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Emotions Studied by Imaging of the
Human Brain: The Somatic and Emotional
Motor Systems
67
Gert Holstege and Hieu K. Huynh
Brief History
Many neurologists think that the so-called corticospinal tract is the most important
part of the motor system because numerous patients suffer from lesions of the
corticospinal tract. For example, an infarction on the left side in the white matter
(internal capsule) interrupts the corticospinal tract leading to great problems with
voluntary movements on the right side and vice versa. Since internal capsule lesions
interrupting the corticospinal tract are not exceptional at all, most neurologists think
that this tract is the main component of the motor system. Although, indeed, in
humans the corticospinal tract is a crucial component of the somatic or voluntary
motor system, the emotional motor system (EMS) is an equally or even more
important part of the motor system.
Introduction
The brain has only two goals, survival of the individual and survival of the species.
The most important tool to accomplish both goals is the motor system. Many
neurologists think that the so-called corticospinal tract is the most important part
of the motor system because numerous patients suffer from lesions of the
corticospinal tract. For example, an infarction on the left side in the white matter
(internal capsule) of the cortex of an individual interrupts this tract leading to great
problems to produce voluntary movements on the right side and vice versa. As the
word says, the corticospinal tract originates in the cortex and terminates in the
spinal cord. Since internal capsule lesions interrupting the corticospinal tract are not
exceptional at all, most neurologists think that this tract is the main component of
G. Holstege (*) • H.K. Huynh
Center for Uroneurology, University Medical Center Groningen, Groningen, The Netherlands
e-mail: g.holstege@med.umcg.nl,h.k.hieu@med.umcg.nl
D.W. Pfaff (ed.), Neuroscience in the 21st Century,
DOI 10.1007/978-1-4614-1997-6_75, #Springer Science+Business Media, LLC 2013
2045
the motor system. In reality, this is not the case. Although, indeed, in humans the
corticospinal tract is a crucial component of the somatic or voluntary motor system,
the emotional motor system (EMS) (Holstege 1992) is an equally important or
perhaps even more important part of the motor system (Holstege et al. 2004)
(Fig. 67.1).
The Somatic or Voluntary Motor System
Motoneurons in Spinal Cord and Brainstem
As mentioned above, the corticospinal tract in humans is a crucial component of the
somatic motor system. Fish, however, do not have a corticospinal tract but still
move through the water smoothly using coordinated muscle movements. This
coordination is not processed by the cortex, as in humans (see below), but by the
brainstem. The cells that innervate and activate the muscles in fish as well as in all
other vertebrates including humans are called motoneurons, located in the spinal
cord and brainstem. Each muscle is innervated by a distinct group of motoneurons.
However, such a group does not decide by itself when to generate muscle move-
ments and when not. Even the so-called premotor interneurons, usually located
close to the motoneuronal cell groups, do not decide when to excite their motoneu-
rons but receive instructions from other areas in the central nervous system (CNS).
Their major task is to excite the motoneurons of the agonist muscle and inhibit the
motoneurons of the antagonist muscle in order to prevent a simultaneous opposite
movement. Therefore, even in fish, the decision whether or not to activate a certain
muscle in the context of moving to another site in the water is not taken by neurons
in the spinal cord but at a higher level in the lower or caudal brainstem. The lowest
or most caudal part of the brainstem is a rostral extension of the spinal cord, which
Motor system
Motoneurons
Basic system
(premotor interneurons)
Emotional motor
system
Voluntary motor
system
Lateral LateralMedial Medial
independent
movements of
the extremities
eye-, neck,
axial and proximal
body movements
specific
emotional
behaviors
gain setting systems
including triggering
mechanisms fo
rhythmical and other
spinal reflexes
Fig. 67.1 The motor system
consists of a somatic or
voluntary and an emotional
motor system. Both consist of
a medial and a lateral
component, but all make use
of the motoneurons and their
premotor interneurons. Please
note that motoneurons not
only meant somatic
motoneurons innervating the
striated muscles but also the
so-called sympathetic and
parasympathetic
preganglionic motoneurons in
brainstem and spinal cord
2046 G. Holstege and H.K. Huynh
continues laterally as the lateral tegmental field. This lateral tegmental field, similar
to the spinal cord, contains motoneurons with their premotor interneurons inner-
vating the muscles of the head, such as tongue, throat, mouth, face, and chewing
muscles (Holstege et al. 1977)(Fig. 67.2). The sensory part of the spinal cord, the
dorsal horn, also extends rostrally in the lateral brainstem, where it is called
trigeminal nucleus.
Medial Component of the Somatic Motor System
In fish, the neurons that coordinate the movements in order to move through the
water are located dorsomedially in the lower brainstem, in the so-called
dorsomedial medulla (Mullins et al. 2011). Ventral to the dorsomedial medulla is
the ventromedial medulla, which plays a role in the EMS (see later). The neurons in
the dorsomedial medulla of the fish send fibers throughout the length of its spinal
cord to inform the motoneurons and their premotor interneurons when to fire. This
relatively simple system works fine, since fish move smoothly through the water
and are able to escape threats as larger fish that want to catch and eat them. The
neurons in the dorsomedial medulla determine which direction the fish has to swim,
but they, in turn, receive instructions from more rostral regions in the brainstem.
