Published Ahead of Print on February 15, 2017 as 10.1212/WNL.

0000000000003751
CLINICAL
IMPLICATIONS OF
NEUROSCIENCE
Nucleus of the solitary tract, medullary
RESEARCH
reflexes, and clinical implications
Section Editor
Eduardo E.
Benarroch, MD

Jeremy K. Cutsforth-
Gregory, MD
Eduardo E. Benarroch,
MD
Correspondence to
Dr. Cutsforth-Gregory:
CutsforthGregory.Jeremy@mayo.edu
The nucleus of the solitary tract (solitary nucleus,
nucleus tractus solitarii [NTS]), located in the dorso-
medial medulla, is the first relay station for general
visceral and taste afferents carried by the cranial
nerves and has a critical role in the initiation and inte-
gration of a wide variety of reflexes controlling cardio-
vascular function, respiration, and gastrointestinal
motility. Though isolated bilateral involvement of
the NTS in neurologic disorders is infrequent, its inti-
mate anatomical relationship with the fourth ventricle
and the area postrema may underlie its major role in
clinical manifestations such as those described in this
representative case.
REPRESENTATIVE CASE A 40-year-old woman
complained of nausea, hiccups, headache with
leaning forward, and exercise intolerance due to
intermittent palpitations. Episodes were worse with
exertion but could also occur from rest; often they
could be aborted with multiple Valsalva
maneuvers. Neurologic examination was normal
except for absent gag reflex bilaterally. Cardiac
monitoring showed inappropriate sinus tachycardia
with superimposed symptomatic episodes of
supraventricular tachycardia to 215 bpm. An
ablation procedure eliminated a slow-fast (typical)
atrioventricular (AV) nodal re-entrant pathway at
the right septum and a fast-slow (atypical) AV
nodal re-entrant pathway at the coronary sinus,
but focal junctional tachycardia persisted. MRI of
the brain showed a fourth ventricular tumor
impinging on the vagal trigone overlying the NTS
(figure 1). Following gross total resection of the
WHO grade I choroid plexus papilloma, episodes
of tachycardia were essentially abolished.
Comment. This case illustrates the cardiovascular
consequences of lesions affecting the dorsal medulla
at the level of the NTS. There have been several re-
ports of disorders of cardiovascular regulation due to
lesions affecting the posterior medulla, including the
NTS.1,2 Involvement of the NTS can also underlie
some manifestations of neuromyelitis optica spec-
trum disorders (NMOSD).3,4 Recent advances in
the understanding of relay and integration of infor-
mation at the level of the NTS provide several
potential therapeutic targets.
ANATOMY OF THE NUCLEUS OF THE SOLITARY
TRACT Anatomical organization. The NTS is the first
visceral relay nucleus in the brain and receives inputs
from essentially all organs of the body. In humans, as
in experimental animals, the NTS can be subdivided
into rostral, intermediate, and caudal regions, each
including different subnuclei defined on the basis
of their position relative to the solitary tract.5 This
tract is a heavily myelinated fiber bundle composed
of fibers of the trigeminal and facial nerves rostrally
and the glossopharyngeal and vagus nerve caudally; it
courses in the dorsal medullary tegmentum from the
level of the facial nucleus down to the spinal cord.
The NTS includes at least 10 subnuclei, including
the paracommissural, commissural, gelatinosus,
medial, ventral, ventrolateral, dorsal, dorsolateral,
intermediate, and interstitial subnuclei5 (figure 2).
These subnuclei contain cells of different size, ace-
tylcholinesterase reactivity, and neurochemical
markers.6–8 The gelatinosus and dorsolateral subnu-
clei contain catecholaminergic cells, for example,
while only the gelatinosus subnucleus expresses sero-
tonin 5-HT3 receptors and the intermediate and
medial subnuclei express dopamine D2 and D4
receptors.
Afferents to the NTS. The NTS receives visceral afferent
inputs primarily via the cranial nerves. Taste afferents
are via the facial, glossopharyngeal, and vagus nerves;
carotid baroreceptor and chemoreceptor afferents via
the glossopharyngeal nerve; and all other afferents,
including afferents from the heart, lung, and gastroin-
testinal tract, via the vagus nerve. There is a functional
topographic organization of afferents to the NTS,9–11

GLOSSARY
ATP 5 adenosine triphosphate; AV 5 atrioventricular; GABA 5 g-aminobutyric acid; mGluR 5 metabotropic glutamate
receptor; NMOSD 5 neuromyelitis optica spectrum disorder; NO 5 nitric oxide; NTS 5 nucleus tractus solitarii; PAR 5
protease-activated receptor; RVLM 5 rostral ventrolateral medulla; TRPV1 5 transient receptor potential vanilloid 1.

From the Department of Neurology, Mayo Clinic, Rochester, MN.

Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

© 2017 American Academy of Neurology 1

ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Figure 1 Blood pressure and heart rate fluctuations in a patient with a dorsal medullary lesion

(A) Ambulatory 24-hour blood pressure and heart rate monitor shows fluctuating hypertension and tachycardia, primarily during wakefulness. (B) Sagittal
T1-weighted postgadolinium MRI shows a heterogeneously enhancing mass in the inferior fourth ventricle, in the region of the area postrema and vagal trig-
one. (C) Histomicrograph of WHO grade I choroid plexus papilloma containing calcifications (black arrows) and epithelium arranged around fibrovascular
cores (red arrows).

confirmed by functional neuroimaging in humans.12
Taste afferents terminate in the rostral portion of the
NTS; gastrointestinal afferents terminate at interme-
diate levels of the NTS at the level of the area post-
rema; and cardiorespiratory afferents terminate at
more caudal levels of the NTS. Afferents from baror-
eceptors and chemoreceptors terminate in the dorso-
lateral and medial NTS; cardiac afferents in the lateral
and to a lesser extent medial NTS; and respiratory
tract and pulmonary afferents in the interstitial, ven-
trolateral, and medial NTS. In each case, the subnuclei
receiving organ-specific afferents participate in specific
reflexes. Some areas of the NTS, particularly the
commissural NTS, receive converging inputs from
gastrointestinal, cardiovascular, and respiratory
afferents and may be primarily involved in relaying
this information to rostral areas of the CNS. In
addition to cranial nerve afferents, the NTS
receives a projection from the spinal cord,
particularly lamina I, conveying inputs from
nociceptors, muscle receptors, thermoreceptors,
and visceral receptors,13 and descending inputs
from the amygdala, hypothalamus, and rostral
brainstem areas. Importantly, the NTS also
receives inputs from the area postrema located in
the floor of the fourth ventricle; this is one of the
circumventricular organs that lacks a blood–brain
barrier and serves as a sensor of signals from blood
and CSF, which are then relayed to the NTS.14
Efferents from the NTS. The NTS relays visceral infor-
mation to medullary effector nuclei, rostral brainstem

