The brainstem: anatomy, assessment, and clinical syndromes.

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The Brainstem: Anatomy, Assessment, and Clinical Syndromes
Robin A. Hurley, M.D., Laura A. Flashman, Ph.D., Tiffany W. Chow, M.D.,
Katherine H. Taber, Ph.D.
Cover and Figure 1.
anatomy of the brainstem is pre-
sented in a simplified, color-coded
format.1–7Cover. The approximate
locations and extents of nuclei that
are important sources for a partic-
ular neurotransmitter are color-
coded onto a sagittal magnetic res-
onanceimage.
approximate locations and extent of
major tracts and nuclei are color-
coded onto simplified axial illustra-
tions of brainstem sections (left
panel). The most common pattern
of arterial territories is also pre-
sented (right panel). All illustra-
tions are oriented in the radio-
graphic perspective.
The internal
Figure1.
The
http://neuro.psychiatryonline.org
J Neuropsychiatry Clin Neurosci 22:1, Winter 2010
WINDOWS TO THE BRAIN
Robin A. Hurley, M.D., L. Anne Hayman, M.D., Katherine H. Taber, Ph.D.
Section Editors

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Overview of Anatomy
T
mood. It is essential to also understand the roles of the
brainstem for these functions. Of particular importance,
the brainstem is the source for the monoamine (norepi-
nephrine [Figure 1, purple], dopamine [Figure 1, green],
and serotonin [Figure 1, yellow]) neurotransmitters that
project widely to modulate these circuits. The major
subdivisions of the brainstem (from rostral to caudal)
are the midbrain, pons, and medulla (Figure 1, left
panel). The brainstem serves as a conduit for many
ascending and descending pathways (Table 1), contains
most cranial nerve nuclei (Figure 1, white, and Table 1),
and is important for many key integrative functions. It
contains the lower motor neurons for the muscles of the
head and does the initial processing of general afferent
information concerning the head. The reticular forma-
tion forms the central core of the brainstem (Figure 1,
area approximated with dashed red lines).1,2It partici-
pates in a wide range of functions including control of
movement, modulation of pain, autonomic reflexes,
arousal, and consciousness. The vascular supply to the
brainstem is primarily from the posterior cerebral ar-
tery and the vertebral-basilar system (Figure 1, right
panel).3In general, the small arteries that penetrate and
supply the brainstem arise directly from larger arteries.3
These regions are at high risk for ischemia because
there is little or no interconnecting surface network to
provide collateral circulation.
The most rostral part of the brainstem is the mid-
brain. It is characterized by four bumps, the paired
superior and inferior colliculi on its dorsal (posterior)
surface, and by the large cerebral peduncles (containing
the descending corticospinal and corticopontine tracts)
on its ventral (anterior) surface. The nuclei for cranial
he focus in neuropsychiatry is usually on the cor-
tical areas that subserve behavior, cognition, and
nerves III, IV, and part of V (sensory) are found in the
midbrain. The ascending superior cerebellar peduncles
cross (decussate) in the caudal midbrain. Fibers enter
the red nucleus and also continue on to the thalamus.
Other key midbrain structures include the substantia
nigra and ventral tegmental area (both dopamine-con-
taining [green]), the pedunculopontine nucleus (acetyl-
Drs Taber and Hurley are affiliated with the Veterans Affairs Mid
Atlantic Mental Illness Research, Education, and Clinical Center, and
the Research and Education Service Line at the W. G. Hefner Veterans
Affairs Medical Center in Salisbury, N.C. Dr. Hurley is affiliated with
the Departments of Psychiatry and Radiology at Wake Forest Uni-
versity School of Medicine in Winston-Salem, N.C., and the Men-
ninger Department of Psychiatry and Behavioral Sciences at Baylor
College of Medicine in Houston. Dr. Flashman is affiliated with Dart-
mouth Medical School in Lebanon, N.H. Dr. Chow is affiliated with
the Rotman Research Institute, University of Toronto in Toronto,
Ontario, Canada. Dr. Taber is affiliated with the Division of Biomed-
ical Sciences at the Virginia College of Osteopathic Medicine in
Blacksburg, Va., and the Department of Physical Medicine and Reha-
bilitation at Baylor College of Medicine in Houston. Address corre-
spondence to Dr. Robin Hurley, Hefner VA Medical Center, 1601
Brenner Ave., Salisbury, NC 28144; Robin.Hurley@va.gov (e-mail).