These neurons are informed about the circumstances in the environment by the
visual system. In fish, the visual system is not, or to only a very limited extent, able
to recognize objects the way humans do, but it distinguishes changes in the visual
field and determines whether these changes are large or small. When the changes
are large, it might represent a large moving object such as a large fish that wants to
eat the smaller fish. Large movements in the visual field, therefore, are interpreted
as dangerous. The rostral brainstem cells of the fish, receiving this information, will
Fig. 67.2 On the left, the lesion in the left brain of a patient in that part of the motor cortex that
controls face musculature. The lesion caused inability of moving the face muscles on the
contralateral side, when asked to show her teeth (middle). However, when told a funny story,
the patient is still able to smile, using the EMS to contract her facial muscles (right)
67 Emotions Studied by Imaging of the Human Brain 2047
then generate a flight response by giving orders to the muscles of the body via
the dorsomedial medulla. In contrast, in case the moving object is smaller than the
fish, it will try to catch and eat it. In that case, the movements will be organized in
such a way that the fish approaches the smaller moving object. Despite the sim-
plicity of this brainstem organization, it seems to work well, since fish still exist.
Fish have no limbs, which explains why the dorsomedial medulla only controls
axial and proximal muscles. In further phylogenetic development, many more
sophisticated body parts develop such as limbs, but the dorsomedial medulla
continues to control axial, proximal, and neck musculature (Fig. 67.3, left) as in
fish, and it still has this function in further developed vertebrates including humans
(Holstege 1988a).
Axial and neck musculature control not only body posture but also the position
of the head on the trunk, thus the position of the visual field. Other muscles that
are involved in visual field control are the extraocular muscles, which, in fish,
produce only horizontal eye movements. The motoneurons innervating these
muscles are also controlled by neurons in the dorsomedial medulla, which is the
reason that they located in this same area. This motoneuronal cell group is called
nucleus abducens. Thus, neurons in the dorsomedial medulla control head and
eye position, i.e., the position of the visual field. Later in the phylogenetic
RN
nV
Vpr Vm
Vsp
BC
BP
CN
XII
VII
Med.
Tegm.
Field
Lat.
Tegm.
Field
Fig. 67.3 The caudal
brainstem consists of a lateral
tegmental field (black) with
motoneurons and premotor
interneurons and a medial
tegmental field, which
consists of a dorsal and
a ventral medial medulla. Vm
motor trigeminal nucleus, Vpr
principal trigeminal nucleus,
Vsp spinal trigeminal tract
and nucleus, VII facial
nucleus, XII hypoglossal
nucleus, BC brachium
conjunctivum, BP brachium
pontis, CN cochlear nuclei,
nV trigeminal nerve, RN red
nucleus
2048 G. Holstege and H.K. Huynh
development, eye muscles evolved that generate vertical eye movements. For this
reason, the cell groups involved in vertical eye movement control are located
further rostrally in the brainstem than those controlling horizontal eye move-
ments. Examples of cell groups controlling vertical eye movements are the
interstitial nucleus of Cajal, which control the position of the eyes in a vertical
plane, and the rostral interstitial nucleus of the MLF that coordinate eye
movements in the vertical plane. Since control of only vertical eye muscle
movements is not sufficient for controlling the position of the visual field in the
vertical plane, both cell groups also send fibers to the neck and axial muscle
motoneurons in the spinal cord in order to coordinate head and eye position in the
vertical plane.
Another group of neurons involved in visual field control comprises the vestib-
ular nuclei because they receive information from the vestibular organs about the
position of the head. They also have access to eye muscle motoneurons and their
premotor interneurons via the medial longitudinal fasciculus (MLF) (Zwergal et al.
2009) as well indirectly via the cells in the dorsomedial medulla (Peterson and
Abzug 1975). Also, the vestibular nuclei have direct access to the motoneurons and
their premotor interneurons of the axial and head muscles in the spinal cord
(Fig. 67.4, right). The vestibular nuclei use two pathways, the medial
vestibulospinal tract that specifically controls neck muscles and the lateral
vestibulospinal tract that coordinates axial as well as neck movements, because it
descends throughout the length of the spinal cord (Holstege 1988a).
Albeit that, in humans, the medial component of the somatic motor system is
largely organized by the cortex, the dorsomedial medulla in the brainstem is still
functional because of its connections with the vestibular nuclei, spinal cord, and eye
muscle motoneurons. The motor cortex part involved in steering proximal and axial
muscles has strong connections with the dorsomedial medulla. In simple terms,
when a control center in the CNS is functioning well, there is no phylogenetic
reason to replace it by other (cortical) structures. In fact, not only in fish but also in
humans, the dorsomedial medulla still plays a crucial role in the control of posture
in general and the position of the visual field in particular. As we will see later, the
EMS in humans also uses caudal brainstem cell groups that function properly at
a basic level.
Lateral Component of the Somatic Motor System
Red Nucleus
Since it was phylogenetically advantageous to move from the sea to the land, fish
developed limbs. As with vertical eye movement control (see above), the neuronal
cell groups coordinating limb movements evolved later, thus further rostrally in the
brainstem than the axial, proximal, and neck muscle control regions. This group of
neurons, called magnocellular red nucleus, sends thick fast fibers to motoneurons
and their premotor interneurons innervating limb muscles. In contrast to the
dorsomedial medulla, the rubrospinal neurons are subdivided into different parts
innervating different muscle groups. In simple terms, one might distinguish three
different rubrospinal cell groups, one innervating face, mouth, and other oral
67 Emotions Studied by Imaging of the Human Brain 2049
muscles, located in the dorsal part of the red nucleus, one innervating the upper
limb, located in the ventromedial red nucleus, and one innervating the lower limb,
located in the ventrolateral red nucleus (Fig. 67.5). The red nucleus decides about
limb movements, i.e., in which direction the animal is moving or when and how it
reaches for food. The red nucleus receives afferent information from the cerebel-
lum, motor and premotor cortex (Kuypers 1981; Holstege 1991), and from the
serotonergic, noradrenergic, and dopaminergic level-setting systems (Huffman and
Davis 1977; Bosler et al. 1983; Domyancic and Morilak 1997), as well as from
the deep layers of the superior colliculus, (personal observation), where visual,
auditory, and somatosensory information is processed.