2 Neurology 88 March 21, 2017

ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Figure 2 General organization of the nucleus of the solitary tract (NTS)

The NTS can be subdivided into rostral, intermediate, and caudal regions and includes at least 10 subnuclei, including the paracommissural, commissural,
gelatinosus, medial, ventral, ventrolateral, dorsal, dorsolateral, intermediate, and interstitial subnuclei. The NTS receives visceral afferent inputs primarily via
the cranial nerves. Taste afferents are via the facial (VII), glossopharyngeal (IX), and vagus (X) nerves; carotid baroreceptor and chemoreceptor afferents via
the glossopharyngeal nerve; and all other afferents, including afferents from the heart, lung, and gastrointestinal tract, via the vagus nerve. Taste afferents
terminate in the rostral NTS, gastrointestinal afferents in the intermediate NTS, and afferents from cardiovascular and respiratory receptors in the caudal
NTS. In addition to termination in specific subnuclei, afferents from different receptors also converge in the commissural and interstitial NTS (not shown).

and forebrain areas, and the spinal cord. The NTS
sends projections to medullary nuclei that contain
the preganglionic parasympathetic, premotor sympa-
thetic, and respiratory neurons mediating gastrointes-
tinal, cardiovascular, and respiratory reflexes. These
include the dorsal motor nucleus of the vagus (dorsal
vagal nucleus), nucleus ambiguus, caudal and rostral
ventrolateral medulla, and ventral respiratory group.
The NTS also projects to the parabrachial nucleus
of the pons, which has a critical role as a relay nucleus
to forebrain areas and as a component of the brain-
stem control mechanisms of respiration, cardiovascu-
lar function, and arousal.15 Direct projections from
the NTS also reach the periaqueductal gray, hypo-
thalamus, amygdala, and thalamus.
TRANSMISSION AND INTEGRATION OF
AFFERENT INPUTS IN THE NTS Transmission of
primary visceral afferent input. Most afferents to the
NTS are unmyelinated slow-conducting C-fibers,
while a smaller portion are myelinated, fast-
conducting A-fibers. Virtually all afferents are
glutamatergic, as first shown for baroreceptor
afferents,16 and their stimulation produces fast
monosynaptic excitatory postsynaptic potentials
in second-order NTS neurons via activation of
both NMDA and non-NMDA receptors.17
Afferents from arterial baroreceptors elicit
a temporally precise and synchronized activation
of second-order NTS neurons during each
systole; afferents for peripheral chemoreceptors elicit
asynchronous and higher latency responses on NTS
neurons.18,19 Some primary afferents release substance
P in addition to L-glutamate and activate second-order
neurons via neurokinin-1 receptors20,21; some may
also co-release adenosine triphosphate (ATP), nitric
oxide (NO), or both.22
Modulation of afferent input in the NTS. Influences
from several sources modulate transmission of affer-
ent input in the NTS. Glutamate may affect its
own release via presynaptic metabotropic glutamate
receptors (mGluRs). Activation of presynaptic group
II and group III mGluRs inhibits glutamate release
from primary afferents, whereas type I mGluRs facil-
itate glutamate release from axon terminals of intrin-
sic interneurons.23 Unmyelinated glutamatergic
afferents express presynaptic transient receptor
potential vanilloid 1 (TRPV1) receptors, while mye-
linated afferent fibers may express both TRPV1 and
purinergic P2X3 receptors activated by ATP.24,25
Some gastrointestinal afferents also express cholecys-
tokinin receptors.26 Activation of presynaptic
TRPV1, P2X3, and cholecystokinin receptors in-
creases glutamate release from primary afferents.24,27
ATP may act as a modulatory cotransmitter of pri-
mary afferents by both presynaptically promoting
glutamate release and postsynaptically inhibiting
glutamate-triggered responses in second-order NTS
neurons.28

