholism and other states of
vitamin B deficiency. This syndrome affects the medial
thalamus and mammillary bodies and is characterized
by an inability to record new memories and recall
events of the recent past. Some patients confabulate to
fill in gaps in their memory. Any bilateral destructive
lesion of the thalami and medial temporal lobes can
cause a similar syndrome. Such lesions include gliomas
that spread bilaterally over the fornix and splenium of
the corpus callosum; bilateral posterior cerebral artery
infarctions, often caused by embolism of the top of the
basilar artery; and herpes simplex encephalitis, a viral
disease with predilection for temporal lobe damage.
Lesions within the Papez circuit affect the “memory
bank.” The patient is unable to recall items despite
being given cues or being asked to select the correct
item to be recalled from a group of alternatives. Uni-
lateral lesions of the left medial temporal lobe and
thalamus can produce amnesia that may last up to
6 months.

Head trauma often disrupts functions of memory.
The severity of a head injury or concussion is often

54 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 2-22 Cerebral Cortex and Neurocognitive Disorders
R Clinical syndromes related to site of region

L

Broca aphasia MRI-FLAIR Wernicke aphasia Angular gyrus-posterior Global aphasia-T2 FLAIR Alexia without agraphia
temporal, inferior parietal

Broca aphasia Wernicke aphasia Angular gyrus Global Alexia without
aphasia agraphia

Pronunciation, Dysarthria, stuttering, Normal, fluent, Normal Very abnormal Normal
speech rhythm effortful loquacious Very abnormal Normal
Very abnormal Normal
Speech content Missed syllables, Use of wrong Often normal Very abnormal Normal
agrammatical, or nonexistent Very abnormal Normal
telegraphic words Normal Very abnormal Normal
Abnormal Normal Very abnormal Normal
Repetition Abnormal but better
of speech than spontaneous Very abnormal

Comprehension Normal
of spoken
language

Comprehension Not as good as for Abnormal but better Very abnormal
of written spoken language than for spoken
language

Writing Clumsy, agrammatical, Penmanship OK Very abnormal,
misspelling but misspelling spelling errors
and inaccuracies

Naming Better than spontaneous Wrong names Often abnormal
speech

Other Hemiplegia, apraxia Sometimes Slight hemiparesis, Hemiplegia Abnormal
hemianopsia trouble calculating, reading
and apraxia finger agnosia,
hemianopsia

â•…

Dominant Hemisphere ability to follow spoken commands (failure to follow a have difficulty with naming of fingers, left-right orien-
Language Dysfunction command may also be due to apraxia or paralysis and tation, calculation, constructional drawing, and writing.
does not necessarily reflect poor comprehension); (4) The lesion causing the disorder is usually located in the
Aphasia, a disorder of language usage and comprehen- consistently name common objects, presented visually, angular gyrus of the dominant hemisphere. The angular
sion, should be distinguished from dysarthria, impaired verbally, or tactilely; (5) read aloud accurately and with gyrus has been implicated in different aphasia forms.
articulation, and mutism, the absence of speech. Usually, comprehension; (6) name words spelled aloud; and (7) This can be due either to its actual role in language or
the presence of aphasia accurately localizes dysfunction write legibly and grammatically. by creating, when damaged, a disconnection syndrome.
to the cerebral hemisphere concerned with speech. Disconnection syndromes in general can present in fas-
In transcortical aphasia, repetition of spoken language cinating, well-defined ways. One of the most famous
To classify an aphasia, it is necessary to determine is preserved. Transcortical motor aphasia is a subtype in language disconnection syndrome is the alexia without
whether the patient can (1) speak fluently, with normal which there is a primary inability to produce spontane- agraphia syndrome, in which patients can write but not
articulation and rhythm and without paraphasic, syn- ous speech, but the ability to understand spoken lan- read. This is most commonly seen as a consequence of
tactic or grammatical errors or use of circumlocutory guage is retained. Transcortical sensory aphasia is a subtype left occipital strokes that damage the visual cortex on
phrases; (2) accurately repeat spoken sounds, words, that is characterized by a failure to understand spoken the left and also perturb the transfer of visual informa-
and phrases; (3) understand spoken language, as evi- language; a transcortical sensory aphasia usually indi- tion from the right occipital visual cortex to the usually
denced by accurate responses to spoken questions and cates a lesion deep in the basal ganglia or in the para- language-dominant left hemisphere.
median frontal lobe. Patients with Gerstmann syndrome

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 55

Plate 2-23 Brain: PART I

A. Constructional dyspraxia and spatial disorientation

Clock face drawn by patient Patient asked to copy Draws this House drawn by patient
B. Neglect of left-sided stimuli

Nondominant Hemisphere
Higher Cortical Dysfunction

When it comes to stroke-induced lateralized deficits, Patient shown picture Sees this Patient shown printed page Sees this
patients with left-sided hemiplegia caused by damage C. Anosognosia Not recognizing
to the nondominant right cerebral hemisphere fre- (unawareness deficit, patient
quently do not recover as well as patients with similar of deficit) insists on trying
left hemisphere lesions, despite the fact that they are Patient with obvious to walk and falls,
not aphasic. Return to the work place and previous left hemiplegia. but still fails
home and family participation occur less frequently Asked, “What is wrong to recognize
after a stroke causing left-sided hemiplegia. Although with you?” deficit
disturbances of higher cortical function and behavior Answers, “Nothing
in patients with right hemisphere disease are more is wrong, I am
subtle, they are equally or more functionally disabling perfectly all right”
than the more obvious aphasia caused by left hemi-
sphere disease. Deficits in right hemisphere disease D. Motor impersistence
include the following.
Patient asked to
Constructional Dyspraxia. The right cerebral hemi- raise arms over head
sphere, especially its inferior parietal lobe, is specialized and to keep them up
for visual-spatial functions. Parietal lesions compromise
the patient’s ability to draw and copy figures and dia- Raises arms but
grams, reproduce block designs or figures made with then drops them
sticks or tongue blades, read a map, and follow or give quickly
directions to a given destination. Spontaneous drawings
are complex and contain all appropriate details, but E. Abnormal recognition of nonlanguage cues (facial expression, voice tone, mood)
proportions, angles, and picture relationships are inac-
curate, and the left half of the drawing often is omitted Patient shown Patient answers,
or minimized. Copying a figure does not significantly picture. Asked, “I don’t know,
improve the performance. “Which is the they are all
happy face?” the same”
Unilateral Spatial Neglect. Patients with right hemi-
sphere lesions, especially those involving the frontal or â•…
parietal lobe or thalamus, often neglect objects, people,
or sounds on their left side. They may also fail to ade- Impersistence. Some patients with nondominant Other Dysfunctions. Damage to the right cerebral
quately dress the left side of their body. When asked to cerebral hemisphere damage are unable to persevere hemisphere can also affect either the ability to perceive
read a headline or paragraph or examine a picture, they with a given task. A command that is quickly followed rhythm, pitch, or tonality, or to read, write, or play
do not appreciate words or objects on the left. When is just as quickly forgotten. When asked to keep their music. Some patients have difficulty in recognizing
instructed to bisect all lines on a piece of paper, patients eyes closed, for example, or to cross off all A’s on a page, familiar faces (prosopagnosia) and may be unable to
with right hemisphere damage often divide the right they begin the task correctly but soon abandon it. visualize from memory the appearance of an object or
side of the line and fail to cross lines on the left side of Questions are often answered before the query is com- a person. Loss of topographic recall of places and errors
the page. Similar spatial neglect of the right side after plete. Impulsive behavior with little forethought and of localization or distance concerning buildings or geo-
left hemisphere damage is unusual. poor perseverance is also functionally disabling. graphic landmarks also occur.

Anosognosia and Blunted Emotional Responses.
Patients who have right hemisphere damage often fail
to recognize or acknowledge an obvious left-sided
hemiplegia. Not only do they verbally deny weakness
or fail to localize it to one side, but they may fall when
attempting to walk. Furthermore, even when they
admit the deficit, these patients seem not to be appro-
priately concerned or distressed, and generally are not
discouraged about their uncertain future.

Testing of patients with right hemisphere lesions also
shows that they have difficulty in appreciating the tone,
mood, and emotional content of facial expressions or
spoken language and miss nonlanguage cues. They also
may be unable to invest their own voice or face with a
given mood. Apathy and blunted recognition and trans-
mission of emotional tone may hamper rehabilitation
and resumption of an active goal-oriented life.

56 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 2-24 Cerebral Cortex and Neurocognitive Disorders
Relative sparing of
Gyral atrophy primary motor and
of frontal sensory cortices
lobe regions

Relative
sparing of
occipital
lobe

Atrophy of temporoparietal area AD
Control

PET imaging with florbetapir reveals
the presence of amyloid plaque
deposits in the brain of an individual
with a clinical diagnosis of
Alzheimer disease (shades of red)
compared to a cognitively normal
older adult with little to no evidence
of amyloid (lighter red and yellow).