C4
C6
C5
T2
T2
T13
T9
L7
S2 S2
L7
C8
Fig. 67.4 Left: After an
injection of
3
H-leucine as
a general tracer in the medial
tegmentum of the pons,
rostral to the ventromedial
tegmentum, the medially
descending pathways can be
observed in dark field
throughout the length of the
spinal cord. On the right,
a very similar projection is
seen when the tracer is
injected in the lateral
vestibular nucleus.
6abducens nucleus, 7facial
nucleus, icp inferior
cerebellar peduncle, LVe
lateral vestibular nucleus,
med. tegm. medial tegmental
field, Py pyramidal tract, sp5
spinal trigeminal nucleus, SO
superior olivary complex
2050 G. Holstege and H.K. Huynh
Fig. 67.5 Schematic drawing of the rubrospinal tract. Note that the face, forelimb, and hind limb
areas project to different parts of the brainstem and spinal cord. III oculomotor nucleus, Vsp spinal
trigeminal tract and nucleus, V spin. caud. caudal spinal trigeminal nucleus, VII facial nucleus, XII
hypoglossal nucleus, CGM corpus geniculatum mediale, CN cochlear nuclei, CU cuneate nucleus,
ECU external cuneate nucleus, Ggracile nucleus, INC interstitial nucleus of Cajal, IO inferior
olive, lat. tegm. field lateral tegmental field, LRN lateral reticular nucleus, ML medial lemniscus,
MLF medial longitudinal fasciculus, NRA nucleus retroambiguus, Ppyramidal tract, PAG
periaqueductal gray, PC pedunculus cerebri, RB restiform body, RN red nucleus, Ssolitary tract,
SN substantia nigra
67 Emotions Studied by Imaging of the Human Brain 2051
Motor Cortex
Without motor memory, it is impossible to generate complicated limb movements.
Sufficient memory involves many premotor interneurons, for which, phylogeneti-
cally speaking, there was no room close to the red nucleus in the upper brainstem.
The same was true for memory neurons for visual, auditory, and somatosensory
systems. The phylogenetic solution was to copy the brainstem motor, visual,
auditory, and somatosensory systems into the most rostral part of the developing
central nervous system, the telencephalon. The result was a cerebral cortex with
a primary motor, visual, auditory, and somatosensory cortex. Those parts of the
primary motor cortex that generates limb movements can be considered as a copy of
the magnocellular red nucleus and the part of the motor cortex that controls axial
and proximal musculature as a copy of the dorsomedial medullary tegmentum.
Nevertheless, in rats, the magnocellular red nucleus is still powerful in steering limb
movements, although its motor cortex has more memory cells to produce certain
movements. In cats, the corticospinal tract is further developed than in rats,
although the rubrospinal tract, with its direct projections to distal forelimb muscle
motoneurons (Holstege 1987a), is further developed than the corticospinal tract. In
monkey, the corticospinal tract becomes more powerful and projects directly to
motoneurons, and the number of memory neurons in the premotor cortex is more
numerous than in cats (Holstege and Tan 1988; Ralston et al. 1988). The reason for
the rubrospinal pathway to still play an important role in the motor system is also
that the motor cortex, by way of strong projections to the rubrospinal cells, uses the
red nucleus for generating limb movements (Kuypers 1958). In humans, however,
the number of fibers of the motor corticospinal tract has become so much higher
than the rubrospinal tract fibers that there was no further need for an operative
rubrospinal tract, and the remaining number of rubrospinal neurons in humans has
been estimated to amount around 300 (Nathan and Smith 1982), while in rats, cats,
and monkey, rubrospinal neurons are much more numerous (Holstege 1991)
(Fig. 67.6). It means that a lesion of the corticospinal tract in rats or cats, not
involving the rubrospinal tract, does not affect the ability to move their limbs,
because the rubrospinal tract takes over. In humans, a similar corticospinal tract
lesion produces complete loss of the ability to move the contralateral body parts, of
which the control of the most precise movements as those of distal limbs or mouth
(Fig. 67.2, left) is affected most.
Speech
The best examples of premotor interneurons in the cortex memorizing how to
produce complicated movements are those involved in speech. These neurons are
located on the left side in the so-called area of Broca. These cells remember how to
produce very complicated movements of the mouth, cheek, soft palate, pharynx, and
larynx in order to generate words and sentences. These Broca cells project to those
neurons in the motor cortex that, in turn, project to the motoneurons and premotor
interneurons in the caudal brainstem (Fig. 67.7, right). This pathway is called
corticobulbar tract because the motoneurons involved are not located in the spinal
cord, but in the bulbus or caudal brainstem or, more precisely, in the bulbar lateral
2052 G. Holstege and H.K. Huynh
tegmental field (Fig. 67.3). Neurons in the area of Broca are able to generate the word
“table” and thousands of other words in different languages. However, the
corticobulbar tract does not produce sound but modulates it, resulting in words and
sentences. As we will discuss later, the sound production as such is a task of the EMS.
In case the area of Broca on the left side is lesioned, the individual cannot produce
complete sentences (motor aphasia) (see Alexander and Hillis 2008) but is still able to
produce sound. However, when those parts of the EMS involved in sound production
(see below) are lesioned, the individual becomes mute and cannot produce any sound,
although the cortex and corticobulbar tract are intact (Esposito et al. 1999).