Copyright © 2010 American Psychiatric Publishing, Inc.
TABLE 1.Cranial Nerve Nuclei and Long Tracts
Structure Symptoms
CN III (Oculomotor)Ipsilesional eye looks down and
laterally
Upper lid droops (ptosis)
Pupil is dilated and unresponsive to
light
May cause diplopia
Ipsilateral loss of sensation from
mandible (midbrain)
Ipsilateral loss of sensation from face
(upper pons)
Ipsilateral loss of pain and temperature
from face (pons, medulla)
Ipsilateral lateral rectus palsy
Eye looks medially
Ipsilateral lower motor neuron facial
weakness
Ipsilateral loss of taste on anterior 2/3
of tongue
Ipsilateral deafness (lower pons)
Vertigo, nystagmus, vomiting
(medulla)
Ipsilateral decreased gag response
Ipsilateral loss of taste on posterior 1/3
of tongue
Ipsilateral paralysis of larynx and soft
palate
Ipsilateral flaccid tongue weakness
CN IV (Trochlear)
CN V (Trigeminal)
CN VI (Abducens)
CN VII (Facial)
CN VIII
(Vestibulocochlear)
CN IX
(Glossopharyngeal)
CN X (Vagus)
CN XII (Hypoglossal)
Corticopontine tracts
Corticobulbar tract
Corticospinal tract
Medial lemniscus
Transient ataxia and hypotonia
Contralateral hemiplegia
Contralateral hemiplegia
May cause contralateral loss of position
and vibration
Internuclear opthalmoplegiaMedial longitudinal
fasiculus
Trigeminothalamic tract
(dorsal)
Spinothalamic tract
(lateral)
Lateral lemniscus
Middle cerebellar
peduncle
Superior cerebellar
peduncle
Inferior cerebellar
peduncle
Vestibulospinal tract
(lateral)
Vestibulospinal tract
(medial)
Ipsilateral loss of pain and temperature
from face
May cause contralateral loss of pain
and temperature from body
Bilateral partial deafness
Ataxia and incoordination
Tremors
Ipsilateral ataxia
Decerebrate posturing
Continuation of Medial longitudinal
fasiculus
Adapted from Hayman et al.3and Marx and Thomke30
HURLEY et al.
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choline-containing [orange]) and the first of the raphe
nuclei (serotonin-containing [yellow]).
Caudal to the midbrain is the pons. The nuclei for
cranial nerves VI, VII, VIII, and part of V (motor) are
found in the pons. Here the corticopontine fibers (blue)
terminate in the pontine nuclei (gray). These nuclei give
rise to the pontocerebellar fibers that cross the midline
to form the middle cerebellar peduncle (blue). This area
is particularly vulnerable to injury in malnourished in-
dividuals, especially if there has been a rapid correction
of electrotype abnormalities.8The classic symmetric ar-
eas of myelin disruption that characterize central pon-
tine myelinolysis are thought to result from osmotically
active factors expelled by the cells within gray matter
that are toxic to myelin. White matter adjacent to edem-
atous gray matter (like the crossing pontocerebellar fi-
bers intermingled with the pontine nuclei) is therefore
the most exposed. The ascending and descending fiber
tracts are compact white matter bundles and much less
affected. Lesions are also found in other gray matter
regions containing heavily myelinated fibers, such as
thalamus, basal ganglia, and cerebellum.