0.5 1.0 1.5 2.0 2.5

Alzheimer Disease: Hippocampal atrophy (more pronounced in older patients)
Pathology Gyral atrophy (more pronounced in younger patients)

Alzheimer disease (AD) is the most common neurode- Widening of sulci Atrophy of
generative disorder and affects 10% of people older Thinning of olfactory bulbs
than age 65 years and nearly 50% of those 85 years and cortical mantle and tracts
older. The brain affected by AD has gross changes of
brain atrophy accompanied by microscopic changes of Ventriculomegaly, Coronal T1-weighted MRI scan showing
amyloid plaques and neurofibrillary tangles. especially temporal atrophy of the hippocampus bilaterally
horn of lateral ventricle (arrows), with enlagement of the
The gross pathology of AD appears as enlargement temporal horns of the lateral ventricles.
of the ventricles and widening of the sylvian fissure Global atrophy is evident with widening
secondary to cortical atrophy. Many convexal gyri are of the sulci and enlargement of sub-
shrunken, and the sulci between these gyri are widened. arachnoid spaces.
The cerebral cortex may appear thin, and the basal â•…
ganglia are relatively small. The hippocampal region of
the medial temporal lobe is affected early in the disease emission tomography (PET) allow the presence and function to stabilize axonal microtubules. Tau protein
process and prominent atrophy of this region is usually burden of amyloid deposits in the brain to be detected found in neurofibrillary tangles is in an abnormal state
observed. This region is responsible for storing new using radioligand labels. The molecular imaging of of hyperphosphorylation, which occurs in conjunction
information, and its degeneration is associated with amyloid deposits has promise as a potential biomarker with its dissociation from microtubules and clumping
the prominent short-term memory impairment that is for AD and possibly may allow the identification of as paired helical filaments. Neurofibrillary tangles are a
characteristic of AD. individuals who are still in the presymptomatic stages ubiquitous accompaniment of aging, and accumulate
of the illness. with age in a predictable pattern. Individuals with AD
Microscopic examination of the affected regions tend to have more tangles, plaques, and neuron loss
reveals plaques and neurofibrillary tangles, the patho- Neurofibrillary tangles are intracellular inclusions than individuals without dementia.
logic hallmarks of AD. Plaques are primarily composed composed of aggregated tau proteins that normally
of extracellular accumulation of insoluble amyloid
protein. The amyloid hypothesis speculates that the
accumulation of amyloid is the critical trigger leading
to the pathologic changes in the brain of AD patients
and results in synapse loss, inflammation, neurofibril-
lary changes, and ultimately neuron death. Amyloid
appears to accumulate years before the clinical symp-
toms and is associated with parallel worsening of brain
atrophy. Neuroimaging techniques using positron

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 57

P late 2-25 Brain: PART I

Hippocampus
Nucleus
basalis

Olfactory
bulb

Alzheimer Disease: In neocortex, primary involvement of association Amygdala
Distribution of Pathology areas (especially temporoparietal and frontal)
with relative sparing of primary sensory cortices
The pathologic diagnosis of Alzheimer disease is deter- (except olfactory) and motor cortices
mined at autopsy based on the presence of its cardinal
histopathologic features, neurofibrillary tangles, and Locus ceruleus Raphe
amyloid plaques. nuclei

Amyloid plaques are abundant in the cerebral cortex Pathologic involvement of limbic system
of individuals with Alzheimer disease, particularly in and subcortical nuclei projecting to cortex
the parietal and frontal regions. Amyloid deposition is
also commonly observed in leptomeningeal arteries as CA2 CA4 CA3
amyloid angiopathy. Autopsy studies, and more recently
amyloid imaging techniques, have revealed that amyloid CA1
plaques begin to accumulate in the brain years, perhaps Subiculum
decades, before the emergence of clinically recogniz-
able symptoms and are found in cortical regions that Dura mater ␤-Amyloid peptide
are highly metabolically active, such as the default- Pia-arachnoid deposition in cortical
mode network that is active when an individual is at rest and leptomeningeal
and not engaged in a specific cognitive task. Regions arterioles
such as the precuneus and posterior cingulate, which
have strong connections with the hippocampus, are I Entorhinal Presubiculum
among the areas affected earliest. II cortex

Neurofibrillary tangles (NFTs) accumulate in a III In hippocampus, neurofibrillary tangles,
predictable fashion as an individual ages and is a ubiq- SP neuronal loss, and senile plaques primarily
uitous accompaniment of aging. Accumulation of located in layer CA1, subiculum, and
neurofibrillary tangles begins in the medial temporal IV entorhinal cortex
lobe (amygdala and entorhinal cortex) gradually extend- V
ing into the limbic system (hippocampus and cingulate
cortices) and later throughout the entire isocortex. VI
This stereotypic pattern of accumulation is used in
pathologic staging of the disease (Braak staging). The NFT
pathologic staging of AD is based on the hierarchic
pattern of the appearance of neurofibrillary tangles Association cortex Characteristic pathologic findings in the brain of
in various regions. There are two “presymptomatic” In association cortex, neurofibrillary tangles (NFTs) a patient with Alzheimer disease: Neuritic plaque
transentorhinal stages, where NFTs remain in the and synaptic and neuronal loss predominate in layer V. and neurofibrillary tangle. Neurtitic plaques (bottom
perirhinal cortex. In stage III, the NFTs involve the Senile plaques (SPs) occur in more superficial layers arrows) are extracellular deposits of amyloid in
limbic regions, and layer II of the entorhinal cortex. the brain. Neurofibrillary tangles (top arrow) are
Stage IV AD is marked by more extensive NFTs in aggregates of hyperphosphorylated tau protein.
the limbic regions, entorhinal layer IV, and hippocam-
pal CA1 region. These latter stages (III and IV) cor- â•…
respond clinically to mild cognitive impairment (MCI),
not dementia. MCI represents an intermediate stage formation of memories, and their degeneration accounts Meynert, which has widespread cholinergic neuron
between normal aging and dementia. Typically, patients for the prominent impairments in short-term memory innervations through most of the cerebral cortex. Selec-
note subjective memory problems, the need to make observed in AD patients. tive degeneration of the basal forebrain cholinergic
lists, and short-term memory “slip ups,” but these neurons results in a cholinergic deficit that contributes
changes are not severe enough to interfere with day-to- Biochemical data from patients with AD reveal an to AD symptoms. These findings led to the develop-
day activities. As the pathologic stage of AD progresses, early decrease in choline acetyltransferase and acetylcholin- ment of the first effective treatments in ameliorating
the NFTs accumulate in the inferotemporal, retrosple- esterase, indicating dysfunction in the neural pathways the symptoms of AD, acetylcholinesterase inhibitors,
nial, and, eventually, association regions of the cortex, that use acetylcholine as a neurotransmitter. The which act by increasing acetylcholine levels in the brain.
while the primary motor cortex is spared. In these number of neurons is reduced in the basal nucleus of
stages, the clinical hallmarks of AD are present and
include impairments in memory, judgment, orientation,
language, and decision-making.

Of interest, some tangle pathology is present in all
older adults, although individuals with AD have a
greater burden of neurofibrillary tangles and a much
more widespread distribution throughout the isocortex.
The CA1 region of the hippocampus and the entorhinal
cortex are particularly susceptible to the accumulation
of both plaques and tangles in the early stages of the
disease. These regions are important for mediating the

58 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 2-26 Cerebral Cortex and Neurocognitive Disorders

Memory loss
“Where is my checkbook?”

Alzheimer Disease:
Clinical Manifestations,
Progressive Phases

The earliest stages of Alzheimer disease are generally Spatial disorientation
marked by cognitive changes in multiple domains of “Could you direct me to my
cognition, including memory, executive function, lan- office? I have the address
guage, and visuospatial function. Of importance, these written down here somewhere
cognitive changes are often well-compensated, and but I can’t seem to find it.”
individuals may still be independent in many activities Circumlocution
in the community, and their symptoms may not be Asks husband, “John dear, please
readily apparent in casual conversation. Observations call that woman who fixes my hair.”
from an attentive family member, relative, or friend
describing cognitive changes interfering even mildly More advanced phase Terminal phase
with the subject’s usual function is a sensitive indicator Sloppily dressed, slow, Bedridden, stiff,
of the earliest stages of AD. apathetic, confused, unresponsive, nearly
disoriented, stooped posture mute, incontinent
1. Memory loss: The clinical hallmark of AD is
memory loss. Patients may be forgetful of details â•…
of recent conversations and events. Family
members frequently report that the patient asks in reading, television, and social gatherings. Less atten- eating, and toilet functions. They cannot venture out
repetitious questions or repeats stories, even in tion is paid to grooming and attire, and even formerly alone and become lost even in their home. They confuse
the same conversation. Patients have difficulty fastidious people allow their house, room, and belong- night and day, and incontinence develops.
remembering appointments, taking their medica- ings to become untidy and disorganized. Occasionally,
tions, and tend to lose things more than before. agitated or belligerent behavior occurs. The course of the disease is usually from 7 to 12
years. In the terminal phase, patients are bedridden,
2. Executive dysfunction: Executive function is loosely In the advanced stage of AD, patients cannot perform mute, and stiff, and patients ultimately succumb to
defined as an ability to organize information and the simple activities of daily living. They remain in bed medical complications such as pneumonia, urosepsis or
pursue goals. Subtle problems in executive func- unless they are helped up and require aid for dressing, decubitus ulcers.
tion are often observed in the early stages as
problems in planning and organizing. This may
manifest as difficulty in managing a checkbook
and the household finances or greater difficulty in
following a recipe. Patients have more difficulty
making decisions and solving problems and are
now more likely to enlist the help of others.

3. Decreased language facility: Communication may
be less precise than normal and contain more
“filler” words and circumlocutory elements.
Patients may have difficulty recalling names of
people and places although they generally retain
the ability to understand and repeat spoken
language and do not make paraphasic errors, in
contrast to patients with aphasia due to stroke.

4. Visuospatial dysfunction: Patients may have naviga-
tional problems while driving and in the early
stages often self-restrict their driving to the most
familiar areas. Ultimately, spatial disorientation
interferes with the ability to navigate even in
the most familiar areas, such as the patient’s
neighborhood.