Neurology 88 March 21, 2017 3

ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 NO is an important modulator of glutamatergic
transmission in the NTS29 and may either facilitate30
or inhibit31 excitatory glutamatergic transmission.32
Facilitation of glutamatergic transmission by NO
potentiates the responses to stimulation of barore-
ceptors, cardiopulmonary receptors, and chemore-
ceptors.30,33,34 NO may contribute to the
hypotensive effects of local administration of angio-
tensin 1–7, which are produced by metabolism of
angiotensin II and antagonize its effect, exerting pro-
tective effects against hypertension.35 NO also mod-
ulates release of brain-derived neurotrophic factor at
baroreceptor afferent synapses in the NTS.36 There
are also complex interactions among peptide and
lipid modulators in the NTS.37 For example, cyto-
kines may interact with elevated body temperature to
increase glutamate release from primary afferents in
the NTS via effects on presynaptic TRPV1 receptors;
this effect may be mediated by prostaglandin E2.38
Role of local inhibitory interneurons. The NTS con-
tains a complex network of local inhibitory inter-
neurons that synthesize g-aminobutyric acid
(GABA).39 These neurons receive glutamatergic
inputs from primary efferents, collaterals of second-
order projection neurons, local excitatory
interneurons, and descending pathways that
modulate NTS-mediated reflexes. Local GABAergic
interneurons may exert inhibitory effects on second-
order projection neurons of the NTS, depending on
convergence of multiple, individually weak
inhibitory influences required to counteract the
monosynaptic excitation that projection NTS
neurons receive from primary afferents.40 Local
GABAergic mechanisms control excitability of
second-order NTS neurons and primary afferent
neurotransmitter release via GABAA and GABAB
receptors.41 Via these mechanisms, descending
projections from the hypothalamus, amygdala,
and periaqueductal gray regulate processing of
afferent information in the NTS, thereby
modulating medullary cardiovascular, respiratory,
and gastrointestinal reflexes in relationship to
emotion, stress, and other behavioral states.
Role of astrocytes in the NTS. Astrocytes have an
important role in regulation of transmission in the
NTS.19,42,43 Astrocytes act within a tripartite synapse
in the NTS, controlling the excitability of both pre-
synaptic vagal afferent terminals and postsynaptic
NTS neurons by releasing glutamate and activating
GluN2B-containing NMDA receptors.44
MEDULLARY REFLEXES TRIGGERED BY
AFFERENT INPUTS TO THE NTS The NTS integra-
tes information for visceral afferents and sends excit-
atory glutamatergic projections to effector areas of the
4 Neurology 88 March 21, 2017
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
medulla that control blood pressure, cardiac function,
respiration, and gastrointestinal motility (figure 3).
These include the reticular formation of the ventro-
lateral medulla, nucleus ambiguus, parabrachial
nucleus of the pons, and dorsal motor nucleus of
the vagus. The effects of NTS projections are direct
or mediated via local interneurons in the target areas.
Important examples of NTS-initiated reflexes are the
baroreceptor reflex, cardiac reflexes, chemoceptor
reflex, bronchopulmonary reflexes, gastrointestinal
reflexes, and vomiting. A comprehensive discussion
of these reflexes is beyond the scope of this review;
only a few points are emphasized here. The functional
integration of afferent inputs from baroreceptor,
cardiac, and peripheral chemoreceptor afferents in
the NTS45 provides for the coordination of
sympathetic, cardiovagal, and respiratory activities
required to match pulmonary ventilation with tissue
perfusion.46–48
Baroreceptor reflex. The arterial baroreceptor reflex, or
baroreflex, is a critical feedback mechanism that pro-
vides continuous buffering of acute fluctuations of
arterial blood pressure in response to changes in pos-
ture, exercise, and emotion. Baroreceptors are mecha-
nosensitive afferent terminals located in the adventitia
of the carotid sinuses and aortic arch; deformation of
the vessel wall elicited by an increase in arterial blood
pressure triggers baroreceptor depolarization and
increased firing. Baroreceptor afferents provide
monosynaptic excitatory input to neurons located in
the dorsolateral NTS, triggering 2 parallel pathways
that control blood pressure on a beat-to-beat basis.
The sympathoinhibitory pathway reduces total
peripheral resistance; the cardioinhibitory pathway
decreases heart rate.49
The sympathoinhibitory pathway involves a pro-
jection from the NTS to a group of inhibitory inter-
neurons in the caudal ventrolateral medulla that send
GABAergic input to sympathoexcitatory neurons
located in the rostral ventrolateral medulla
(RVLM).50 These RVLM neurons send a direct excit-
atory projection to preganglionic neurons of the in-
termediolateral cell column and have a critical role in
both tonic maintenance and reflex control of arterial
blood pressure, mediating not only the baroreflex but
also other NTS-triggered reflexes.51
The baroreflex-cardioinhibitory pathway involves
a direct input from the NTS to vagal preganglionic
neurons located in the ventrolateral portion of the
nucleus ambiguus.52 These neurons project to cholin-
ergic cardiac ganglion neurons that inhibit the autom-
atism of the sinus node and elicit bradycardia. The
baroreflex-triggered cardioinhibitory pathway pro-
vides for the beat-to-beat control of the heart rate.
The cardioinhibitory pathway may also be activated
 Figure 3 Examples of medullary reflexes triggered by activation of the nucleus of the solitary tract (NTS)

The NTS integrates information for visceral afferents and sends excitatory glutamatergic projections to effector areas of the medulla that control blood
pressure, cardiac function, respiration, and gastrointestinal motility. The arterial baroreceptor reflex, or baroreflex, provides continuous buffering of acute
fluctuations of arterial blood pressure. Baroreceptor afferents are activated by an increase in arterial pressure and provide monosynaptic excitatory input to
neurons located in the dorsolateral NTS, triggering a sympathoinhibitory and a cardioinhibitory pathway. The sympathoinhibitory pathway (A) involves a pro-
jection from the NTS to interneurons in the caudal ventrolateral medulla that send an inhibitory input to sympathoexcitatory neurons located in the rostral
ventrolateral medulla; this results in a decrease in sympathetic vasomotor tone and thus total peripheral resistance. The baroreflex-cardioinhibitory (B) path-
way involves a direct input from the NTS to vagal preganglionic neurons located in the ventrolateral portion of the nucleus ambiguus, which project to cho-
linergic cardiac ganglion neurons that inhibit the automatism of the sinus node and elicit bradycardia. Chemoreceptors in the carotid bodies (C) sense arterial
levels of O2, CO2, and other chemical signals. Carotid body stimulation by hypoxia or hypercapnia activates NTS neurons that project to the ventrolateral
medulla, providing excitatory input to sympathoexcitatory neurons of the RVLM and to neurons of the ventral respiratory group, including the inspiratory
neurons; these projections increase sympathetic activity and tachypnea. Vomiting (D) is a complex response coordinated by the NTS and triggered by several
signals: blood-borne signals have access to the NTS via the area postrema, signals such as gastric distention or intestinal luminal contents reach the NTS via
vagal afferents, and motion signals are relayed via vestibular inputs. Neurons from the NTS project to a central pattern generator in the reticular formation
that coordinates the activity of neurons mediating the sequence of events during emesis. These include neurons of the nucleus ambiguus innervating the
larynx, pharynx, and upper esophagus; the dorsal motor nucleus of the vagus innervating the lower esophagus and stomach; and respiratory premotor
neurons in the caudal medulla providing inputs to spinal motoneurons innervating the diaphragm and abdominal muscles.