The Emotional Motor System
Similar to the somatic motor system, the EMS has a medial and a lateral compo-
nent. The medial component consists of neurons sending diffusely projecting
pathways to the spinal cord as well as the cell groups that control the neurons that
generate these diffuse pathways. The lateral component, on the other hand, consists
of specific motor output systems that are under control of particular emotional
brain regions.
Medial Component of the EMS
As explained in previous paragraphs, the spinal cord consists of a motor part on the
ventral side with motoneurons and premotor interneurons and of a sensory part on
the dorsal side called dorsal horn. The latter part processes stretch-sensitive infor-
mation from muscles and tendons and somatosensory information from skin
Rubrospinal tract
Cat
Rhesus monkey
Human
Corticospinal tract
Fig. 67.6 Schematic
drawing of the rubrospinal
and corticospinal tract in cat,
rhesus monkey, and human.
Note the strength of the
rubrospinal tract in cat and
monkey but the weakness or
even absence of this tract in
humans. Note also that the
corticospinal tract gets
stronger going from cat to
monkey to humans
67 Emotions Studied by Imaging of the Human Brain 2053
through thick afferent fast-conducting fibers. This information is crucial for the
motor system to coordinate muscle contractions. There are also thin slow-
conducting fibers, which are hard to excite. Only stimuli that might be harmful or
noxious to the individual are able to excite these fibers. Such information is called
nociception, of which pain perception is the best example, but it also involves heat
and cold.
Ventromedial Medulla
Neurons in the dorsomedial medulla coordinate axial, neck, and external eye
muscles. Neurons, located ventral to the dorsomedial medulla, i.e., in the ventro-
medial medulla, have a completely different function. They send fibers throughout
the length of the spinal cord. Neurons in the caudal half of the ventromedial medulla
send fibers to all somatic motoneurons and their premotor interneurons, as well as to
all preganglionic sympathetic and parasympathetic motoneurons with their
premotor interneurons. This projection is very diffuse; the fiber of one particular
neuron gives off collaterals to the cervical as well as to the thoracic, lumbar, sacral,
and coccygeal ventral horn (Huisman et al. 1981). The cells in the rostral half of the
PREFRONTAL CORTEX
SPEECH
VOWELS and SYLLABLESVOCALIZATION
area of Broca
orbitofrontal cortex,
amygdala, BNST,
lateral hypothalamus
periaqueductal gray (PAG)
premotor interneurons
in medullary lateral
tegmental field
nucleus retroambiguus
(NRA)
motoneurons
innervating
mouth opening,
lower mouth, and
tongue muscles
motoneurons
innervating
soft palate, pharynx, larynx,
diaphragm, intercostal, abdominal,
and pelvic floor muscles
motor cortex
premotor interneurons
in medullary lateral
tegmental field
motoneurons
innervating
mouth opening, peri-oral,
pharynx, and tongue muscles
Fig. 67.7 Summary diagram of the systems that produce speech. On the left, the EMS; on the
right, the somatic motor system
2054 G. Holstege and H.K. Huynh
ventromedial medulla project to the neurons in the dorsal horn. Neurons located
most rostrally in the ventromedial medulla project to laminae III and IV where
nonnociceptive information is processed. Neurons caudal to these, but still
in the rostral half of the ventromedial medulla, project specifically to neurons in
Rexed’s laminae I and V that are involved in processing nociceptive information
(Holstege 1988b). Altogether, the neurons in the ventromedial medulla determine
the so-called level setting of all spinal cord neurons in the dorsal as well as ventral
horn. In simple terms, they determine the level of activation of these spinal neurons,
i.e., determine the amount of energy that is needed by other, more specific systems
to generate an effect. For example, electrical stimulation of cells in the rostral half
of the ventromedial medulla results in complete disappearance of nociception or
pain (Fields and Basbaum 1978).
Neurotransmitters in the Ventromedial Medulla
There are several neurotransmitters that play a role in the level-setting system of the
ventromedial medulla to the motoneurons in the spinal cord. Most well known is
serotonin, which facilitates motoneurons possibly by acting directly on CA
2+
conductance or indirectly by reduction of K
+
conductance of the motoneuronal
membrane and, thus, enhances the excitability of the motoneurons for inputs from
other sources as the corticospinal tract (see above). Not all the diffusely projecting
neurons in the ventromedial medulla contain serotonin as is often thought. Other
peptides playing a role in these diffuse pathways to the spinal cord are substance P,
thyrotropin-releasing hormone (TRH), somatostatin, methionine (M-ENK), and
leucine-enkephalin (L-ENK), while some cells in the ventromedial medulla contain
vasoactive intestinal peptide (VIP) and cholecystokinin (CCK). Several of these
peptides coexist in the same cell with serotonin. Also acetylcholine, somatostatin,
and even GABA play a role, which means that the diffuse pathways have facilita-
tory as well as inhibitory effects.
In the cat, the termination of diffuse pathways that originate from regions
with a great many serotonergic neurons differ from those of laterally adjoining
regions that do not or only to a very limited extent contain serotonergic neurons
(Fig. 67.8), see (Holstege 1991) for review. The serotonergic neurons in the
ventromedial medulla send fibers not only to the spinal cord but also to the lateral
medulla (lateral tegmental field) with motoneurons and premotor interneurons.
Actually, the serotonergic neurons are located in various medial cell groups
extending from the ventromedial medulla until the dorsal raphe nucleus in the
mesencephalon. The more rostrally located serotonergic neurons project to all
rostral regions of the CNS, e.g., to diencephalon and telencephalon, which means
that all cortical regions receive serotonergic afferents.