As the disease relentlessly progresses into the moder-
ate stages, greater cognitive and functional decline
reflects more widespread involvement of neocortical
regions. Increasing difficulties with instrumental activi-
ties of daily living are prominent, such as cooking,
cleaning, and dressing. Apraxia, a disorder of skilled
movement despite intact strength, sensation, and coor-
dination, develops as typical AD progresses but is not a
prominent early feature. This may manifest as greater
difficulty in using tools (such as silverware, unlocking a
door with a key) and dressing in the proper sequence.
Behavioral changes may be prominent. Patients may
become increasingly apathetic and less interested in
others and in their environment. They also lose interest

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 59

Plate 2-27 Brain: PART I

Decreased concern
and empathy for others
Atrophy of frontal
and/or temporal areas

Clinical Oral fixation:
features increased eating
of frontal causes weight
lobe variant gain

Decrease
in speech

Frontotemporal Dementia

Frontotemporal dementia (FTD) is a heterogeneous Loss of
spectrum of disorders marked by degeneration in the awareness
frontal and anterior temporal lobes, resulting in various of personal
symptoms of disturbed personality, behavior, and lan- appearance
guage. FTD is the third most common form of neuro- and hygiene
degenerative dementia, ranking after Alzheimer disease
and dementia with Lewy bodies, accounting for perhaps T1-weighted MRIs demonstrating significant atrophy in the frontal (left) and temporal lobes (right)
5% of all dementia cases. FTD generally presents at a in a patient with frontotemporal dementia
younger age than Alzheimer disease and has a mean age
at onset of 58 years. â•…

Behavioral and personality changes are prominent impairment in semantics (word meaning), resulting in with complex visuoperceptual dysfunction, such as
early features in individuals with FTD reflecting patho- empty, fluent speech and a loss of speech comprehen- prosopagnosia and visual object recognition.
logic involvement of the frontal lobes, most commonly sion. Speech may be effortless and without hesitancies,
the right hemisphere. Symptoms include disinhibition, but little meaningful information is conveyed. These Neuroimaging should be obtained to rule out the
impulsivity, impaired judgment, and disturbed social patients have prominent comprehension problems (i.e., presence of structural lesions (e.g., stroke, tumor) and
skills. An individual with FTD may have inappropriate following commands) despite their fluent and effortless may reveal the presence of disproportionate atrophy in
behavior, such as swearing, off-color jokes, and loss of speech. Because the language network prominently the frontal and temporal lobes. Additionally, functional
social tact. Dietary habits may change, and an individual involved (Wernicke’s area) abuts the visual association imaging in the form of positron emission tomography
may only eat certain foods, such as sweets. Prominent networks, semantic dementia may also be associated (PET) may reveal altered metabolic activity in the
personality changes are disturbing to the patient’s frontal and temporal lobes.
family, yet the patients themselves are typically uncon-
cerned and lack insight and empathy regarding how
these changes affect their families. Some individuals
develop repetitious or compulsive behavior. Severe
amnesia and visuospatial impairment are typically not
present. In fact, many FTD patients are oriented and
able to keep track of day-to-day affairs.

The language presentation of FTD varies, depending
on the distribution of the pathology and includes dis-
turbances in speech fluency and comprehension. Broca’s
area is located in the inferior and middle gyri of the left
frontal lobe and is involved in generating articulation
sequences that transform thoughts into statements.
Neurodegeneration affecting Broca’s area results in
progressive nonfluent aphasia that is characterized by
loss of fluent speech and prominent anomia. The
speech may have a halting quality due to frequent
pauses for word-finding. Circumlocutions are common,
because the patient has difficulty retrieving the concise
words and substitutes other words or statements for the
desired word. Wernicke’s area in the left temporopari-
etal junction mediates the sensory associations encod-
ing word meaning. Neurodegeneration affecting this
region results in semantic dementia, marked by early

60 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 2-28 Cerebral Cortex and Neurocognitive Disorders

Dementia
Masklike
facies

Rigidity
and
flexed
posturing

Tremor Visual hallucinations are hallmark finding

Patients exhibit parkinsonian
motor disturbances

Short Cortical Lewy bodies
shuffling and loss of dopamine
gait projections to frontal
cortex and basal ganglia
result in dementia

Lewy bodies are found in substantia
nigra as well as other brainstem
nuclei and cortex

Lewy body

Dopamine Dopamine Neuron
Normal Lewy body dementia

Dementia with Lewy Bodies

Dementia with Lewy bodies (DLB) is the second most Lewy bodies are intracellular inclusions that appear as an eosinophilic
common cause of dementia, accounting for 10% to inclusion with a halo when stained with hemotoxylin and eosion (left).
15% of dementia cases. The pathologic hallmark of Newer immunostaining techniques using antibodies to alpha-synuclein
DLB is the presence of Lewy bodies in neurons of the densely label Lewy bodies (right).
brainstem, primarily the substantia nigra, and through-
out the cerebral cortex. Lewy bodies are primarily â•…
composed of abnormal aggregations of the synaptic
protein alpha-synuclein. Interestingly, brain changes disease. Individuals with DLB typically present with DLB and other synucleinopathies such as Parkinson
of Alzheimer disease (plaques and tangles) frequently recurrent episodes of confusion on a background of disease. REM sleep behavior disorders are manifested
co-occur with typical Lewy body pathology. progressive deterioration. The fluctuations in cognitive as vivid or frightening dreams associated with simple
function are manifest as shifting attention and levels of or complex motor behavior. Additionally, autonomic
In patients with DLB, the cognitive and functional alertness that may vary over minutes, hours, or days. abnormalities are common in DLB and include ortho-
decline of dementia is accompanied by a combination static hypotension and carotid-sinus hypersensitivity.
of clinical features that include visual hallucinations, Other features that are commonly observed in DLB These abnormalities can result in “dizziness,” presyn-
parkinsonism, and fluctuating cognitive impairment. patients include additional neuropsychiatric symptoms cope, syncope, and falls as common aspects of the clini-
Visual hallucinations may present early in the clinical of delusions, apathy, and anxiety. Rapid eye movement cal presentation.
course and tend to persist throughout the course. Typi- (REM) sleep behavior disorders are frequently seen in
cally, the visual hallucinations are vivid images of
animate objects (e.g., children, animals) as opposed to
nonspecific visual phenomena. Parkinsonism (rigidity,
tremor, bradykinesia, gait abnormalities) develops in
most DLB patients at some time in the course of the

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 61

Plate 2-29 Brain: PART I

CLINICAL CHARACTERISTICS OF VASCULAR (MULTIINFARCT) DEMENTIA
Dementia,
personality
and mood
changes

Vascular Dementia Cardiac Hyperreflexia
and renal
Vascular dementia is interesting in that many of those disease
who do have a true vascular dementia are not diagnosed
with it, while many who probably do not have a vascular Hypertension
dementia are diagnosed with it. The most straightfor-
ward presentations are those in which an individual Babinski sign
with normal cognition has a large stroke that causes a
combination of cognitive signs, such as aphasia and a Hemiparesis
memory retrieval problem. If the patient cannot resume
their prestroke day-to-day level of function because of Urinary frequency Bilateral infarcts usually required
these new cognitive deficits, the criteria for vascular or urgency for development of dementia
dementia are met, but because the stroke so clearly Patients with symptoms of vascular dementia
caused the deficits, they are held to simply represent may have risk factors for stroke
the consequences of a stroke (as opposed to a frank
vascular dementia). On the other hand, some patients Arteriolar intra- Cortical infarcts may cause
will present with a gradually progressive dementia, a cranial disease focal signs and symptoms
retention-type memory deficit, no motor signs, no related to area of cortex
history of sensory or motor changes, and a neuroimag- Intracranial medium- involved
ing study that shows subcortical changes that could be size-vessel disease
consistent with “small vessel cerebrovascular disease.” Extracranial large- Subcortical (lacunar) infarcts
In the elderly, such patients almost always have the vessel disease cause signs and symptoms
plaques and tangles that are expected in Alzheimer of subcortical dementia
disease. In such cases, despite the neuroimaging
changes, it is probably more appropriate to consider Cerebrovascular disease results in multiple occlusions in cerebral
Alzheimer disease as the primary etiology. Still, the vascular tree, causing scattered cortical and subcortical infarcts
frequent association between Alzheimer disease and
cerebrovascular pathology suggests these conditions Disease progression (years)
may be linked in some way. 12345 6

Vascular dementias can be subclassified depending on Vascular
whether the stroke or strokes responsible for the cogni- dementia
tive change are single versus multiple, and large vessel
versus small vessel. As mentioned above, a single large Alzheimer
vessel stroke can cause a dementia syndrome. Such disease
presentations are often obvious because they typically
present within the context of an acute, clearly diagnos- Clinical progression. Vascular dementia exhibits abrupt onset and stepwise progression in contrast to
able large vessel stroke. Some patients will have gradual onset and progression of Alzheimer disease
multiple large vessel strokes. Greater amounts of
stroke-related brain damage commonly associate with â•…
greater degrees of cognitive dysfunction.
more patchy or punctuate pattern. When this white represent a consequence of the true underlying disease
Single small strokes can alter cognition when they matter change is indeed driving the dementia, then a as opposed to a cause of the dementia. When consider-
happen to fall within and damage specific areas that diagnosis of subcortical ischemic vascular dementia ing such cases, the overall clinical picture, including the
are critical to cognitive performance. The thalamus, should be considered and a pathologic survey may clinical history, general neurologic exam, and cognitive
caudate head, and fornix constitute some examples in reveal changes consistent with Binswanger disease. neurologic exam needs to be synthesized and inter-
which a strategically placed small stroke can impact However, nondemented elderly individuals and patients preted very cautiously. Sometimes these patients will
cognition. Cognitive decline severe enough to qualify with neurodegenerative dementias may also show ultimately receive a diagnosis of a mixed vascular-
for a syndromic dementia diagnosis also results from similar patterns of subcortical white matter change. In degenerative dementia, or “Alzheimer disease plus
multiple small vessel strokes that, on neuroimaging, the latter situation, the white matter change may cerebrovascular disease.”
appear as multiple lacunar strokes. As is the case with
large vessel multi-infarct dementias, this type of small
vessel multi-infarct vascular dementia often presents
within the context of a stepwise decline in which the
stepwise decline occurs in association with diagnosed
acute strokes.