by afferent inputs from chemoreceptors, cardiac re-
ceptors, and pulmonary C-receptors integrated at the
level of the NTS.
The cardiovagal neurons of the nucleus ambiguus
are also responsible for the modulation of heart rate
with the frequency of breathing, which is referred
to as respiratory sinus arrhythmia. This depends on
central modulation of cardiovagal output by the med-
ullary respiratory pattern generator as well as by NTS-
mediated mechanical stretch receptor feedback from
the lungs and baroreflex. The physiologic function
of respiratory sinus arrhythmia is to minimize the
work done by the heart while maintaining physiologic
levels of arterial CO2.47,53
Neurons of the NTS activated by vagal afferents
from baroreceptors or cardiac receptors elicit secretion
of arginine vasopressin by magnocellular neurons of
the supraoptic and paraventricular nuclei of the hypo-
thalamus.54 There is continuous modulation of the
baroreceptor reflex depending on the prevailing
behavioral and physiologic conditions, such as exer-
cise or stress. This modulation contributes to both the

Neurology 88 March 21, 2017 5

ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 short- and long-term control of arterial blood pres-
sure. Modulatory influences from muscle afferents,
hypothalamus, or periaqueductal gray reset the bar-
oreflex, reducing its gain during responses to exercise
or stress.55 These inhibitory influences are largely
mediated by GABAergic interneurons in the
NTS.39,40,56 Many other neurochemical signals,
including locally released NO, angiotensin II, and
circulating AVP, exert differential modulation of the
baroreflex.
Chemoreflex and other respiratory reflexes. The NTS
has a major role in coordinating respiratory and sym-
pathetic activities.48,57 Chemoreceptors in the
carotid bodies sense arterial levels of O2, CO2, glu-
cose, and other chemical signals. Carotid body stim-
ulation by hypoxia or hypercapnia may activate
or inhibit a complex network of NTS neurons, par-
ticularly in the commissural nucleus. Many
hypoxia-responsive NTS neurons project to the
ventrolateral medulla, providing excitatory input to
sympathoexcitatory neurons of the RVLM and to
neurons of the ventral respiratory group, including
the inspiratory neurons of the pre-Bötzinger
complex. These excitatory projections increase
sympathetic activity and tachypnea.58 In contrast,
baroreceptor activation reduces respiratory
frequency via activation of postinspiratory neurons
in the Bötzinger complex, which provides an
additional pathway for the sympathoinhibitory
component of the baroreflex.48 The commissural
NTS also innervates the Kölliker-Fuse nucleus and
lateral parabrachial subnuclei, which are essential
components of the lower brainstem circuit that
generates eupneic breathing, and the retrotrapezoid
nucleus located in the ventral medullary surface and
critical for central chemosensitivity to CO2.59–61 The
NTS may thus affect sympathetic and cardiovagal
output both directly and via the respiratory pattern
generator region.46
In addition to chemoreceptor-activated neurons,
other cell groups in the NTS mediate activation or
inhibition of respiration.62 NTS neurons that receive
vagal afferents mediate both the Hering-Breuer reflex
(triggered by slowly adapting pulmonary stretch
receptor afferents and resulting in inhibition of inspi-
ration)22 and the laryngeal chemoreflex (an airway-
protective reflex that causes apnea and bradycardia).63
The NTS is also the first relay station for irritant-
sensitive vagal afferents from the airways that trigger
bronchoconstriction. This involves a projection from
the NTS to preganglionic neurons of the dorsal
motor nucleus of the vagus that innervate the
airway.64
Vomiting. Vomiting is a complex response coordi-
nated by the NTS and triggered by several signals.65
6 Neurology 88 March 21, 2017
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Blood-borne signals, such as chemotherapeutic or
other emetic agents, have access to the NTS via the
area postrema66; signals such as gastric distention or
intestinal luminal contents reach the NTS via vagal
afferents; and motion signals are relayed via
vestibular inputs.67 Neurons from the NTS project
to a central pattern generator in the reticular
formation that coordinates the activity of neurons
mediating the sequence of events during emesis.
These include neurons of the nucleus ambiguus
innervating the larynx, pharynx, and upper
esophagus; the dorsal motor nucleus of the vagus
innervating the lower esophagus and stomach; and
respiratory premotor neurons in the caudal medulla
providing inputs to spinal motoneurons innervating
the diaphragm and abdominal muscles.68 Serotonin
5-HT3 receptor antagonists (e.g., ondansetron)
reduce neurotransmitter release from gastrointestinal
vagal afferents in the NTS. Neurokinin-1 receptor
antagonists (e.g., aprepitant) reduce the responses of
vagal efferent neurons.
The NTS receives direct input from the vestibular
nuclei and is critical for vomiting triggered by vestib-
ular stimulation. There is a functional convergence of
vagally mediated and vestibular inputs on individual
NTS neurons. For example, the activity of NTS neu-
rons activated by vagal gastrointestinal input triggered
by emetic stimuli can be modulated by head rotations
in the vertical plane, indicating that detection and
processing of visceral inputs by NTS neurons can
be altered according to the direction of ongoing
movements.67
CLINICAL AND THERAPEUTIC IMPLICATIONS
Baroreflex failure. As in the representative case, there
have been several reports of disorders of cardiovascu-
lar regulation, including manifestations of baroreflex