Caudal to the pons is the medulla, containing the
nuclei for cranial nerves IX, X, XI, XII and a portion of
V. Ascending spinocerebellar tracts form the inferior
cerebellar peduncle at this level. The ascending sensory
tracts from the body (posterior columns) terminate in
the posterior column nuclei (gracilis, cuneatus) in the
lower medulla. These nuclei are the origin of the spi-
nothalamic tracts that cross (sensory decussation) in the
lower medulla and ascend to form the medial lemniscus
(pink).
Neuropsychological Deficits
The common perception has long been that brainstem
injury results primarily in motor and cranial nerve def-
icits. More recent work has focused on the transient and
permanent cognitive deficits that can occur in conjunc-
tion with brainstem lesions. Individuals have been de-
scribed as being unable to return to their baseline levels
of functioning in daily life activities, even after physical
and neurological deficits have resolved.9Although the
literature is somewhat limited, there have been several
case reports and case series examining cognitive func-
tioning in small cohorts of individuals with brainstem
insults.9–13The most frequently reported deficits fol-
lowing isolated brainstem lesions are impaired atten-
tion and executive functioning. These have been ob-
served across a variety of tests, including letter fluency
and category fluency, the Trail Making test, letter can-
cellation tests, various sorting tests (Weigl sorting test,
Modified Card Sorting Test), the Test of Every Day
Attention (visual elevator subtest), and the Stroop Color
and Word Test. Impaired naming ability also occurs
relatively frequently in individuals with brainstem in-
jury. Memory impairment has been reported much less
commonly, and sensory-perceptual deficits are not typ-
ically reported. Interestingly, one study noted declines
in general intellectual ability in approximately 50% of
children following resection of low-grade brainstem tu-
mors.14
Injury to the ventral pons can result in locked-in syn-
drome, characterized by paralysis of all four limbs and
mutism (paralytic).15Using testing based on eye-coded
(yes/no) responding, several studies have examined
cognitive abilities in individuals with this condition. A
self-report survey study of patients (N?44) with
chronic locked-in syndrome indicated that six patients
(14%) reported impaired attention and 19% reported
memory difficulties.16A recent study utilized neuro-
psychological testing in patients (N?9) with chronic
locked-in syndrome due to isolated brainstem injury.17
While cognitive functioning was generally preserved in
the group, individual-specific deficits included mental
calculation and problem solving, auditory and visual
recognition, and receptive language. In contrast, a case
report of two patients with chronic locked-in syndrome
found no cognitive deficits on neuropsychological as-
sessment.18Similarly, a case series (N?10) reported that
locked-in patients can recover intact cognitive levels in
cases of pure brainstem lesions.19Although the authors
of that study concluded that injuries to additional areas
of the brain were most likely responsible for reported
deficits in this population, other studies (as noted
above) have reported deficits in patients with isolated
brainstem insults.
In summary, the literature indicates a variety of cir-
cumscribed cognitive deficits may occur after brainstem
insults, and these do not always completely resolve.
The profile of deficits seen in well-studied individuals
implicates disruption of the frontal-subcortical system,
with specific impact on regions involved in attentional
and executive functioning. The brain areas that are pri-
marily associated with the performance of executive
functions are the prefrontal and the anterior cingulate
cortices.20,21These areas are reciprocally interconnected
with the brainstem.22,23The findings of pervasive atten-
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tional and executive impairment, with naming and re-
ceptive language deficits often present, serve to remind
us that specific cognitive abilities can be disrupted by
injury to areas remote from the cortical circuitry that is
primarily associated with these domains. The implica-
tions of these cognitive deficits are important. Several
studies examining functional outcome in rehabilitation
following stroke have shown that cognition, particu-
larly attention and executive abilities such as abstract
thinking, judgment, problem solving, short-term verbal
attention and memory, and comprehension can play an
important role in determining length of hospital stay
and in predicting functional status at time of dis-
charge.24–28
Higher-order cognitive skills such as
awareness, accurate understanding of one’s impair-
ments, and the capacity to learn and generalize func-
tional skills also impact successful rehabilitation. Un-
fortunately, individuals who demonstrate significant
physical improvement may not make concomitant
gains in cognition and therefore may leave rehabilita-
tion with less functional independence and a greater
need for follow-up services.