Afferent Projections to the Ventromedial Medulla
None of the more than 100 billion neurons in the CNS function by themselves but
are always instructed by other neurons in the CNS. This is also true for the neurons
in the ventromedial medulla. The strongest projection to the ventromedial medulla
originates in the midbrain periaqueductal gray (PAG), but there also exist afferent
67 Emotions Studied by Imaging of the Human Brain 2055
projections from diencephalon, such as the medial hypothalamus and preoptic area
(Holstege 1987b) as well as from the telencephalon (ventromedial orbitofrontal
cortex) (Kuipers et al. 2006). Remarkably, only the rostral half of the ventromedial
medulla, which sends fibers to the dorsal horn, receives afferents from more lateral
parts of the limbic system, such as the lateral hypothalamus (Holstege 1987b),
amygdala (Hopkins and Holstege 1978), and bed nucleus of the stria terminalis
(BNST) (Holstege et al. 1985). Also the ventromedial orbitofrontal cortex projects
to only that part of the ventromedial medulla. In conclusion, the ventromedial
medulla contains a great many neurons with many different neurotransmitters and
neuromodulators. Its rostral half controls the dorsal horn, its caudal half the ventral
horn of the spinal cord. Both parts receive very strong connections from the PAG
but the rostral half also from many higher level parts of the limbic system including
the medial orbitofrontal cortex. Through this pathway, these regions can have direct
control of nociception throughout the body.
A5, A7, and A11
The neurons in the ventromedial medulla are not the only ones that send diffuse
pathways to the spinal cord. Others are the noradrenergic neurons in the locus
coeruleus/subcoeruleus (A7 cell group) in the dorsolateral pons and A5 cell group
in the caudal pontine ventrolateral tegmentum. Similar to the serotonergic neurons,
also these neurons send fibers to all parts of the CNS from the frontal cortex to the
coccygeal spinal cord. Unlike the serotonergic neurons that are located throughout
the rostrocaudal extent of the brainstem, the noradrenergic neurons are exclusively
located in the dorsolateral pons (locus coeruleus and subcoeruleus). The locus
coeruleus receives afferents from the same areas as the ventromedial medulla,
e.g., the PAG (Mantyh 1983), central nucleus of the amygdala, BNST, and lateral
hypothalamus (Nieuwenhuys et al. 2008).
The third cell group that sends diffuse projections to the spinal cord is the A11
nucleus in the caudal hypothalamus containing dopaminergic neurons. There are
1030 1051
Fig. 67.8 Bright-field photomicrographs of autoradiographs in a somatic motoneurons cell group in
the lumbar 7 ventral horn in cats after injections of
3
H-leucine in the ventral medial medulla. On the
left, the injection was made in the ventral medulla not involving the raphe nuclei; on the right,the
projection to the same cell group after an injection in the raphe pallidus. Note the differences in
termination patterns, probably representing important differences in function. Bar represent 0.1 mm
2056 G. Holstege and H.K. Huynh
many cell groups in the rostral brainstem that contain dopaminergic neurons,
sending dopaminergic fibers to all parts of the CNS, but only the A11 cell group
send fibers to all parts of the spinal cord (Holstege et al. 1996; Barraud et al. 2010).
Also the dopaminergic A11 cell group receives afferents from many limbic struc-
tures as hypothalamus, PAG, insula, orbitofrontal cortex, amygdala, and BNST.
Role of the PAG in the Medial Component of the EMS
As indicated by its name “periaqueductal gray,” the neurons of the PAG are
located in the area around the aqueduct. The lateral border is formed by tectobul-
bospinal fibers that originate in the deep layers of the superior colliculus. The
tectospinal fibers cross the midline already in the midbrain to further descend into
the caudal brainstem and upper cervical cord. However, this lateral PAG border is
artificial because the cells lateral to these tectospinal fibers are involved in similar
functions as those within the PAG. The PAG, thus including the cells just lateral
to it, is best known for its role in pain perception because electrical stimulation of
the PAG in animals resulted in an almost complete disappearance of nociception.
This observation led neurosurgeons to electrically stimulate the PAG in patients
that suffered from extreme pain, e.g., caused by malignant outgrowths in different
parts of the body. Although this PAG stimulation indeed eliminated the pain
sensation in these patients, they also became very emotional and felt extreme fear,
panic, anxiety, terror, or even feelings of immediate death (Nashold et al. 1969;
Schvarcz 1975). In later studies, stimulation in more rostral parts of the PAG
resulted in much better pain treatment, without the emotional feelings (Bittar et al.
2005). Nevertheless, the first PAG stimulations demonstrated that the PAG does
not function exclusively as a pain inhibitory center but as a cell group that plays
a central role in basic survival. One of these functions is changing the level setting
in the spinal cord. For example, in a situation in which the individual is threatened
by events in its immediate surroundings, e.g., a car driving in his/her direction or
a person threatening him/her, it is necessary to fight, flight, or fright, i.e., attack,
flee, or freeze. It has been shown in cats with a permanent needle in the caudal
PAG in a very relaxed situation that electrical stimulation resulted in a sudden
attack of whatever person in its immediate surroundings, even when this person is
known to the cat as nonthreatening and providing food (Bandler 1975). Termi-
nating the PAG stimulation resulted inanimmediatestopofthisaggressive
behavior. Stimulation in more ventral parts of the PAG in rats, on the other
hand, resulted in immediate freezing behavior (Bandler and Keay 1996). These
results demonstrate that the PAG is able to produce complete behaviors directly
related to basic survival. The PAG, therefore, is used as a tool for higher level
structures as amygdala, BNST, lateral hypothalamus, preoptic region, and, espe-
cially in humans, the medial orbitofrontal cortex and insula to generate basic
survival behavior. Hence, although these regions play crucial roles in basic
defensive mechanisms, they need the PAG to bring about the appropriate emo-
tional behavior. Large lesions of the PAG usually results in the death of the
individual or, in rare cases, in akinetic mutism, a situation in which the patient
is breathing but no longer aware of his/her existence. In case of parenteral or
67 Emotions Studied by Imaging of the Human Brain 2057
intravenous nutrition, the patient may remain in this condition for 10 years or
more. In such cases, the family members often decide to stop the parenteral
nutrition in order to let the patient pass away.