dysfunction such as tachycardia and fluctuating
hypertension, with lesions affecting the posterior
medulla and NTS. These include a fourth ventricle
anaplastic ependymoma,2 cerebellar hemangioblasto-
ma,1 ischemic lesions,69 and Leigh disease.70
Role of NTS astrocytes in gastrointestinal manifestations
of neurologic disease. Stroke, trauma, and inflamma-
tory disorders of the nervous system may be associ-
ated with gastrointestinal dysfunction and
vomiting.71 One common factor in many of these
acute injuries is an increase in the production of
thrombin, which both catalyzes the proteolysis of
fibrinogen and activates protease-activated receptors
(PARs). The PAR1 receptor is expressed in astrocytes
in the NTS, and its activation triggers an increase in
cytoplasmic calcium and glutamate release from
astrocytes.72 This mechanism modulates the activity
of presynaptic vagal afferent terminals and
postsynaptic neurons in the NTS and can trigger
 gastric vagovagal reflexes that slow gastric transit.42
Consistent with these findings, intractable hiccups
and nausea may be the salient initial manifestation
of NMOSD, and these symptoms are typically
associated with medullary lesions involving the
area postrema and the NTS.3,4 In this disorder,
NMO–immunoglobulin G antibodies against
aquaporin-4 expressed in astrocytes may lead to
dysfunction and loss of these cells,73 potentially
affecting water, potassium, and glutamate
homeostasis.74 This would conceivably result in
abnormal transmission of visceral afferent
information in the NTS, triggering not only
vagovagal gastrointestinal reflexes but also reflexes
regulating cardiovascular function. Consistent with
this possibility, patients with NMOSD manifesting
with intractable hiccups, nausea, and vomiting may
also experience severe bradycardia and hypotension
(unpublished observations).
Hypertension. Several experimental studies indicate
that both impaired reflex control of blood pressure
due to local inflammation and oxidative stress at
the level of the NTS and increased sympathetic
activity due activation of peripheral chemoreceptors
play major roles in the development of hypertension.
For example, there is upregulation of proinflamma-
tory molecules such as junctional adhesion
molecule-1, which triggers cytokine release, in
endothelial cells in the NTS in spontaneously
hypertensive rats (an animal model of human
essential hypertension).75–78 Upregulation of
leukotriene B4 and its receptors in astrocytes may
contribute to hypertension in this model.79
Oxidative stress in the NTS in the setting of
hypertension depresses the cardiac vagal baroreflex
via dynamic alterations in the connectivity between
the NTS and nucleus ambiguus.80 In conditions
such as chronic intermittent hypoxia, as occurs in
obstructive sleep apnea, chronic activation of
chemoreceptors leads to plastic changes in neurons
of the NTS in part mediated by brain-derived
neurotrophic factor81,82 and results in increased
responsiveness to chemoreceptor activation.
Chemoreflex sensitization also involves plastic
changes in downstream effects of the NTS, such as
the inspiratory neurons of the pre-Bötzinger
complex, resulting in increased sympathetic
activity and development of hypertension.83,84
These changes may be triggered by upregulation of
P2X3 channels in nodose ganglion cells that provide
chemoreceptor input to the NTS.85
The preclinical evidence of both impaired barore-
flex gain and excessive chemoreflex activation has pro-
vided the rationale for approaches to treat patients
with resistant hypertension. For example, stimulation
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
of carotid sinus baroreflex afferents acutely inhibited
sympathetic activity and decreased arterial blood pres-
sure in hypertensive patients, without negative effects
on physiologic baroreflex regulation.86 Also, blockade
of P2X3 receptors and carotid body deafferentation
elicit sympathoinhibition in experimental models of
hypertension and provide potential new therapeutic
targets for treatment of human hypertension.87,88
PERSPECTIVE Recent studies have provided new
insights into the integration and modulation of vis-
ceral afferent inputs at the level of the NTS and its
role in the autonomic manifestations of neurologic
disorders. Acute changes in cardiovascular, respira-
tory, or gastrointestinal functions may thus have
localizing value for lesions affecting the dorsal
medulla. The NTS may also have a major role in epi-
lepsy. Whereas the beneficial effects of vagus nerve
stimulation may depend on ascending NTS pathways
targeting the locus ceruleus and other regions,89–91
seizure-induced neuron loss in the NTS may impair
the integrative cardiorespiratory functions of the
NTS, result in poor homeostatic responses during
seizures, and predispose to sudden unexpected
death in epilepsy.92
STUDY FUNDING
No targeted funding reported.
DISCLOSURE
J.K. Cutsforth-Gregory reports no disclosures. E.E. Benarroch receives
a stipend in his capacity as section editor of Clinical Implications of Neu-
roscience Research for Neurology®. Go to Neurology.org for full
disclosures.
REFERENCES
1. Ideguchi M, Kajiwara K, Yoshikawa K, et al. Continuous
hypertension and tachycardia after resection of a hemangio-
blastoma behind the dorsal medulla oblongata: relation-
ship to sympathetic overactivity at the neurogenic
vasomotor center. J Neurosurg 2010;113:369–373.
2. Martin-Gallego A, Andrade-Andrade I, Dawid-Milner
MS, et al. Autonomic dysfunction elicited by a medulla
oblongata injury after fourth ventricle tumor surgery in
a pediatric patient. Auton Neurosci 2016;194:52–57.
3. Misu T, Fujihara K, Nakashima I, Sato S, Itoyama Y.