When it comes to diagnosing a vascular dementia,
the most difficult cases are those in which the patient
has developed a clinical dementia, there is no clinical
history of a previously diagnosed acute stroke, but a
neuroimaging study reveals extensive stroke-induced
damage to the brain. In many such instances, the
imaging shows extensive changes to the subcortical
white matter. These changes may appear confluent or
more anatomically restricted. The changes may coalesce
around the lateral ventricles and may or may not also
separately project into other white matter areas in a

62 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 2-30 Cerebral Cortex and Neurocognitive Disorders

Treatable Dementias Brain tumor Subdural hematoma

Although in some ways cognitive performance abilities Metabolic latrogenic
evolve throughout adulthood, many elderly people Overmedication
remain mentally sharp into their ninth and tenth Hypothyroidism Drug side effects
decades. The emergence of uncharacteristic changes in Hyperparathyroidism
an individual’s cognition that impacts their usual activi- (hypercalcemia) Depressive pseudodementia
ties should, therefore, trigger an evaluation for possible Emphysema (CO2 narcosis)
etiologies. Liver disease
Pancreatic disease
Because Alzheimer disease is the most common cause (hypoglycemia)
of intellectual decline in later life, symptoms or signs Cortisol excess
that are unusual in Alzheimer disease should particu- (Cushing syndrome)
larly alert the physician to a different diagnosis and the Nutritional disorder
possibility of reversing the dementing process. Such (malabsorption, pellagra)
features include early age at onset; prominent headache; Vitamin B12 deficiency
disturbances of gait or incontinence early in the course (pernicious anemia)
of the illness; epileptic seizures; fever; precipitous
decline over a period of weeks or months; alteration of Alcohol or drug abuse
consciousness, especially sleepiness, stupor or delirium;
history of head trauma; focal neurologic signs, such as â•…
lateralized visual, motor, or sensory abnormalities;
accompanying dysfunction of peripheral nerves charac- dementia, although depression is often an early expres- decline. Usually, the patient also has a history of an
terized by paresthesias and absent distal reflexes; and sion of Alzheimer neuropathologic changes in the abrupt decline, as well as hypertension and coronary or
known systemic cancer, collagen vascular disease, or brain. Depression in Alzheimer patients contributes peripheral vascular disease.
endocrinopathy. The presence of any of these features to greater functional decline and should be treated
should dictate further evaluation and consideration of aggressively. Diagnostic Studies. Screening of biochemical param-
the following treatable dementias. eters, especially the vitamin B12 level and thyroid, renal,
Cerebrovascular Disease. Strokes can decimate the liver, and lung function can be important in evaluating
Metabolic Disease with Encephalopathy. When regions of the brain that govern thought processes. potential causes of dementia. Neuroimaging, electroen-
intellectual decline is caused by systemic metabolic When this occurs, motor and reflex abnormalities cephalography, and CSF analysis may also detect unsus-
disease, there are usually four associated features: usually parallel or exceed the degree of intellectual pected causes of dementia.
diminished alertness; asterixis; a global decrease in
mental function, often with a flight of ideas; and vari-
ability of intellectual function during the day. The
metabolic dysfunction can be either endogenous or exog-
enous. An endogenous abnormality indicates too much
or too little of a substance or metabolite usually found
in the body, such as calcium, sodium, thyroid hormone,
sugar, and so forth, may be responsible.

Failure of the lungs, kidneys, or liver is also in this
category. Exogenous metabolic dysfunction is caused by
a deficiency of a dietary substance, such as vitamin B12
or nicotinic acid, or by intoxication with a growing
variety of agents, such as alcohol, barbiturates, or
narcotics.

Brain Tumors. Primary benign brain tumors, such as
meningiomas, that affect the olfactory grooves and
frontal lobes decrease mental function by pressing on
brain tissue or by obstructing the ventricular system.
Malignant primary metastatic tumors can also cause
intellectual decline, usually with focal or multifocal
signs and seizures.

Head Trauma. A history of head injury, sleepiness,
and slight lateralized weakness are clues, particularly to
a subdural hematoma. The physician should be aware
of this possibility because many patients will have for-
gotten the inciting trauma by the time they seek medical
attention.

Normal-Pressure Hydrocephalus. In most patients,
this occult condition is unrecognized until the patho-
logic state causes overt symptoms.

Infection. An altered mental state, usually with head-
ache and cerebrospinal fluid (CSF) pleocytosis, may be
the first indication of central nervous system (CNS)
syphilis, tuberculosis, or fungal meningitis.

Depression. Depression is associated with measure-
able declines in some aspects of memory and memory
complaints are a frequent symptom of depression.
Depressive pseudodementia is a concept that arose to char-
acterize depression as a potential mimic of dementia.
Depression should be considered in patients with

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 63

P late 2-31 Brain: PART I

Masked facies

Normal-Pressure Speech terse, abbreviated, telegraphic; difficulty in persevering—noted in counting
Hydrocephalus backward 20..19...18......17...........16

The “plumbing system” of the central nervous system Stooped posture Fades out
(CNS) operates in a delicate balance. Fluid produced in Incontinence
the choroid plexus of the lateral ventricles circulates
through the third ventricle, cerebral aqueduct (of Magnetic gait; wide
Sylvius), and fourth ventricle. After exiting from the based with short steps
roof of the fourth ventricle, the cerebrospinal fluid as if feet glued to floor
(CSF) circulates around the brain within the subarach-
noid cisterns, and is ultimately absorbed by the arach- Ventricles distended, compressing brain tissue
noid granulations into the circulation. If more CSF is
produced than is absorbed, the ventricles and subarach- Subdural hematoma Hemorrhage
noid space distend with fluid. In the adult, this imbal-
ance leads to enlargement of the ventricles, which then Shunting may potentially relieve symptoms
encroach on the normal cerebral white matter, espe- but may cause hemorrhage along cannula
cially frontally. tract, brain edema, subdural hematoma,
and infection.
Conditions known to cause scarring of the pia- Pus
arachnoid membranes, such as meningeal infection,
subarachnoid hemorrhage, or bleeding from past Cisternography after introduction of a radionuclide Axial FLAIR images
trauma, can cause hydrocephalus by decreasing the by lumbar puncture may be of value in assessing abnor- demonstrate moderate
effectiveness of CSF absorption. In most elderly mal CSF flow patterns. Unfortunately, however, there enlargement of the
patients, communicating hydrocephalus has no easily is no single definitive test that reliably predicts whether third and lateral
identifiable cause. Although it could possibly result the patient will improve after surgical placement of a ventricles, more
from degeneration of the arachnoid granulations and ventricular drain. normal sulcal pattern,
membranes, there has been little detailed study of the and patchy periven-
morphologic structure of the arachnoid in either Ventricular shunts seem to be most effective in tricular increased
normal persons or patients with hydrocephalus. Because patients who have the classic triad of symptoms and T2 changes.
the CSF pressure is usually high in obstructive hydro- in whom the course of the dementia has been short
cephalus due to tumor and, for uncertain reasons, is and a cause of the disorder, such as past subarachnoid â•…
within normal range in communicating hydrocephalus,
the latter disorder has been called normal-pressure hemorrhage, can be identified. Complications of
hydrocephalus. ventriculoperitoneal shunts in adults include intraÂ

SECTION 3â•…

EPILEPSY

Plate 3-1 Brain: PART I

Electrode placement and lead identification

Electroencephalography F7 Fp1 Fp2 A2
A1 T3 F8
The electroencephalogram (EEG) is a record of the
electrical activity of the nerve cells in the brain. The F3 Fz F4
EEG is based on the measurement of electrical fields
generated by volume conduction of ionic currents from C3 Cz C4 T4
nerve cells through the extracellular space. Recorded
EEG potentials arise from extracellular current flow P3 Pz P4 T6
from summated excitatory postsynaptic potentials
(EPSPs) and inhibitory postsynaptic potentials (IPSPs). T5 O2
The EEG does not record activity from single neurons, O1
but is dependent on the summation of thousands to
millions of postsynaptic potentials (PSPs), and there- Odd numbers, left side;
fore represents activity from a large neuronal aggrega- even numbers, right side;
tion. Although nerve action potentials have higher z locations, midline
voltage changes than EPSPs and IPSPs, due to the lack
of summation and short duration of action potentials, EEG in normal awake person, eyes closed Normal sleep
they usually add little to EEG activity. During seizures,
there is synchronous firing of large ensembles of action Fp1-F3 ␤ F3-A1
potentials from neurons, which may contribute to the F3-C3 F4-A2
EEG signal. The usual way to record an EEG is to C3-P3 ␣ C3-A1
attach small metal disc electrodes to the scalp in stan- P3-O1 ␤ C4-A2
dardized positions. The signal from these electrodes is Fp2-F4 P3-A1
then amplified, digitized, and electronically stored. The F4-C4 P4-A2
EEG is then read on a computer screen. O1-A1
C4-P4 O2-A2
Brain Wave Activity. Brain activity consists of wave-
forms that vary in polarity, shape, and frequency, and P4-O2 ␣ Fp1-F7 Sleep spindles
usually range in voltage from 20 to 60 microvolts. Scalp F7-F3 Epilepsy
EEG activity shows oscillations at a variety of frequen- Right temporal tumor T3-T5
cies, representing synchronized activity over a network Fp1-F7 Right temporal ␦ activity T5-O1
of neurons. EEG waveforms are labeled according to F7-F3 Fp2-F8
their frequency, measured in cycles per second or Hertz T3-T5 F8-T4
(Hz). Alpha activity ranges between 8 and 13╯Hz. The T5-O1 T4-T6
alpha rhythm is predominantly over the posterior head Fp2-F8 T6-O2
region and is the characteristic background frequency
of the normal awake person. It occurs when the eyes F8-T4 â•…
are closed and attenuates when the eyes are open. Beta T4-T6
activity is low amplitude, fast activity with a frequency
of 13 to 30╯Hz and is usually present over the anterior T6-O2
head regions. Theta activity ranges from 4 to 7╯Hz, and
delta activity occurs at a frequency of less than 4╯Hz. Right temporal spikes
There is a developmental maturation of the EEG. For
example, in the newborn infant, the EEG does not seizures. Suppression of activity can be either focal or usually requires long-term monitoring with video. For
show continuous mixed-waveform activity, as would be diffuse, and it indicates a severe derangement of brain some disease processes, the EEG shows specific diag-
expected in an adult. Instead, an infant has continuous function. nostic patterns, such as generalized periodic sharp
amorphous delta activity. The other waveform frequen- waves in Creutzfeldt-Jakob disease. The EEG is also
cies progressively emerge as the infant’s brain develops. Indications for EEG. The main indications for very useful in the evaluation of comatose patients.
EEG patterns change during different stages of sleep obtaining an EEG are to assess for seizure disorders, There may be distinctive patterns that can confirm that
and contribute to the definition of sleep stages. The intracranial disease processes, coma, and brain death. diagnosis of an underlying condition, such as triphasic
EEG patterns are very different for rapid eye move- The most common reason for an EEG is to character- waves in hepatic coma, spike discharges in nonconÂ