Lateral Component of the EMS
The PAG, which maintains such an essential position in basic survival, not only
controls level setting including pain perception and motor output but also generates
more specific motor outputs, which, together, constitute the lateral component of
the EMS. Examples of such specific motor output systems are blood pressure and
heart rate control, breathing, vocalization, vomiting, micturition, and parturition
(Fig. 67.9).
Blood Pressure and Heart Rate Control
“I love you with all my heart,” “from the bottom of my heart,” “broken hearted,”
“learn by heart,” “accept Jesus in your heart,” “a heartfelt plea,” “break my heart,”
and many other phrases suggest that the EMS is located in the heart instead of the
CNS. It demonstrates the enormous impact of emotional processing on heart
function. Obviously, events in the surrounding of the individual that are estimated
by the brain as critical for survival of the individual or of the species call for an
immediate response by the EMS. The heart is almost always involved in this
response because the body needs more blood going to those parts that perform
the necessary defensive actions as fight, flight, and fright. Therefore, there exist
specific pathways from the dorsal and lateral PAG to the ventrolateral tegmental
field just caudal to the facial nucleus, a region called retrofacial nucleus, that
increase blood pressure and heart rate (Lovick 1985; Carrive et al. 1989;
Hamalainen and Lovick 1997; Kubo et al. 1999), while the ventrolateral PAG
generates a decrease of blood pressure and heart rate (Carrive and Bandler 1991),
also in humans (Green et al. 2010; Pereira et al. 2010). Even stimulation on the
orbitofrontal cortex that maintains direct connections with the retrofacial nucleus
(Kuipers et al. 2006) results in hypotension (Crippa et al. 2000). It is clear that the
EMS indeed has a great impact on blood pressure and on the heart itself, completely
dependent of what behavior is generated. For fight and flight, a higher blood
pressure is needed (dorsal and lateral PAG); in case of fright (freezing), a lower
blood pressure is generated (Bandler and Keay 1996).
Breathing
Breathing is the motor system that inhales air from the surrounding of the individual
to the lungs and vice versa in order to get access to oxygen and to get rid of the
carbon dioxide. In order to inhale the air, we need a muscle that enlarges the
intrathoracic space so that the lower pressure produces an airflow into the thorax.
This action is called inspiration. Oxygen is taken up from this air by the lungs, and
carbon dioxide is released. The most important muscle, contraction of which
decreases intrathoracic pressure, is the diaphragm, which is innervated by moto-
neurons in the phrenic nucleus located in humans at the C3–C5 level of the cervical
cord (Routal and Pal 1999). Other muscles involved in intrathoracic cavity pressure
2058 G. Holstege and H.K. Huynh
caudal ventromedial
medullary tegmental field
ventral horn
throughout the length
of the spinal cord
diffuse excitation
and inhibition of
autonomic and somatic
motoneurons
nociception
control
cardiovascular
changes
respiration micturition parturition vocalization vomiting coughing
sneezing
mating
behavior
pupil
dilatation
defensive
posture
?
dorsal horn
throughout the length
of the spinal cord
intermediolateral
cell group in the
thoracic cord
phrenic
and external
intercostal
motoneurons
intermediolateral
cell group in the
sacral cord
motoneurons of the
larynx, pharynx, soft palate,
internal intercostal, abdominal,
and pelvic floor muscles
motoneurons of
hindlimb and
axial muscles
T1-T2
intermediolateral
cell column
lamina VIII and
medial lamina Vll
C1-S3
central canal
bordering cells
C4-T8
rostral ventromedial
medullary tegmental field
subretrofacial
nucleus
respiratory cellgroups
in lateral medulla
pontine pelvic organ
stimulating center
limbic system
periaqueductal gray (PAG)
specific emotional behaviorslevel settin
g
systems
function spinal cord brainstem
nucleus
retroambiguus
Fig. 67.9 Summary diagram of the motor systems controlled by the periaqueductal gray (PAG)
67 Emotions Studied by Imaging of the Human Brain 2059
are the external intercostal muscles located between the ribs. For expiration during
quiet breathing, called eupnea, no muscle activation is necessary to let the air leave
the thorax, because the forces of gravity are sufficient. However, for forced
expiration during strong efforts as fighting or sports, gravity is not enough, because
the intrathoracic pressure has to be actively increased, which is taken care of by
increasing the intra-abdominal pressure. For such an increase, contraction of the
abdominal muscles, as well as of the costal diaphragm and pelvic floor muscles, is
required.
There is one specific premotor interneuronal cell group in the central nervous
system that has specific access to all the motoneurons of the pharynx, larynx,
diaphragm, external and internal intercostal, and abdominal and pelvic floor mus-
cles. It is the so-called nucleus retroambiguus (NRA) (Holstege 1989; Subramanian
and Holstege 2009). The NRA is located ventrolaterally in the most caudal part of
the medulla, caudal to the obex. The obex is the level of the transition between the
fourth ventricle and the central canal that continues throughout the length of the
spinal cord. The reason that these premotor interneurons are located in the caudal
medulla is that at this level, information related to intrathoracic and intra-abdominal
pressure enters the central nervous system through the vagal nerve. Since the
NRA is the only group of neurons that specifically projects to all the motoneurons
that control intra-abdominal pressure (Holstege and Kuypers 1982), the NRA is
used as a tool for those regions in the CNS that control abdominal pressure.