Intractable hiccup and nausea with periaqueductal lesions
in neuromyelitis optica. Neurology 2005;65:1479–1482.
4. Popescu BF, Lennon VA, Parisi JE, et al. Neuromye-
litis optica unique area postrema lesions: nausea, vom-
iting, and pathogenic implications. Neurology 2011;
76:1229–1237.
5. McRitchie DA, Tork I. The internal organization of the
human solitary nucleus. Brain Res Bull 1993;31:171–193.
6. Ohuoha DC, Knable MB, Wolf SS, Kleinman JE, Hyde
TM. The subnuclear distribution of 5-HT3 receptors in
the human nucleus of the solitary tract and other struc-
tures of the caudal medulla. Brain Res 1994;637:222–226.
7. Lynn RB, Hyde TM, Cooperman RR, Miselis RR. Dis-
tribution of bombesin-like immunoreactivity in the
nucleus of the solitary tract and dorsal motor nucleus of
Neurology 88 March 21, 2017 7
 the rat and human: colocalization with tyrosine hydroxy-
lase. J Comp Neurol 1996;369:552–570.
8. Hyde TM, Knable MB, Murray AM. Distribution of
dopamine D1-D4 receptor subtypes in human dorsal vagal
complex. Synapse 1996;24:224–232.
9. Kalia M, Fuxe K, Hokfelt T, et al. Distribution of neuro-
peptide immunoreactive nerve terminals within the sub-
nuclei of the nucleus of the tractus solitarius of the rat.
J Comp Neurol 1984;222:409–444.
10. Jordan D, Spyer KM. Brainstem integration of cardiovas-
cular and pulmonary afferent activity. Prog Brain Res
1986;67:295–314.
11. Altschuler SM, Bao XM, Bieger D, Hopkins DA, Miselis
RR. Viscerotopic representation of the upper alimentary
tract in the rat: sensory ganglia and nuclei of the solitary
and spinal trigeminal tracts. J Comp Neurol 1989;283:
248–268.
12. Topolovec JC, Gati JS, Menon RS, Shoemaker JK, Ce-
chetto DF. Human cardiovascular and gustatory brainstem
sites observed by functional magnetic resonance imaging.
J Comp Neurol 2004;471:446–461.
13. Leah J, Menetrey D, de Pommery J. Neuropeptides in
long ascending spinal tract cells in the rat: evidence for
parallel processing of ascending information. Neuroscience
1988;24:195–207.
14. Johnson AK, Gross PM. Sensory circumventricular organs
and brain homeostatic pathways. FASEB J 1993;7:678–
686.
15. Benarroch EE. Parabrachial nuclear complex: multiple
functions and potential clinical implications. Neurology
2016;86:676–683.
16. Talman WT, Perrone MH, Reis DJ. Evidence for L-glu-
tamate as the neurotransmitter of baroreceptor afferent
nerve fibers. Science 1980;209:813–815.
17. Ohta H, Talman WT. Both NMDA and non-NMDA
receptors in the NTS participate in the baroreceptor reflex
in rats. Am J Physiol 1994;267:R1065–R1070.
18. Accorsi-Mendonca D, Machado BH. Synaptic transmis-
sion of baro- and chemoreceptors afferents in the NTS
second order neurons. Auton Neurosci 2013;175:3–8.
19. Accorsi-Mendonca D, Zoccal DB, Bonagamba LG, Ma-
chado BH. Glial cells modulate the synaptic transmission
of NTS neurons sending projections to ventral medulla of
Wistar rats. Physiol Rep 2013;1:e00080.
20. Feldman PD. Neurokinin1 receptor mediation of the vas-
odepressor effects of substance P in the nucleus of the
tractus solitarius. J Pharmacol Exp Ther 1995;273:617–
623.
21. Nichols NL, Powell FL, Dean JB, Putnam RW. Substance
P differentially modulates firing rate of solitary complex
(SC) neurons from control and chronic hypoxia-adapted
adult rats. PLoS One 2014;9:e88161.
22. Gourine AV, Dale N, Korsak A, et al. Release of ATP and
glutamate in the nucleus tractus solitarii mediate pulmo-
nary stretch receptor (Breuer-Hering) reflex pathway.
J Physiol 2008;586:3963–3978.
23. Ohi Y, Kimura S, Haji A. Modulation of glutamatergic
transmission by metabotropic glutamate receptor activa-
tion in second-order neurons of the guinea pig nucleus
tractus solitarius. Brain Res 2014;1581:12–22.
24. Jin YH, Bailey TW, Li BY, Schild JH, Andresen MC.
Purinergic and vanilloid receptor activation releases gluta-
mate from separate cranial afferent terminals in nucleus
tractus solitarius. J Neurosci 2004;24:4709–4717.
8 Neurology 88 March 21, 2017
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
25. Hermes SM, Andresen MC, Aicher SA. Localization of
TRPV1 and P2X3 in unmyelinated and myelinated vagal
afferents in the rat. J Chem Neuroanat 2016;72:1–7.
26. Browning KN, Wan S, Baptista V, Travagli RA. Vanilloid,
purinergic, and CCK receptors activate glutamate release
on single neurons of the nucleus tractus solitarius centralis.
Am J Physiol Regul Integr Comp Physiol 2011;301:
R394–R401.
27. Fawley JA, Hofmann ME, Andresen MC. Distinct cal-
cium sources support multiple modes of synaptic release
from cranial sensory afferents. J Neurosci 2016;36:8957–
8966.
28. Accorsi-Mendonca D, Bonagamba LG, Leao RM, Macha-
do BH. Are L-glutamate and ATP cotransmitters of the
peripheral chemoreflex in the rat nucleus tractus solitarius?
Exp Physiol 2009;94:38–45.
29. Lin LH. Glutamatergic neurons say NO in the nucleus
tractus solitarii. J Chem Neuroanat 2009;38:154–165.
30. Dias AC, Vitela M, Colombari E, Mifflin SW. Nitric
oxide modulation of glutamatergic, baroreflex, and
cardiopulmonary transmission in the nucleus of the
solitary tract. Am J Physiol Heart Circ Physiol 2005;
288:H256–H262.
31. Kong SZ, Fan MX, Zhang BH, Wang ZY, Wang Y. Nitric
oxide inhibits excitatory vagal afferent input to nucleus
tractus solitarius neurons in anaesthetized rats. Neurosci
Bull 2009;25:325–334.
32. Wang S, Paton JF, Kasparov S. Differential sensitivity of
excitatory and inhibitory synaptic transmission to modu-
lation by nitric oxide in rat nucleus tractus solitarii. Exp
Physiol 2007;92:371–382.
33. Granjeiro EM, Machado BH. NO in the caudal NTS
modulates the increase in respiratory frequency in response
to chemoreflex activation in awake rats. Respir Physiol