Clinical Brainstem Syndromes
The clinician needs to be familiar with how neuroana-
tomical functional units cluster in the brainstem. These
can be summarized as cranial nerve nuclei; pigmented
nuclei (red nucleus, substantia nigra [“black nucleus”],
and locus ceruleus [“blue spot”]); and tracts (e.g., cor-
ticospinal, corticopontine, spinothalamic, spinocerebel-
lar) that pass through. When any two of these three
categories show impairment simultaneously, particu-
larly when there are alternating signs, the lesion is
likely to be within the brainstem. Thus, if the patient
has cranial nerve deficits (Table 1) accompanied by par-
kinsonism or cranial nerve deficits and a crossed corti-
cospinal neurological sign, the first place to localize the
lesion would be the brainstem. Lesion location can be
approximated (Table 2) by combining cranial nerve-
related symptoms (which provide rostral-caudal local-
ization) and long tract-related symptoms (which pro-
vide medial-lateral localization).29There are multiple
named brainstem syndromes, most known by eponym
(Table 3).3,30It has been noted that many of these are
seldom encountered in clinical practice. The combina-
TABLE 2.Key Structures and Symptoms for Brainstem Lesion Localization
Medial Injury Lateral Injury
Ipsilesional Symptoms
Contralesional
SymptomsIpsilesional SymptomsContralesional Symptoms
Midbrain
Cranial nerve III (oculomotor): eye
turned down and laterally; upper lid
droops (ptosis); pupil is dilated and
unresponsive to light
Cranial nerve IV (trochlear): eye unable
to look down when turned inward
(may cause diplopia)
Medial longitudinal fasciculus:
internuclear ophthalmoplegia
Corticospinal tract:
weakness (body)
Oculosympathetic tract: Horner’s
syndrome
Spinothalamic tracts: loss of pain
and temperature (body)
Medial lemniscus: loss
vibration and
proprioception (body)
Pons
Cranial nerve VI (abducens): eye looks
medially
Medial longitudinal fasciculus:
internuclear ophthalmoplegia
Corticospinal tract:
weakness (body)
Medial lemniscus: loss
vibration and
proprioception (body)
Oculosympathetic tract: Horner’s
syndrome
Spinocerebellar tracts (inferior
cerebellar peduncle): ataxia
(body)
Cranial nerve V (trigeminal-
sensory): loss of pain and
temperature (face)
Spinothalamic tracts: loss of pain
and temperature (body)
Medulla
Cranial Nerve XII (hypoglossal): flaccid
tongue weakness
Medial longitudinal fasciculus:
internuclear ophthalmoplegia
Corticospinal tract:
weakness (body)
Medial lemniscus: loss
vibration and
proprioception (body)
Oculosympathetic tract: Horner’s
syndrome
Spinocerebellar tracts (inferior
cerebellar peduncle: ataxia
(body)
Spinothalamic tracts: loss of pain
and temperature (body)
Adapted from Gates.29
HURLEY et al.
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tion of symptoms is the critical factor. Thus, the Weber,
Claude, Benedict, Nothnagel, and Parinaud syn-
dromes, all resulting from midbrain lesions, have oc-
ulomotor nerve palsy (CN III) in common. This gen-
erally causes diplopia on lateral gaze, but there could
also be disconjugate vertical gaze. Use of the Maddox
Rod and a penlight can help the clinician disentangle
the direction in which the eyes are disconjugate.31
The Millard-Gubler syndrome localizes to the pons
with its facial palsy (CN VII) and sometimes lateral
rectus palsy (CN VI, another way to achieve diplo-
pia). Avellis, Jackson, and Wallenberg syndromes
arise from medullary lesions that cause oropharyn-
geal deficits (CN IX-XII).32,33
The differential diagnosis for brainstem syndromes
can be fairly easy to remember. These are typically focal
lesions due to stroke, neoplasm, or multiple sclerosis.