Breathing, and especially forced expiration, is an example, during which the
NRA is used to acquire the extra oxygen necessary for running or for other
heavy physical efforts. It is interesting that EMS structures, such as the amygdala,
BNST, the lateral or other parts of the hypothalamus, preoptic area, and the
orbitofrontal, which have strong access to the medulla, do not have access to the
NRA (Holstege 1991; Kuipers et al. 2006). The PAG is the only suprabulbar
structure that has direct contact with the NRA (Holstege 1989), and it uses this
pathway to achieve those specific motor outputs that involve intra-abdominal
pressure changes.
Vocalization
Vocalization is an example of a motor output system that involves changes in
intra-abdominal and intrathoracic pressure. It explains why in animals, including
monkeys, the PAG is crucial for the production of sound (vocalization). A lesion of
the PAG in these animals resulted in complete mutism (Adametz and Oleary 1959),
i.e., the animals are no longer able to communicate via sound production.
Stimulation in the PAG resulted in vocalization. The PAG projection to the NRA
is the basis of sound production because via the NRA, the PAG has access to the
motoneurons that innervate the muscles that drive air through the larynx, necessary
for the vocal cords to produce sound. Animals are also able to produce different
sounds, for which the PAG but also the amygdala, BNST, lateral hypothalamus, and
medial orbitofrontal cortex have access to premotor interneurons in the lateral
medulla that in turn control the motoneurons of the muscles that are able to modify
the sound, such as pharynx, tongue, and mouth (Fig. 67.7, left).
2060 G. Holstege and H.K. Huynh
In humans, the sound production is basically the same, although that is not
known to most neuroscientists that study speech. Lesions in the PAG in humans,
not leading to death, are rare, but three cases have been published in which PAG
lesions led to mutism (Esposito et al. 1999). However, speech in humans is
a combination of sound production and its modification. This modification of the
sound produces words and sentences, and in order to produce these, the voluntary
or somatic motor system is needed because of its great amount of memory
(see paragraph on speech of the somatic motor system).
Micturition, Parturition, and Defecation
One of the motor systems that belong to the lateral component of the EMS is the
system that controls micturition and parturition. Also for this system, the PAG plays
a crucial role. First of all, it receives all the information concerning the level of
bladder filling from a cell group called Gert’s nucleus (GN) in the sacral cord
(Holstege 2010). GN receives, via A-∂fibers from the bladder, precise information
concerning the amount of bladder filling, but it also receives A-∂fibers from the
uterus (Kawatani et al. 1990) and the rectum, so that GN cells are also aware of the
pressures in these two organs. GN, in turn, relays this information to the central part
of the PAG (Fig. 67.10) but not to higher centers in the brain. The PAG, in turn, has
a strong connection with the so-called pontine pelvic organ stimulating center
(PPOSC). Until now, this cell group has been called pontine micturition center
because of its strong control over micturition. Stimulation in the PPOSC has been
shown to elicit micturition by exciting the parasympathetic preganglionic moto-
neurons innervating the bladder as well as, via the inhibitory GABAergic and
glycinergic premotor interneurons medial to the preganglionic motoneurons, relax-
ation of the external urethral muscle (Holstege 2010)(Fig. 67.11). However, the
PPOSC does not only project to the bladder parasympathetic motoneurons but also
to those innervating uterus and rectum. Studies on stimulating the PPOSC have only
examined the bladder and external urethral sphincter and not at the same time the
uterus and rectum, so that the physiological effects of the PPOSC on these organs
Fig. 67.10 Photograph of
the periaqueductal gray after
injecting WGA-HRP in the
sacral cord. Note the strong
projection to the central parts
of the PAG especially
contralaterally (left side). This
projection is specifically from
the sacral cord. Similar
projections from other parts
of the spinal cord to the PAG
do not exist
67 Emotions Studied by Imaging of the Human Brain 2061
are not known. Based on the anatomical substrates, we predict that the PPOSC
control of the uterus and rectum is as strong as that on the bladder. Further support
for this idea comes from the finding of Holstege et al. (1986) that stimulating the
PPOSC not only inhibits the external urethral sphincter but the complete pelvic
floor, i.e., also the external anal sphincter and the muscles at the exit of the vagina in
females. Another argument in favor of the PPOSC not only controlling micturition
is that in case of patients suffering from complete transection of the spinal cord, not
only micturition is in great jeopardy but also parturition, which often leads to great
problems. It shows that the spinal cord plays an important role in parturition, and we
predict that especially the damage of the PPOSC fibers to the sacral cord causes this
problem. Transection of the spinal cord in patients also resulted in uncontrollable
reflex defecation, and the persistence of external anal sphincter contraction during
straining impaired fecal expulsion (Sun et al. 1995). These observations are in
agreement with our concept that the PPOSC not only controls micturition but also
parturition and defecation.
The reason for such a long spinal cord-PAG-PPOSC-spinal cord reflex system is
that the emotional brain needs control of when to micturate, parturate, or defecate.