Plate 3-2 Epilepsy

Seizures and Epilepsy Focal seizures FOCAL (PARTIAL) SEIZURES Focal motor. Tonic-
Somatosensory. clonic movements of
Epilepsy is medically defined as a condition character- Tingling of contra- Central upper (or lower) limb
ized by an individual having two or more unprovoked lateral limb, face, Postcentral gyrussulcus Precentral gyrus Grim-
seizures. A seizure is a paroxysmal disorder character- or side of body acing
ized by an abnormal excessive, hypersynchronous dis- Leg
charge of neurons that results in an alteration of normal
brain function. This alteration of function can be quite Trunk
dramatic, such as during a generalized tonic-clonic Arm
(GTC; grand mal) seizure, or much more subtle, such
as during an absence (petit mal) seizure. If the seizures Face
are consistently provoked, such as by fever or hypogly-
cemia, the term epilepsy should not be used. Epilepsy Visual. Sees flashes of light, EEG: Focal motor seizure, left arm and hand Contraversive:
is not a single disorder, but rather a symptom of an scotomas, unilateral or head and eyes
underlying brain disorder. Epilepsy is a chronic disor- bilateral blurring Fp1-F3 turned to
der, although many children will go into remission. F3-C3 opposite side
Although many people with epilepsy are normal in all HHISISS.S.S....... C3-P3
other respects, approximately 50% will also have addi- P3-O1 Autonomic.
tional cognitive or behavioral impairments. Auditory. Hears ringing Fp2-F4 Sweating,
or hissing noises F4-C4 flushing or
The history and neurologic examination are the C4-Pv pallor,
cornerstones of neurologic diagnosis. When assessing and/or
when a patient may have had a seizure, it is important P4-O2 epigastric
to obtain a description of a paroxysmal change in Repetitive sharp waves over right central region sensations
behavior, whether there was a loss of consciousness, the
duration of the spell, and whether stimuli were encoun- Focal seizures with altered consciousness Formed auditory
tered that might precipitate a seizure. A family history hallucinations.
of epilepsy should always be ascertained. Of particular Impairment of consciousness: Hears music, etc.
importance in the history is the description of the initial cognitive, affective symptoms
signs or symptoms. For example, the approach to a
patient with an aura before a GTC is quite different Frontal lobe Parietal lobe
from the patient who has a GTC without an aura. In
the former case, it is likely that the patient has a focal Posterior
onset to the seizure, increasing the chances that there temporal
is a structural lesion responsible for the seizure, while Dreamy state; blank, gyrus Occipital
in the latter instance, it is likely the patient has a vacant expression; lobe
seizure-inducing stimulus, such as low blood sugar or déjà vu; jamais vu; Formed visual hallucinations.
perhaps an underlying genetic condition. Postictal fea- or fear Superior Sees house, trees that are not there
tures can also be helpful. Absence seizures of childhood temporal
are brief, typically lasting 30 seconds or less, and have gyrus Bad or
a rapid offset, with the child quickly returning to unusual
normal mental status. Complex partial seizures are of EEG: left temporal lobe seizure smell
longer duration, lasting 30 seconds to several minutes, Olfactory hallucinations
and typically have some degree of confusion and tired- Fp1-F7
ness after the event. F7-T3 Psychomotor Aphasia
T3-T5 phenomena.
There are many episodic disorders that resemble sei- T5-O1 Chewing
zures. Episodes such as night terrors, breath-holding Fp2-F8 movements,
spells, or syncope may resemble epileptic seizures. The F8-T4 wetting lips,
timing of the event is important. When nocturnal, epi- T4-T6 automatisms
leptic seizures typically occur in the early morning T4-O2 (picking at
hours, while sleep disorders such as night terrors typi- clothing)
cally occur several hours after the child falls asleep. A Repetitive sharp waves over left temporal region
young child for whom the event always occurs in asso- â•…
ciation with provoked crying likely has breath-holding
spells. Individuals who feel light-headed and clammy classified further into those without impairment of con- consist of rhythmic or semirhythmic clonic movements
before losing conscious likely have syncope rather than sciousness or awareness (simple partial seizures) and of the face, arm, or leg. There is usually no difficulty in
epilepsy. If there is doubt about the diagnosis, it is those with impairment of consciousness or awareness diagnosing this type of seizure. Seizures with somato-
usually better to wait before beginning therapy. (complex partial seizures). Seizures without impairment sensory, autonomic, and psychic symptoms (halluciÂ

Plate 3-3 Brain: PART I

Seizures and Epilepsy GENERALIZED TONIC-CLONIC SEIZURES

(Continued) A. Tonic phase Incontinence EEG: tonic phase

formerly termed temporal lobe or psychomotor sei- Epileptic cry Fp1-F3
zures, are one of the most common seizure types Fp2-F4
encountered in both children and adults. The begin- Cyanosis Generalized stiffening C3-P3 100 ␮V
ning of the focal seizure may serve as a warning to the of body and limbs, back C4-P4 1 sec
patient (i.e., aura) that a more severe seizure is pending. arched (opisthotonus)
It is important to recognize that the aura may enable P3-O1
the clinician to determine the cortical area from which
the seizure is beginning. P4-O2
Generalized fast,
The impairment of consciousness or awareness may repetitive spikes
be subtle. For example, the patient may either not and muscle artifact
respond to commands or respond in an abnormally
slow manner. Although focal seizures with altered Incontinence
consciousness or awareness may be characterized by
simple staring and impaired responsiveness, behavior B. Clonic phase EEG: clonic phase
is usually more complex during the seizure. AutoÂ

P late 3-4 Epilepsy

Seizures and Epilepsy ABSENCE SEIZURES

(Continued) Cortex

slowing, which gradually decreases as the patient recov- Absence seizures
ers from the seizure. represent abnormal
interactions between
GENERALIZED SEIZURES: ABSENCE cortical and thalamic
(PETIT MAL) SEIZURES transmissions
Absence seizures typically begin and end in childhood,
although they can be seen in adults. Absences start Thalamus
abruptly without an aura, lasting from a few seconds to
half a minute and ending abruptly. Absence seizures are Generalized bilateral seizure activity
generalized seizures indicating bihemispheric initial
involvement clinically and electroencephalographically. Sudden onset Loss of attention
Absence seizures have an abrupt onset and offset. There 2-15 seconds Vacant stare
is typically a sudden cessation of activities with a blank, Sudden cessation
distant look to the face. As the seizure continues, there Eye may
are often automatisms and mild clonic motor activity, blink or
such as jerks of the arms and eye blinking. The patient roll up
is often unaware that he or she has had a seizure, but
usually recognizes that he or she has had a “blank” Child alert and attentive
period. before and after seizure

In the untreated patient, absence seizures can occur Fp1-F3 Typical absence seizure.
quite frequently during the day. They sometimes occur F3-C3 Impaired awareness
in clusters, particularly when the child is tired or and responsiveness for
drowsy. In a child not on antiepileptic drugs, typical Fp1-P3 2-15 seconds.
absence seizures can almost always be precipitated by Fp2-F4
hyperventilation. F4-C4
C4-P4
There are four major syndromes in which typical
absence seizures are a major component: childhood EEG. Atypical absence pattern. Atypical absence
absence epilepsy (pyknolepsy), juvenile absence epi- seizures may be associated with mental retardation
lepsy, juvenile myoclonic epilepsy, and epilepsy with and tonic or atonic seizures.
myoclonic absences. The absence epilepsies appear to
have a complex genetic basis. Atypical absence seizures, F7-T3
a form of absence seizures, usually occur in cognitively F3-C3
impaired children who have other seizure types. Unlike
typical absence seizures, atypical absence seizures are C3-P3
often longer and have a less distinct onset. F3-T4
F4-C4
The EEG reveals a bilateral, synchronous symmeÂ