Less common etiologies for brainstem syndromes
would include infectious diseases (especially some
meningitides that center on the base of the brain like
tuberculosis), vascular malformation, traumatic brain
injury, hyponatremia causing a central pontine myeli-
nolysis, and the neurodegenerative movement disor-
ders progressive supranuclear palsy (PSP) and multi-
system atrophy. Although not commonly considered a
brainstem syndrome, Parkinson’s disease almost al-
ways extends beyond the cardinal signs of parkinson-
ism (resting tremor, postural instability, akinesia, gait
changes) associated with degeneration of the substantia
nigra.34,35Depression is highly prevalent among pa-
tients with Parkinson’s disease, at times manifesting as
a prodrome and certainly complicating disease man-
agement.36,37Antidepressant effects of l-dopa and lack
of correlation of severities of depressive symptoms with
motor disability imply that depression in the Parkin-
son’s disease context results from the dopaminergic
deficit. Autonomic system impairments also impact
heavily on Parkinson’s disease quality of life, possibly
related to vagal neuropathy (lower pons).38Parkinson’s
disease occurs in one of every 272 people in the popu-
lation, whereas multiple sclerosis occurs in one of every
700.
While most clinicians are familiar with the cardinal
signs of parkinsonism as described above, PSP is less
TABLE 3.Brainstem Syndromes
Syndrome Symptoms
Midbrain
Weber
Claude
Benedict
Nothnagel
Parinaud
Pons
Raymond-Cestan
Raymond
Ataxic hemiparesis
Millard-Gubler or
Gubler
Foville
Medulla
Wallenberg
CN III palsy (ipsilesional); weakness and vertical gaze palsy (contralesional)
CN III palsy (ipsilesional); ataxia, tremor and vertical gaze palsy (contralesional)
CN III palsy (ipsilesional); ataxia, tremor and weakness (contralesional)
CN III palsy (ipsilesional); ataxia and vertical gaze palsy (contralesional)
Paralysis of upgaze, convergence-retraction nystagmus, lid retraction and light near dissociation
Internuclear ophthalmoplegia (ipsilesional); ataxia and weakness (contralesional)
CN VI palsy (ipsilesional); weakness (contralesional)
Weakness and ataxia (contralesional)
CN VI and VII palsy (ipsilesional); weakness (contralesional)
CN VI and sometimes VII palsy (ipsilesional); weakness and sensory loss (contralesional)
Ataxia, loss of pain and temperature for face, weakness of soft palate, larynx and pharynx,
Horner’s (ipsilesional); loss of pain and temperature for body (contralesional)
Ataxia, loss of pain and temperature for face, weakness of soft palate, larynx and pharynx,
Horner’s (ipsilesional); weakness and loss of pain and temperature for body (contralesional)
Loss of pain and temperature for face, weakness of soft palate, larynx and pharynx, Horner’s
(ipsilesional); weakness and loss of pain and temperature for body (contralesional)
Ataxia, loss of pain and temperature for face, weakness of soft palate, larynx, pharynx and
tongue, Horner’s (ipsilesional); weakness and loss of touch, pain and temperature for body
(contralesional)
Weakness of soft palate, larynx, and pharynx (ipsilesional); weakness and loss of touch for
body (contralesional)
Weakness of palate, CN XI palsy, decreased taste posterior tongue (ipsilesional); weakness
(contralesional)
CN XII palsy, weakness of soft palate, larynx, and pharynx (ipsilesional); weakness
(contralesional)
CN XII palsy (ipsilesional); hemiplegia and sometimes loss of position and vibration
(contralesional)
Babinski-Nageotte
Cestan-Chenias
Reinhold
Avellis
Vernet
Jackson
Dejerine
Adapted from Hayman et al.3and Marx and Thomke30
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