Neurobiol 2009;166:32–40.
34. Montero S, Lemus M, Luquin S, et al. Nitric oxide in the
commissural nucleus tractus solitarii regulates carotid che-
moreception hyperglycemic reflex and c-Fos expression.
Nitric Oxide 2014;36:87–93.
35. Wu ZT, Ren CZ, Yang YH, et al. The PI3K signaling-
mediated nitric oxide contributes to cardiovascular effects
of angiotensin-(1-7) in the nucleus tractus solitarii of rats.
Nitric Oxide 2016;52:56–65.
36. Hsieh HY, Robertson CL, Vermehren-Schmaedick A, Bal-
kowiec A. Nitric oxide regulates BDNF release from
nodose ganglion neurons in a pattern-dependent and
cGMP-independent manner. J Neurosci Res 2010;88:
1285–1297.
37. Andresen MC, Fawley JA, Hofmann ME. Peptide and
lipid modulation of glutamatergic afferent synaptic trans-
mission in the solitary tract nucleus. Front Neurosci 2012;
6:191.
38. Xia L, Bartlett D Jr, Leiter JC. Interleukin-1beta and
interleukin-6 enhance thermal prolongation of the LCR
in decerebrate piglets. Respir Physiol Neurobiol 2016;230:
44–53.
39. Zubcevic J, Potts JT. Role of GABAergic neurones in the
nucleus tractus solitarii in modulation of cardiovascular
activity. Exp Physiol 2010;95:909–918.
40. McDougall SJ, Andresen MC. Low-fidelity GABA trans-
mission within a dense excitatory network of the solitary
tract nucleus. J Physiol 2012;590:5677–5689.
41. Ruggeri P, Cogo CE, Picchio V, Molinari C, Ermirio R,
Calaresu FR. Influence of GABAergic mechanisms on
 baroreceptor inputs to nucleus tractus solitarii of rats. Am J
Physiol 1996;271:H931–H936.
42. Hermann GE, Van Meter MJ, Rood JC, Rogers RC. Pro-
teinase-activated receptors in the nucleus of the solitary
tract: evidence for glial-neural interactions in autonomic
control of the stomach. J Neurosci 2009;29:9292–9300.
43. Lin LH, Moore SA, Jones SY, McGlashon J, Talman WT.
Astrocytes in the rat nucleus tractus solitarii are critical for
cardiovascular reflex control. J Neurosci 2013;33:18608–
18617.
44. Vance KM, Rogers RC, Hermann GE. NMDA receptors
control vagal afferent excitability in the nucleus of the
solitary tract. Brain Res 2015;1595:84–91.
45. Paton JF. Pattern of cardiorespiratory afferent convergence
to solitary tract neurons driven by pulmonary vagal C-fiber
stimulation in the mouse. J Neurophysiol 1998;79:2365–
2373.
46. Dick TE, Baekey DM, Paton JF, Lindsey BG, Morris KF.
Cardio-respiratory coupling depends on the pons. Respir
Physiol Neurobiol 2009;168:76–85.
47. Ben-Tal A, Shamailov SS, Paton JF. Evaluating the phys-
iological significance of respiratory sinus arrhythmia: look-
ing beyond ventilation-perfusion efficiency. J Physiol
2012;590:1989–2008.
48. Zoccal DB, Furuya WI, Bassi M, Colombari DS, Colom-
bari E. The nucleus of the solitary tract and the coordina-
tion of respiratory and sympathetic activities. Front
Physiol 2014;5:238.
49. Dampney RA, Polson JW, Potts PD, Hirooka Y, Horiuchi
J. Functional organization of brain pathways subserving
the baroreceptor reflex: studies in conscious animals using
immediate early gene expression. Cell Mol Neurobiol
2003;23:597–616.
50. Schreihofer AM, Guyenet PG. The baroreflex and beyond:
control of sympathetic vasomotor tone by GABAergic
neurons in the ventrolateral medulla. Clin Exp Pharmacol
Physiol 2002;29:514–521.
51. Guyenet PG. The sympathetic control of blood pressure.
Nat Rev Neurosci 2006;7:335–346.
52. Gourine AV, Machhada A, Trapp S, Spyer KM. Cardiac
vagal preganglionic neurones: an update. Auton Neurosci
2016;199:24–28.
53. Farmer DG, Dutschmann M, Paton JF, Pickering AE,
McAllen RM. Brainstem sources of cardiac vagal tone
and respiratory sinus arrhythmia. J Physiol 2016;594:
7249–7265.
54. Renaud LP. CNS pathways mediating cardiovascular reg-
ulation of vasopressin. Clin Exp Pharmacol Physiol 1996;
23:157–160.
55. Dampney RA. Central neural control of the cardiovascular
system: current perspectives. Adv Physiol Educ 2016;40:
283–296.
56. Potts JT. Inhibitory neurotransmission in the nucleus trac-
tus solitarii: implications for baroreflex resetting during
exercise. Exp Physiol 2006;91:59–72.
57. Molkov YI, Zoccal DB, Baekey DM, et al. Physiological
and pathophysiological interactions between the respira-
tory central pattern generator and the sympathetic nervous
system. Prog Brain Res 2014;212:1–23.
58. Guyenet PG. Regulation of breathing and autonomic out-
flows by chemoreceptors. Compr Physiol 2014;4:1511–
1562.
59. Song G, Xu H, Wang H, Macdonald SM, Poon CS.
Hypoxia-excited neurons in NTS send axonal projections
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
to Kolliker-Fuse/parabrachial complex in dorsolateral
pons. Neuroscience 2011;175:145–153.
60. Alheid GF, Jiao W, McCrimmon DR. Caudal nuclei of
the rat nucleus of the solitary tract differentially innervate
respiratory compartments within the ventrolateral
medulla. Neuroscience 2011;190:207–227.
61. Guyenet PG, Stornetta RL, Abbott SB, Depuy SD, For-
tuna MG, Kanbar R. Central CO2 chemoreception and
integrated neural mechanisms of cardiovascular and respi-
ratory control. J Appl Physiol 2010;108:995–1002.
62. Subramanian HH, Chow CM, Balnave RJ. Identification
of different types of respiratory neurones in the dorsal
brainstem nucleus tractus solitarius of the rat. Brain Res
2007;1141:119–132.
63. Donnelly WT, Bartlett D Jr, Leiter JC. Serotonin in
the solitary tract nucleus shortens the laryngeal chemo-
reflex in anaesthetized neonatal rats. Exp Physiol 2016;
101:946–961.
64. Kc P, Martin RJ. Role of central neurotransmission and
chemoreception on airway control. Respir Physiol Neuro-
biol 2010;173:213–222.
65. Hornby PJ. Central neurocircuitry associated with emesis.
Am J Med 2001(suppl 8A):106S–112S.
66. Mori F, Perez-Torres S, De Caro R, et al. The human area