Plate 3-5 Infantile spasms (West syndrome) Brain: PART I
Arms abducted
Epileptic Syndromes Neck and F4-C4
torso flexed C4-O2
F3-C3
Legs C3-O1
extended
Jackknife seizure EEG. Hypsarrhythmia typical of interictal pattern in
children with infantile spasms
Juvenile myoclonic epilepsy

Once the seizure type has been identified, it is very Jerking Normal Normal
helpful for the clinician to try to determine the of arms,
epileptic syndrome. An epileptic syndrome is a cluster shoulders,
of clinical and electroencephalographic features that and head
occur together more commonly than by chance. Epi-
leptic syndrome identification aides in identifying etiol- Chromosome 6
ogy and provides the clinician with guidance regarding
long-term prognosis. Episodes typically occur EEG. 3-6–Hz spikes and polyspikes and slow waves
soon after awakening
An example of an epileptic syndrome with general-
ized seizures is juvenile myoclonic epilepsy (JME). The Benign rolandic epilepsy
seizure types are generalized tonic-clonic, absence, or Heterozygous affected
myoclonic, which often occur upon awakening. The
seizures begin in adolescence or early adulthood in Normal Fp2-F8
an otherwise healthy individual. The interictal EEG
reveals spike-and-wave activity at a frequency of 3.5 to F8-T4
6.0╯Hz, while neuroimaging is normal. Although the
seizures are usually controlled with antiepileptic drugs, Dominant inheritance T4-T6
the condition is lifelong. A single-gene mutation has pattern
not been identified, and many investigators feel the Motor, sensory or C3-Cz
condition likely involves multiple genes. Once diag- autonomic seizures
nosed with JME, the patient can be provided specific involve face or Cz-C4
information regarding prognosis and treatment. oropharynx
C4-T4
Benign rolandic epilepsy, also called benign childhood Seizures often occur during sleep EEG. Pattern typical of benign rolandic epilepsy
epilepsy with central-temporal spikes, is a genetic dis- â•…
order confined to children, which is characterized by
nocturnal generalized seizures of probable focal onset cerebral insult before, at, or shortly after birth, or from waves. During the spasm, the EEG shows an abrupt
and diurnal simple partial seizures arising from the an insult or disease process occurring within the first generalized decrement in the amplitude of the ongoing
lower rolandic area and an EEG pattern consisting of few months to 1 year after birth. One of the most activity.
midtemporal–central spike foci. The characteristic fea- common types of infantile spasm is characterized by
tures of daytime seizures include (1) somatosensory forward flexion of the head and body, with the arms Infantile spasms are often treated with adrenocorti-
stimulation of the oral-buccal cavity, (2) speech arrest, flung forward or outward. The EEG in infantile spasms cotropic hormone or corticosteroids. Clonazepam has
(3) preservation of consciousness, (4) drooling, and (5) shows a characteristic pattern called hypsarrhythmia, been used occasionally, and in some refractory condi-
tonic or tonic-clonic activity of the face. Less often, the consisting of high-amplitude multifocal spikes and slow tions, a ketogenic diet may be helpful in controlling the
somatosensory sensation spreads to the face or arm. seizures.
Most attacks involve the face, and arrest of speech may
initiate the attack or occur during its course. Con-
sciousness is rarely impaired during the daytime attacks,
although, because of the motor involvement, the child
cannot speak. Often the child’s gestures will indicate to
the parents that the child is totally aware during the
event. The characteristic interictal EEG abnormality is
a high-amplitude, usually diphasic spike, with a promi-
nent following slow wave. The spikes or sharp waves
appear singly or in groups in the midtemporal and
central (rolandic) region (C3, C4).

Infantile spasms are brief episodes of tonic flexor or
extensor movements, or both, of the body and limbs.
These spasms are seen in infants and young children up
to 4 years of age and usually result from a severe

70 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-6 Epilepsy

The most common seizure type in neonates is focal. In this example, the newborn is having focal
clonic activity of the left arm with eye deviation to the left. The EEG shows electrographic
seizures with rhythmic spikes coming from the right hemisphere. The seizure in the right hemi-
sphere is responsible for both the left arm jerking and eye deviation.

Neonatal Seizures Left
temporal

Neonatal seizures are one of the most common, yet Left
most ominous, neurologic signs in newborns. Because central
seizures may be the first and only sign of a central Right
nervous system disorder, their recognition is extremely central
important. A considerable difference is apparent in the Right
behavior observed during seizures in neonates and the temporal
behaviors seen in older children and adults. Infants are
unable to sustain organized generalized epileptiform The rhythmic spike in the right central region of the EEG corresponds to the brain
discharges, and generalized tonic-clonic and absence region in which the seizure is arising.
seizures do not occur. The age-dependent clinical and
EEG features of seizures in neonates are a result of the â•…
immaturity of cortical organization and myelination.
posture, pedaling movements of the legs or paddling associated with epileptiform discharges can also be seen
Neonatal seizures are classified as clonic, tonic, and movements of the arms, blinking, momentary fixation in sick neonates.
myoclonic. Clonic seizures consist of rhythmic jerking of gaze with or without eye deviation, nystagmus, and
of groups of muscles and occur in either a focal or apnea. However, when these behaviors are observed Whereas the diagnosis of seizures relies primarily on
multifocal pattern. In multifocal clonic seizures, move- during EEG recordings, epileptiform activity is usually clinical observation, the EEG may be extremely valu-
ments may migrate from one part of the body to not recorded. Likewise, when tonic posturing involves able in confirming the presence of epileptic seizures. In
another. Although focal seizures may be seen with all four extremities and the trunk, an associated EEG- addition, the EEG is very useful in the detection of
localized brain insults, such as neonatal strokes, they epileptiform discharge rarely appears. Myoclonus not electrographic seizures in paralyzed infants or in assess-
may also be seen in disorders that diffusely affect the ing response to antiepileptic medications.
brain, such as asphyxia, subarachnoid hemorrhage,
hypoglycemia, and infection. In tonic seizures, the
infant develops asymmetric posturing of the trunk or
deviation of the eyes to one side. Myoclonic seizures
are similar to those seen in older children, consisting of
rapid jerks of muscles. The myoclonic seizures can
consist of bilateral jerks, although occasionally unilat-
eral or focal myoclonus can occur.

Sick neonates often display repetitive, stereotyped
behavior that may be confused with seizures. These
behaviors include repetitive sucking and other oral-
buccal-lingual movements, assumption of an abnormal

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 71

P late 3-7 Brain: PART I
EEG monitored
Lorazepam ECG monitored
Phenytoin IV Endotracheal
Phenobarbital inDjreucgtesd tube
General
anesthesia (e.g.,
midazolam,
sodium
thiopental,
propofol) with
ventilator
support

Ventilator

Status Epilepticus BP monitored

Incontinence
Repetitive tonic-clonic jerks of body and limbs

Status epilepticus is the situation in which the mecha- EEG: status epilepticus
nisms that usually terminate seizures have failed. It
is usually defined as a seizure or series of seizures Fp1-A2 100 ␮V
without full recovery of consciousness between the Fp2- 1 sec
seizures, which last at least 30 minutes. There are F3-
two major types of status epilepticus; convulsive and F4-
nonconvulsive.
C3-
Convulsive status epilepticus (CSE) is one of the most C4-
common medical neurologic emergencies and conÂ

Plate 3-8 Epilepsy

Primary Extracranial

Unknown (genetic or Metabolic Anoxia
biochemical predisposition) Electrolyte Hypoglycemia
Biochemical
Inborn errors Drugs
of metabolism Drug withdrawal
Alcohol
withdrawal

Intracranial

Causes of Seizures

The etiology of epilepsy is classified into three broad Tumor Vascular (infarct or hemorrhage) Lissencephaly
categories: genetic, structural, and unknown. Trauma Infection
(depressed fracture, (abscess,
Genetic and Neurometabolic Causes. There are penetrating wound) encephalitis)
many genetic and neurometabolic causes that lead to
seizures, typically beginning in childhood. Genetic dis- Congenital and Tuberous sclerosis complex
orders include disorders such as severe myoclonic epi- hereditary diseases â•…
lepsy of childhood, tuberous sclerosis, Rett syndrome, (tuberous sclerosis)
Angelman syndrome, and fragile X. Neurometabolic
disorders, which may also have a genetic cause, result with cerebral abscesses have a high incidence of seizures, Systemic Causes. Disease processes or disorders that
in disturbances of metabolism and can lead to seizures. and encephalitis and meningoencephalitis may be associ- can cause seizures include various types of metabolic,
Disorders such as urea cycle defects, pyridoxine depen- ated with either focal or generalized seizures. electrolyte, and biochemical disturbances; hypoxia;
dency, biotinidase deficiency, and glucose transporter hypoglycemia; toxic processes; drugs; or abrupt with-
deficiencies can cause severe seizures. Congenital brain malformations are a common cause drawal from drugs or alcohol. Various conditions, such
of childhood seizures. With improved neuroimaging, as fever, fatigue, sleep deprivation, flashing lights,
Structural Causes. The most common types of brain many patients who were thought to have idiopathic sound, or emotional factors may also precipitate sei-
lesions causing seizures are tumors, vascular lesions, epilepsy have now been found to have brain malforma- zures in susceptible individuals. In young children,
head trauma, infectious diseases, congenital malforma- tions. The severity of the seizures is related to the type fever is a common cause of seizures.
tion of the brain, and biochemical or degenerative and extent of the malformation.
disease processes affecting the brain.

Brain tumor is an important cause of seizures, particu-
larly in the adult patient, becoming an increasingly
likely cause after the second decade of life and one
of the main causes in the fourth and fifth decades.
A brain tumor should be suspected in any person who
has onset of seizures, especially focal seizures, after
age 20 years.