Periaqueductal gray
Pontine
micturition center
Secondary
afferents GABA-ergic/glycinergic neuron
s
IC
BC
SC
PON
S2
(+)
(+)
(+)
(−)
(+)
Bladder
External
urethral
sphincter
Bladder
motoneurons
Onuf’s nucleus
Primary
afferents
Fig. 67.11 Schematic
drawing of the afferents and
efferents as well as the
ascending and descending
systems involved in bladder
control. Note that the same
system controls uterus, distal
colon, and rectum. BC
brachium conjunctivum, IC
inferior colliculus, PON
pontine nuclei, SC superior
colliculus
2062 G. Holstege and H.K. Huynh
The reason is that during these activities, the individual is not able to defend itself in
case of danger, which makes it very important to verify that the environmental
conditions allow these activities to take place. All structures involved in determin-
ing the presence of danger, such as amygdala, BNST, and hypothalamus, but in
humans also the insula and orbitofrontal cortex, have strong access to the PAG, so
that they can decide whether or not micturition, parturition, or defecation can take
place. Regarding micturition and defecation, humans are usually aware of this, but
since it also concerns parturition, it is of importance to take care that women in
parturition find themselves in a secure and relaxed situation. If not, the brain might
not give permission to the PAG to let parturition take place.
Sexual Activity
In cats, it has been demonstrated that the NRA has also direct access to a specific
group of motoneurons in the lumbosacral cord that induce movements that together
produce the posture necessary for sexual activity (Vanderhorst and Holstege 1995).
This posture differs slightly between male and female cats. In female cats, the
strength of this NRA motoneuronal projection differs greatly depending on whether
or not the cat is in estrous. In estrous cats, the NRA projection is almost ten times as
strong as in nonestrous cats, which difference can also be obtained after giving the
nonestrous cat estrogen intraparentally (VanderHorst and Holstege 1997a)
(Fig. 67.12). In male cats, the pathway is always the same, stronger than in
nonestrous cats but less strong than estrous cats (Vanderhorst and Holstege
1997b). It has also been shown that the PAG plays a crucial role in sexual behavior
for which it uses its pathway to the NRA to produce the proper postures. Estrous
cats in which the NRA pathway to the motoneurons was interrupted were interested
to have sex with a male cat but were not able to produce the right posture, despite
non-estrous estrous
NRA-axon NRA-axon
growth cone
terminal
motoneuron
Fig. 67.12 The difference between the nucleus retroambiguus (NRA) projection to lumbar
motoneurons in the nonestrous cat (left) and estrous cat (right)
67 Emotions Studied by Imaging of the Human Brain 2063
the male cat trying this ardently (personal observations). Also this pathway is based
on afferent information concerning sexual organs reaching the PAG via GN. The
PAG, in turn, controls sexual activity because it can only take place when the
situation is safe. The decision whether this is the case is taken by higher brain
regions such as amygdala, BNST, but especially insular and orbitofrontal cortex.
All these regions have strong direct access to the PAG and, thus, can inhibit sexual
activity to take place if the situation is threatening.
Sexual Intercourse in Humans
In animals as well as in humans, in situations during which the individuals are not
safe and relaxed, sexual activities are difficult to perform. The reason is that the
brain wants sexual activity to take place in a quiet relaxed surrounding (see above),
also because the child, the result of sexual intercourse, needs to be born in a secure
place. The newborn would not have a fair chance to survive in threatening condi-
tions. For example, the menstrual cycle immediately stops in female prisoners
entering concentration camps. This shows that survival of the individual is more
important than survival of the species. Because of their findings in cats, Holstege
et al. have also studied the brain activity of humans during sexual stimulation and
orgasm (Holstege and Huynh 2011). The main result is that during successful
sexual orgasm in men as well as in women, an enormous deactivation takes place
on both sides of the brain but especially on the left side in the temporal lobe and
prefrontal cortex (Fig. 67.13). Also these results indicate that the environment for
sexual activities has to be nonthreatening, similar to micturition, defecation, and
parturition.
Outlook
Both the somatic and the emotional motor system consist of a medial and a lateral
component. The medial component of the somatic motor system controls the axial
and proximal musculature of the body and of the position of the head on the trunk
and the position of the eyes in the orbit. This component, therefore, determines the
posture of the body as well as the position of the visual field. The lateral component,
on the other hand, controls precise and specific movements of limbs as well as the
muscles of the face, mouth, and throat. The specific limb movements produce script
by means of a pen or on the keyboard of a computer. The most precise movements
are made while producing speech, albeit that the sound during speech is produced
by the EMS.
The medial component of the EMS is involved in a general level-setting
procedure; the lateral component consists of a series of specific emotional output
systems such as blood pressure control, heart rate, breathing, vocalization, vomiting
(Miller 1999), parturition, micturition, and defecation, as well as aggressive behav-
ior and freezing. All these behaviors are coordinated by the periaqueductal gray,
which, in turn, receives information from the spinal cord as well as a great many
instructions from higher brain levels including the prefrontal cortex and insula.
2064 G. Holstege and H.K. Huynh
These regions do not decide by themselves but receive information from the visual,
auditory, and somatosensory cortex as well as from the many cortical regions
representing the emotional memory of these regions.
Fig. 67.13 Rendered brain images of the activation (red) and deactivation areas in men (left)and
women (right) during ejaculationand orgasm. The resultsare from studies in which theactivation was
measured for 2 min in a PET scanner,while the ejaculation and orgasm only took 10–20 s. The result,
therefore, is strongly diluted but still shows strong deactivation mainly on the left side of the brain
67 Emotions Studied by Imaging of the Human Brain 2065
The goal of both systems is survival of the individual and survival of the
species, as already described by Benedictus de Spinoza in 1678 in Part 3
Proposition 6 of his Ethica Ordine Geometrico Demonstrata. We, neuroscientists,
it can be seen, are discovering the mechanisms anticipated by ancient “natural
philosophers.”
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