postrema and other nuclei related to the emetic reflex
express cAMP phosphodiesterases 4B and 4D. J Chem
Neuroanat 2010;40:36–42.
67. Sugiyama Y, Suzuki T, DeStefino VJ, Yates BJ. Integrative
responses of neurons in nucleus tractus solitarius to visceral
afferent stimulation and vestibular stimulation in vertical
planes. Am J Physiol Regul Integr Comp Physiol 2011;
301:R1380–R1390.
68. Onishi T, Mori T, Yanagihara M, Furukawa N, Fukuda
H. Similarities of the neuronal circuit for the induction of
fictive vomiting between ferrets and dogs. Auton Neurosci
2007;136:20–30.
69. Biaggioni I, Whetsell WO, Jobe J, Nadeau JH. Baroreflex
failure in a patient with central nervous system lesions
involving the nucleus tractus solitarii. Hypertension
1994;23:491–495.
70. Pamphlett R, Harper C. Leigh’s disease: a cause of arterial
hypertension. Med J Aust 1985;143:306–308.
71. Liff JM, Labovitz D, Robbins MS. Profound gastroparesis
after bilateral posterior inferior cerebellar artery territory
infarcts. Clin Neurol Neurosurg 2012;114:789–791.
72. Vance KM, Rogers RC, Hermann GE. PAR1-activated
astrocytes in the nucleus of the solitary tract stimulate
adjacent neurons via NMDA receptors. J Neurosci 2015;
35:776–785.
73. Popescu BF, Guo Y, Jentoft ME, et al. Diagnostic utility
of aquaporin-4 in the analysis of active demyelinating le-
sions. Neurology 2015;84:148–158.
74. Yang X, Ransom BR, Ma JF. The role of AQP4 in neuro-
myelitis optica: more answers, more questions.
J Neuroimmunol 2016;298:63–70.
75. Fisher JP, Paton JF. The sympathetic nervous system and
blood pressure in humans: implications for hypertension.
J Hum Hypertens 2012;26:463–475.
76. Waki H, Gouraud SS, Maeda M, Raizada MK, Paton JF.
Contributions of vascular inflammation in the brainstem
for neurogenic hypertension. Respir Physiol Neurobiol
2011;178:422–428.
77. Waki H, Gouraud SS, Maeda M, Paton JF. Evidence of
specific inflammatory condition in nucleus tractus solitarii
Neurology 88 March 21, 2017 9
 of spontaneously hypertensive rats. Exp Physiol 2010;95:
595–600.
78. Narkiewicz K, Ratcliffe LE, Hart EC, et al. Unilateral
carotid body resection in resistant hypertension: a safety
and feasibility trial. JACC Basic Transl Sci 2016;1:313–
324.
79. Waki H, Hendy EB, Hindmarch CC, et al. Excessive
leukotriene B4 in nucleus tractus solitarii is prohyperten-
sive in spontaneously hypertensive rats. Hypertension
2013;61:194–201.
80. Tsai CY, Su CH, Baudrie V, et al. Visualizing oxidative
stress-induced depression of cardiac vagal baroreflex by
MRI/DTI in a mouse neurogenic hypertension model.
Neuroimage 2013;82:190–199.
81. Kline DD. Chronic intermittent hypoxia affects integra-
tion of sensory input by neurons in the nucleus tractus
solitarii. Respir Physiol Neurobiol 2010;174:29–36.
82. Moreau JM, Ciriello J. Chronic intermittent hypoxia
induces changes in expression of synaptic proteins in
the nucleus of the solitary tract. Brain Res 2015;1622:
300–307.
83. Barnett WH, Abdala AP, Paton JF, Rybak IA, Zoccal DB,
Molkov YI. Chemoreception and neuroplasticity in respi-
ratory circuits. Exp Neurol 2017;287:153–164.
84. Moraes DJ, Machado BH, Paton JF. Carotid body over-
activity induces respiratory neurone channelopathy con-
tributing to neurogenic hypertension. J Physiol 2015;
593:3055–3063.
10 Neurology 88 March 21, 2017
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
85. Abdala AP, McBryde FD, Marina N, et al. Hyperten-
sion is critically dependent on the carotid body input
in the spontaneously hypertensive rat. J Physiol 2012;
590:4269–4277.
86. Heusser K, Tank J, Brinkmann J, et al. Acute response to
unilateral unipolar electrical carotid sinus stimulation in
patients with resistant arterial hypertension. Hypertension
2016;67:585–591.
87. McBryde FD, Abdala AP, Hendy EB, et al. The carotid
body as a putative therapeutic target for the treatment of
neurogenic hypertension. Nat Commun 2013;4:2395.
88. Pijacka W, Moraes DJ, Ratcliffe LE, et al. Purinergic re-
ceptors in the carotid body as a new drug target for con-
trolling hypertension. Nat Med 2016;22:1151–1159.
89. Rijkers K, Aalbers M, Hoogland G, et al. Acute seizure-
suppressing effect of vagus nerve stimulation in the amyg-
dala kindled rat. Brain Res 2010;1319:155–163.
90. Magdaleno-Madrigal VM, Martinez-Vargas D, Valdes-
Cruz A, Almazan-Alvarado S, Fernandez-Mas R. Preemp-
tive effect of nucleus of the solitary tract stimulation on
amygdaloid kindling in freely moving cats. Epilepsia 2010;
51:438–444.
91. Arle JE, Carlson KW, Mei L. Investigation of mechanisms
of vagus nerve stimulation for seizure using finite element
modeling. Epilepsy Res 2016;126:109–118.
92. Tolstykh GP, Cavazos JE. Potential mechanisms of sud-
den unexpected death in epilepsy. Epilepsy Behav 2013;
26:410–414.
 Nucleus of the solitary tract, medullary reflexes, and clinical implications
Jeremy K. Cutsforth-Gregory and Eduardo E. Benarroch
Neurology published online February 15, 2017
DOI 10.1212/WNL.0000000000003751

This information is current as of February 15, 2017

Updated Information & including high resolution figures, can be found at:
Services http://www.neurology.org/content/early/2017/02/15/WNL.0000000000
003751.full.html
Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in
its entirety can be found online at:
http://www.neurology.org/misc/about.xhtml#permissions
Reprints Information about ordering reprints can be found online:
http://www.neurology.org/misc/addir.xhtml#reprintsus

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since
1951, it is now a weekly with 48 issues per year. Copyright © 2017 American Academy of Neurology. All
rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.