Head trauma is a major cause of seizures, which may
occur shortly after the head injury or, more often,
several months to several years later. Factors that
increase the chance of development of post-traumatic
seizures are a penetrating head injury, severe damage to
the brain, prolonged periods of unconsciousness, post-
traumatic amnesia, complications of wound healing,
and a persistent neurologic deficit.

Vascular disease is one of the most common causes of
seizures in older persons, particularly after age 50 years.
Seizures can occur transiently after an acute stroke
(thrombotic, embolic, or hemorrhagic) or may develop
later as a sequela of cerebrovascular disease. Although
uncommon, arteriovenous malformations are fre-
quently associated with seizures. Other vascular causes
include subdural hematomas, venous thrombosis, and
hypertensive encephalopathy.

Seizures may occur with any acute infection of the
nervous system or as a complication of damage to the
nervous system by the inflammatory process. Patients

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 73

P late 3-9 Brain: PART I

A. The movement of ions across the cell membrane is dependent B. Ions are attracted to charges of the opposite polarity. In this
upon both concentration and electrostatic forces. Ions flow from example, K+ ions flow from the extracellular environment, which
Neurobiology of Epilepsy high concentrations to lower concentrations as depicted by the is positive in retationship to the intracellular space, which is neg-
flow of K+ ions from inside the cell, where the concentration is ative. Both concentration and electrostatic forces determine flow of
The core feature of brain electrochemical signals is high, to outside the cell, where the concentrations is lower. ions. The equilibrium potential for the ion is the membrane potential
the neuron membrane. Like all cell membranes, the at which a particular ion does not diffuse through the membrane in
neuron membrane is a phospholipid bilayer. This lipid Na+ Cl– Na+ Cl– either direction. Na+
bilayer prevents the exchange of ionized substrates Cl– Cl– Na+ K+
between the cell and its environment, which is critical
for electrical signaling. The inside of the cell at rest is Cl– Na+ Na+ K+ Cl– Extracellular
negatively charged compared with the outside of the Na+
cell, due to concentration differences in ions. Sodium
(Na+), calcium (Ca2+), and chloride (Cl−) are predomi- +++ + ++++++
nantly found extracellularly, whereas K+ and organic
ions are concentrated intracellularly. These concentra- Concentration Electrical potential
tion differences are due to specific ion transporters that Kgr+adoiuetnot fmcoevlles dKi+ffeinretoncceelml oves
use the cell’s energy supply to continuously move ions
in and out of the cell. These pumps create concentra- X– K+ X– ––– K+ – ––––––
tion differences (between the inside and outside of the K+ X– K+
neuron) by transporting ions against their concentra- X– X– X–
tion gradients (from regions of low concentration to K+ X– X– X– K+
regions of high concentration). This concentration gra-
dient across the membrane provides the electrochemi- X– Intracellular
cal energy to drive signaling. These ions will flow K+
through the membrane through protein channels. Most
channels are ion-selective and will allow the passage of Three states of the sodium channel. C. In the resting state, no ion flow occurs due to closure of the activation gate. D. When the mem-
a specific ion. Unlike the continuous transport by the brane begins to depolarize, the activation channel opens and ion flow occurs. E. As the cell becomes depolarized, the inactivation gate
ion pumps, transport by the ion channels is noncon- closes and no further ion flow occurs. Only when the cell repolarizes does the sodium channel return to the resting state.
tinuous. Ion channels open or close in response to C D Activated (open)
signals from their environment. Voltage-gated channels Resting (closed) Na+ Na+ Na+ E Inactivated (closed) Na+
open or close in response to changes in electrical poten- Na+ Na+
tial across the cell membrane, whereas ligand-gated Na+ Na+ Na+ Na+
channels require a binding of a particular signaling
molecule to open or close. ++ ++ – – – – – – – –

The two most important ions in the transmission of ––– –– – – ++++ ++++ ++++ ++++
action potentials are Na+ and potassium K+. Voltage-
gated Na+ channels have three types of states: deacti- Activation Depolarization Inactivation gate Repolarization
vated (closed), activated (open), and inactivated (closed). gate Na+ closes
During excitation of the cell, Na+ channels are activated
through removal of an intracellular “activation gate,” Inactivation
and Na+ begins flowing into the cell. Once some Na+ gate
ion channels begin opening, the voltage drops further,
causing more channels to open until the membrane F. An action potential is a short-lasting event in which the G. The release of a neurotransmitter is triggered by the arrival
depolarizes. Na+ channels are more sensitive to voltage electrical membrane potential of a cell rapidly rises and falls. of a nerve impulse (or action potential) and occurs through a
change than K+ channels are and open more rapidly. Action potentials begin with an inward flow of Na+ ions, which process called exocytosis. Within the presynaptic nerve terminal,
Thus in a depolarization, the Na+ ions will rush into the changes the electrochemical gradient, which in turn produces vesicles containing neurotransmitter sit “docked” and ready at
cell faster than the K+ ions move outward. This sudden a further change in the membrane potential. This then causes the synaptic membrane. The arriving action potential produces
depolarization, called an action potential, will briefly more channels to open, producing a greater electric current. an influx of Ca2+ ions through voltage-dependent, Ca2+-selective
result in a +30 millivolt potential difference. Once the The process proceeds until most of the available ion channels ion channels. Ca2+ ions then bind with the proteins found within
slowly-opening voltage-gated K+ ion channels have open, resulting in a large upswing in the membrane potential. the membranes of the synaptic vesicles, allowing the vesicles to
opened and allowed K+ to flow out, the action potential The rapid influx of Na+ ions causes the polarity of the plasma “dock” with the presynaptic membrane, resulting in the creation
is ended. Once Na+ channels are activated, they quickly membrane to reverse, and the ion channels then rapidly of a fusion pore. The vesicles then release their contents to
are inactivated due to an “inactivation gate” that blocks inactivate. Potassium channels are then activated, and there the synaptic cleft.
the inside of the channel shortly after it has been acti- is an outward current of K+ ions, returning the electrochemical
vated. During an action potential, the channel remains gradient to the resting state. After an action potential has occurred,
inactivated for a few milliseconds after depolarization. there is a transient negative shift, called the afterhyperpolarization,
The inactivation is removed when the membrane or refractory period, due to additional potassium currents.
potential of the cell repolarizes after the falling phase G Na+
of the action potential. This allows the channels to be F
activated again during the next action potential. Thus 40 K+
the Na+ ion channels initiate the action potential, and Membrane potential difference (mV)
the K+ ion channels terminate it. The channels then 30
close, and the sodium pump can restore the resting
potential of −70 millivolts. 20 Action potential

Membrane polarity is also affected by ligand-gated 10 Na+ Ca2+
channels that open when neurotransmitters, the ligands 0
of synaptic transmission, bind to specific receptors con- Ca2+ K+
nected to the channels. Glutamate is the primary excit- –10
atory neurotransmitter and gamma-aminobutyric acid
(GABA), the principal inhibitory transmitter. Synaptic –20 Na+ conductance Ca2+
transmission is mediated by glutamate that is released –30

74 –40 K+ conductance Ca2+
–50

–60

–70 Excitatory neurotransmitter Na+

Ligand-gated Na+ channel Na+

â•…

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 3-10 Epilepsy

Neurobiology of Epilepsy A. Postsynaptic neuron at which several presynaptic afferent fibers terminate. Fibers colored in pink convey
excitatory information across the synaptic cleft to the postsynaptic neuron, whereas the inhibitory fiber is blue
(Continued) and conveys inhibitory information to the postsynaptic neuron.

from the pyramidal neurons and depolarizes and excites Inhibitory fiber
the target neurons via ionotropic receptors (NMDA,
α-amino-3-hydroxy-5-methylisoxazole-4-proprionic Excitatory fiber
acid [AMPA], and kainic acid [KA]). Glutamate channel
opening allows Na+ and Ca2+ to enter the cell, resulting Ca2+ Presynaptic Na+ Ca2+ Presynaptic Na+
in depolarization, whereas with GABA channel opening, neuron Na+ GABAergic Na+
Cl− enters the cell, resulting in hyperpolarization.
Ca2+ neuron
Once the action potential is generated, it propagates Ca2+
to the synapse. Depending on the type of cell, an
excitatory or inhibitory neurotransmitter is released. Glutamate GABA
The effect of the neurotransmitter on the postsynaptic Cl–
membrane will determine current flow into or out of Na+ K+
the postsynaptic cell, thus determining whether the
postsynaptic cell will generate action potentials. Na+ Ca2+

Epilepsy is a paroxysmal disorder characterized by Mg2+ AMPA GABAA receptor GABAB K+
abnormal neuronal discharges. Although epilepsy has receptor Postsynaptic receptor
many causes, the fundamental disorder is secondary to Postsynaptic NMDA Na+
abnormal synchronous discharges of a network of neuron receptor neuron Cl–
neurons. Epilepsy is secondary to an imbalance between Na+
excitatory and inhibitory input to cells. Ca2+ EPSP Summated
+ potential
The hallmark of epileptic neurons in experimental EPSP =
models of epilepsy is membrane depolarization, which
results in an interictal spike recorded by EEG. During B. Excitatory fiber. At the excitatory IPSP
an interictal discharge, the cell membrane near the synaptic cleft, glutamate is released.
soma undergoes a relatively high-voltage (approxi- Glutamate passes across the cleft and C. Inhibitory fiber. The inhibitory neurotransmitters, prin-
mately 10 to 15 mV) and relatively long (100 to 200 act as agonists at the AMPA and NMDA cipally GABA, act on GABA receptors in the postsynaptic
µsec) depolarization. The long depolarization has the ionotropic receptor. The excitatory neuro- neuron membrane, permitting the entry of Cl– ions, shifting
effect of generating a train of action potentials that transmitters signal the AMPA channel to open, the membrane potential to a more negative potential, i.e.,
are conducted away from the soma along the axon permitting the inflow of Na+.This results in depolar- hyperpolarization. An inhibitory postsynaptic potential (IPSP)
of the neuron. This large depolarization is called the ization in the membrane potential so that the is generated. In normal synaptic transmission, there is a
paroxysmal depolarization shift (PDS). The PDS is difference in potential across the membrane is shifted balance between excitatory and inhibitory neurotransmitters
caused by an imbalance of excitation over inhibition. toward the positive, i.e., depolarization. With depolar- so that the summation of EPSP and IPSP maintains the polar-
This enhanced excitation, or reduced inhibition, can be ization, there is a release of Mg2+ from the NMDA ization of the membrane at a level below the threshold at
secondary to a variety of abnormalities, including dis- receptor, permitting Na+ and Ca2+ ions to enter the which bursts of firing occur, termed the resting potential.
turbances in the intrinsic properties of neuronal mem- postsynaptic neuron. An excitatory postsynaptic
branes, excess excitation through NMDA and AMPA potential (EPSP) is generated.
receptors, reduced inhibition through GABA channels,
and abnormalities of potassium and calcium channels. Presynaptic Na+ Presynaptic Na+
The net effect is an imbalance of excitation over inhibi- neuron GABAergic
tion. The interictal PDS is followed by a large hyper- Ca2+ Ca2+
polarization, which serves to limit the duration of neuron
interictal paroxysms. It is important to remember that
an epileptic area is made up of numerous abnormal Ca2+ Na+ Ca2+ Na+
neurons that discharge in an abnormal synchronous
manner. The PDS may occur because of intrinsic mem- Increased Na+ Decreased K+
brane abnormalities in a group of neurons or because glutamate GABA
of excessive excitatory input (or reduced inhibitory Na+ Ca2+
input) to a group of neurons. Cl–

With time, a progressive loss of hyperpolarization Mg2+ NMDA AMPA GABAA receptor GABAB K+
after the PDS may occur in the epileptic focus. During Postsynaptic receptor receptor Postsynaptic receptor
seizures, the epileptic neurons undergo prolonged Na+ Cl–
depolarization with waves of action potentials during neuron Na+ Ca2+ neuron
the tonic phase of the seizure and oscillations of mem- EPSP
brane potentials with bursts of action potentials, sepa- + Summated EPSP Summated
rated by quiet periods during the clonic phase. An EEG potential + potential
recorded at the scalp at this time shows continuous =
spikes, which generally coincide with the tonic stage of =
a generalized tonic-clonic seizure. During the next
stage, large inhibitory potentials occur (with slowing or IPSP IPSP
flattening on surface EEG) and alternate with recur- D. Increase in glutamate EPSP. With an increase in
rent, rhythmic PDSs (with spikes on surface EEG). excitatory neurotransmitters, the postsynaptic neuron E. Decrease in IPSP. When there is a decrease in inhibitory
This pattern generally coincides with the clonic stage membrane becomes more positive, producing an neurotransmitters, the IPSP decrease and the postsynaptic
of the seizure. increase in EPSP. The summation of the excitatory neuron membrane becomes more positive. The summation
and inhibitory signals moves across the threshold of the excitatory and inhibitory signals moves across the
Focal seizures may spread along the cortex and prop- value, and an action potential occurs. threshold value and an action potential is fired.
agate to distant regions via white matter tracts. Many
patients with focal seizures will have an aura at the â•…
75
THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 3-11 Brain: PART I

Spike Ictal discharge Spike-wave

Neurobiology of Epilepsy Paroxysmal Tonic phase Clonic phase
depolarization
(Continued) Potential difference (mV) shift (PDS)
0
onset. The type of aura is dependent upon the region
of the brain in which the seizure originated. For -20
example, patients with temporal lobe onset may experi- -40 100 ms
ence déjà vu (the experience of feeling sure that one has
already witnessed or experienced a current situation), -60 1 sec
whereas a patient with parietal lobe onset may experi-
ence a sensation of numbness or tingling. With propa- -80
gation, more and more neurons are recruited into A. Paroxysmal depolarization shift (PDS) is a cellular marker of epilepsy and consists of a large depolarization of
synchronous firing, which could culminate in a general- a group of neurons with action potentials, as indicated by the vertical lines on the large depolarization. The PDS
ized tonic-clonic seizure. is followed by repolarization. The PDS and repolarization corresponds to a spike and wave on the EEG. A seizure
occurs when there is a massive depolarization of cells without intervening periods of repolarization. This would
GENERALIZED SEIZURES correspond to the tonic phase of the seizure. As inhibition increases during the seizure, there is a cycle of PDS
Unlike focal seizures, which involve a relatively followed by repolarization. This corresponds to the clonic phase of the seizure
restricted group of neurons at onset, generalized sei-
zures result from dysfunction of networks of neurons Carbamazepine Voltage-gated Excitatory Voltage-gated Carbamazepine
involving multiple brain regions. The basic underlying Gabapentin calcium channel presynaptic sodium channel Oxcarbazepine
mechanism in absence seizures, and possibly other gen- Lamotrigine Felbamate
eralized seizure types, involves thalamocortical circuitry Levetiracetam Ca2+ neuron Na+ Lacosamide
and the generation of abnormal oscillatory rhythms in Oxcarbazepine Lamotrigine
the neuronal network. The neuronal circuit responsible Phenytoin Ca2+ Na+ Phenytoin
for the generation of the oscillatory thalamocortical Topiramate Rufinamide
burst-firing observed during absence seizures includes Ezogabine Potassium K+ Topiramate
cortical pyramidal neurons, thalamic relay neurons, and channel Zonisamide
the nucleus reticularis thalami (NRT). The principal Levetiracetam
synaptic connections of the thalamocortical circuit K+
include glutamatergic fibers between neocortical pyra- Glutamate release
midal cells and the NRT; GABAergic connections
between cells of the NRT, which activate GABAA recep- Felbamate Topiramate
tors; and GABAergic fibers from NRT neurons, which
activate GABAA and GABAB receptors on thalamic relay NMDA AMPA
neurons. receptor receptor
Postsynaptic neuron
The cellular events that underlie the ability of NRT Na+ Ca2+ Na+
neurons to shift between an oscillatory and tonic firing
mode are the low-threshold (T) Ca2+ spikes that are B. Examples of molecular targets of antiepileptic drugs that reduce excitability. This may occur through blockage
present in thalamocortical and NRT neurons. These of calcium, sodium, and potassium channels or through reducing ion flow through NMDA and AMPA receptors.
T-type Ca2+ channels are a key membrane property Levetiracetam binds to synaptic vesicles, which may lead to reduced neurotrasnmiter release.
involved in burst-firing excitation and are associated
with the change from oscillatory to burst-firing in thal- C Valproate GABA Inhibitory
amocortical cells. Mild depolarization of these neurons Vigabatrin presynaptic
is sufficient to activate these channels and to allow the GABA Tiagabine GABA-T
influx of extracellular Ca2+. Further depolarization pro- Glia GABA-T neuron
duced by Ca2+ inflow will exceed the threshold for firing Succinic
a burst of action potentials. After T-channels are acti- Succinic semialdehyde
vated, they become inactivated rather quickly, hence the semialdehyde
name transient. Deinactivation of T-channels requires
a relatively lengthy hyperpolarization. GABAB receptor– GABA transporter GABA Levetiracetam
mediated hyperpolarization is a primary factor in the Benzodiazepines displaces zinc to
deinactivation of T-channels. Barbituates Zn2+ increase inhibitory
Cl– current
Recurrent collateral GABAergic fibers from the
NRT neurons activate GABAA receptors on adja- Postsynaptic neuron GABAA receptor
cent NRT neurons. Activating GABAA receptors in the
NRT therefore results in an inhibition of inhibitory Cl–
output to the thalamic relay neurons. Because of the
decreased GABAB activation, there would be a reduced C. Examples of molecular targets of antiepileptic drugs that enhance inhibition. Drugs may increase amount of GABA
likelihood that Ca2+ deinactivation would occur. This postsynaptically by blocking GABA uptake or increase intracellular GABA by reducing degradation of GABA. Enhan-
would result in decreased oscillatory firing. However, cing chloride flow through the GABA receptor is a common mechanism of inhibitory drugs, such as barbiturates and
direct GABAA and GABAB activation of thalamic relay benzodiazepines. Levetiracetam displaces zinc from the GABA receptor, which results in increased chloride currents.
neurons would be expected to have detrimental effects,
increasing hyperpolarization and therefore increasing â•…
the likelihood of deinactivation of the T-channels. The
abnormal oscillatory rhythms in absence seizures can be THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS
caused by abnormalities of the T-type Ca2+ channels or
enhanced GABAB function.

76

P late 3-12 Epilepsy

Electrical studies PREOPERATIVE EVALUATION
Language Motor
Sensory Subdural electrode
strips and grids

Language

Seizure Grid mapping
focus

Preoperative evaluation should identify Low-voltage electrical stimulation
seizure focus and areas of vital function. of subdural electrodes allows
mapping of language, motor, and
Electrical other vital areas.
contacts
Electrical
Depth contacts
electrode
Subdural
Hippocampus electrode
Sphenoidal electrode strip
(outside of brain) Sodium amobarbital (Wada) test
Anterior Hemispheric anesthesia
hippocampus

Treatment of Epilepsy

Although there are a variety of treatment options in Temporal
treating seizures, the three main approaches are anti- lobe lesion
epileptic drugs, dietary therapy, and surgery. (poor
memory
The vast majority of patients are treated with antiÂ